149 results on '"Ricardo Spielberger"'
Search Results
2. Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status
- Author
-
Ibrahim Aldoss, Anh Pham, Sierra Min Li, Ketevan Gendzekhadze, Michelle Afkhami, Milhan Telatar, Hao Hong, Abbas Padeganeh, Victoria Bedell, Thai Cao, Samer K Khaled, Monzr M Al Malki, Amandeep Salhotra, Haris Ali, Ahmed Aribi, Joycelynne Palmer, Patricia Aoun, Ricardo Spielberger, Anthony S Stein, David Snyder, Margaret R O’Donnell, Joyce Murata-Collins, David Senitzer, Dennis Weisenburger, Stephen J Forman, Vinod Pullarkat, Guido Marcucci, Raju Pillai, and Ryotaro Nakamura
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P
- Published
- 2017
- Full Text
- View/download PDF
3. Brentuximab vedotin plus nivolumab after autologous haematopoietic stem-cell transplantation for adult patients with high-risk classic Hodgkin lymphoma: a multicentre, phase 2 trial
- Author
-
Alex F Herrera, Lu Chen, Yago Nieto, Leona Holmberg, Patrick Johnston, Matthew Mei, Leslie Popplewell, Saro Armenian, Thai Cao, Leonardo Farol, Firoozeh Sahebi, Ricardo Spielberger, Robert Chen, Auayporn Nademanee, Sandrine Puverel, Mary Nwangwu, Peter Lee, Joo Song, Alan Skarbnik, Neena Kennedy, Lacolle Peters, Steven T Rosen, Larry W Kwak, Stephen J Forman, and Tatyana Feldman
- Subjects
Hematology - Published
- 2023
4. Results of a Phase 2 Trial of Allogeneic Hematopoietic Stem Cell Transplantation using 90Y-Ibritumomab Tiuxetan (Zevalin®) in Combination with Fludarabine and Melphalan in Patients with High-Risk B-Cell Non-Hodgkin's Lymphoma
- Author
-
Matthew Mei, Joycelynne Palmer, Nicole Ni-Chun Tsai, Jennifer Simpson, James O'Hearn, Anthony Stein, Stephen Forman, Ricardo Spielberger, Ji-Lian Cai, Myo Htut, Ryotaro Nakamura, Monzr M Al Malki, Alex Herrera, Jeffrey Wong, and Auayporn Nademanee
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2023
5. Anti-CD25 radioimmunotherapy with BEAM autologous hematopoietic cell transplantation conditioning in Hodgkin lymphoma
- Author
-
Jennifer Simpson, Ni-Chun Tsai, Diane Lynne Smith, John E. Shively, Firoozeh Sahebi, Dave Yamauchi, Joo Y. Song, Ricardo Spielberger, Vikram Adhikarla, Auayporn Nademanee, Sandra H. Thomas, Matthew Mei, David Colcher, Paul J. Yazaki, James R. Bading, S.V. Dandapani, Robert W. Chen, Alex F. Herrera, Pamela McTague, Erasmus Poku, Anna M. Wu, Thai Cao, Leslie Popplewell, Joycelynne Palmer, Eileen P. Smith, Nicole Karras, Stephen J. Forman, and Jeffrey Y.C. Wong
- Subjects
Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Salvage therapy ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Microenvironment ,medicine ,Humans ,Tissue Distribution ,Yttrium Radioisotopes ,Brentuximab vedotin ,Stomatitis ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Radioimmunotherapy ,medicine.disease ,Hodgkin Disease ,Transplantation ,Clinical trial ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL, and we hypothesized that the addition of 90Y-antiCD25 (aTac) to carmustine, etoposide, cytarabine, melphalan (BEAM) AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled in this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution, and a third developed an unrelated catheter-associated bacteremia; therefore, 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed, and 0.6 mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive >2500 cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with ≥3 risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL, and we are further evaluating the efficacy of this approach in a phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT01476839.
- Published
- 2021
6. Safety and Disease Outcomes of Commercial CD19 CAR T-Cell Therapy in Patients with Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma: A Single Institution Experience
- Author
-
Liana Nikolaenko, Leslie Popplewell, Yan Wang, Geoffrey Shouse, Tanya Siddiqi, Ricardo Spielberger, Shin Yeu Ong, Annette Brown, Joycelynne Palmer, and L. Elizabeth E. Budde
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
7. Long Term Outcomes of Patients with Chronic Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation in the Era of Oral Tyrosine Kinase Inhibitors
- Author
-
Paul Koller, Haoyue Shan, Joycelynne Palmer, Peter Curtin, Karamjeet S. Sandhu, Vaibhav Agrawal, Ricardo Spielberger, Joshua Mansour, Amanda Blackmon, Salman Otoukesh, Shukaib Arslan, Idoroenyi Amanam, Eileen Smith, Forrest Stewart, Brian Ball, Amandeep Salhotra, Ahmed Aribi, Ibrahim Aldoss, Andrew S. Artz, Anthony S. Stein, Guido Marcucci, Stephen J. Forman, Monzr M. Al Malki, Ryotaro Nakamura, David S Snyder, and Haris Ali
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
8. Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients 75 Years and Older: Another Age Barrier Crossed?
- Author
-
Paul Koller, Haoyue Shan, Dana Platt, Vaibhav Agrawal, Ibrahim Aldoss, Haris Ali, Idoroenyi Amanam, Ahmed Aribi, Shukaib Arslan, Brian Ball, Amanda Blackmon, Pamela S. Becker, Peter Curtin, Salman Otoukesh, Hoda Pourhassan, Vinod Pullarkat, Amandeep Salhotra, Karamjeet S. Sandhu, Ricardo Spielberger, Forrest Stewart, Eileen Smith, Anthony S. Stein, William Dale, Guido Marcucci, Monzr Al-Malki, Stephen J. Forman, Ryotaro Nakamura, and Andrew S. Artz
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
9. Real-World Outcomes of CD19 CAR T Cell Therapy in Adult Patients with Relapsed Refractory Transformed Diffuse Large B-Cell Lymphoma
- Author
-
Swetha Kambhampati, Leslie Popplewell, Yan Wang, Matthew Mei, Liana Nikolaenko, Geoffrey Shouse, Alex F. Herrera, Jasmine Zain, Tanya Siddiqi, James Godfrey, Dr. John H Baird, Steven Rosen, Alexey V. Danilov, Ji-Lian Cai, Ricardo Spielberger, Joycelynne Palmer, Annette Brown, Larry W. Kwak, Eileen Smith, Stephen J. Forman, and L. Elizabeth E. Budde
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
10. Interim Results of a Phase 1/2 Study of Pembrolizumab Combined with Blinatumomab in Patients with Relapsed/Refractory (r/r) ALL
- Author
-
Karamjeet S. Sandhu, Alan Macias, Marissa Del Real, Asuscena L. Beltran, Young Sun Kim, Jianying Zhang, Joycelynne Palmer, Marjorie Robbins, Reyna Loomis, Mojtaba Akhtari, Ahmed Aribi, Shukaib Arslan, Amandeep Salhotra, Matthew Mei, Hoda Pourhassan, Paul B. Koller, Idoroenyi Amanam, Vaibhav Agrawal, Peter T. Curtin, Ricardo Spielberger, Vinod A. Pullarkat, Ibrahim Aldoss, F. Mark Stewart, Eileen P. Smith, Stephen J Forman, Anthony S. Stein, Guido Marcucci, and L. Elizabeth Budde
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
11. Long Term Outcomes of Patients with Chronic Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation in the Era of Oral Tyrosine Kinase Inhibitors
- Author
-
Paul B. Koller, Haoyue Shan, Joycelynne Palmer, Peter T. Curtin, Karamjeet S. Sandhu, Vaibhav Agrawal, Ricardo Spielberger, Joshua Mansour, Amanda Blackmon, Salman Otoukesh, Shukaib Arslan, Idoroenyi Amanam, Eileen P. Smith, Forrest M. Stewart, Brian J Ball, Amandeep Salhotra, Ahmed Aribi, Ibrahim Aldoss, Vinod A. Pullarkat, Anthony S. Stein, Andrew S. Artz, Guido Marcucci, Stephen J Forman, Ryotaro Nakamura, Monzr M. Al Malki, David S Snyder, and Haris Ali
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Frequent Early Geriatric Complications after Allogeneic Hematopoietic Cell Transplantation (HCT) in Older Adults Impairs Disability-Free Survival (DiFS)
- Author
-
Jorge M. Ramos Perez, Haoyue Shan, Dongyun Yang, Leana Cabrera Chien, Carolina Uranga, Jaroslava Salman, Ibrahim Aldoss, Haris Ali, Ahmed Aribi, Saro H. Armenian, Shukaib Arslan, Vinod A. Pullarkat, Amandeep Salhotra, Karamjeet S. Sandhu, Ricardo Spielberger, Anthony S. Stein, Guido Marcucci, Monzr M. Al Malki, Stephen J Forman, William Dale, Ryotaro Nakamura, and Andrew S. Artz
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
13. Association of pre-transplant vancomycin resistant enterococcus colonization status on long-term outcomes of allogeneic-hematopoietic cell transplantation
- Author
-
Amandeep Salhotra, Karamjeet S. Sandhu, Dongyun Yang, Sally Mokhtari, James O’Hearn, Bernard Tegtmeier, Monzr M. Al Malki, Justine Abella, Akemi Meguro, Jana Dickter, Swetha Khambapati, Ricardo Spielberger, Andrew Artz, Stephen J. Forman, Eileen Smith, Ryotaro Nakamura, and Sanjeet S. Dadwal
- Subjects
Transplantation ,Hematology - Published
- 2022
14. Long-Term Follow-Up of Multiple Myeloma Patients Treated with Tandem Autologous Transplantation Following Melphalan and Upon Recovery, Total Marrow Irradiation
- Author
-
Colton Ladbury, George Somlo, Andy Dagis, Dongyun Yang, Saro Armenian, Joo Y. Song, Firoozeh Sahebi, Ricardo Spielberger, Leslie Popplewell, Pablo Parker, Stephen Forman, David Snyder, Amalia Rincon, An Liu, Paul Frankel, and Jeffrey Wong
- Subjects
Male ,Transplantation ,Bone Marrow ,Hematopoietic Stem Cell Transplantation ,Molecular Medicine ,Immunology and Allergy ,Humans ,Cell Biology ,Hematology ,Multiple Myeloma ,Melphalan ,Transplantation, Autologous ,Follow-Up Studies - Abstract
Total body irradiation in combination with melphalan for multiple myeloma (MM) has been shown to be prohibitively toxic. To ameliorate toxicity, total marrow irradiation (TMI) has been administered as the sole ablative modality during the second cycle of tandem autologous stem cell transplantation (TASCT) for MM patients on a phase I-II trial. Patients with MM in response or with stable disease and ≤18 months from diagnosis received melphalan 200 mg/m
- Published
- 2021
15. Total Marrow and Lymphoid Irradiation with Post-Transplantation Cyclophosphamide for Patients with AML in Remission
- Author
-
Anthony S. Stein, Monzr M. Al Malki, Dongyun Yang, Joycelynne M Palmer, Ni-Chun Tsai, Ibrahim Aldoss, Haris Ali, Ahmed Aribi, Andrew Artz, Savita Dandapani, Len Farol, Susanta Hui, An Liu, Ryotaro Nakamura, Vinod Pullarkat, Eric Radany, Joseph Rosenthal, Amandeep Salhotra, James F Sanchez, Ricardo Spielberger, Guido Marcucci, Stephen J Forman, and Jeffrey Wong
- Subjects
Adult ,Transplantation ,Lymphatic Irradiation ,Graft vs Host Disease ,Cell Biology ,Hematology ,Middle Aged ,Article ,Tacrolimus ,Leukemia, Myeloid, Acute ,Young Adult ,Bone Marrow ,Recurrence ,Quality of Life ,Humans ,Molecular Medicine ,Immunology and Allergy ,Cyclophosphamide - Abstract
BACKGROUND: Graft versus host disease (GVHD) has remained the main cause of posttransplantation mortality and morbidity after allogeneic hematopoietic cell transplantation (alloHCT), adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GVHD among patients in complete remission (CR) without increasing the risk of relapse. OBJECTIVE: In this study, we have tested a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplant cyclophosphamide (PTCy) for patients with acute myeloid leukemia in first or second CR, to attenuate the risk of chronic GVHD by using PTCy, while using escalated targeted radiation conditioning before allografting to offset the possible increased risk of relapse. The primary objective was to evaluate the safety/feasibility of combining a TMLI transplant conditioning regimen with a post-transplant high dose cyclophosphamide (PTCy)-based GVHD prophylaxis strategy, through the assessment of adverse events in terms of type, frequency, severity, attribution, time course, duration, and complications, including acute GVHD, infection, and delayed neutrophil/platelet engraftment. Secondary objectives included estimation of non-relapse mortality (NRM), OS, relapse-free survival, acute and chronic GVHD, and GVHD-relapse-free survival (GRFS). STUDY DESIGN: A patient safety lead-in was first conducted to ensure there were no unexpected toxicities and was expanded on the basis of lack of dose limiting toxicities (DLTs). The patient safety lead-in segment followed 3+3 dose expansion/(de-)escalation rules based on observed toxicity through day +30; the starting dose of TMLI was 2000 cGy, and a de-escalation to 1800 cGy was considered. After the safety lead-in segment, an expansion cohort of up to 12 additional patients was to be studied. TMLI was administered on days −4 to 0, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Cyclophosphamide was given on days +3 and +4 after alloHCT, 50 mg/kg each day for GVHD prevention; tacrolimus was given until day +90 and then tapered. RESULTS: Among 18 patients with a median age of 40 years (range 19-56), the highest grade toxicities were grade 2 Bearman bladder toxicity and stomatitis. No grade 3-4 Bearman toxicities or toxicity-related deaths were observed. The cumulative incidence of acute GVHD (aGVHD) grade 2-4 and moderate-to-severe chronic GVHD were 11·1% and 11·9%, respectively. At a median follow up of 24·5 months, two-year estimates of OS and relapse-free survival were 86·7% and 83·3%, respectively. Disease relapse at 2 years was 16·7%. The estimates of NRM at 2 years was 0%. The GVHD−/relapse-free survival (GRFS) rate at 2 years was 59·3% (95%CI: 28·8-80·3). CONCLUSION: This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe, with no NRM. Preliminary results suggest an improved GRFS rate.
- Published
- 2022
16. Chronic oral graft-versus-host disease: induction and maintenance therapy with photobiomodulation therapy
- Author
-
Judith E. Raber-Durlacher, Ricardo Spielberger, Geena L. Epstein, Joel B. Epstein, Dimitrios Tzachanis, Mette D. Hazenberg, Hematology, Hematology laboratory, Oral and Maxillofacial Surgery, Clinical Haematology, Oral Medicine, Maxillofacial Surgery (AMC), and Academic Centre for Dentistry Amsterdam
- Subjects
medicine.medical_specialty ,Oral graft-versus-host disease ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Induction therapy ,03 medical and health sciences ,0302 clinical medicine ,Maintenance therapy ,SDG 3 - Good Health and Well-being ,immune system diseases ,Internal medicine ,medicine ,In patient ,030212 general & internal medicine ,Low level laser therapy ,business.industry ,fungi ,Oncology ,030220 oncology & carcinogenesis ,Graft versus host disease induction ,Photobiomodulation therapy ,business - Abstract
This study presents follow-up of a prior study of patients with chronic symptomatic oral chronic graft-versus-host-disease (cGVHD) managed with photobiomodulation therapy (PBM therapy for 1 month. Here, we report long-term follow-up of a series of patients where PBM therapy in patients with oral cGVHD for maintenance follows the initial period of PBM therapy for continuing management. Patients and methods: We report continuing follow-up of 7 cases of oral cGVHD that were treated with PBM therapy. PBM therapy was continued in these patients with the goal of determining the best management schedule of PBM to maintain or improve control of each patient’s symptoms and signs of oral cGVHD. Results: Oral sensitivity and mucosal changes of cGVHD were controlled with a continuing schedule of PBM therapy of up to 6–8-week treatment intervals in patients with continuing GVHD. These findings suggest that PBM therapy represents an additional approach for continuing management of oral cGVHD and that the frequency of treatment should be individualized for each patient to provide best control of oral findings. In one case weekly PBM treatment was continued, while in others, management on a monthly or bimonthly basis was associated with control of the oral condition. PBM may be individualized and provided based upon best control of the symptoms and signs of oral GVHD.
- Published
- 2021
17. Allogeneic Hematopoietic Cell Transplantation for Relapsed and Refractory Philadelphia Negative B Cell ALL in the Era of Novel Salvage Therapies
- Author
-
Ahmed Aribi, David S. Snyder, Vinod Pullarkat, Sally Mokhtari, Dongyun Yang, Ryotaro Nakamura, Ricardo Spielberger, Joshua Mansour, Matthew Mei, Samer K. Khaled, Thai Cao, Andrew S. Artz, Ibrahim Aldoss, Stephen J. Forman, Shukaib Arslan, Monzr M. Al Malki, Haris Ali, Anthony S. Stein, Amandeep Salhotra, Guido Marcucci, Karamjeet S. Sandhu, and Paul Koller
- Subjects
Oncology ,Adult ,medicine.medical_specialty ,medicine.medical_treatment ,Salvage therapy ,Refractory ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,B cell ,Retrospective Studies ,Salvage Therapy ,Transplantation ,Chemotherapy ,B-Lymphocytes ,business.industry ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Confidence interval ,medicine.anatomical_structure ,Molecular Medicine ,Blinatumomab ,business ,medicine.drug - Abstract
Introduction of novel salvage therapies and expansion of the donor pool within the past decade have allowed more patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) to receive allogeneic hematopoietic cell transplantation (alloHCT). The impact of each salvage therapy on transplant outcomes have not been compared. Our primary objective was to determine post-HCT relapse-free survival (RFS) in adult patients with r/r Philadelphia-chromosome negative (Phneg) B-ALL. We retrospectively studied alloHCT outcomes in 108 adult patients with r/r Phneg B-ALL transplanted in morphological remission achieved by salvage therapy. Salvage therapies were chemotherapy-based combination (n = 45, 42%), blinatumomab (n=43, 40%), inotuzumab (n = 14, 13%), or CAR T cells (n = 6, 6%). The 2-year RFS and overall survival (OS) were 44% and 50%, respectively. In multivariable analysis, conditioning with reduced-intensity or non-myeloablative regimens (hazard ratio [HR] = 2.23, 95% confidence interval [CI], 1.31-3.80; P = .003), having received ≥3 lines of therapies prior to transplant (HR = 2.66, 95% CI, 1.56-4.54; P
- Published
- 2020
18. Outcomes of Allogeneic Hematopoietic Cell Transplantation after Salvage Therapy with Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
- Author
-
Stephen J. Forman, David S. Snyder, Matthew Mei, Sally Mokhtari, Ryotaro Nakamura, Monzr M. Al Malki, Ahmed Aribi, Thai Cao, Haris Ali, Samer K. Khaled, Vinod Pullarkat, Elizabeth Budde, Karamjeet S. Sandhu, Ibrahim Aldoss, Dongyun Yang, Amandeep Salhotra, Ricardo Spielberger, Guido Marcucci, and Anthony S. Stein
- Subjects
Adult ,Subset Analysis ,Oncology ,medicine.medical_specialty ,Platelet Engraftment ,Salvage therapy ,Article ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,Antibodies, Bispecific ,Medicine ,Humans ,Salvage Therapy ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Minimal residual disease ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Cohort ,Blinatumomab ,business ,030215 immunology ,medicine.drug - Abstract
Historically, outcomes of adult patients with relapsed acute lymphoblastic leukemia (ALL) who fail to enter remission with conventional chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. Although allogeneic hematopoietic cell transplant (HCT) is the recommended consolidation therapy for patients with r/r ALL who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remain largely unknown. We treated 89 patients with r/r ALL with blinatumomab, of whom 43 patients (48%) achieved remission. Here we describe our single-center experience in the subset of patients who responded to blinatumomab salvage therapy for eradication of either gross (n = 24) or minimal residual disease (n = 11) before HCT. Overall survival at 1 and 2 years after allogeneic HCT was 77% and 52%, respectively. Leukemia-free survival at 1 and 2 years were 65% and 40%, respectively. Additionally, with blinatumomab administration pre-HCT, no unusual toxicities such as delayed neutrophil/platelet engraftment or graft failure were observed. Acute grades II to IV graft-versus-host disease (GVHD) at day +100 post-HCT was at 43% and 2-year chronic GVHD was 36%, both comparable with historic control subjects. Finally, results of our subset analysis based on pre-HCT minimal residual disease (MRD) status indicated no significant difference in survival outcomes among patients undergoing transplant in MRD-negative status and the entire cohort. In conclusion, based on results of this study, blinatumomab may be considered as a safe and effective agent for r/r ALL patients before HCT.
- Published
- 2020
19. Predictive Factors for Early Relapse in Multiple Myeloma after Autologous Hematopoietic Stem Cell Transplant
- Author
-
Andrew Mayer Pourmoussa, Ricardo Spielberger, Ji-Lian Cai, Odelia Khoshbin, Thai Cao, Leonardo Farol, and Firoozeh Sahebi
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Comorbidity ,Severity of Illness Index ,Disease-Free Survival ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Maintenance therapy ,Recurrence ,Internal medicine ,Severity of illness ,medicine ,Humans ,Stage (cooking) ,Multiple myeloma ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Age Factors ,Hematopoietic Stem Cell Transplantation ,Hematopoietic stem cell ,Retrospective cohort study ,General Medicine ,Middle Aged ,Original Research & Contributions ,medicine.disease ,Haematopoiesis ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Multiple Myeloma ,business ,030215 immunology - Abstract
INTRODUCTION: Despite advances in therapy for multiple myeloma, patients have continued to experience relapse. We sought to better understand this. OBJECTIVE: To identify factors that predict early relapse in patients with multiple myeloma who receive autologous hematopoietic peripheral stem cell transplant (HSCT). METHODS: Retrospective analysis of Kaiser Permanente Southern California patients who received HSCTs between 2008 and 2012. RESULTS: A total of 141 patients were included. Factors found to be associated with inferior progression-free survival were disease status less than complete response at the time of HSCT, no use of maintenance therapy after HSCT, International Staging System stage III, and high Freiburg Comorbidity Index. Disease status less than complete response, stage III, higher Freiburg Comorbidity Index, no use of maintenance therapy, and male sex were the most predictive factors for early relapse (< 18 months). DISCUSSION: Our results identified a subgroup of high-risk individuals with multiple myeloma who will continue to do poorly after HSCT with the best available treatment using a combination of proteasome inhibitors and immunomodulatory drugs. These results highlight the need for consideration of alternative therapy in such instances.
- Published
- 2019
20. Therapy-related acute lymphoblastic leukemia has distinct clinical and cytogenetic features compared to de novo acute lymphoblastic leukemia, but outcomes are comparable in transplanted patients
- Author
-
Ni-Chun Tsai, Thomas P. Slavin, Ahmed Aribi, Thai Cao, Stephen J. Forman, Joo Y. Song, Ricardo Spielberger, Haris Ali, Tracey Stiller, Monzr M. Al Malki, Ibrahim Aldoss, Matthew Mei, N. Achini Bandara, Guido Marcucci, Vinod Pullarkat, Anthony S. Stein, Amandeep Salhotra, Ryotaro Nakamura, Margaret R. O'Donnell, David S. Snyder, and Samer K. Khaled
- Subjects
Oncology ,medicine.medical_specialty ,Myeloid ,business.industry ,Lymphoblastic Leukemia ,Cytogenetics ,hemic and immune systems ,Hematology ,Gene rearrangement ,3. Good health ,Transplantation ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adult Acute Lymphoblastic Leukemia ,business ,Survival rate ,030215 immunology - Abstract
Therapy-related acute lymphoblastic leukemia remains poorly defined due to a lack of large data sets recognizing the defining characteristics of this entity. We reviewed all consecutive cases of adult acute lymphoblastic leukemia treated at our institution between 2000 and 2017 and identified therapy-related cases - defined as acute lymphoblastic leukemia preceded by prior exposure to cytotoxic chemotherapy and/or radiation. Of 1022 patients with acute lymphoblastic leukemia, 93 (9.1%) were classified as therapy-related. The median latency for therapy-related acute lymphoblastic leukemia onset was 6.8 years from original diagnosis, and this was shorter for patients carrying the MLL gene rearrangement compared to those with other cytogenetics. When compared to de novo acute lymphoblastic leukemia, therapy-related patients were older (P
- Published
- 2018
21. A Randomized Open Label Pilot Study of Clostridium Butyricum Miyairi 588 (CBM588) in Recipients of Allogeneic Hematopoietic Cell Transplantation
- Author
-
Leslie Popplewell, Dongyun Yang, Karamjeet S. Sandhu, Amandeep Salhotra, Guido Marcucci, Ricardo Spielberger, Stephen J. Forman, Vinod Pullarkat, Sarah K. Highlander, Sanjeet Dadwal, Thai Cao, Andrew S. Artz, Ibrahim Aldoss, Harry Xu, Myo Htut, Lucy Ghoda, Anthony S. Stein, Monzr M. Al Malki, Haris Ali, Elizabeth Budde, Lauren Reining, Sally Mokhtari, and Ryotaro Nakamura
- Subjects
biology ,Hematopoietic cell ,business.industry ,Immunology ,Cell Biology ,Hematology ,biology.organism_classification ,Biochemistry ,Transplantation ,Medicine ,Open label ,business ,Clostridium butyricum - Abstract
The gut microbiota plays an important role in maintaining intestinal homeostasis by regulating the maturation of the mucosal immune system, which constitutes an immune barrier for the integrity of the intestinal tract. In recent years, the role of the human GI microbiota in graft-versus-host disease (GVHD) and other outcomes after allogeneic hematopoietic cell transplantation (HCT) has been increasingly evaluated in observational studies. However, there have been limited interventional trials specifically designed to alter the microbiota of HCT recipients. CBM588 (clostridium butyricum MIYAIRI 588) is a novel Live Biotherapeutic Product (LBP) that produces short chain organic acids, mainly butyric acid, which plays a key role in the maintenance of colonic homeostasis by regulating fluid and electrolyte uptake, epithelial cell growth, and inflammatory responses. In this pilot trial (NCT03922035) we sought to determine the safety, feasibility, biologic activities, and preliminary efficacy of CBM588 in HCT recipients. Patients age ≥18 years, scheduled to undergo HCT from an 8/8 or 7/8 matched related/unrelated donor with reduced intensity conditioning (RIC) were eligible. Following the patient safety lead-in (SLI; n=6), 30 patients were randomized (1:1 ratio) to receive either standard peri-transplant supportive care alone (control arm) or with CBM588 (treatment arm, open label) at the fixed dose of 160 mg orally (2x/day) from day -8 or hospital admission until day +28 or discharge (figure 1). Patients received prophylactic antibiotics per intuitional SOPs. Study objectives were to evaluate the safety/feasibility of CBM588 (Primary), and to compare the incidence and severity of adverse events (AE), HCT outcomes including GVHD, and gut microbiome diversity between the Treatment and Control arms. Feasibility was defined as the ability to consume CDM588 for 14 days during the SLI phase. For microbiome analysis, we isolated DNA from weekly collected stool samples, and amplified the V4 region of the bacterial 16S rRNA gene from each total DNA sample. Between April, 2018 and January, 2020, we enrolled 36 patients (20 were female) at the median age of 66 years (range: 34-77). The indication for HCT was Leukemias (n=22), MDS (n=5), lymphoma (n=3), myeloma (n=3), or other (n=3). All but one patient received fludarabine/melphalan-based RIC and tacrolimus/sirolimus-based GVHD prophylaxis. Graft source was peripheral blood stem cell from a matched related (n=13) or unrelated (n=23) donor (Table 1). One patient assigned to the Treatment arm declined to receive CBM588 before the first dose; but remained on the study with clinical data/biospecimen collections and safety/feasibility/biologic endpoints were analyzed as treated for this patient. All the other patients who were assigned to the treatment arm (n=21, including the patients in SLI segment) were able to take the prescribed study drug; with the median 52 doses (range: 0-55), and 19 of 21 subjects (90.5%) consumed at least 14 days of the study drug. There were no serious adverse events (SAE) related to CBM588. The overall AEs and infection- or GI-specific AEs were similar between the Treatment and Control arms. All but one patient (who died of sepsis in the Control arm - on day 8) engrafted with a median of 15 days for neutrophils. The 100-day non-relapse mortality (NRM) was 0% in the Treatment and 6.7% in the Control arm. According to the intent-to-treat principle, acute GVHD (grade 2-4) was observed in 4 of 15 patients in the Treatment arm and 5 of 15 in the Control arm. The lower GI GVHD was seen in 2 patients in the Treatment and 4 in the control arm. As treated analyses showed the overall grade 2-4 GVHD in 3 of 14 (21.4%) with the use of CBM588 and 6 of 16 (37.5%) without CBM588 (one case of lower GI GVHD with CBM, 5 cases without; (Table 2). The Shannon Diversity Index was similar between the two groups at each time point tested. (Figure 1). However, had favorable microbial profile was detected as the pathogens Enterobacteriaceae, Clostridium baratii, and Clostridiodes difficile were reduced in the treatment group. (Figure 2) In summary, our data demonstrate the feasibility and safety of CBM588 administration during the peri-transplant period, which was associated with an intended biologic impact on the gut microbiome, and an early favorable sign of GI-GVHD incidence and HCT outcomes in this older population who underwent RIC HCT. Figure 1 Figure 1. Disclosures Dadwal: Astellas: Speakers Bureau; Aseptiscope: Consultancy; Shire/Takeda: Research Funding; AlloVir: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Other: Investigator; Karius: Other: Investigator. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria. Al Malki: CareDx: Consultancy; Neximmune: Consultancy; Hansa Biopharma: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Budde: Roche: Consultancy; BeiGene: Consultancy; IGM Biosciences: Research Funding; Merck, Inc: Research Funding; Gilead: Consultancy; AstraZeneca: Research Funding; Mustang Bio, Inc: Research Funding; Novartis: Consultancy; Amgen: Research Funding. Popplewell: Hoffman La Roche: Other: Food; Pfizer: Other: Travel; Novartis: Other: Travel. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.
- Published
- 2021
22. The Impact of Letermovir (LTV) Prophylaxis on Early Cytomegalovirus Infection (CMVi) and Outcomes in the Adult Allogeneic Hematopoietic Cell Transplantation (alloHCT) Recipients with High-Risk Donor Type
- Author
-
Sanjeet S Dadwal, Dongyun Yang, Guido Marcucci, Sally Mokhtari, Bernard Tegtmeier, Joycelynne Palmer, Eileen P. Smith, Randy Taplitz, Andrew S. Artz, Peter T. Curtin, Ricardo Spielberger, Amandeep Salhotra, Anthony S. Stein, Stephen J Forman, Monzr M. Al Malki, and Ryotaro Nakamura
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
CMV recipient seropositivity (R+) and CMVi are independent risk factors for increased mortality after alloHCT. Preemptive therapy (PET) was standard of care until LTV approval by the FDA in November 2017 for CMVi prevention in CMV R+ alloHCT patients (pts). In a registration trial, LTV led to a significant reduction in clinically significant CMVi (CS-CMVi) defined as CMVi requiring PET in both high-risk (HR) or low-risk (LR) recipients. In the HR-group, defined as mismatched related / unrelated donor with at least one mismatch in one of the four HLA-gene loci of HLA-A, -B, -C or -DRB1, haploidentical donor, umbilical cord source or grade ≥2 acute graft-versus-host disease (aGVHD) at randomization, the impact of LTV on CS-CMVi was more robust. Small studies have confirmed the positive impact of LTV on CS-CMVi. Here, we compared the natural history of CMVi and CS-CMVi between the pre-LTV and LTV era in the first 100 days after HR-alloHCT. We also explored the impact on non-relapse mortality (NRM), overall survival (OS), disease free survival (DFS), and incidence of aGVHD between the two eras. In this IRB approved retrospective study, we identified 450 consecutive HR-alloHCT pts who underwent their first HCT from 1/1/2016 to 12/31/2020 at our center. Pre-LTV era was from 1/1/2016 to 2/28/2018 and LTV era was from 3/1/2018 onwards when prophylaxis became standard of care (SOC) for all R+ alloHCT at our institution. In the HR-alloHCT, the uptake of the new SOC was consistent in all HR-R+ pts beginning LTV prophylaxis on day +7 post-HCT. We defined R+ HR-alloHCT pts at high-risk for CMVi or CS-CMVi as described above except for aGVHD (not recorded at time of institution of LTV). CMVi was defined as first time viral load (VL) of >500 genomic copies/ml (gc/ml). CS-CMVi was defined as a VL >500 gc/ml (910 IU/ml) on two consecutive tests done atleast 48 hours apart, that triggered PET (ganciclovir, valganciclovir, foscarnet, cidofovir), or had identification of CMV end organ disease . The incidence of CMVi and CS-CMVi in R+ allo-HCT was compared by LTV era using Gray test. Kaplan-Meier curves and log-rank tests were used for OS and DFS by LTV era. NRM, relapse, acute and chronic GVHD were compared using cumulative incidence curves and Gray test. All tests were 2-sided at 0.05 level. Of the 450 HR-alloHCT pts, 146 were R+ in pre-LTV vs. 246 R+ in LTV era. R+ patient, their eligible underlying disease, and HCT characteristics are shown in Table 1. There was a significant reduction in both CMVi and CS-CMVi in LTV era vs pre-LTV era (24.1% vs 45.2%, and 22.3% vs 44.5% respectively; p Although there were no significant differences in OS, DFS, NRM, relapse, and chronic GVHD between the two eras at 6, 12, and 18 months post-HCT in R+ pts, a trend towards improved OS and DFS in LTV era was noted (p=0.06 and p=0.07) in this patient population. There was a significantly lower rate of grade III-IV acute GVHD in the LTV era (9.2% vs 17.8% at day 100, p=0.012 with HR = 0.49). No case of CMV disease was identified in the first 100 days. LTV has substantially reduced CS-CMVi in the first 100 days post-HCT in HR-R+ pts and resultant burden from PET. We identified a significant reduction in grade III - IV aGVHD in LTV era suggesting that with reduced CMVi, LTV may have a salutary impact on development of aGVHD; this is in agreement with studies showing bidirectional relationship between CMVi and onset of aGVHD. We did not observe a significant difference in OS, DFS, NRM amongst the two eras but there was trend towards higher OS and DFS in LTV era that requires further assessment in a larger multicenter cohort. Lastly, significant burden persists from CS-CMVi in this patient population during the first 100 days of alloHCT that underscores the need of efforts to identify other novel methods to mitigate it. One of the limitations in the LTV era is identifying the clinical scenarios surrounding the CMVi and CS-CMVi that may relate to compliance, absorption from gastrointestinal tract, and affordability or coverage of LTV after discharge from hospital. Figure 1 Figure 1. Disclosures Dadwal: Astellas: Speakers Bureau; Aseptiscope: Consultancy; AlloVir: Research Funding; Shire/Takeda: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Other: Investigator; Karius: Other: Investigator. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Taplitz: Merck: Membership on an entity's Board of Directors or advisory committees. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Al Malki: Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; CareDx: Consultancy; Rigel Pharma: Consultancy; Hansa Biopharma: Consultancy.
- Published
- 2021
23. Total Marrow and Lymphoid Irradiation to 20 Gy Combined With Post-Transplant Cyclophosphamide Graft vs. Host Disease (GvHD) Prophylaxis is Associated With Low Non-Relapse Mortality Rates and Favorable GvHD-Free/Relapse-Free Survival in AML
- Author
-
Joycelynne Palmer, Vinod Pullarkat, Dongyun Yang, Ricardo Spielberger, S.V. Dandapani, An Liu, S.J. Forman, Chunhui Han, Joseph Rosenthal, M. Al Malki, Len Farol, Guido Marcucci, S.K. Hui, Anthony S. Stein, Amandeep Salhotra, Ryotaro Nakamura, and J.Y.C. Wong
- Subjects
Cancer Research ,medicine.medical_specialty ,Radiation ,Cyclophosphamide ,business.industry ,Spleen ,medicine.disease ,Relapse free survival ,Gastroenterology ,Tacrolimus ,Transplantation ,medicine.anatomical_structure ,Oncology ,Internal medicine ,Toxicity ,medicine ,Radiology, Nuclear Medicine and imaging ,Esophagus ,business ,Stomatitis ,medicine.drug - Abstract
Purpose/Objective(s) Allogeneic hematopoietic cell transplantation (alloHCT) offers the highest curative rate for AML with intermediate or high-risk cytogenetics in remission. GvHD is a main cause of alloHCT mortality and morbidity. This trial evaluated the feasibility of a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 20 Gy combined with post-transplant cyclophosphamide (PTCy), which was designed to reduce the chronic GvHD risks using PTCy and reduce relapse rates with TMLI, thereby improving GRFS rates compared to standard myeloablative conditioning regimens. Materials/Methods Eighteen patients with AML in first or second complete remission were treated with TMLI 20 Gy (2 Gy twice daily) to bone, lymph nodes and spleen (liver and brain 12 Gy) on days -4 to 0; stem cell infusion on day 0; PTCy 50 mg/kg/day on days +3 and +4; and tacrolimus 1 mg continuous infusion on days +5 to +90. Endpoints included toxicity, GRFS at 1 year, engraftment, overall survival (OS), and non-relapse mortality (NRM). GRFS was defined as grade 3-4 acute GvHD (aGvHD), chronic GvHD (cGvHD) requiring systemic treatment, relapse, or death (from any cause). Results The median age was 40 (range 19-56). Seventeen of 18 patients had intermediate to high-risk cytogenetics. The average (range) Dmean organ doses (Gy) were lungs 8.1 (7.5-9.5), kidneys 7.5 (6.3-9.2), heart 7.3 (6.6-8.3), oral cavity 4.4 (3.0–6.7), esophagus 6.4 (4.7-7.6), upper GI 9.1 (7.3-12.0), lower GI 10.2 (8.9-12.1), and bladder 10.0 (6.8-14.6). Median follow-up was 12.5 months (range 5.9 to 25.4) for surviving patients (n = 17). All patients engrafted. Bearman toxicity data were available for all patients. Grade 2 toxicities were bladder (n = 3) and stomatitis (n = 1). No grade 3-4 toxicities or toxicity-related deaths were observed. aGvHD developed in 2 patients with grade III-IV in only 1 patient (100-day Grade III-IV aGvHD: 5.6%, 95% CI: 0.3-23.1). Five patients developed chronic GvHD with one patient developing moderate to severe cGVHD (1-year cGvHD rate: 28.6%, 95% CI: 7.5%-54.7%). The GRFS rate at 1 year was 60.6% (95% CI: 34.6-79.0). One-year estimates of OS and relapse-free survival were 100% and 83.3% (95% CI: 62.8-96.1), respectively. Disease relapse at 1 year was 16.7% (95% CI: 3.9-37.2). The estimates of NRM at 100 days and 1 year were both 0%. Relapsed disease after transplant occurred in 3 patients (16.7%). One patient died after relapse. Conclusion This TMLI 20 Gy only conditioning regimen, together with PTCy and tacrolimus, is associated with low toxicity and NRM. All patients achieved engraftment. Participants with ≥ 1-year follow-up have discontinued immunosuppressive therapy. The results suggest an improved GRFS rate compared to traditional myeloablative regimens reported. A larger phase II trial is planned.
- Published
- 2021
24. Poster: ALL-440: Promising Safety and Efficacy Results from an Ongoing Phase 1/2 Study of Pembrolizumab in Combination with Blinatumomab in Patients (pts) with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)
- Author
-
Karamjeet S. Sandhu, Quy Huynh-Tran, Elise Elise Cooper, Jianying Zhang, Joycelynne Palmer, Ni-Chun Tsai, Sandra Thomas, Marjorie Robbins, Ahmed Aribi, Amandeep Salhotra, Mathew Mei, Ji-Lian Cai, Ricardo Spielberger, Paul Koller, Ibrahim Aldoss, Anthony Stein, Guido Marcucci, and L. Elizabeth Budde
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2021
25. ALL-440: Promising Safety and Efficacy Results from an Ongoing Phase 1/2 Study of Pembrolizumab in Combination with Blinatumomab in Patients (pts) with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)
- Author
-
Jianying Zhang, Ibrahim Aldoss, Paul Koller, L. Elizabeth Budde, Ahmed Aribi, Karamjeet S. Sandhu, Ji-Lian Cai, Sandra H. Thomas, Ricardo Spielberger, Guido Marcucci, Quy Huynh-Tran, Joycelynne Palmer, Anthony S. Stein, Elise Elise Cooper, Marjorie A. Robbins, Ni-Chun Tsai, Mathew Mei, and Amandeep Salhotra
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Side effect ,business.industry ,Lymphoblastic Leukemia ,Hematology ,Pembrolizumab ,medicine.disease ,Cytokine release syndrome ,Refractory ,Internal medicine ,Toxicity ,medicine ,In patient ,Blinatumomab ,business ,medicine.drug - Abstract
Background: Blinatumomab, a bispecific anti-CD19/CD3 antibody, demonstrated single-agent efficacy with 42% CR/CRh in R/R B-ALL. Upregulation of immune inhibitory molecules has been shown to confer resistance to blinatumomab. Here, we set out to test the combination of pembrolizumab and blinatumomab in a phase 1/2 trial (NCT03512405). Methods: Pts [≥18 years old (yo); ECOG Results: As of February 1, 2021, 7 pts were enrolled to phase 1, with one unevaluable. Six treated and evaluable pts received a median of 2 (1–5) cycles of treatment. At baseline, the median age was 51 yo (29–74) with median 2 (2–4) prior lines of regimens and median 29% (0–83) BM blasts. Two pts had extramedullary disease. In cycle 1, all 6 pts experienced grade (gr) 1–2 cytokine release syndrome. Neurologic toxicities were all reversible with only 1 ≥ gr3 AE. All-non-hematologic gr3 toxicities, were reversible. No dose-limiting toxicity, ≥ gr4 non-hematologic toxicity, or treatment-related deaths were seen. Five of 6 evaluable pts (83%) achieved MRD-negative CR after a median of 1 (1–2) cycle. Three pts in CR received alloHCT, all engrafted. With a median follow-up of 2.8 (1.1–9.6) months, 4 CRs are ongoing (1 post-transplant), and 5 of 6 pts are still alive at the data cut-off. Conclusions: The combination of pembrolizumab and blinatumomab in phase 1 of this study in pts with B-ALL was deemed safe with a manageable side effect profile and encouraging anti-leukemic activity. The study is now open for phase 2 with the primary objective of overall response rate.
- Published
- 2021
26. Healthcare Resource Utilization in Transplant Patients Who Are at a Higher-Risk to Develop Cytomegalovirus Infection during Their Primary Transplant-Related Hospitalization
- Author
-
Eileen P. Smith, Alfredo G. Puing, Vinod Pullarkat, Bernard Tegtmeier, Deepa Nanayakkara, Dongyun Yang, Monzr M. Al Malki, John A. Zaia, David S. Snyder, Ricardo Spielberger, Joycelynne Palmer, Sally Mokhtari, Stephen J. Forman, Ryotaro Nakamura, Anthony S. Stein, Karamjeet S. Sandhu, Amandeep Salhotra, Randy Taplitz, Jana Dickter, and Sanjeet Dadwal
- Subjects
medicine.medical_specialty ,business.industry ,Medical record ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Transplantation ,Letermovir ,Internal medicine ,Epidemiology ,Cohort ,medicine ,Lost to follow-up ,business ,Packed red blood cells ,Viral load ,medicine.drug - Abstract
Cytomegalovirus reactivation commonly referred to as CMV infection (CMVi) is a frequent event after allogeneic hematopoietic cell transplantation (HCT), with studies associating CMVi within the first 100 days post-HCT with higher risk of non-relapse mortality (NRM) and decreased overall survival (OS). In addition, understanding the impact of CMVi on resource utilization during the primary HCT admission is critical. Together, this knowledge of epidemiology and resource utilization may be used to inform preventive strategies to minimize CMVi, e.g., use of antiviral agent letermovir. After receiving IRB approval, we retrospectively reviewed institutional electronic medical records and CMVi database from 824 patients who underwent their first allogeneic HCT between 2011 and 2016 at City of Hope (pre-letermovir era). Patients were censored at death, disease relapse or lost to follow up. Data collected: demographics, HCT indication, conditioning regimen, CMV serostatus of the donor and recipient (D/R), length of stay (LOS) for primary HCT admission (all allo HCT were performed as inpatient), readmission rates in first 100 days, and use of supportive care. CMV viral load of >250 genomic copies/ml constituted a diagnosis of CMVi. CMV viral load surveillance in MUD recipients began at engraftment or day +21 post-HCT, whichever occurred earlier. For Haplo and cord blood (CB) HCT, CMV viral load surveillance started on day +14. The primary endpoint of the study was LOS for HCT admission. Supportive care use, transfusions, growth factors and antiviral usage were secondary endpoints. The differences in resource utilization between different groups were examined by CMVi during the primary HCT admission period, using Wilcoxon test or chi-square test whenever appropriate. Median age of patients at the time of HCT was 52 years (range: 1-78), with 57% of patients being male. The most common diagnoses included: AML (39%), ALL (21%) and MDS/MPN (17%). Patients underwent MUD (n=627, 76%), Haplo (n=102, 12%), or CB-HCT (n=95, 12%), and 44% of patients received myeloablative conditioning regimen. Majority of the patients were CMV seropositive (83.7%). Graft source was peripheral blood stem cells in 75% of the recipients. Most commonly used graft-versus-host disease prophylaxis consisted of post-transplant cyclophosphamide (100%), Tacrolimus/sirolimus (83%), and cyclosporine/cellcept (78%) in Haplo, MUD, and CB-HCT recipients, respectively. During the primary HCT admission, rate of CMVi was 7%, 36% and 28% in all of MUD, Haplo, and CB-HCT, respectively (compared to 25%, 71.6%, and 50.5% in MUD, Haplo and CB-HCT respectively in the first 100 days after HCT). Rate of CMVi in CMV+ recipients was 8.2% in MUD, 41.6% Haplo and 34.2% in CB-HCT (Table 1). Majority of patients with CMVi received antiviral therapy (85.8%), with Haplo and CB-HCT more likely to be treated than MUD (p=0.023). LOS was longer among CMVi patients compared to no CMVi patients in each donor type, median of 59 vs. 36 days for the overall cohort (p0.2). Transfusion of packed red blood cells (PRBC) and platelet units were significantly higher among CMVi recipients of MUD and Haplo (p0.82). There was no significant difference in hospital readmission by CMVi across donor type in the first 100 days (p>0.5). In conclusion, the rate of CMVi during primary HCT admission was high, particularly in the Haplo and Cord HCT (>50% of the CMVi occurring within 100 days of HCT). Given the relatively high CMV viral load cut-off values and later CMV surveillance initiation, the rate could, in fact, have been underestimated in our cohort. CMVi during primary HCT admission was associated with significantly higher health care resource utilization; longer hospital LOS and supportive care utilization (CMV specific antiviral usage, transfusion and growth factors use). Prophylactic strategies to prevent early CMVi in alloHCT should be considered to decrease NRM and improve value based care delivery. Disclosures Dadwal: Shire/ Takeda: Research Funding; Karius: Research Funding; Astellas: Speakers Bureau; Janssen: Other: Advisory board meeting; Ansun Biopharma: Research Funding; Chimerix: Research Funding; Gilead: Research Funding; Merck: Consultancy, Honoraria, Other: Advisory board meeting, Research Funding, Speakers Bureau. Pullarkat:Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Taplitz:Merck: Other: Immunocompromised Advisory Group. Al Malki:Neximmune: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy. Nakamura:NapaJen Pharma: Consultancy; Magenta Therapeutics: Other: Advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Viracor: Consultancy; Merck: Other: advisory board meeting; Kadmon Corporation: Other: Advisory board meeting.
- Published
- 2020
27. Total Marrow and Lymphoid Irradiation (TMLI) at a Dose of 2000cGy in Combination with Post-Transplant Cyclophosphamide (PTCy)-Based Graft Versus Host Disease (GvHD) Prophylaxis Is Safe and Associated with Favorable GvHD-Free/Relapse-Free Survival at 1 Year in Patients with Acute Myeloid Leukemia (AML)
- Author
-
Susanta K. Hui, David S. Snyder, Andrew S. Artz, Ryotaro Nakamura, Samer K. Khaled, Ni-Chun Tsai, Joycelynne Palmer, Vinod Pullarkat, Guido Marcucci, Joseph Rosenthal, Ahmed Aribi, Len Farol, Jeffrey Y.C. Wong, Ibrahim Aldoss, Anthony S. Stein, Stephen J. Forman, Dongyun Yang, Ricardo Spielberger, Amandeep Salhotra, Monzr M. Al Malki, Eric Radany, Haris Ali, An Liu, James F. Sanchez, and Chatchada Karanes
- Subjects
Oncology ,medicine.medical_specialty ,Post transplant cyclophosphamide ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Relapse free survival ,Graft-versus-host disease ,Internal medicine ,Medicine ,Gvhd prophylaxis ,In patient ,business - Abstract
Background: Allogeneic hematopoietic cell transplantation (alloHCT) is the approach that offers the highest curative rate for acute myelogenous leukemia (AML) with intermediate or high-risk cytogenetics. Graft versus host disease (GvHD) has remained the main cause of post-transplantation mortality and morbidity, despite advances in prophylaxis and therapy, adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GvHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have developed a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplant cyclophosphamide (PTCy), to 1) reduce the possibly increased risk of relapse from PTCy, by using escalated radiation doses of TMLI, as increasing radiation doses has the potential to decrease the post-transplantation relapse rate (Blood, vol 76, pp. 1867-1871, 1990); and 2) reduce the risk of chronic GvHD by using PTCy. The major goal of this pilot study of TMLI and PTCy (clinicaltrials.gov: NCT03467386), was to thus improve GvHD-free/relapse-free survival (GRFS), reported to be 45% from total body irradiation (TBI) and tacrolimus/sirolimus prophylaxis (BBMT, vol 26(2), pp. 292-299, 2020), in patients with AML in remission. Patients and Methods: A total of 18 patients were enrolled and treated (see Table) between March 2018 and December 2019. Key criteria were ages 18 to 60, first or second CR, minimal residual disease negative by multi-color flow cytometry, and normal organ function. TMLI was administered on days -4 to 0 without addition of chemotherapy. The radiation dose for all patients (n=18) was 2000 cGy, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Remaining organs were considered non-targeted. All patients received peripheral blood stem cells on day 0. Cyclophosphamide was given on days +3 and +4, 50 mg/kg each day for GVHD prevention. Tacrolimus, 1 mg continuous infusion adjusted to maintain levels from 5 to 10 ng/mL was given from day +5 to day +90, and G-CSF 5 µg/kg daily was administered at day +5 until recovery of neutrophil counts. Endpoints included toxicity, GRFS at 1 year, engraftment, overall survival (OS), and non-relapse mortality (NRM). Toxicities were defined according to the Bearman and CTCAE 4.03 scales, the latter for hematologic toxicity. A patient safety lead-in segment (n=6) was conducted to ensure that there were no unexpected toxicities, allowing for a dose de-escalation to 1800 cGy. GRFS was defined as grade 3-4 acute GvHD, chronic GvHD requiring systemic treatment, relapse, or death (from any cause), whichever occurred first. Results: Bearman toxicity data are available for all patients. Among these patients, grade 2 toxicities were bladder toxicity and stomatitis. No grade 3-4 toxicities or toxicity-related deaths were observed. Acute GVHD (aGVHD) developed in 2 of patients (100-day Grade II-IV aGVHD: 11.1%, 95%CI: 1.7-30.4); of those, only 1 patient developed Grades III-IV (100-day Grade III-IV aGVHD: 5.6%, 95%CI: 0.3-23.1). Five patients developed mild chronic GVHD (1-year cGVHD rate: 28.6%, 95%CI: 7.5%-54.7%). The GRFS rate at 1 year was 59.3% (95% CI: 28.8-80.3) (Figure). The median follow up was 11.3 months (range 4.7 to 25.4) for surviving patients (n=17). All patients engrafted. Time to neutrophil and platelet recovery were 14 days (range 13-32 days) and 20 days (range 11-49 days), respectively. One-year estimates of OS and relapse-free survival were 100% and 80.8% (95% CI: 50.5-93.6), respectively (Figure). Disease relapse at 1 year was 19.2% (95% CI: 4.1-42.6). The estimates of NRM at 100 days and 1 year were both 0%. Relapsed disease after transplant occurred in 3 patients (16.7%). One patient died after relapse. Conclusions: 1) This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe and feasible, with no NRM. 2) All patients achieved engraftment. 3) Participants with ≥1 year follow-up have discontinued immunosuppressive therapy, reducing financial burden and leading to improved quality of life. The preliminary results suggest an improved GRFS rate. A larger phase 2 trial is in preparation to corroborate these data. Disclosures Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Al Malki:Neximmune: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Rigel Pharma: Consultancy. Ali:Incyte Corporation: Consultancy. Aribi:Seattle Genetics: Consultancy. Marcucci:Novartis: Speakers Bureau; Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Abbvie: Speakers Bureau; Merck: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Nakamura:Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Pullarkat:AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salhotra:Celgene: Research Funding; Kadmon: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2020
28. Phase II Study of Yttrium-90 Ibritumomab Tiuxetan Plus High-Dose BCNU, Etoposide, Cytarabine, and Melphalan for Non-Hodgkin Lymphoma: The Role of Histology
- Author
-
James F. Sanchez, Ni-Chun Tsai, Stephen J. Forman, Joycelynne Palmer, Leslie Popplewell, Dave Yamauchi, Robert T. Chen, Jennifer Simpson, Ricardo Spielberger, Auayporn Nademanee, and Amrita Krishnan
- Subjects
Oncology ,Melphalan ,medicine.medical_specialty ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Etoposide ,Preparative Regimen ,CD20 ,Transplantation ,biology ,business.industry ,Hematology ,medicine.disease ,Lymphoma ,Regimen ,030220 oncology & carcinogenesis ,biology.protein ,Cytarabine ,Nuclear medicine ,business ,030215 immunology ,medicine.drug - Abstract
Standard-dose 90yttrium-ibritumomab tiuxetan (.4 mci/kg) together with high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (Z-BEAM) has been shown to be a well-tolerated autologous hematopoietic stem cell transplantation preparative regimen for non-Hodgkin lymphoma. We report the outcomes of a single-center, single-arm phase II trial of Z-BEAM conditioning in high-risk CD20+ non-Hodgkin lymphoma histologic strata: diffuse large B cell (DLBCL), mantle cell, follicular, and transformed. Robust overall survival and notably low nonrelapse mortality rates (.9% at day +100 for the entire cohort), with few short- and long-term toxicities, confirm the safety and tolerability of the regimen. In addition, despite a high proportion of induction failure patients (46%), the promising response and progression-free survival (PFS) rates seen in DLBCL (3-year PFS: 71%; 95% confidence interval, 55 to 82%), support the premise that the Z-BEAM regimen is particularly effective in this histologic subtype. The role of Z-BEAM in other strata is less clear in the context of the emergence of novel agents.
- Published
- 2017
29. Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status
- Author
-
Victoria Bedell, Ricardo Spielberger, Ketevan Gendzekhadze, Vinod Pullarkat, Thai Cao, Raju Pillai, Anh Pham, David S. Snyder, Ahmed Aribi, Stephen J. Forman, Sierra Min Li, Milhan Telatar, Monzr M. Al Malki, Hao Hong, Dennis D. Weisenburger, Samer K. Khaled, David Senitzer, Abbas Padeganeh, Joyce Murata-Collins, Patricia Aoun, Ibrahim Aldoss, Haris Ali, Ryotaro Nakamura, Joycelynne Palmer, Guido Marcucci, Amandeep Salhotra, Michelle Afkhami, Margaret R. O'Donnell, and Anthony S. Stein
- Subjects
Oncology ,medicine.medical_specialty ,Allogeneic transplantation ,Disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,business.industry ,Myelodysplastic syndromes ,Neoplasms, Second Primary ,Hematology ,medicine.disease ,Prognosis ,Transplantation ,ETV6 ,Leukemia, Myeloid, Acute ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Immunology ,Mutation ,Stem cell ,Tumor Suppressor Protein p53 ,business ,Complication ,030215 immunology - Abstract
Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P
- Published
- 2017
30. Ruxolitinib as Salvage Therapy for Chronic Graft-versus-Host Disease
- Author
-
Michael Hernandez-Henderson, Dongyun Yang, Ryotaro Nakamura, Pablo Parker, Monzr M. Al Malki, Haris Ali, Ricardo Spielberger, Jonathan Cotliar, Stephen J. Forman, Jasmine Zain, Erin Kopp, Sally Mokhtari, Karen Huelsman, Badri Modi, Sanjeet Dadwal, Amandeep Salhotra, and Jeremy Klein
- Subjects
Adult ,Male ,Ruxolitinib ,medicine.medical_specialty ,Salvage therapy ,Graft vs Host Disease ,Disease-Free Survival ,Prednisone ,Internal medicine ,Nitriles ,medicine ,Humans ,Aged ,Retrospective Studies ,Salvage Therapy ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Allografts ,Survival Rate ,Regimen ,Graft-versus-host disease ,Pyrimidines ,Cohort ,Chronic Disease ,Pyrazoles ,Female ,business ,medicine.drug - Abstract
Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval, .388 to .673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost.
- Published
- 2018
31. Palifermin for prevention of oral mucositis in allogeneic hematopoietic stem cell transplantation: a single-institution retrospective evaluation
- Author
-
Stephen J. Forman, Sepideh Shayani, Joycelynne Palmer, Ricardo Spielberger, Diana T. Nguyen, Andrew Dagis, and Joel B. Epstein
- Subjects
Adult ,Male ,medicine.medical_specialty ,Fibroblast Growth Factor 7 ,Adolescent ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,law.invention ,Young Adult ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Mucositis ,Humans ,Etoposide ,Retrospective Studies ,Stomatitis ,business.industry ,Incidence ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Length of Stay ,Middle Aged ,Total body irradiation ,medicine.disease ,Parenteral nutrition ,Oncology ,Palifermin ,Quality of Life ,Female ,Parenteral Nutrition, Total ,business ,Whole-Body Irradiation ,medicine.drug - Abstract
The purpose of this study is to assess the impact of palifermin on oral mucositis (OM) and its sequelae in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) who were conditioned with fractionated total body irradiation (FTBI) and etoposide. This retrospective chart review study compared the effect of palifermin on the development of OM in patients who received this agent during an allo-HSCT (n = 99) to those who did not (n = 30). The primary end points were severity and duration of OM. Secondary end points included requirements for opioids, total parenteral nutrition (TPN), and intensive oral care; incidence of infection; length of hospital stay; and overall survival. There was no significant difference in the incidence of all grades of OM, but incidence of severe OM was decreased in palifermin-exposed patients (34 vs 80 %, p
- Published
- 2015
32. Phase I trial of total marrow and lymphoid irradiation transplant conditioning in patients with relapsed/refractory acute leukemia
- Author
-
Chatchada Karanes, An Liu, Firoozeh Sahebi, Ahmed Aribi, Anna B. Pawlowska, Monzr M. Al Malki, Ryotaro Nakamura, David S. Snyder, Ibrahim Aldoss, Sandra H. Thomas, Ni-Chun Tsai, T.E. Schultheiss, Samer K. Khaled, James F. Sanchez, Haris Ali, Vinod Pullarkat, Ricardo Spielberger, Joseph Rosenthal, Margaret R. O'Donnell, Amandeep Salhotra, Jeffrey Y.C. Wong, Pablo Parker, Joycelynne Palmer, Anthony S. Stein, Guido Marcucci, Len Farol, Stephen J. Forman, and Eric Radany
- Subjects
Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,Adolescent ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Gastroenterology ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Bone Marrow ,Recurrence ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Etoposide ,Salvage Therapy ,Transplantation ,Chemotherapy ,Acute leukemia ,Leukemia ,Lymphatic Irradiation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Dose-Response Relationship, Radiation ,Hematology ,Total body irradiation ,Middle Aged ,medicine.disease ,Survival Analysis ,Surgery ,030220 oncology & carcinogenesis ,Acute Disease ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation.
- Published
- 2017
33. Real World Experience of Letermovir (LTV) Prophylaxis (Px) for the Prevention of Cytomegalovirus Infection (CMVi) in the Adult CMV Seropositive Recipients (R+) of Allogeneic Hematopoietic Cell Transplantation (HCT) Patients (pts)
- Author
-
Margaret R. O'Donnell, James I. Ito, Bernard Tegtmeier, Chatchada Karanes, John A. Zaia, Jana Dickter, Ibrahim Aldoss, Ryotaro Nakamura, Eileen P. Smith, Stephen J. Forman, Anthony S. Stein, David S. Snyder, Monzr M. Al Malki, Sally Mokhtari, Karamjeet S. Sandhu, Matthew Mei, Amandeep Salhotra, J. Ross, Guido Marcucci, Vinod Pullarkat, Joycelynne Palmer, Dongyun Yang, Ricardo Spielberger, Auayporn Nademanee, and Sanjeet Dadwal
- Subjects
Transplantation ,medicine.medical_specialty ,Hematopoietic cell ,business.industry ,Hematology ,Gastroenterology ,Cytomegalovirus infection ,Letermovir ,Internal medicine ,Baseline characteristics ,medicine ,Methotrexate ,Cumulative incidence ,business ,Viral load ,medicine.drug - Abstract
CMVi leads to significant morbidity in R+ HCT and preemptive therapy (PET) has been the standard of care. LTV was FDA-approved in Nov. 2017 for CMVi prevention in R+ HCT. Besides the clinical trials, there is are real world data on LTV. Upon IRB approval, we retrospectively studied consecutive R+ HCT pts with their first HCT between 1/1/2017 and 6/30/2018. LTV group included pts with HCT between 2/20/18 and 6/30/2018, who had LTV Px started within 28 days of HCT (n=59), and R+ HCT between 1/1/2017 and 2/19/2018 (n=307) served as control (ctrl). We compared CMVi rates in first 100 days of HCT, and time to engraftment between the 2 groups. Risk stratification: high risk - haplo/cord HCT & ATG use, low risk - all others. CMVi was defined as viral load (VL) of 625 IU/ml to 1250 IU/ml or higher (CMV assay conversion factor of 1 genomic copy/ml = 2.5 IU/ml). CMV VL less than 625 IU/ml is reported negative, VL between 625 and 1250 IU/ml is qualitative positive but numeric value is provided only for VL ≥ 1250 IU/ml. PET was recommended for VL >1250 IU/ml (500 copies/ml) in high risk and > 3750 IU/ml (1500 copies/ml) in low risk HCT (including those on LTV requiring PET). Descriptive statistics was done for baseline characteristics. Cumulative incidence curves were generated for CMVi within 100 days post-HCT and Gray's test was used to compare the difference between the 2 groups. In both groups, median age was 54 years and HCT indications were similar. Donor type in LTV/ Ctrl groups: MRD (27 vs 36%), MUD (44 vs 47%), haplo (27 vs 15%), cord (1.7 vs 1.6%). PBMC was graft source in 90% of both groups. Myeloablative conditioning: 40.7% in LTV and 35% in Ctrl. GVHD Px: Cellcept (32 vs 25%), methotrexate (7 vs 9%), tacro/siro (58 vs 65), and others (3.4 vs 0.3%) in LTV & Ctrl respectively. A majority (n=36) received both intravenous & oral LTV formulation while 23 received oral only. Median time from HCT to LTV start was 13 days (range: 4-26). LTV group had significant reduction in CMVi rate (22.4% [95%CI: 12.7-34.0]) compared with ctrl group (41.1% [95%CI: 35.4-46.7], p=0.008, Fig 1). In a subgroup of high-risk HCT LTV was significantly reduced CMVi rate (22.2%) compared with ctrl (62.8%, p=0.004, Fig 2) while statistical difference was not reached in low-risk HCT pts (22.8% vs. 35.6%, p=0.11). In the LTV Px, clinically significant (CS)-CMVi requiring PET occurred in 8.4% (n=5) and on excluding 2 pts who were not on LTV at the time of CMVi, the rate was 5% (Fig 1). CMVi cleared without PET in 8/13 LTV pts and LTV was continued; all pts had VL LTV use in a real world setting is associated with significant reduction of CMVi and CS-CMVi without any discernible myelosuppression. The low level CMVi resolved spontaneously in majority with continued LTV Px and PET was not necessary. The high-risk HCT had most benefit with LTV Px.
- Published
- 2019
34. Effect of Vancomycin-Resistance Enterococci Colonization Status Prior to Allogeneic Hematopoietic Cell Transplantation on Transplant Outcomes: A Single Center Retrospective Experience
- Author
-
Dongyun Yang, Ricardo Spielberger, Auayporn Nademanee, Guido Marcucci, Ryotaro Nakamura, Stephen J. Forman, Margaret R. O'Donnell, Akemi Meguro, Jasmine Zain, Jana Dickter, Anthony S. Stein, Ibrahim Aldoss, Monzr M. Al Malki, J. Ross, David S. Snyder, Sally Mokhtari, Sanjeet Dadwal, James I. Ito, Haris Ali, Bernard Tegtmeier, Matthew Mei, Karamjeet S. Sandhu, and Amandeep Salhotra
- Subjects
medicine.medical_specialty ,biology ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,medicine.disease ,Single Center ,biology.organism_classification ,Biochemistry ,Tacrolimus ,Transplantation ,Graft-versus-host disease ,Enterococcus ,Bacteremia ,Internal medicine ,medicine ,business ,Fungemia - Abstract
The prevalence of vancomycin-resistance Enterococci colonization (VRE-C) in patients undergoing allogeneic hematopoietic cell transplantation (aHCT) is between 23-40%. Pre-HCT VRE-C is shown to be associated with high risks of VRE bloodstream infection (VRE-BSI), non-relapse mortality (NRM) and lower overall survival. Recent studies investigating the association between VRE-C and risk of acute graft-versus-host disease (aGVHD) after aHCT has demonstrated conflicting results, possibly due to the heterogeneous transplant conditioning and GVHD prophylactic regimens. Here, we sought to examine the VRE-C prevalence and determine its impact on aHCT outcomes, in patients receiving tacrolimus and sirolimus (T/S) as aGVHD prophylaxis. To explore the association between pre-HCT VRE-C and transplant outcomes, we retrospectively reviewed medical records of a cohort of 1074 consecutive patients who underwent aHCT at City of Hope from 2014 to 2017. Patients with stool culture screening within 30 days pre-aHCT (n=862) were identified from the microbiology database and were grouped as VRE-C and non-colonized (VRE-NC). Data was not available on VRE-C in 185 patients and they were not included in analysis. Overall survival (OS) and progression-free survival (PFS) were examined by Kaplan-Meier curves and log-rank tests. Non-relapse mortality (NRM), VRE-BSI, and GVHD rates of the 2 groups were compared by cumulative incidence rates and Gray's test. Multivariate analyses were performed when adjusting for prognostic factors. Two-sided P value of ≤0.05 was considered significant. Of the 862 evaluated patients, 68 had VRE-C (7.9% prevalence). Median age of patients in VRE-C and VRE-NC groups were 53 and 55 years, respectively. Gender distribution, transplant indications, stem cell source, proportion of unrelated donors, GVHD prophylaxis with T/S and other clinical variables including intensity of conditioning regimen and HCT-CI were similar between the two groups (Table 1) . Karnofsky performance status (KPS) of 90-100 and 70-80 were seen in 40% and 53% of patients with VRE-C compared to 47% and 48% of VRE-NC patients (p=0.12). Overall, VRE-BSI episodes were rare (n=7) with 4 patients in VRE-C (6.1%) and 3 patients in VRE-NC (0.4 %); p At a median follow-up duration of 19.4 months (range: 2.7-48.4), similar 1-year OS was achieved in both groups (67.4% in VRE-C and 76.5% in VRE-NC; p=0.11) but 1 year PFS was significantly lower in the VRE-C cohort (55.6% Vs. 69.4%; p=0.038). Higher NRM was achieved in the VRE-C cohorts on days +100 and +365 (11.8% Vs. 7.2% and 25.1% Vs. 14.4%, respectively, p=0.041). (Figure 1) There were no differences in rates of day 100 aGVHD (grades II-IV) (Figure 2) and relapse rates at 12 months between the two groups. Conditioning regimen intensity, donor type, KPS, and primary diagnosis were significantly associated with NRM. When these variables were included in the multivariate model, VRE-C was found to be independently associated with higher NRM (HR=1.82, 95%CI: 1.12-2.93; p=0.015). In conclusion, in our cohort of patients receiving predominantly T/S-based aGVHD prophylaxis, no association was detected between VRE-C and aGVHD incidence. Higher rate of VRE-BSI in the VRE-C group is in accordance with published data, albeit lower rates of VRE-BSI was seen in our cohort. VRE-C contributed to higher NRM at days 100 and 365 post-aHCT and was an independent risk factor for poor HCT outcomes Since VRE-C is a potentially modifiable risk factor, our data supports continued efforts for specific interventional strategies (i.e. antimicrobial stewardship) to reduce drug resistant bacterial colonization, and for clinical research to reverse the impact of VRE-C, such as the use of agents, which may modulate gut microbiome. Disclosures Salhotra: Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Dadwal:AiCuris: Research Funding; Gilead: Research Funding; MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding.
- Published
- 2018
35. Total Marrow Irradiation: A New Ablative Regimen as Part of Tandem Autologous Stem Cell Transplantation for Patients with Multiple Myeloma
- Author
-
Jeffrey Y.C. Wong, Amrita Krishnan, Neil Kogut, Firoozeh Sahebi, Stephen J. Forman, Timothy E. Schultheiss, David S. Snyder, George Somlo, Paul Frankel, Ricardo Spielberger, Chatchada Karanes, An Liu, Leslie Popplewell, and Pablo M. Parker
- Subjects
Ablation Techniques ,Adult ,Male ,Melphalan ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Urology ,Antineoplastic Agents ,Transplantation, Autologous ,Dexamethasone ,Article ,Autologous stem-cell transplantation ,Maintenance therapy ,Bone Marrow ,medicine ,Humans ,Multiple myeloma ,Aged ,Neoplasm Staging ,Pneumonitis ,business.industry ,Dose-Response Relationship, Radiation ,Radiotherapy Dosage ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Survival Analysis ,Thalidomide ,Surgery ,Regimen ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,Female ,Bone marrow ,Multiple Myeloma ,business ,Follow-Up Studies ,Stem Cell Transplantation ,medicine.drug - Abstract
Purpose: To establish feasibility, maximum tolerated dose (MTD), and potential efficacy of ablative dose total marrow irradiation (TMI) delivered by helical tomotherapy in patients with multiple myeloma (MM). Experimental Design: Patients with responding or stable MM received tandem autologous stem cell transplants, first with melphalan 200 mg/m2, and 60 days or later with TMI. TMI doses were to be escalated from 1,000 cGy by increments of 200 cGy. All patients received thalidomide and dexamethasone maintenance. Results: Twenty-two of 25 enrolled patients (79%) received tandem autologous stem cell transplantation (TASCT): TMI was administered at a median of 63.5 days (44–119) after melphalan. Dose-limiting toxicities at level 5 (1,800 cGy) included reversible grade 3 pneumonitis, congestive heart failure, and enteritis (1), and grade 3 hypotension (1). The estimated median radiation dose to normal organs was 11% to 81% of the prescribed marrow dose. Late toxicities included reversible enteritis (1), and lower extremity deep venous thrombosis during maintenance therapy (2). The complete and very good partial response rates were 55% and 27% following TASCT and maintenance therapy. At a median of 35 months of follow-up (21–50+ months), progression-free and overall survival for all patients were 49% (95% CI, 0.27–0.71) and 82% (0.67–1.00). Conclusion: Ablative dose TMI as part of TASCT is feasible, and the complete response rate is encouraging. Careful monitoring of late toxicities is needed. Further assessment of this modality is justified at the 1,600 cGy MTD level in MM patients who are candidates for ASCT. Clin Cancer Res; 17(1); 174–82. ©2010 AACR.
- Published
- 2011
36. Phase II Trial of a Transplantation Regimen of Yttrium-90 Ibritumomab Tiuxetan and High-Dose Chemotherapy in Patients With Non-Hodgkin's Lymphoma
- Author
-
Amrita Krishnan, Arturo Molina, Stephen J. Forman, Peter Falk, Henry C. Fung, Roberto Rodriguez, Andrew Raubitschek, Ricardo Spielberger, Auayporn Nademanee, Joycelynne Palmer, and Dave Yamauchi
- Subjects
Adult ,Male ,Melphalan ,Cancer Research ,Ibritumomab tiuxetan ,Lymphoma, Mantle-Cell ,Disease-Free Survival ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Yttrium Radioisotopes ,Lymphoma, Follicular ,Etoposide ,Aged ,Podophyllotoxin ,Carmustine ,business.industry ,Lymphoma, Non-Hodgkin ,Cytarabine ,Antibodies, Monoclonal ,Middle Aged ,Radioimmunotherapy ,medicine.disease ,Combined Modality Therapy ,Non-Hodgkin's lymphoma ,Transplantation ,Regimen ,Treatment Outcome ,Oncology ,Female ,Lymphoma, Large B-Cell, Diffuse ,Neoplasm Recurrence, Local ,business ,Nuclear medicine ,Stem Cell Transplantation ,medicine.drug - Abstract
Purpose This phase II trial evaluated the safety and efficacy of combining yttrium-90 (90Y) ibritumomab tiuxetan with high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) and autologous stem-cell transplantation in patients with non-Hodgkin's lymphoma who were considered ineligible for total-body irradiation because of older age or prior radiotherapy. Patients and Methods Between May 2002 and January 2006, 14 days before autologous stem-cell transplantation, 41 patients with non-Hodgkin's lymphoma received standard-dose 90Y ibritumomab tiuxetan (14.8 MBq/kg [0.4 mCi/kg]) followed by high-dose BEAM. Results The median age was 60 years (range, 19 to 78 years), and the median number of previous therapies was two (range, one to six). Disease histologies were diffuse large B-cell (n = 20), mantle cell (n = 13), follicular (n = 4), and transformed lymphoma (n = 4). With a median follow-up of 18.4 months (range, 5.5 to 53.3 months) the estimated 2-year overall and progression-free survival were 88.9% (95% CI, 75.3% to 95.2%) and 69.8% (95% CI, 56.4% to 79.7%). The median time to WBC engraftment was 11 days (range, 9 to 26 days) and time to platelet engraftment was 12 days (range, 3 to 107 days). Adverse events were similar to those seen historically with high-dose BEAM alone, and included grade 3 or 4 pulmonary toxicity in 10 patients. Conclusion Adding 90Y ibritumomab tiuxetan to high-dose BEAM with autologous stem-cell transplantation is feasible and has a toxicity and tolerability profile similar to that observed with BEAM alone. Rates of progression-free survival seen in these patients are promising and warrant additional study.
- Published
- 2008
37. Economic Impact of Palifermin on the Costs of Hospitalization for Autologous Hematopoietic Stem-Cell Transplant: Analysis of Phase 3 Trial Results
- Author
-
Scott B. Cantor, Ricardo Spielberger, Catherine D. Cooksley, William I. Bensinger, Ya Chen Tina Shih, Patrick J. Stiff, Linda S. Elting, and Christos Emmanoulides
- Subjects
Adult ,Male ,medicine.medical_specialty ,Fibroblast Growth Factor 7 ,Population ,Medicare ,Transplantation, Autologous ,law.invention ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,Mucositis ,medicine ,Humans ,Intensive care medicine ,education ,health care economics and organizations ,Randomized Controlled Trials as Topic ,Cancer ,Stomatitis ,education.field_of_study ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Economic analysis ,Hematology ,Middle Aged ,Palifermin ,Total body irradiation ,medicine.disease ,United States ,Hospitalization ,Clinical trial ,Clinical Trials, Phase III as Topic ,Hematologic Neoplasms ,Costs and Cost Analysis ,Cost of illness ,Female ,Stem cell transplant ,business ,Whole-Body Irradiation ,Febrile neutropenia ,medicine.drug - Abstract
A double-blind, randomized trial showed that, compared with placebo, palifermin (recombinant human keratinocyte growth factor) reduced the frequency and duration of oral mucositis in patients with hematologic malignancies undergoing high-dose chemotherapy and total-body irradiation with autologous stem-cell support. This previously published study also showed a significant reduction in the incidence of adverse subsequent outcomes. The objective of this study was to estimate the impact of palifermin prophylaxis on hospital costs of transplantation in the trial. This was a retrospective, economic analysis of estimated costs for a previously published clinical trial. Costs were not collected during the trial. Therefore, we estimated the direct medical costs of hospitalization using hospital charges from similar patients' hospitalization charges selected from the National Inpatient Sample, a population-based, nationally representative sample of hospital claims. Costs were estimated from charges using Medicare's state-specific cost-to-charge ratios. These cost estimates were applied to the outcome data (incidence of febrile neutropenia, bacteremia/fungemia, or pneumonia, and use of total parenteral nutrition) from the clinical trial. Patients were those with hematologic malignancies who received high-dose chemotherapy and total-body irradiation with autologous stem cell transplant. We compared the estimated total hospital costs (in 2005 United States dollars) incurred by patients who received palifermin in the clinical trial with those incurred by patients who received placebo. Costs were analyzed from the provider's perspective. The mean cost of a hospital day in this population varied between $2,834, when no adverse outcomes occurred, and $4,663, when all 4 outcomes occurred. Reductions in adverse outcomes and their associated hospital stay offset the acquisition price of palifermin. A nonsignificant mean savings of $3,595 per patient (95% confidence interval: $2,090-$5,103) was observed. In sensitivity analyses, this observation was robust to all plausible values of per diem hospital costs and hypothetic per diem outpatient costs. In addition to its previously demonstrated clinical benefit, palifermin prophylaxis offers a favorable economic profile among patients with hematologic malignancies who receive total body irradiation and autologous stem cell support.
- Published
- 2007
- Full Text
- View/download PDF
38. A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma
- Author
-
Stephen J. Forman, Firoozeh Sahebi, Neil Kogut, Jasmine Zain, Peter Falk, Arturo Molina, Andrew Dagis, Vinod Pullarkat, Ricardo Spielberger, Amrita Krishnan, Cheuk S. Kwok, David D. Smith, Auayporn Nademanee, Roberto Rodriguez, Anne-Line Anderson, Leslie Popplewell, David S. Snyder, Margaret R. O'Donnell, Mark Kirschbaum, Ryotaro Nakamura, Andrew Raubitschek, Pablo Parker, Dave Yamauchi, Christine White, Anthony S. Stein, Eileen P. Smith, and Henry C. Fung
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Ibritumomab tiuxetan ,Follicular lymphoma ,Transplantation, Autologous ,Biochemistry ,Autologous stem-cell transplantation ,Recurrence ,medicine ,Humans ,Yttrium Radioisotopes ,Cyclophosphamide ,Survival rate ,Etoposide ,Transplantation ,business.industry ,Lymphoma, Non-Hodgkin ,Antibodies, Monoclonal ,Cell Biology ,Hematology ,Middle Aged ,Radioimmunotherapy ,Prognosis ,medicine.disease ,Surgery ,Survival Rate ,Positron-Emission Tomography ,Absolute neutrophil count ,Drug Therapy, Combination ,Female ,Nuclear medicine ,business ,Stem Cell Transplantation ,medicine.drug - Abstract
We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2) followed by autologous stem cell transplantation (ASCT) in 31 patients with CD20+ non-Hodgkin lymphoma (NHL). Patients underwent dosimetry (day -21) with 5 mCi (185 MBq) 111In-ibritumomab tiuxetan following 250 mg/m2 rituximab, followed a week later by 90Y-ibritumomab tiuxetan to deliver a target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day -7 to estimate radiation dose and stem cells were reinfused when the radiation dose was estimated to be less than 5 cGy. The median 90Y-ibritumomab tiuxetan dose was 71.6 mCi (2649.2 MBq; range, 36.6-105 mCi; range, 1354.2-3885 MBq). Histology included follicular lymphoma (n = 12), diffuse large B-cell (n = 14), and mantle cell (n = 5). The median number of prior chemo-therapy treatments was 2. The treatment was well tolerated. The median times to reach an absolute neutrophil count greater than 500/μL and platelet count more than 20 000/μL were 10 days and 12 days, respectively. There were 2 deaths and 5 relapses. At a median follow-up of 22 months, the 2-year estimated overall survival and relapse-free survival rates are 92% and 78%, respectively. We conclude that high-dose 90Y-ibritumomab tiuxetan can be combined safely with high-dose etoposide and cyclophosphamide without an increase in transplant-related toxicity or delayed engraftment. (Blood. 2005;106:2896-2902)
- Published
- 2005
39. Simultaneous Reconstitution of Multiple Cytomegalovirus‐Specific CD8+Cell Populations with Divergent Functionality in Hematopoietic Stem‐Cell Transplant Recipients
- Author
-
Ricardo Spielberger, Joy Martinez, Simon F. Lacey, Wahajul Haq, Stephen J. Forman, Lia Thao, John A. Zaia, Don J. Diamond, Jeff Longmate, and Ghislaine Gallez-Hawkins
- Subjects
Cytotoxicity, Immunologic ,Cellular immunity ,T cell ,Molecular Sequence Data ,Cytomegalovirus ,Blood Donors ,Human leukocyte antigen ,CD8-Positive T-Lymphocytes ,Viral Nonstructural Proteins ,Biology ,Cell Degranulation ,Epitope ,Viral Matrix Proteins ,Epitopes ,Antigen ,Antigens, CD ,Lysosomal-Associated Membrane Protein 1 ,Lysosomal-Associated Membrane Protein 2 ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Amino Acid Sequence ,Histocompatibility Antigens Class I ,Hematopoietic Stem Cell Transplantation ,Lysosome-Associated Membrane Glycoproteins ,T lymphocyte ,Phosphoproteins ,Virology ,DNA-Binding Proteins ,Infectious Diseases ,medicine.anatomical_structure ,Cytomegalovirus Infections ,Immunology ,Peptides ,CD8 - Abstract
A panel of 7 human cytomegalovirus (CMV) epitope peptides and corresponding major histocompatibility class 1 tetramers was used to evaluate cellular immunity in healthy seropositive donors and in hematopoietic stem-cell transplant recipients. Broad CMV-specific T cell responses to epitopes were found within several CMV polypeptides and were restricted by multiple human leukocyte antigen alleles. Their cytotoxic functionality was evaluated by use of an assay that measures transient surface levels of lysosomal membrane proteins LAMP-1 (CD107a) and LAMP-2 (CD107b) after peptide stimulation. This assay can be combined with tetramer staining of antigen-specific CD8(+) T lymphocytes and has potential as a surrogate marker for cytotoxic function. CD8(+) T lymphocytes specific for epitopes within the pp65 or pp50 gene products exhibited significantly higher functionality, compared with populations recognizing CMV major immediate early-1 epitopes. These functional differences between T lymphocyte populations within the same individual may have implications for protection against CMV.
- Published
- 2005
40. Cyclosporine and mycophenolate mofetil prophylaxis with fludarabine and melphalan conditioning for unrelated donor transplantation: a prospective study of 22 patients with hematologic malignancies
- Author
-
George Somlo, David S. Snyder, Roberto Rodriguez, David Senitzer, Pablo M. Parker, Aparna Krishnan, A P Nademanee, Stephen J. Forman, Ricardo Spielberger, Marilyn L. Slovak, Leslie Popplewell, Henry C. Fung, Sandra Cohen, Neil Kogut, David D. Smith, J. Schriber, M R O'Donnell, M. Angelopoulou, Firoozeh Sahebi, Zaid S Al-Kadhimi, Anthony S. Stein, and Peter M. Falk
- Subjects
Adult ,Male ,Melphalan ,medicine.medical_specialty ,Transplantation Conditioning ,Myeloid ,Adolescent ,Premedication ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Opportunistic Infections ,Gastroenterology ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Cumulative incidence ,Prospective Studies ,Aged ,Transplantation ,business.industry ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Mycophenolic Acid ,medicine.disease ,Survival Analysis ,Tissue Donors ,Surgery ,Fludarabine ,Regimen ,Treatment Outcome ,surgical procedures, operative ,Graft-versus-host disease ,medicine.anatomical_structure ,Hematologic Neoplasms ,Cyclosporine ,Female ,business ,Vidarabine ,medicine.drug - Abstract
In an attempt to decrease toxicity in high-risk patients undergoing unrelated donor hematopoietic stem cell transplantation (URD HSCT), we tested a combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis with the reduced-intensity conditioning regimen fludarabine/melphalan (Flu/Mel). A total of 22 adult patients with advanced myeloid (n=15) and lymphoid (n=7) malignancies were treated. All patients received Flu 25 mg/m2 for 5 days and Mel 140 mg/m2, with CSP 3 mg/kg daily and MMF 15 mg/kg three times a day. The median age was 49 years (range 18-66). Durable engraftment was seen in all but one patient with myelofibrosis. The 1-year nonrelapse mortality was 32%, 27% from GVHD. The cumulative incidence of acute GVHD grade 2-4 and 3-4 was 63 and 41%, respectively. With a median follow-up of 18 months, the disease-free survival (DFS) and overall survival (OS) are 55 and 59%, respectively. For patients with AML and MDS (n=14), the DFS and OS is 71%. For patients undergoing a second transplant (n=14), the DFS and OS is 57%. In conclusion, this regimen is associated with acceptable toxicity but high rates of GVHD in high-risk patients undergoing URD HSCT. Encouraging disease control for patients with advanced myeloid malignancies was observed.
- Published
- 2004
41. A long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: impact of cytogenetic characteristics on transplantation outcome
- Author
-
Ricardo Spielberger, Eileen P. Smith, Ravi Bhatia, Robert Sweetman, Leslie Popplewell, Neil Kogut, David D. Smith, Anthony S. Stein, Arturo Molina, Peter Falk, Henry C. Fung, George Somlo, Stephen J. Forman, N. Vora, David S. Snyder, Joseph Rosenthal, Smita Bhatia, Sandra Cohen, Pablo M. Parker, Roberto Rodriguez, Kim Margolin, Aparna Krishnan, M R O'Donnell, Marilyn L. Slovak, Warren Chow, Firoozeh Sahebi, and A P Nademanee
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Myeloid ,Adolescent ,Acute myelogenous leukemia ,Salvage therapy ,Myelogenous ,Refractory ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Transplantation, Homologous ,Medicine ,Child ,Survival analysis ,Bone Marrow Transplantation ,Retrospective Studies ,Salvage Therapy ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,Middle Aged ,Prognosis ,Cytogenetic characteristics ,medicine.disease ,Survival Analysis ,Allogeneic stem cell transplantation ,Surgery ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,surgical procedures, operative ,medicine.anatomical_structure ,Treatment failure ,Child, Preschool ,Cytogenetic Analysis ,Female ,business ,Follow-Up Studies - Abstract
The prognosis of patients with primary refractory acute myelogenous leukemia (AML) is poor. Our initial report suggested that some patients could achieve durable remission after allogeneic stem cell transplantation (SCT). Herein, we update our initial experience and report further analysis of this group of patients to determine whether there are pre-SCT prognostic factors predictive of posttransplantation relapse and survival. We reviewed the records of 68 patients who consecutively underwent transplantation at the City of Hope Cancer Center with allogeneic SCT for primary refractory AML between July 1978 and August 2000. Potential factors associated with overall survival and disease-free survival were examined. With a median follow-up of 3 years, the 3-year cumulative probabilities of disease-free survival (DFS), overall survival (OS), and relapse rate for all 68 patients were 31% (95% confidence interval [CI], 20%–42%), 30% (95% CI, 18%–41%), and 51% (95% CI, 38%–65%), respectively. In multivariate analysis, the only variables associated with shortened OS and DFS included the use of an unrelated donor as the stem cell source (relative risk, 2.23 [OS] and 2.05 [DFS]; P = .0005 and .0014, respectively) and unfavorable cytogenetics before SCT (relative risk: 1.68 [OS] and 1.58 [DFS]; P = .0107 and .0038, respectively). Allogeneic SCT can cure approximately one third of patients with primary refractory AML. Cytogenetic characteristics before SCT correlate with transplantation outcome and posttransplantation relapse.
- Published
- 2003
- Full Text
- View/download PDF
42. Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed
- Author
-
David S. Snyder, Leslie Popplewell, Arturo Molina, Kim Margolin, Stephen J. Forman, David D. Smith, Aparna Krishnan, M R O'Donnell, Pablo M. Parker, Neil Kogut, Sandra Cohen, Anthony S. Stein, N. Vora, Peter Falk, Ricardo Spielberger, Roberto Rodriguez, A P Nademanee, George Somlo, David Senitzer, Henry C. Fung, Ravi Bhatia, and Firoozeh Sahebi
- Subjects
Adult ,Male ,Melphalan ,medicine.medical_specialty ,medicine.medical_treatment ,Reduced intensity ,Hematopoietic stem cell transplantation ,Transplantation, Autologous ,Gastroenterology ,Autologous stem-cell transplantation ,Recurrence ,Transplantation Immunology ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Treatment Failure ,Transplantation ,business.industry ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Total body irradiation ,medicine.disease ,Combined Modality Therapy ,Survival Analysis ,Allogeneic stem cell transplantation ,Fludarabine ,Surgery ,Leukemia ,Treatment Outcome ,Hematologic Neoplasms ,Female ,business ,Progressive disease ,medicine.drug - Abstract
Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m2) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.
- Published
- 2003
- Full Text
- View/download PDF
43. Detection of NPM/MLF1 fusion in t(3;5)-positive acute myeloid leukemia and myelodysplasia
- Author
-
Daniel A. Arber, Karen L. Chang, Victoria Bedell, Marilyn L. Slovak, Ricardo Spielberger, and Mark H. Lyda
- Subjects
Adult ,Male ,medicine.medical_specialty ,Recombinant Fusion Proteins ,medicine.medical_treatment ,Cell Cycle Proteins ,Chromosomal translocation ,Hematopoietic stem cell transplantation ,Ribophorin ,Translocation, Genetic ,Pathology and Forensic Medicine ,hemic and lymphatic diseases ,medicine ,Humans ,RNA, Neoplasm ,Cloning, Molecular ,In Situ Hybridization, Fluorescence ,integumentary system ,medicine.diagnostic_test ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cytogenetics ,Nuclear Proteins ,Proteins ,Myeloid leukemia ,Middle Aged ,medicine.disease ,DNA-Binding Proteins ,Leukemia, Myeloid, Acute ,Myelodysplastic Syndromes ,Cancer research ,biology.protein ,Chromosomes, Human, Pair 5 ,Chromosomes, Human, Pair 3 ,Refractory cytopenia with multilineage dysplasia ,Nucleophosmin ,Myeloid leukemia factor 1 ,Fluorescence in situ hybridization - Abstract
Balanced translocations are rare in myelodysplasia (MDS) and acute myeloid leukemia (AML) with multilineage dysplasia; however, the t(3;5)(q25;q35) and insertion variant occur in a subset of patients. To evaluate the possible genes involved in this translocation, we studied 6 cases with a t(3;5) by fluorescence in situ hybridization with probes directed against the nucleophosmin (NPM), EVI1, and Ribophorin genes, as well as a newly developed myeloid leukemia factor 1 (MLF1) BAC clone. The histologic spectrum of the cases was variable, ranging from refractory cytopenia with multilineage dysplasia to AML with multilineage dysplasia in the World Health Organization classification. An NPM/MLF1 fusion was identified in 5 of 6 cases, whereas the EVI1 and Ribophorin genes were not involved in any of the cases. The NPM/MLF1-positive cases were predominantly young adult males (median age, 33 years) who responded well to hematopoietic stem cell transplantation. These findings suggest that an NPM/MLF1 fusion is the primary molecular abnormality in t(3;5) MDS and AML with multilineage dysplasia, and also that cases with NPM/MLF1 may be clinically distinct from other MDS-associated disease.
- Published
- 2003
44. Interleukin-2 After Autologous Stem-Cell Transplantation for Adult Patients With Acute Myeloid Leukemia in First Complete Remission
- Author
-
David S. Snyder, George Somlo, Daniel A. Arber, Stephen J. Forman, Ricardo Spielberger, Amrita Krishnan, Marilyn L. Slovak, Auayporn Nademanee, Shirong Wang, Andrew Dagis, Joyce C. Niland, Anthony S. Stein, Henry C. Fung, Margaret R. O'Donnell, Pablo Parker, Roberto Rodriguez, Arturo Molina, and Nayana Vora
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Allogeneic transplantation ,Antineoplastic Agents ,Gastroenterology ,Disease-Free Survival ,Autologous stem-cell transplantation ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Confidence Intervals ,medicine ,Humans ,Idarubicin ,business.industry ,Cytarabine ,Myeloid leukemia ,Middle Aged ,medicine.disease ,Confidence interval ,Surgery ,Transplantation ,Leukemia ,Oncology ,Leukemia, Myeloid ,Interleukin-2 ,Female ,business ,Stem Cell Transplantation ,medicine.drug - Abstract
Purpose: To determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus leukemia effect observed in allogeneic transplantation. Patients and Methods: Fifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 × 106 U/m2/24 h for 4 days, followed by 10 days of IL-2 1.6 × 106 U/m2/24 h on hematologic recovery. Results: Eighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval [CI], 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate. Conclusion: These results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin–mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.
- Published
- 2003
45. Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation
- Author
-
Ghislaine Gallez-Hawkins, Daniel Levitt, Karl G. Blume, Terri Cunningham, Nelson J. Chao, Ricardo Spielberger, Raleigh A. Bowden, Barry E. Storer, John A. Zaia, Michael Boeckh, and D. Kathryn Tierney
- Subjects
Ganciclovir ,Adult ,Male ,medicine.medical_specialty ,Platelet Engraftment ,medicine.medical_treatment ,pp65 antigenemia ,Congenital cytomegalovirus infection ,Cytomegalovirus ,Viremia ,Hematopoietic stem cell transplantation ,Placebo ,Antibodies, Viral ,Gastroenterology ,Antiviral Agents ,Serology ,Placebos ,MSL-109 ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Prospective Studies ,Transplantation ,Dose-Response Relationship, Drug ,business.industry ,Stem cell transplantation ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Antibodies, Monoclonal ,Hematology ,medicine.disease ,Survival Rate ,surgical procedures, operative ,Treatment Outcome ,Immunology ,Cytomegalovirus Infections ,Female ,business ,medicine.drug - Abstract
MSL-109 is a monoclonal antibody specific to the cytomegalovirus (CMV) glycoprotein H with high neutralizing capacity. In a prospective, randomized, double-blind study, allogeneic hematopoietic stem cell transplantation (HSCT) recipients with positive donor and/or recipient serology for CMV before transplantation received either 60 mg/kg MSL-109 (n = 59), 15 mg/kg MSL-109 (n = 60), or placebo (n = 60) intravenously every 2 weeks from day -1 until day 84 after transplantation. CMV pp65 antigenemia, CMV-DNA load in plasma, and viremia by culture were tested weekly. Primary end points were development of pp65 antigenemia at any level and/or viremia for which ganciclovir was given. There was no statistically significant difference in CMV pp65 antigenemia or viremia among patients in the 60-mg group (pp65 antigenemia, 47%; viremia, 15%), the 15-mg group (52%; 23%), and the placebo group (45%; 17%). There was also no difference in maximum levels of pp65 antigenemia, time to clearance of pp65 antigenemia after start of ganciclovir, CMV disease, invasive bacterial and fungal infections, time to neutrophil and platelet engraftment, acute graft-versus-host disease, days of hospitalization, and overall survival rate among the 3 groups. However, a subgroup analysis of CMV-seronegative recipients with a seropositive donor (D+/R-) showed a transiently improved survival rate by day 100 in MSL-109 recipients (mortality: 60-mg group, 1/13; 15-mg group, 1/12; placebo group, 6/10 [P = .02 for 60-mg versus placebo groups; P = .08 for 15-mg versus placebo groups]); by the end of follow-up, the difference was no longer statistically significant. The improved survival rate in D+/R- patients could not be attributed to a reduction in CMV disease; however, MSL-109 was associated with improved platelet engraftment and less grade III to IV acute graft-versus-host disease in this subgroup. In a subgroup analysis of CMV-seropositive recipients of MSL-109 (D+/R+ and D-/R+), overall mortality was increased compared to that of the placebo group (P = .12 for the 60-mg versus placebo groups, P = .05 for the 15-mg versus placebo groups, and P = .04 for the dose levels combined versus placebo). MSL-109 was well tolerated and no immune response to the drug was observed. Thus, MSL-109 was safe but did not reduce CMV infection in allogeneic HSCT recipients. The transient survival advantage seen early after transplantation in CMV D+/R- patients and the negative effect on survival in seropositive patients remain unexplained. Thus, there is no evidence that MSL-109 is beneficial in CMV-seropositive HSCT recipients.
- Published
- 2001
- Full Text
- View/download PDF
46. Effects of allogeneic bone marrow transplantation on recipient bone mineral density: A prospective study
- Author
-
Stephen J. Forman, Joyce C. Niland, Ricardo Spielberger, Roberto Rodriguez, Auayporn Nademanee, Dave Yamauchi, Amrita Krishnan, Ashwin Kashyap, Anthony S. Stein, Henry C. Fung, Joycelynne Palmer, Arturo Molina, Fouad Kandeel, Jerry L. Nadler, Ravi Bhatia, David S. Snyder, Pablo Parker, and Margaret R. O'Donnell
- Subjects
Adult ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,Bone density ,Antineoplastic Agents ,Bone and Bones ,Cohort Studies ,Absorptiometry, Photon ,Bone Density ,Risk Factors ,Prednisone ,medicine ,Humans ,Transplantation, Homologous ,Prospective Studies ,Prospective cohort study ,Bone Marrow Transplantation ,Bone mineral ,Minerals ,Transplantation ,Lumbar Vertebrae ,Myeloproliferative Disorders ,business.industry ,Racial Groups ,Hematology ,Middle Aged ,musculoskeletal system ,Combined Modality Therapy ,Surgery ,Bone Diseases, Metabolic ,surgical procedures, operative ,Hematologic Neoplasms ,Myelodysplastic Syndromes ,Cohort ,Osteoporosis ,Female ,Hip Joint ,Methotrexate ,business ,medicine.drug ,Cohort study - Abstract
Allogeneic bone marrow transplant (BMT) recipients have many known risk factors for developing decreased bone mineral density (BMD) after transplantation. We performed a prospective sequential evaluation of BMD in the lumbar spine and nondominant hip using dual-energy x-ray absorptiometry (DEXA) in a cohort of 47 adult patients (median age, 43 years) who were undergoing radiation-based BMT for hematologic malignancies. Baseline DEXA studies were performed before BMT and repeated at 3 to 4 months, 6 to 8 months, and 12 to 14 months after BMT. The majority of patients (60%) had been minimally treated with combination cytotoxic chemotherapy, having received no more than 1 treatment regimen before BMT. Graft-versus-host disease prophylaxis consisted of cyclosporine in combination with either methotrexate or prednisone, or both. Mean lumbar spine and hip BMD were normal before BMT (spine: 1.01 g/cm2, z score = 96%; hip: 0.86 g/cm2, z score = 100%) and gradually decreased (spine: 0.98 g/cm2, z score = 94%; hip: 0.76 g/cm2, z score = 91%) at 12 to 14 months. These declines were statistically significant (P < .006 and < .002 for lumbar spine; P < .001 and < .001 for hip). In addition, the sharpest decline occurred during the first 6 months after BMT and was more marked in the hip than the lumbar spine. These data suggest that BMT adversely affects BMD in this patient population.Biol Blood Marrow Transplant 2000;6(3A):344-51.
- Published
- 2000
47. Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors
- Author
-
Ashwin Kashyap, Smita Bhatia, Amrita Krishnan, Marilyn L. Slovak, Irena Sniecinski, Ricardo Spielberger, Stephen J. Forman, Pablo Parker, Auayporn Nademanee, Daniel A. Arber, David S. Snyder, Joyce C. Niland, Anthony S. Stein, Arturo Molina, Margaret R. O'Donnell, Henry C. Fung, and Ravi Bhatia
- Subjects
Oncology ,medicine.medical_specialty ,Autologous Stem Cell Rescue ,Transplant Conditioning ,business.industry ,Immunology ,Case-control study ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,Transplantation ,Leukemia ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Autologous transplantation ,business ,Cohort study - Abstract
We analyzed data on 612 patients who had undergone high-dose chemoradiotherapy (HDT) with autologous stem cell rescue for Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) at the City of Hope National Medical Center, to evaluate the incidence of therapy-related myelodysplasia (t-MDS) or therapy-related acute myeloid leukemia (t-AML) and associated risk factors. A retrospective cohort and a nested case-control study design were used to evaluate the role of pretransplant therapeutic exposures and transplant conditioning regimens. Twenty-two patients developed morphologic evidence of t-MDS/t-AML. The estimated cumulative probability of developing morphologic t-MDS/t-AML was 8.6% +/- 2.1% at 6 years. Multivariate analysis of the entire cohort revealed stem cell priming with VP-16 (RR = 7.7, P = 0.002) to be independently associated with an increased risk of t-MDS/t-AML. The influence of pretransplant therapy on subsequent t-MDS/t-AML risk was determined by a case-control study. Multivariate analysis revealed an association between pretransplant radiation and the risk of t-MDS/t-AML, but failed to reveal any association with pretransplant chemotherapy or conditioning regimens. However, patients who had been primed with VP-16 for stem cell mobilization were at a 12. 3-fold increased risk of developing t-AML with 11q23/21q22 abnormalities (P = 0.006). Patients undergoing HDT with stem cell rescue are at an increased risk of t-MDS/t-AML, especially those receiving priming with VP-16 for peripheral stem cell collection. (Blood. 2000;95:1588-1593)
- Published
- 2000
48. Interleukin-2-activated autologous bone marrow and peripheral blood stem cells in the treatment of acute leukemia and lymphoma
- Author
-
Koen van Besien, Anthony S. Stein, Doni Woo, Joyce C. Niland, George Somlo, Ricardo Spielberger, Eileen P. Smith, Margaret R. O'Donnell, Ashwin Kashyap, Arturo Molina, Auayporn Nademanee, Richard E. Champlin, Pablo Parker, Henry C. Fung, Michael W. Thomas, Christine L. Wright, David S. Snyder, Kim Margolin, Irena Sneicinski, and Stephen J. Forman
- Subjects
Adult ,Male ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Adolescent ,Lymphoma ,medicine.medical_treatment ,Pilot Projects ,Hematopoietic stem cell transplantation ,Transplantation, Autologous ,Gastroenterology ,Internal medicine ,medicine ,Humans ,Infusions, Intravenous ,Bone Marrow Transplantation ,Acute leukemia ,Transplantation ,Leukemia ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Pancytopenia ,Treatment Outcome ,Acute Disease ,Immunology ,Interleukin-2 ,Female ,Chills ,medicine.symptom ,business - Abstract
In this pilot trial of interleukin (IL)-2-treated autologous bone marrow (BM) and peripheral stem cell (PSC)-supported high-dose chemoradiotherapy, we report 36 patients with poor-prognosis leukemia and lymphoma who received BM and/or granulocyte colony-stimulating factor (G-CSF)-mobilized autologous PSCs that had been exposed to IL-2 for 24 hours ex vivo. Patients then received IL-2 by low-dose continuous intravenous (i.v.) infusion until hematologic reconstitution and then by intermediate-dose continuous i.v. infusion for six 2-week maintenance cycles given at 1-month intervals. The median Day to neutrophils over 500/microL was 22 with BM and 10 with PSCs (p = 0.01). The median Day to platelets >20,000/microL was 50 for BM and 25 for PSCs, and to platelets >50,000/microL was 138 for BM and 34 for PSCs (p not significant). After the first three patients received IL-2 at 2 mIU x m(-2) x day(-1) and had slow reconstitution, four patients were treated without IL-2 until the maintenance phase following reconstitution. The remaining 29 patients received the initial "post-infusion" IL-2 at 1 mIU x m(-2) x day(-1). Toxicities associated with the infusion of IL-2-activated cells consisted of chills and fever in about one-half of the patients and transient hypotension in 12%. Low-dose IL-2 by continuous i.v. infusion in the early posttransplant period was associated with exacerbation of fever, diarrhea, and altered mental status in a minority of patients. The major dose-limiting toxicities of maintenance IL-2 were fever, fatigue, gastrointestinal symptoms, skin rash, and dyspnea. Among 24 lymphoma patients, nine are in continuous complete remission (CCR) from 18-48 months, and 15 have died (12 due to relapse and three of therapy-related toxicities). Of 12 acute leukemia patients, two with acute lymphoblastic leukemia (ALL) are in CCR at 38 and 43 months, and one patient who was in cytogenetic but not molecular remission of Philadelphia chromosome-positive ALL died of progressive leukemia at Day 108. Three of nine with myeloid leukemia are in CCR at 21, 46, and 53 months; one is in hematologic and cytogenetic remission of acute promyelocytic leukemia at 55 months with multiple new cytogenetic abnormalities; one is alive at 54 months with pancytopenia after incomplete hematologic recovery followed by multiple new cytogenetic abnormalities (myelodysplasia); and one had an unrelated donor transplant after relapsing 4 months following protocol therapy. One myeloid leukemia patient remains without evidence of relapse, but is transfusion-dependent at 15 months following transplant. Biol Blood Marrow Transplant 1999;5(1):36-45.
- Published
- 1999
- Full Text
- View/download PDF
49. Results of High-Dose Therapy and Autologous Bone Marrow/Stem Cell Transplantation During Remission in Poor-Risk Intermediate- and High-Grade Lymphoma: International Index High and High-Intermediate Risk Group
- Author
-
Margaret R. O'Donnell, David S. Snyder, Warren Chow, Stephen J. Forman, George Somlo, Kim Margolin, Ricardo Spielberger, Ina Planas, Auayporn Nademanee, Nayana Vora, Pablo M. Parker, Anthony S. Stein, Henry Fung, Joyce C. Niland, K.K. Wong, Ashwin Kashyap, Arturo Molina, Karl G. Blume, Andrew C. Dagis, Irena Sniecinski, and Eileen P. Smith
- Subjects
medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Aggressive lymphoma ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Total body irradiation ,Biochemistry ,Gastroenterology ,Bone marrow purging ,Surgery ,Transplantation ,International Prognostic Index ,Internal medicine ,Medicine ,business ,Etoposide ,medicine.drug - Abstract
We have conducted a pilot study to investigate the role of high-dose therapy and autologous bone marrow/stem cell transplantation (ASCT) during first complete or partial remission in 52 patients with poor-risk aggressive lymphoma. There were 42 patients with intermediate-grade or immunoblastic lymphoma who were considered to be high (60%) and high-intermediate risk (40%) groups at diagnosis based on the age-adjusted International Prognostic Index (IPI) and 10 patients with high-grade, SNCCL (small non-cleaved cell, Burkitt's, and non-Burkitt's), who at presentation had poor-risk features defined as elevated serum lactate dehydrogenase level, stage IV, and bulky mass ≥10 cm. The median age was 34 years (range, 16 to 56 years). Thirty-nine were transplanted in first complete remission and 13 in first partial remission after conventional therapy. Conditioning regimens consisted of total body irradiation (TBI) administered as a single fraction 750 cGy in 3 patients and in fractionated doses for a total of 1,200 cGy in 44 patients, in combination with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide. Five patients with prior radiotherapy received 450 mg/m2 carmustine instead of TBI. Stem cell sources were either bone marrow and/or peripheral blood. No in vitro purging was used. All patients engrafted. Two SNCCL patients died of venoocclusive disease at 25 days and acute leukemia at 27 months posttransplantation. There were six relapses at 1.5 to 12.8 months posttransplantation. At a median follow-up of 44 months (range, 1 to 113 months), the estimated 3-year overall survival (OS) and disease-free survival (DFS) for all patients was 84% (95% confidence interval [CI], 70% to 92%) and 82% (95% CI, 68% to 91%), respectively. In the subset of patients with intermediate-grade and immunoblastic lymphoma, the 3-year DFS was 89% (95% CI, 74% to 96%) for all patients, 87% (95% CI, 67% to 96%) for high-risk patients, and 92% (95 CI, 61% to 99%) for high-intermediate risk patients. The 3-year OS and DFS for SNCCL patients were identical at 60% (95% CI, 30% to 84%). These results suggest that high-dose therapy and ASCT during first remission may improve the survival and prognosis of patients with poor-risk intermediate- and high-grade lymphoma. A prospective randomized study comparing high-dose therapy and ASCT with conventional chemotherapy in IPI high-risk patients with aggressive non-Hodgkin's lymphoma should be undertaken.
- Published
- 1997
50. dic(5;17): A recurring abnormality in malignant myeloid disorders associated with mutations ofTP53
- Author
-
Elizabeth M. Davis, M. Thangavelu, Michelle M. Le Beau, Nanding Zhao, Kiera Iannantuoni, Ricardo Spielberger, Richard A. Larson, and Pauline Wang
- Subjects
Oncology ,Cancer Research ,Monosomy ,medicine.medical_specialty ,Myeloid ,medicine.diagnostic_test ,Chronic lymphocytic leukemia ,Myeloid leukemia ,Biology ,medicine.disease ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Internal medicine ,Immunology ,Genetics ,medicine ,Rhabdomyosarcoma ,Multiple myeloma ,Chronic myelogenous leukemia ,Fluorescence in situ hybridization - Abstract
We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy-related MDS and/or AML (t-MDS/t-AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t-MDS/t-AML were breast carcinoma and Hodgkin's disease in two patients each, and non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere-specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients.
- Published
- 1997
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.