23 results on '"Moussab Damlaj"'
Search Results
2. Favourable Outcome of Non Myeloablative Allogeneic HSCT in Adult Patients with Severe Sickle Cell Disease: A Single Center Experience of 110 Patients
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Giamal Gmati, Moussab Damlaj, Tahani Alanazy, Maybelle Balili, Heba Alshobaki, Walid Mashaqbeh, Husam Mazin Alsadi, Abdulrahman Raiza, Mohsen Alzahrani, Hind Salama, Ayman Hejazi, Muhammad Qureshi, Khadega A. Abuelgasim, Mazin Ahmed, Bader Alahmari, Ahmed Alaskar, and Abdulrahman Alghamdi
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medicine.medical_specialty ,Anemia ,business.industry ,Immunology ,Organ dysfunction ,Cell Biology ,Hematology ,Single Center ,medicine.disease ,Biochemistry ,End stage renal disease ,Discontinuation ,Median follow-up ,Internal medicine ,medicine ,Alemtuzumab ,medicine.symptom ,business ,Stroke ,medicine.drug - Abstract
Background: Allogeneic HSCT for adult patients with sickle cell disease (SCD) is potentially curative but not commonly utilized therapy due to complications such as graft failure (GF) and organ toxicity. At our center, we adopted a non-myeloablative (NMA) conditioning regimen in adult patients with severe SCD. Herein, we are reporting our outcome data of up to 5-years of follow up post HSCT. Methods: Following IRB approval, adult patients that underwent HSCT from 2015 to 2020 for severe SCD with at least 6 months of follow up were included. Indications for HSCT were; presence of recurrent vaso-occlusive crisis (VOC), end organ damage, multiple joint AVN, recurrent priapism, transfusion dependency, or RBC alloimmunization. Conditioning regimen consisted of alemtuzumab (1 mg/kg divided over 5 days on days -7 to -3) and 300 cGy TBI on day -2 or -1. Pre-transplant preparation consisted of Hydroxyurea at maximum tolerated dose for 2-3 months. Peripherally mobilized stem cells targeting 10x106/kg of CD34 cells were used. For GVHD prophylaxis sirolimus was started on day -1 and continued for one year with tapering off if lymphoid chimerism is > 50%. EFS was defined as time from HSCT to graft failure or death from any cause whereas OS was defined as time from HSCT to death or last documented follow up. Results: A. Baseline Characteristics: A total of 110 patients were included with a median (range) age of 27 years (14-43), 59% of patients were male. Baseline median hemoglobin and hemoglobin S (HbS) was 95 g/L (64-121) and 74 % (17 -97), respectively. Regular hydroxyurea use was among 108 (98%) and 109 (99%) of patients required at least ≥ 1 transfusion annually. Narcotic pain killers were used regularly in 21 (19%) of patients. Median pre-HSCT ferritin was 1062 and iron chelation was used in 36 (33%). The most common indications for HSCT were (overlapping) recurrent VOC in 93%, ACS in 36%, stroke in 28% and RBC allo-immunization in 26%. Furthermore, 18 patients had 3 indications, 45 had 2 indications while the remaining 47 patients had one indication. Furthermore, 10 (9%) patients had Moya-Moya disease, 5 (5%) had sickling hepatopathy and or liver cirrhosis with total bilirubin up to 670 mmol/L and 1 (1%) patient had end stage renal disease on peritoneal-dialysis. A total of 61 (55%) donors were SC trait and underwent GCSF mobilization without major adverse events as previously reported (Damlaj et al., BMT 2018). 8 (7%) and 15 (14%) had major and minor ABO incompatibility, respectively. The remaining characteristics are found in table 1 B. Transplant Characteristics and Post HSCT Outcome: Median infused CD34x106/kg was 12.4 (6.4-24.9) and 108 (98%) patients had successful engraftment. A total of 12 patients experienced GF; 2 as primary and 10 as secondary within a median time of 129 days (40-583). Outcome post GF was as follows; recurrence of SCD in 6 (50%), aplastic bone marrow in 6 (50%) of whom 4 underwent a second allogeneic HSCT with Flu-Cy-ATG platform and all from MRD. Among second HSCT recipients, 3 are still alive and in SCD free disease status. Among patients with GF, 5 (42%) had minor ABO incompatibility while the remaining 7 (58%) were ABO matched HSCT. Mild acute skin GVHD (grade I to II) occurred in 3 cases and 4 cases developed autoimmune haemolytic anemia that resolved with steroids. Only one patient had CNS bleeding 2 years post-transplant in a background of history of stroke and Moya-Moya disease. A total of 53 (48%) patients successfully discontinued sirolimus while an additional 40 (35%) are on active taper. There were a total of 4 successful pregnancies in 3 patients; 3 pregnancies completed to term while 1 miscarried. Median follow up for the cohort is 16.8 (2-66) months. Estimated 2-year EFS and OS was 87.3% (+/- 0.036) and 97% (+/-0.017). All deaths were due to GF. There was no difference in outcome (EFS or OS) between patients receiving graft from normal vs. SC trait. Post HSCT Hb and chimerism results are shown in table 2. Conclusions: Herein, we present a large real-life experience demonstrating feasibility and favourable outcome of NMA HSCT in adult patients with severe SCD including patients with significant organ dysfunction or neurologic vasculopathy. Successful pregnancies and long-term discontinuation of immune suppression was possible. Longer follow up is warranted to ascertain stability of graft function over time. Disclosure: The authors declare they have no relevant conflicts of interest Disclosures No relevant conflicts of interest to declare.
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- 2020
3. Middle East Respiratory Syndrome (MERS) Infection in Hematological and Oncological Patients: A Case Series from a Tertiary Care Center in Saudi Arabia
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Mohsen Alzahrani, May Anne Mendoza, Bader Alahmari, Moussab Damlaj, Ahmed Alaskar, Hina Rehan, Giamal Gmati, Mostafah Abolfotouh, Hind Salama, Khadega A. Abuelgasim, Naila A. Shaheen, Mohammed Bosaeed, Adel Othman, and Ayman Alhejazi
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Pediatrics ,medicine.medical_specialty ,Middle East respiratory syndrome coronavirus ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Tertiary care ,Intensive care unit ,law.invention ,Health personnel ,law ,904.Outcomes Research-Non-Malignant Conditions ,medicine ,Middle East respiratory syndrome ,business - Abstract
We present the largest to date of a case series of nine patients with hematological and oncological malignancies who were infected with Middle East Respiratory Syndrome Coronavirus (MERS-CoV). MERS-CoV is a novel beta-coronavirus with a high fatality rate in comorbid patients. The majority of MERS cases globally were reported from Saudi Arabia (1983 cases, including 745 related deaths with a case-fatality rate of 37.5%) according to the WHO update of February 2019. All were clinically stable before acquiring the virus. Most of the cases had an active disease as relapse or refractory with three cases being neutropenic. The clinical presentation and radiological features of the patients were variable and inconsistent (Table 1). Diagnosis was confirmed with RT-PCR assays targeting upstream of the E gene and the open-reading frame gene 1a which had to be done repeatedly and required an average of 3 (with max. of 7) samples for a test to be positive (Table 2). All the patients developed respiratory failure, were admitted to the critical care unit (ICU) and required mechanical ventilation. The length of hospital stay ranged from 15 - 48, with an average of 24 days. Unfortunately, all nine patients died within days after admission to the ICU. In addition, the time from diagnosis to death has an average of 9 days ranging from 2-24 days, respectively. In conclusion, MERS CoV infection in hematology/oncology patients has a very poor prognosis regardless of the status of the underlying disease. The clinical presentation is not distinctive and confirming the diagnosis requires numerous respiratory samples. Measures to prevent nosocomial outbreaks should include proper compliance with personal protection equipment by health-care workers when managing patients with suspected and confirmed MERS-CoV infection and prompt isolation of infected patients. Future research is required to enhance our understanding of the disease and to evaluate superior diagnostic and therapeutic options. Disclosures No relevant conflicts of interest to declare.
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- 2021
4. Hematological Profile in the Saudi Population: Reference Intervals By Gender, Age and Regions
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Areej Al Mugairi, Aljowhara Alsahan, Mushtaq Rather, Anita Immanuel, Ayman Alhejazi, Anwar Ahmed, Giamal Gmati, Ahmed Alaskar, Mohsen Alzahrani, Hina Rehan, May Anne Mendoza, Bader Alahmari, Khadega A. Abuelgasim, Hind Salama, and Moussab Damlaj
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Hematological disorders ,education.field_of_study ,Percentile ,business.industry ,Immunology ,Population ,Reference range ,Mean age ,Cell Biology ,Hematology ,Biochemistry ,Reference intervals ,Reference values ,Medicine ,education ,business ,Screening study ,Demography - Abstract
Background: Although the prevalence of genetic hematological disorders varies widely between geographical regions, region-specific hematological reference ranges have not been defined in Saudi Arabian adults. Methods: A multicenter retrospective cross-sectional study was conducted with 1127 participants who completed their pre-employment screening and recruitment process between January 2013 and December 2016. Data related to the demographic and hematological indices were extracted. Results: The mean age was 28.0±5.2 years (range 19.4-72.8 years) and gender was distributed equally (47.5% female vs. 52.5% male). The WBC reference range was 3.3-11.4 ×109/L; hemoglobin 111-174 gm/l; platelet 163-412 ×109/L; MCV 80-95.7 fl, and neutrophils 1.2-8.8 ×109/L. A robust regression model was used to evaluate the effect of the participant's characteristics on the hematological indices. Except for WBC, the rest of the hematological indices were significantly influenced by gender, region, and age. The 2.5 percentile hemoglobin values were 135 gm/L in males and 104 gm/L in females, while platelet values were 173 x109/L in females and 159 x109/L in males. Conclusion: The study defined local hematological reference ranges, which were mostly lower than reported in international studies used in our center. Hematological values were mainly influenced by gender and region. A community nationwide screening study is required to create reference ranges specifically for the Saudi population. Disclosures No relevant conflicts of interest to declare.
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- 2019
5. Chemotherapy Effect on Fertility in Male Patients with Hodgkin and Non-Hodgkin Lymphoma
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Ahmed Alaskar, Shatry Hind, Giamal Gmati, Saba Alsuhaymi, Nouf Alqahtani, Khadega A. Abuelgasim, Abin Thomas, Moussab Damlaj, Mahmoud Salam, Mohsen Alzahrani, Mohsen Alhazmi, Noura Alhmanai, May Anne Mendoza, Zaha Jamaan, Hind Salama, Ayman Alhejazi, Naila A. Shaheen, Nouf Bin Muammar, and Bader Alahmari
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Oncology ,Infertility ,Chemotherapy ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,medicine.medical_treatment ,Immunology ,Fertility ,Cell Biology ,Hematology ,medicine.disease ,Sperm bank ,Biochemistry ,Chemotherapy regimen ,Acute lymphocytic leukemia ,Internal medicine ,medicine ,Hodgkin lymphoma ,Rituximab ,business ,media_common ,medicine.drug - Abstract
Introduction: The chemotherapeutic agents are effective in destroying cancerous cells for patient with hematological malignancies, but can damage the germinal cells. Hence, the infertility is the therapy-induced complication, which can be transient or permanent, depending on type of treatment protocol used and other factors. The aim of the study was to assess the fertility status among patients treated for Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL). Methods: A chart review was done for patients followed up in hematology clinic. All male patients treated for hematological malignancies during the period from 2004-2014 were assessed. The infertility status was assessed using WHO infertility criteria. The fertility status was defined based on semen analysis or having a child post chemotherapy. The data was captured for type of protocol, number of cycles, fertility status, having a child pre and post chemotherapy, and sperm bank utilization. Results were summarized as frequency and percentages. Data was analyzed using SAS. Results: 400 medical charts were reviewed. 208/400 were included based on age inclusion criteria (18-60 years). 59/208 included based on available fertility data, of which 31 were diagnosed with HL, 21 NHL, 4 acute lymphocytic leukemia, and 3 acute myeloid leukemia. Only HL and NHL were considered for further analysis. 9/31 (29%) with HL and 1/21 (4.7%) with NHL had infertility prior to starting chemotherapy based on semen analysis with no follow-up fertility assessment done post-treatment. The final sample consisted of 42 patients who had data available on their fertility status post-treatment (22 HL and 20 NHL) (Figure 1). The mean age was 38 ± 8 years. 25(68%) had advanced disease. Among HL, 8/22 (36.36%) were fertile (7 conceived a child and 1 with normal semen analysis) (Figure 2). This includes 6 out of 9 (66.7%) patients who received ABVD protocol alone, 0 out of 6 who received ABVD + BEACOPP protocol, and 2 (28.6%) out of 7 who received salvage chemotherapy. Among the NHL, 11/20 (55%) were fertile (8 conceived a child and 3 with normal semen analysis) (Figure 2). This includes 7 out of 11 (63.6%) who received CHOP +/-Rituximab protocol, 3 out of 5 (60%) who received CHOP + other chemotherapy (MTX/CVP), 1 out of 3 (33.3%) who received only other chemotherapies (Hyper CVAD/MTX) (Figure 2). 9 out of 22( 41%) HL and 6 out of 20 NHL patients had sperm banking done, and only two utilized their sperms with one successful conception in a patient with NHL (Figure 3). Conclusion: Although the sample size is very small, we found a trend that may suggest HL to affect fertility and that ABVD protocol may not be as safe as it thought to be on fertility. The advanced stage of the disease being the majority may have influenced this finding. We found the documentation of fertility status among patients receiving chemotherapy to be scarce. Hence, it is important to educate physicians and dedicate a protocol for assessment of fertility pre- and post-treatment with encouragement to utilize sperm banking. Disclosures No relevant conflicts of interest to declare.
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- 2019
6. Reduced Intensity Conditioning (RIC) Regimens Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML): A Comparison of Fludarabine/Busulfan (FB) and Fludarabine/Melphalan (FM) Based Regimens from the CIBMTR
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Muhammad Wagas Khan, Gulrayz Ahmed, Mrinal M. Patnaik, Gerhard C. Hildebrandt, Moussab Damlaj, Zartash Guth, Hassan B. Alkhateeb, Rajneesh Nath, Wael Saber, Marcos de Lima, Jan Cerny, Brenda M. Sandmaier, Mark R. Litzow, Khalid Bo-Subait, Daniel J. Weisdorf, Zheng Zhou, and Hai-Lin Wang
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Minimal residual disease ,Fludarabine ,Transplantation ,Regimen ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Alemtuzumab ,business ,Busulfan ,medicine.drug - Abstract
Background: There is limited data comparing the outcomes of the two most common (FM or FB) RIC regimens in AML. Previous smaller retrospective studies suggest increased non-relapse mortality (NRM) but decreased relapse with FM based RIC with a variable effect on overall survival as compared to FB. Methods: AML patients aged ≥18 years who had their 1st allo HCT using FM or FB (iv Bu only) RIC between 2001-2015 who had data reported to CIBMTR were studied. Patients with cord blood or identical twin donors, TBI as a part of conditioning, GVHD prophylaxis with T cell depletion/CD34 selection or post HCT Cyclophosphamide were excluded. Primary endpoint was overall survival (OS), and secondary endpoints included non-relapse mortality (NRM), relapse, leukemia free survival (LFS) and acute and chronic GVHD. Cox proportional hazards multivariable regression was used to compare the two RIC regimens while adjusting for significant patient, disease and transplant related factors. Major subgroup analysis included patients in CR pre-HCT. Results: 622 patients received FB and 791 had FM RIC. Median age of the FM group was 59 years, range (18 to 76) and median age of FB group was 61 years, range (18- 77). Compared to FB RIC regimen, FM group had more patients with active disease (36% vs 18%), with mismatched donors (24% vs 15%), with bone marrow grafts (19% vs 9%), HCT before 2005 (29% vs 12%) and without ATG/alemtuzumab (58 % vs 48%); but fewer patients in CR1 (46% vs 62%) and matched sibling donor grafts (21% vs 30%). There was significantly increased NRM in the FM vs FB within 3 mo post HCT (hazard ratio (HR)=3.85 (95% confidence intervals [CI] 2.46-6.03), but not beyond 3 mo FM vs FB , HR= 1.14 (95% CI 0.88-1.47). There was significantly decreased relapse for FM vs FB, (HR=0.65 (0.55-0.76), p Conclusion: The current study of this large CIBMTR AML transplant cohort has showed that in these two most common RIC regimens for allogeneic HCT, long-term survival with FM was similar to FB. While the FM regimen showed higher early NRM, it was associated with lower risks of relapse. Further analysis to evaluate FB and FM regimens in relationship to comorbidities, comprehensive geriatric assessments, and presence of minimal residual disease is warranted to better define the relative efficacy of these two RIC regimens in AML. Disclosures Weisdorf: Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; SL Behring: Consultancy; FATE: Consultancy; Equillium: Consultancy.
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- 2018
7. Outcome of Age-Adapted Approach to HLA-Identical Related Hematopoietic Stem Cell Transplantation in Severe Sickle Cell Disease: Saudi Experience
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Ahmed Alaskar, Giamal Gmati, Hind Salama, Mohsen Alzahrani, Khadega A. Abuelgasim, Abdulrahman Alsultan, Ayman Hejazi, Rodaina Abujoub, Bader Alahmari, Enas Basher, Samer Ghazi, Moussab Damlaj, and Mohammed F. Essa
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medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,030204 cardiovascular system & hematology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,0502 economics and business ,medicine ,Aplastic anemia ,business.industry ,05 social sciences ,Cell Biology ,Hematology ,Total body irradiation ,medicine.disease ,Sickle cell anemia ,Transplantation ,Regimen ,Graft-versus-host disease ,Alemtuzumab ,050211 marketing ,business ,medicine.drug - Abstract
Sickle cell disease (SCD) is one of the most common inherited disorders in Saudi Arabia with nearly 60,000 affected individuals (Alsultan et al. Ped. Transplant. 2016). Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment in SCD. A recent international survey showed excellent long-term survival of SCD patients after HLA-identical sibling HSCT; however, patients aged 16 years or older had higher risk of GVHD and mortality (Gluckman et al. Blood 2017). HLA-identical related HSCT in adult SCD patients using non-myeloablative (NMA) conditioning consisting of alemtuzumab, 300 cGy total body irradiation (TBI), and sirolimus was successful in establishing long term stable donor chimerism with minimal toxicity and GVHD (Hsieh et. al. JAMA 2014). In this study, we reviewed the outcome of SCD patients who underwent transplant at our institution using standard protocols (NMA regimen in patients ≥14 years and myeloablative regimen in < 14 years) to address whether age remains a risk factor that influences HSCT outcome in SCD. Children ( 50,000/uL during HSCT. Supportive care included penicillin V, acyclovir, antifungal, and Pneumocystis jiroveci pneumonia prophylaxis. Levetiracetam was used as seizure prophylaxis. Strict monitoring of blood pressure and magnesium was performed. Graft failure and death from any cause were considered as events. A total of 51 patients with severe SCD were transplanted at our center, 17 children and 34 adults. Patient and transplant characteristics are summarized in Table. Indications for HSCT included recurrent severe pain crisis (n=33), stroke (n=14), avascular necrosis (n=2), sickle cell hepatopathy (n=1), and priapism (n=1). All patients engrafted successfully for both neutrophil and platelets. There was no acute or chronic GVHD among adult patients. Two pediatric patient had mild grade I acute GVHD in the skin that was controlled with topical treatment and none of pediatric patients had chronic GVHD. Three adult patients developed secondary graft failure on day 61, 170, and 225 post transplant with aplastic marrow in two patients despite full donor chimerism and autologous recovery in the third patient. Among the two patients who had aplastic anemia, one died secondary to sepsis and one underwent successful second transplant using cyclophosphamide, Flu, and ATG. Thirty-one adults have stable donor chimerism. Event free survival (EFS) at 2 years was 90% in adult patients and 100% in children (P=0.3). Overall survival (OS) at 2 years was 97% in adults and 100% in children (P=0.4). Median follow up duration was 416 days (range, 61-1256) in adults and 203 (range, 30-2505) days in children. We demonstrated that age-adapted approach in guiding the choice of conditioning regimen intensity in severe SCD is associated with excellent outcome and minimal risk of graft rejection, GVHD, and transplant-related mortality. This real world data is important to encourage patients and transplant physicians to consider this curative treatment. Longer follow up duration is needed to confirm our findings. Disclosures No relevant conflicts of interest to declare.
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- 2018
8. Prognostic Impact of Blood Count Recovery Based Complete Remission Prior to Allogeneic Transplantation in Patients with Acute Leukemia
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Hend Salama, Walid Mashaqbeh, Moussab Damlaj, Mushtaq Rather, Giamal Gmati, Ahmed Askar, Ghazi Samer, Ayman Hejazi, Khadega A. Abuelgasim, and Mohsen Al Zahrani
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medicine.medical_specialty ,Acute leukemia ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Total body irradiation ,medicine.disease ,Biochemistry ,Minimal residual disease ,Surgery ,Transplantation ,Log-rank test ,Median follow-up ,Internal medicine ,medicine ,business ,Lymphoid leukemia - Abstract
Background: Morphologic complete remission (CR) is the gold standard for assessing response in acute leukemia. Patients who achieve CR with incomplete count recovery (CRi) in acute myeloid leukemia typically have inferior overall survival and lower event free survival (Walter et al, JCO 2010 and Chen et al, JCO 2015). Incomplete hematologic recovery is likely not an independent risk factor for inferior outcome but possibly correlates with adverse disease characteristics such as high risk cytogenetics or minimal residual disease post therapy. Furthermore, remission status prior to allogeneic stem cell transplantation (SCT) is an important predictor of post-transplant outcome. However, the prognostic role hematologic recovery carries prior to allogeneic transplantation for acute leukemia is not known. Aim: To study the impact of CRi with corresponding impact on relapse incidence (RI), non-relapse mortality (NRM) and overall survival (OS) in allogeneic SCT for acute leukemia. Methods: Patients with acute myeloid or lymphoid leukemia who received allogeneic SCT at our institution between 2010-2015 were identified. All clinical and pathologic data were retrospectively extracted. All patients were deemed in morphologic remission at the time of transplant without evidence of active disease. CR and CRi were defined in accordance to previous international working group definitions. Categorical and continuous variables were analyzed using Pearson's chi-squared and Wilcoxon / Kruskal-Wallis, respectively. Survival estimates were calculated using the Kaplan-Meier and log-rank test. RI was estimated accounting NRM on a competing event analysis using Grey's model. Methods: Patients with acute myeloid or lymphoid leukemia who received allogeneic SCT at our institution between 2010-2015 were identified. All clinical and pathologic data were retrospectively extracted. All patients were deemed in morphologic remission at the time of transplant without evidence of active disease. CR and CRi were defined in accordance to previous international working group definitions. Categorical and continuous variables were analyzed using Pearson's chi-squared and Wilcoxon / Kruskal-Wallis, respectively. Survival estimates were calculated using the Kaplan-Meier and log-rank test. RI was estimated accounting NRM on a competing event analysis using Grey's model. Results: A. Baseline characteristics: A total of 68 patients were identified. A total of 36 were in CR while 32 were in CRi. Baseline patient, disease and transplant characteristics stratified by group are shown (Table 1). Importantly, there were no significant differences between the cohorts with regards to gender, disease status at SCT, intensity of conditioning regimen, use of total body irradiation (TBI), HLA and ABO matching. B. Transplant outcomes: Median follow up of the entire cohort was 13.6 (2-64.9) months. During which 2-year rates of RI, NRM and OS were 42.4, 12.8% and 63.9%, respectively. Stratified by count recovery, the 2-year rates of RI for CR and CRi were 36.2 vs. 43.1, respectively (p = 0.39). 2-year NRM for CR and CRi were 21.7% vs. 11%, respectively (p = 0.1). 2-year OS for CR and CRi were 59% vs. 61.8%, respectively (p = 0.58). Conclusion: We observed comparable post-transplant outcomes between CR and CRi. This suggests that in contrast to acute myeloid leukemia, SCT had a role in mitigating the negative prognostic implication of CRi. These results could have implications as physicians may not need to postpone SCT to await hematologic recovery. This important question should be further validated in a larger cohort of patients. Table 1 Patient characteristics stratified by count recovery Table 1. Patient characteristics stratified by count recovery Figure 1 Cumulative incidence of relapse stratified by count recovery Figure 1. Cumulative incidence of relapse stratified by count recovery Figure 2 Overall survival stratified by count recovery Figure 2. Overall survival stratified by count recovery Disclosures No relevant conflicts of interest to declare.
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- 2016
9. Role of FDG-PET/CT for Detection of Occult Bone Marrow Involvement in Patients from the Middle East and North Africa Region with Hodgkin Lymphoma
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Abdul Rahman Jazieh, Giamal Gmati, Hejazi Ayman, Mushtaq Rather, Khadega A. Abuelgasim, Ahmed Askar, Ghulam Syed, Salama Hend, Moussab Damlaj, and Mohsen Al Zahrani
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medicine.diagnostic_test ,business.industry ,Incidence (epidemiology) ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Lymphoma ,medicine.anatomical_structure ,Nodular sclerosis ,Trephine ,Positron emission tomography ,Biopsy ,medicine ,Bone marrow ,Stage (cooking) ,business ,Nuclear medicine - Abstract
Background: Routine bone marrow biopsy (BMB) for the initial staging of Hodgkin Lymphoma (HL) is not recommended in the era of FDG-PET/CT staging (J Clin Oncol. 2014;32(27):3059). However, patients from the Middle East and North Africa (MENA) region have epidemiologic and clinical features of lymphoma that are different from patients of other ethnicities (J Natl Compr Canc Net2010;8:S-29-S-35). Therefore, it is unknown whetherFDG-PET/CT can substitute for staging BMB in this population.At our center, we perform routine BMB for all newly diagnosed lymphoma cases. Aim: To investigate whether routine BMB is essential in detecting bone marrow disease where FDG-PET/CT is used in initial staging for HL in patients from the MENA region. Methods: Patients with HL at our institution between 2010 - 2015 were identified. Inclusion criteria included newly diagnosed patients who had BMB and FDG-PET/CT as part of initial staging. All baseline and laboratory features were retrospectively extracted. Pathology reports of bone marrow aspirate and trephine biopsies were reviewed by two independent Hematologists. All written FDG-PET/CT reports were retrieved and carefully reviewed and cases with positive skeletal uptake were re-interpreted by an experienced radiologist. Pattern of skeletal FDG-PET/CT uptake was determined and classified as unifocal or multifocal. Sensitivity and specificity was computed while defining bone marrow disease by positive BMB and / or focal skeletal uptake on FDG-PET/CT. Categorical and continuous variables were analyzed using Pearson's chi-squared and Student's t-test, respectively. Results: A. Baseline characteristics: A total of92 patients met the inclusion criteria and were considered for this analysis. All patients were from the MENA region and > 90% were from the Arabian peninsula. From this cohort, bone marrow disease was detected in 7 (7.6%) patients using BMB while 20 (21.7%) patients had unifocal or multifocal bone marrow uptake on FDG-PET/CT. An additional 21 patients (23%) had diffuse homogenous FDG uptake and was not considered to represent HL. The cohort was characterized by a male to female ratio of 1.4 and a median age at diagnosis of 27 years (6-83). About two thirds of the cases were classical HL of the nodular sclerosis subtype (Table 1). Almost 60% of cases were stage III - IV with corresponding median IPS of 2 (0-6). Incidence of bulky disease and B-symptoms among the entire cohort was 32% and 50%, respectively. B. Comparison of FDG-PET/CT and BMB No patient with involved BMB (iBMB) had early stage disease on FDG-PET/CT and BMB identified only one patient with positive BM involvement yet negative skeletal uptake on FED-PET/CT. Involvement by BMB upstaged 3 patients previously assessed by CT scan as having stage III, however, none of the patients were allocated to a different treatment plan based on the BMB result. On the other hand, FDG-PET/CT upstaged 24 patients (26%); 9 patients from stage III to IV and 14 patients from early to advanced stage resulting in change of therapeutic plan in the latter group. Focal skeletal FDG-PET/CT lesions identified positive marrow disease with a sensitivity and specificity of 95.2% and 70.4%, respectively. On the other hand, sensitivity and specificity of BMB was 35% and 100%, respectively (Table 2). Abnormal skeletal FDG uptake was seen in a total of 20 patients (21.7%); 11 (55%) had unifocal / bifocal while 9 (45%) had multifocal disease of the axial skeleton. Patients with iBMB compared to those with negative BMB but positive unifocal / multifocal skeletal FDG-PET/CT lesions were more likely to be male (p = 0.002), have B-symptoms (p = 0.028), extranodal disease (p = 0.017) and more likely to have multifocal uptake on FDG-PET/CT (0.017) (Table 3). Conclusion:To our knowledge, this is the first analysis to examine the role of FDG-PET/CT for detection of bone marrow involvement in HL in a patient cohort from the MENA region. We observed that FDG-PET/CT had a higher sensitivity and negative predictive value compared to BMB leading to a treatment change in a significant proportion of patients. This analysis highlightsthat FDG-PET/CT can substitute for BMB in routine staging for newly diagnosed patients with HL from the MENA region. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
10. Clinical Outcomes Related to the Use of Monoclonal Antibody Therapy for Steroid Refractory Acute Graft-Versus Host Disease after Allogeneic Hematopoietic Cell Transplantation
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Ankit Kansagra, Robert C. Wolf, William J. Hogan, Hassan B. Alkhateeb, Moussab Damlaj, Kristen B. McCullough, Mrinal M. Patnaik, Fevzi Firat Yalniz, Mehrdad Hefazi, and Mark R. Litzow
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Gastroenterology ,Infliximab ,Surgery ,Transplantation ,Clinical trial ,chemistry.chemical_compound ,Tocilizumab ,chemistry ,Internal medicine ,Concomitant ,medicine ,business ,Adverse effect ,Monoclonal antibody therapy ,medicine.drug - Abstract
Background: Acute graft versus host disease (aGVHD) is the leading cause of morbidity and mortality following allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first line treatment although Methods: Patients with SR-aGVHD that received therapy with either Infliximab or Tocilizumab between January 2003 and May 2016 were retrospectively identified. Clinical grading of aGVHD was per the Glucksberg criteria (Glucksberg et. al.; 1974). SR-aGVHD was defined as any grade progression within 3 days or failure to achieve at least one grade improvement within 7 days of initiation of systemic steroids. Infliximab and Tocilizumab were administered intravenously at 10mg/kg and 8mg/kg weekly for a total of 4 doses, respectively. Clinical response was evaluated at 4 weeks and 12 weeks post mAb treatment. Complete response (CR) was defined as sustained resolution of all clinical signs of aGVHD; partial response (PR) was defined as overall improvement of 1 or more grades; no response (NR) was defined as neither improvement nor worsening of the overall aGVHD grade. Overall response (OR) was defined as either CR or PR. Overall survival (OS) was calculated from the first day of mAb treatment until death or last available follow up. Results: Forty-three patients (median age 54, range 29-74 years; male 67%) with severe SR- aGVHD were included in the study. Of these, 35 (81%) received Infliximab for a median of 4 (range 1-6) cycles and 8 (19%) received Tocilizumab for a median of 3 (range 1-4) cycles. Both groups were comparable with regards to age, gender, conditioning regimen, graft source, degree of HLA match, ABO blood group, CMV incompatibility, and GVHD prophylaxis regimens. Only differences seen were a higher proportion of unrelated donor (p = 0.004) and cord blood HCT (p = 0.031) in the Tocilizumab group. Twenty (57%) of 35 patients treated with Infliximab and 6 (75%) of 8 patients treated with Tocilizumab had an overall aGVHD grade of IV prior to initiation of mAb therapy (p = 0.44). Organ specific distribution and severity of aGVHD are described in table 1. At 4 weeks post mAb therapy, 17 (40%) patients had an OR, 7 (16%) had no response, and 19 (44%) had died. Twenty-six (60%) patients died at 12 weeks, with OR and no response observed in 9 (21%) and 8 (19%) patients, respectively (table 2). Overall response for Tocilizumab versus Infliximab was comparable at 4 weeks (38% vs. 40%; p = 1.0) and at 12 weeks (38% vs. 17%; p = 0.33). Outcomes per aGVHD grade and gastrointestinal-specific stage at 4 weeks and 12 weeks are shown in figures 1-A and 1-B, with organ specific responses shown in figures 1-C and 1-D, respectively. The estimated median OS was 41 (range 4-3837) days for patients treated with Infliximab and 60 (range 10-756) days for those treated with Tocilizumab (p = 0.48). Disease relapse occurred in 5 (11%) patients treated with Infliximab and in none (0%) treated with Tocilizumab (p = 0.56). Thirty-four (79%) patients had infectious complications during and up to one month after mAb therapy. These included 31 (72%) patients with bacterial blood stream infection and 10 (23%) with invasive fungal infections. Overall, infectious complications were comparable (Infliximab - 83% vs. Tocilizumab - 63%; p = 0.33). CMV reactivation occurred in 11 (31%) and in 2 (25%) patients who were treated with Infliximab and Tocilizumab, respectively (p = 1.0). Given the retrospective nature of the study and the concomitant presence of aGVHD, it was difficult to attribute and grade gastrointestinal and hepatobiliary side effects. Conclusions: The use of anti-inflammatory monoclonal antibody therapy in patients with steroid refractory acute GVHD is associated with significant infectious complications (~80%) and poor response rates (~20% at 12 weeks). Current data, limited by a small sample size, does not show any advantages of using Tocilizumab over Infliximab or vice versa. Prospective clinical trials addressing this question are needed. Disclosures No relevant conflicts of interest to declare.
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- 2016
11. Early T-Lymphocyte Chimerism Kinetics Is Influenced By Conditioning Regimen in Reduced Intensity Allogeneic Stem Cell Transplantation
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Farhadfar, Nosha, primary, Moussab, Damlaj, additional, Dias, Ajoy L., additional, Alkhateeb, Hassan B, additional, Litzow, Mark R, additional, Hashmi, Shahrukh K., additional, Patnaik, Mrinal M, additional, and Hogan, William J, additional
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- 2015
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12. Prognostic Impact of Peripheral Blood Count Recovery and Cytogenetic Remission Prior to Reduced Intensity Allogeneic Transplantation in Patients with Acute Myelogenous Leukemia and Myelodysplastic Syndromes
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William J. Hogan, Mrinal M. Patnaik, Daniel K. Partain, Naseema Gangat, Aref Al-Kali, Hassan B. Alkhateeb, Mark R. Litzow, Mehrdad Hefazi, Moussab Damlaj, and Shahrukh K. Hashmi
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medicine.medical_specialty ,biology ,business.industry ,Myelodysplastic syndromes ,Immunology ,C-reactive protein ,Hazard ratio ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Transplantation ,Log-rank test ,Leukemia ,Median follow-up ,Internal medicine ,Cohort ,biology.protein ,Medicine ,business - Abstract
Background:Morphologic complete remission (CR) is the gold standard for assessing response in acute myelogenous leukemia (AML). CR with incomplete count recovery (CRi) and CR with incomplete platelet recovery (CRp) are associated with inferior overall survival post induction therapy (Walter et al, JCO 2010 and Chen et al, JCO 2015). Furthermore, residual cytogenetic disease is associated with a higher relapse compared with patients with cytogenetic CR (CCR; Chen et al, JCO 2011). There is a paucity of literature regarding the impact of CRi, CRp and CCR prior to allogeneic transplantation. Aim:To study the impact of CRi, CRp and CCR and their impact on relapse incidence (RI), non-relapse mortality (NRM) and overall survival (OS) in reduced intensity allogeneic stem cell transplantation (RIC-SCT). Methods:After due IRB approval, patients (pts) with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who received RIC-SCT at our institution between 2008-2014 were identified. All clinical and pathologic data were retrospectively extracted. CR, CRi, CRp and CCR were defined in accordance to the international working group definition. Categorical and continuous variables were analyzed using Pearson's chi-squared and Wilcoxon/Kruskal-Wallis, respectively. Survival estimates were calculated using the kaplan-meier and log-rank test. RI was estimated on a competing event analysis using Grey's model. Cox proportional regression was used to compute hazard ratios (HR). Results: A. Baseline characteristics: A total of 134 patients were identified. A total of 70 (52%) were in CR, 40 (30%) in CRi and 24 (18%) in CRp. 129 patients had evaluable cytogenetic data pre-SCT; 81 (63%) were in CCR and 48 (37%) had persistent cytogenetic disease. Baseline patient, disease and transplant characteristics stratified by peripheral count recovery pre-SCT are shown (Table 1). Significantly more patients in CR had higher KPS, higher proportion AML diagnosis, more likely to be in first complete remission (CR1), higher rate of cytogenetic CR and a higher proportion of minor ABO mismatched donor. No other significant variables were identified between the three cohorts. B. Transplant outcomes: Median follow up of the entire cohort was 41.9 months and the 2-yr OS, RI and NRM were 61.7%, 25.7% and 21.9%. Patients in CR, CRi and CRp had a similar 2-year rates of RI (26.3%, 18.4% and 28.9%, respectively; p = 0.66), 2-year NRM (20.5%, 38.8% and 22.1%, respectively; p = 0.18) and 2-year OS (61.8%, 55.1% and 58.6%, respectively; p = 0.82). RI was significantly lower for patients in CCR pre-SCT with HR 0.25 (95% CI 0.11-0.51 p = 0.0001) without a difference in overall survival HR 0.68 (0.41-1.15; p = 0.14). However, we observed a similar RI in CR, CRi and CRp patients who had persistent cytogenetic disease pre-SCT (p = 0.55). The outcome remained similar between strata after excluding MDS patients (data not shown). Conclusion: We observed equivalent post-transplant outcomes between CR, CRi and CRp despite the presence of persistent cytogenetic disease. This suggests that RIC SCT had a role in mitigating the negative prognosis associated incomplete hematologic recovery. These findings have implications as physicians may not need to postpone SCT to await count recovery. This important question should be further validated in a larger cohort of patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding.
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- 2015
13. The Adverse Impact of Age and Central Nervous System Involvement on Survival in Adult T-ALL, an Analysis of 92 Consecutive Patients
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Michelle A. Elliott, Moussab Damlaj, Carrie A. Thompson, Grzegorz S. Nowakowski, Thomas E. Witzig, Mark R. Litzow, Mrinal M. Patnaik, Tasha Lin, Mehrdad Hefazi, Naseema Gangat, Stephen M. Ansell, Hassan B. Alkhateeb, William J. Hogan, and Aref Al-Kali
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Univariate analysis ,medicine.medical_specialty ,Palliative care ,business.industry ,Immunology ,Lymphoblastic lymphoma ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,Log-rank test ,Regimen ,Median follow-up ,Acute lymphocytic leukemia ,Internal medicine ,Cohort ,medicine ,business - Abstract
Background: Adult T-cell acute lymphoblastic leukemia / lymphoma (T-ALL) is a rare and aggressive hematological malignancy. Unlike B-cell ALL, apart from age and presenting WBC, additional prognostic factors remain largely unknown. Additionally, the prognostic impact of a monosomal karyotype, which has a negative impact on survival in myeloid neoplasms, remains to be determined in T-ALL (Kenderian et al, BCJ 2013) Aim: To study predictors of survival including the role of a monosomal karyotype in T-ALL. Methods: After due IRB approval, adults diagnosed with T-ALL from 1990-2014 at Mayo Clinic Rochester were identified. All clinical and pathologic data including FISH studies and cytogenetics were retrospectively reviewed. Chi-square test was used to compare variables. Survival was estimated and compared using the Kaplan-Meier Method and log-rank test. Univariate and multivariate analysis was performed using the Cox regression model. Results: Between 1990 and 2014, a total of 92 consecutive patients (pts) with T-ALL were identified, 41 had acute lymphoblastic lymphoma (LBL), and 51 (55%) acute lymphoblastic leukemia (ALL). Median age at diagnosis was 33 years (range; 18-88 years) with 72%males. Median follow up of our cohort was 25 months (range; 0.9-260 months) during which time 42 deaths (45%) were documented. A. Baseline characteristics: Fifty six (67%) had constitutional symptoms, and 63 (77%) had lymphadenopathy at diagnosis. Mediastinal mass was identified in 49 (55%) pts with palpable splenomegaly in 16 (20%) pts. Fifty one (58%) pts had extranodal disease, and 17 (19%) pts had CNS involvement. Pleural and pericardial effusion were evident in 16 (19%), and 6 (7%) pts, respectively. Median laboratory values included; LDH 288 U/L (115-6590), hemoglobin (Hb) 12.8 g/dl (4.5-18.2), WBC 8.65 x109 (1.4-406), platelets 169 x109 (8-485), bone marrow blasts 29% (0-99). B. Treatments: Induction therapies were variable and included; 11 (12%) CHOP like regimens, 7 (8%) modified NHL regimens (Asparginase+CHOP), 54 (58%) ALL like regimens (CALGB 9111, E2993, or HyperCVAD), 13 (14%) Pediatric regimens (ALL 10403, CCG 1961, BFM, Augmented BFM, GRAALL 2003, or Hoelzer regimen), with 7 (8%) patients' receiving palliative care only. Seventy-one (77%) pts achieved complete remission (CR1) during induction therapy while eight pts had refractory disease (8%). Thirty-three (35%) pts underwent stem cell transplant; 7 (21%) autologous and 26 (79%) allogeneic. Forty one (44%) pts had disease relapse and median time to relapse was 10.8 months (range; 8.2-16 months) C. Predictors of survival: In univariate analysis, that included age > 60 years, leukocyte count Hb, Plt, Blast percentage, mediastinal mass, LDH and CNS involvement, only age >60 and CNS involvement were predictors of inferior survival and both retained significance in the multivariable analysis with HR 3.9 (CI 1.5 - 9; p=0.0055) and 2.8 (1.3 - 5.7; p =0.0085), respectively (Figure 1 and 2). In this cohort age >60 was a better stratification that the conventionally used age above 40 (p = 0.1). Among 56 pts with evaluable cytogenetics data, 7 (13%) pts had MK which did not have an impact on survival with HR 1.9 (CI 0.4-5.6; p=0.33). Conclusion: In this large cohort of adult T-ALL patients, we observed that age >60 years and CNS involvement were independent predictors of inferior survival. MK was infrequent, but unlike in myeloid neoplasms, does not seem to impact overall survival. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding. Witzig:Novartis: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Spectrum: Research Funding; Valeant Pharma: Equity Ownership.
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- 2015
14. Early CMV Infection Detected By Quantitative Nucleic Acid Testing (QNAT) Is Associated with Lower Risk of Relapse after Reduced Intensity, but Not Myeloablative, Hematopoietic Cell Transplantation in Acute Myeloid Leukemia
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Moussab Damlaj, William J. Hogan, Aref Al-Kali, Hassan B. Alkhateeb, Mrinal M. Patnaik, Shahrukh K. Hashmi, Mehrdad Hefazi Torghabeh, Mark R. Litzow, and Raymund R. Razonable
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Melphalan ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Total body irradiation ,Lower risk ,Biochemistry ,Gastroenterology ,Surgery ,Fludarabine ,Transplantation ,Median follow-up ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Cumulative incidence ,business ,Busulfan ,medicine.drug - Abstract
Background The impact of cytomegalovirus (CMV) infection on the risk of relapse after Hematopoietic Cell Transplantation (HCT) remains controversial, with some studies demonstrating lower risk (Green et al, Blood 2013), while others demonstrating no impact (Schmidt-Hieber et al, Blood 2013), or lower relapse risk only in myeloablative (MA) (Manjappa et al, BBMT, 2014) or in reduced intensity conditioning (RIC) (Cichocki et al, ASH 2014) HCT. Furthermore, the majority of studies have used antigenemia for CMV monitoring, while there is limited data with the use of Quantitative Nucleic Acid Testing (QNAT). Aim To determine the impact of CMV infection, as detected by QNAT, on transplant-related outcomes for patients with acute myeloid leukemia (AML), stratified by MA or RIC HCT. Methods After IRB approval, consecutive adults with AML who underwent allogenic HCT from HLA-matched peripheral blood (PB) grafts at our institution between 2006 and 2014 were retrospectively reviewed. All grafts were T-cell replete. Early CMV infection was defined as any positive CMV result by PCR assay during the first 100 days post HCT. Relapse incidence (RI), non-relapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) were compared between patients with and without CMV infection, and stratified according to MA or RIC. DFS and OS were estimated using the Kaplan-Meier method, and compared with log-rank test. Cumulative incidence of relapse and NRM were analyzed as competing events, using Gray's test. Multivariable analyses adjusting for patient's age, disease status at transplant, cytogenetic risk, and ABO incompatibility were performed using Cox's proportional hazards regression, and the Fine and Gray approach. Results A total of 190 consecutive patients, including 94 (49%) MA and 96 (51%) RIC HCT were analyzed. Patients, disease, and transplant characteristics are shown in table 1. Of the 94 MA HCT (median age 45 y, 50% male), 66 (70%) received total body irradiation. After a median follow up of 18 m, 36 (38%) CMV infection, 16 (17%) relapses, 22 (23%) NRM and 35 (37%) deaths occurred in the MA group. Median time to CMV infection and to relapse in this group was 38 (range 8-241) and 140 (29-1690) days, respectively. Among the recipients of MA HCT, patients with early CMV infection showed no difference in the RI (figure 1), but had a significant trend towards higher NRM and significantly lower DFS and OS in both univariate and multivariable analysis (figure 2) (P values shown in table 2). Among 96 RIC HCT (median age 59 y, 56% male), fludarabine plus melphalan was used in 62 (65%) and fludarabine plus busulfan in 34 (35%) patients. In this group, early CMV infection occurred in 33 (34%), relapse in 25 (26%), NRM in 25 (26%), and deaths in 46 (48%) patients after a median follow up of 21 m (1-91 m). Among the recipients of RIC HCT, median time to CMV infection and to relapse was 40 (17-175) and 291 (19-1971) days, respectively. In the RIC group, early CMV infection was associated with a significant trend towards lower RI (figure 1) and higher NRM in both univariable and multivariable analysis, but no difference in DFS and OS (figure 2). Conclusion Our study of a large homogenous group of AML patients who underwent a uniform HLA-matched PB HCT demonstrates a significantly lower risk of relapse associated with early CMV infection detected by QNAT following RIC, but not MA HCT. Early CMV infection in MA HCT is associated with higher NRM and therefore inferior survival, whereas in the RIC HCT, there is no impact on survival as the benefit of lower relapse is offset by the higher NRM. Table 1. Patients, disease and transplant characteristics according to CMV infection All Patients Patients with CMV Viremia Patients without CMV Viremia P value Patients, no (%) 190 (100) 69 (36) 121 (64) - Median age, y (range) 54 (18-72) 54 (26-70) 54 (18-72) 0.75 Male Patients, no (%) 104 (55) 30 (43) 74 (61) 0.02 D/R CMV Serostatus, no (%) Disclosures Al-Kali: Novartis: Research Funding.
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- 2015
15. Comparative Analysis of Azacitidine and Decitabine in Myelodysplastic Syndromes: A Systematic Review and Network Meta-Analysis
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Jehad Almasri, M. Hassan Murad, Moussab Damlaj, Aref Al-Kali, Zhen Wang, and Hassan B. Alkhateeb
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medicine.medical_specialty ,Pediatrics ,business.industry ,Myelodysplastic syndromes ,Immunology ,Azacitidine ,Decitabine ,Cell Biology ,Hematology ,medicine.disease ,Lower risk ,Biochemistry ,Transplantation ,International Prognostic Scoring System ,Internal medicine ,Meta-analysis ,Relative risk ,medicine ,business ,medicine.drug - Abstract
Background: Myelodysplastic syndromes (MDS) are clonal hematological diseases which present with cytopenias. Hematopoietic cell transplantation is usually limited to fit patients with higher risk MDS and donor availability. Hypomethylating agents (azacitidine and decitabine) have been the mainstay option for the management of MDS with different clinical efficacy in low versus high risk MDS trials. No trials have compared the two agents. Aim: To conduct a systematic review and network analysis comparing the efficacy of azacitidine to decitabine. Methods: The protocol of the systematic review was developed a priori. A comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus) was conducted from each database's earliest inception through November 20th, 2014 without language restrictions. Trials enrolling adults diagnosed with MDS who received hypomethylating agents (azacitidine or decitabine) therapy were included. Studies were screened by two independent reviewers and differences were resolved by consensus. The Cochrane Risk of bias tool was used to appraise the trials. Random effects model was used to pool relative risks (RR) of outcomes (overall survival, overall response rate, hematologic improvement and grade 3 or 4 toxicity). Adjusted indirect comparisons were used to estimate RR for indirect comparisons (Glenny AM, et al. Health Technol Assess. 2005). All statistical analyses were conducted using STATA, version 13 (StataCorp LP, College Station, TX). Results: Only four trials met the eligibility criteria (Figure 1). Two trials compared Azacitidine (75mg/m²/day SC x 7 days) to the best suppurative care (BSC) and included 549 patients (278 azacitidine and 271 BSC, age average: 69; range: 31-92), and the other 2 compared decitabine (15 mg/m² IV q 8 hours x9) to BSC and included 403 patients (208 Decitabine and 195 BSC, age average: 69.7; range: 60-90) (Table 1). The proportion of patients with intermediate-2 and high-risk myelodysplastic syndrome (based on International Prognostic Scoring System (IPSS)) in trials comparing decitabine to BSC was 82.21% and 83.08%; respectively, and in trials comparing azacitidine to BSC was 62.59% and 61.26%; respectively. The risk of bias was moderate overall. Compared to BSC, azacitidine was significantly associated with lower risk of death (RR=0.83, 95% CI: 0.74-0.94, p=0.002) whereas the effect of decitabine did not reach statistical significance (RR=0.88, 95% CI: 0.77-1.001, p=0.053). Both drugs were superior to BSC in terms of partial and complete response. Head to head comparisons were not statistically significant (except for the outcome of complete response where low certainty evidence suggested that azacitidine treated patients were less likely to have complete response compared to decitabine (RR=0.11, 95% CI= 0.01, 0.86, p=0.04). (Table 2). Conclusion: Azacitidine and decitabine are both superior to BSC. The available indirect evidence comparing the two agents warrants low certainty and cannot reliably confirm superiority of either agent. Head-to-head trials are needed. In the meantime, the choice of agent should be driven by patients' preferences, drug availability and cost. Table 2. Results of meta-analysis Outcome Azacitidine VS. Decitabine Azacitidine VS. BSC Decitabine VS. BSC RR LCI HCI P value RR LCI HCI P value RR LCI HCI P value Death 0.95 0.79 1.13 0.54 0.83 0.74 0.94 0.002 0.88 0.77 1.001 0.05 Complete response 0.11 0.01 0.86 0.04* 2.56 1.44 4.58 0.001 23.46 3.22 170.84 0.002 Partial response 0.35 0.04 3.03 0.34 4.91 2.27 10.63 Disclosures Al-Kali: Celgene: Research Funding.
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- 2015
16. Fludarabine Busulfan Compared to Fludarabine Melphalan Is Associated with Increased Relapse Risk in Reduced Intensity Conditioning Transplant Despite Pharmacokinetic Dosing
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Daniel K. Partain, Dennis A. Gastineau, Shahrukh K. Hashmi, Hassan B. Alkhateeb, Mark R. Litzow, Mehrdad Hefazi, Aref Al-Kali, Mrinal M. Patnaik, Naseema Gangat, Robert C. Wolf, Moussab Damlaj, Jehad Almasri, and William J. Hogan
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medicine.medical_specialty ,business.industry ,Immunology ,Hazard ratio ,Area under the curve ,Cell Biology ,Hematology ,Biochemistry ,Gastroenterology ,Fludarabine ,Surgery ,Median follow-up ,Internal medicine ,medicine ,Absolute neutrophil count ,Cumulative incidence ,Progression-free survival ,business ,Busulfan ,medicine.drug - Abstract
Background: Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are two commonly used reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (SCT). A recent analysis showed that both regimens had similar overall survival (OS) but relapse incidence (RI) was significantly higher with FB with a trend towards higher non-relapse mortality (NRM) in FM (Baron et al., Cancer 2015). However, that cohort included patients treated with oral and intravenous busulfan without pharmakokinetic targeting of intravenous which may impact anti-leukemic activity. Aim: Compare transplant related outcomes of FB vs. FM using intravenous (IV) busulfan targeted to the area under the curve (AUC). Methods: After due IRB approval, patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) receiving RIC-SCT from 2008-2014 were identified. All baseline and laboratory features were retrospectively extracted. Busulfan dose in FB was 0.8 mg/kg IV for 10 doses with therapeutic AUC target of 900-1500 mcmol/L (min). All patients received T-cell replete grafts. Categorical and continuous variables were compared using Pearson's chi-squared and Wilcoxon/Kruskal-Wallis, respectively. Survival estimates were calculated using the Kaplan-Meier method and curves were compared using the log-rank test. Cumulative incidence was computed as competing events using Grey's model. Univariate and multivariate analyses were performed using Cox regression modeling. Results: A. Baseline characteristics and AUC monitoring: 134 pts were identified (47 FB and 87 FM). Median follow up of the entire cohort was 40 months (0-63.3) and at last follow up, 60% and 29% have died or relapsed, respectively. Baseline characteristics stratified according to conditioning regimen are shown in table 1. Younger age (60 yrs FB vs. 61 yrs FM, p = 0.015) and a trend towards a higher CMV R-/D- status (28% FB vs. 14% FM p = 0.064) were the only significant differences identified. All patients in the FB group received intravenous busulfan and 46/47 patients had evaluable AUC data with a range of 732-1354 mcmol/L (min). A total of 19 patients were outside of range, all B. Engraftment and toxicity data: The median time for platelet engraftment was 19 days (0-48) for FB vs. 16 days (14-183) for FM (p = 0.0023) whereas the median time to absolute neutrophil count (ANC) engraftment was 18 days (7-30) for FB and 15 days (11-40) for FM (p = 0.077). Cumulative incidence of grade II-IV, III-IV acute GVHD and chronic GVHD at 2-yr was 57.3%, 11% and 52.8% for FB and 48.6%, 17% and 63.4% for FM (p = 0.73, 0.4 and 0.21, respectively). Two patients in the FM group died of cardiac causes (heart failure and sudden cardiac arrest). No cases of sinusoidal obstructive syndrome were observed in either arm C. Transplant outcomes: A significantly higher 2-yr relapse incidence (RI) was associated with FB vs. FM at 35.6% vs 17.3%, respectively (p = 0.0058). 2-yr progression free survival (PFS) was also significantly lower in the FB vs. FM at 51.2% vs. 65.1%, respectively (p 0.031). However, 2-yr OS and NRM was similar for FB vs. FM (53.1% and 22.9% vs 63.9% and 21.9%, respectively p = 0.26 and 0.89). Necessitating a dose adjustment based on AUC did not increase the risk for relapse or affect NRM. In multivariate analysis, FB was associated with increased RI with hazard ratio (HR) 2.29 (1.07-4.88; p = 0.033). Other factors significantly associated with RI on multivariate analysis were secondary/therapy related disease with HR 2.84 (1.34-6.02; p = 0.0067) and CR1 vs. other with HR 0.39 (0.17-5.32; p = 0.019). The significance of the results remained unchanged after exclusion of MDS patients (data not shown) Conclusion: Despite AUC dose adjustment, FB compared to FM was associated with increased RI with a similar OS and NRM. AUC dose adjustment did not impact transplant outcomes and its routine use in RIC should be further evaluated. Given the wide use of FB as a conditioning regimen, these important observations should be prospectively studied in a randomized fashion. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding. Wolf:Janssen Scientific Affairs, LLC: Consultancy.
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- 2015
17. Clinical Characteristics and Outcome of Adult Acute Erythroleukemia; Mayo Clinic Experience
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William J. Hogan, Michelle A. Elliott, Hassan B. Alkhateeb, Naseema Gangat, Mark R. Litzow, Moussab Damlaj, Mrinal M. Patnaik, and Aref Al-Kali
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Oncology ,medicine.medical_specialty ,Univariate analysis ,business.industry ,Immunology ,Acute erythroid leukemia ,Myeloid leukemia ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Leukemia ,Median follow-up ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Pure Erythroid Leukemia ,business ,Survival analysis - Abstract
Background: Acute erythroleukemia (AML-M6) is an aggressive myeloid leukemia, with poor outcomes (median survival < 12months). In 2008, the WHO further sub-classified this disease into two subgroups- erythroid leukemia and pure erythroid leukemia, based on the number of erythroblasts and myeloblasts. We carried out this study to evaluate differences in presenting features and outcomes between erythroid leukemia and pure erythroid leukemia. Methods: After due IRB approval, out of 923 AML, 43(4.6%) pts who met the 2008 WHO criteria for acute erythroleukemia (2000-2014) were identified, and clinical characteristics retrospectively reviewed. A diagnosis of erythroid leukemia (M6a) was considered if > 50% of the total nucleate BM cells were of erythroid lineage and > 20% of non-erythroid cells were myeloblasts. Pure erythroid leukemia (M6b) was diagnosed in pts who presented with > 80% of BM nucleate cells consisting of immature erythroid precursors. Cytogenetic risk stratification was based on NCCN AML guidelines. Statistical comparisons were performed with the χ2 test for categorical variables and the Wilcoxon test for continuous variables. Univariate and multivariate analyses were performed with the Cox logistical regression. Survival analysis was based on the Kaplan-Meier method and log rank test. For all analyses, P ≤ 0.05 was considered statistically significant. Results: The median age at diagnosis was 65 years (27-90) and 34(79%) were male. 30 (69%) had M6a and 13 (30%) had M6b. 27 (62%) had de novo AML M6, whereas 16 (37%) had secondary AML (9 underlying MDS and 7 therapy related).The median time to leukemic transformation for pts with underlying MDS was 8 months (2-83). Median follow up in our cohort was 7.2 months (2-157) at which time 13 (30%) deaths were documented. A. Patient characteristics: At time of diagnosis median laboratory values included; Hemoglobin 8.5 g/dL (4.6-11), WBC 2x109 (0.7-11.1), ANC 0.47x109 (0.01-4.07), Platelet 33x 109 (7-177), peripheral blast % 2 (0-35), and bone marrow blast % 11 (0-84). Cytogenetic information was available in 38 pts; of which 6(16%) were diploid, 21(55%) were complex/monosmal and 1(3%) was complex/non monosomal. Intermediate risk cytogenetic was observed in 15 pts (39%), and poor risk cytogenetic was identified in 23(61%). Comparing M6a and M6b, we observed that pts with M6a tend to have more leukopenia and neutropenia and higher marrow blast percentage compared to M6b (Table 1). None of the patients experienced extramedullary disease or CNS involvement. B. Outcome and prognostics: We did observe a trend towards worse survival in pts with M6b, 7 months vs 12.9 months with M6a (p= 0.08) (Figure 1). There was no difference in survival in acute erythroleukemia compared to other acute myeloid leukemias, 10.1 vs 14 months (p= 0.28), respectively (Figure 2). In univariate analysis, WBC, ANC, and cytogenetic risk impacted survival (Table 2), however only cytogenetic risks retained significance in the multivariate model; Intermediate risk HR 0.18 (0.05-0.51; p = 0.0009) and poor risk HR 5.4 (1.9-17.6; p = 0.0009). Conclusion: Acute Erythroid Leukemia is a rare leukemia with ~5% incidence in our cohort. We observed that regardless of the percentage of bone marrow erythroblasts and myeloblasts, survival in patients with Acute Erythroleukemia are predominantly impacted by cytogenetic risk stratification. This raises a question on the clinical relevance of the sub-categorization of acute erythroleukemia into erythroid leukemia and pure erythroid leukemia. Larger studies are needed to validate our results. Figure 1. Figure 1. Disclosures Al-Kali: Celgene: Research Funding.
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- 2015
18. Survival Trends in Adult T-Acute Lymphoblastic Leukemia / Lymphoma (ALL), a Comparative Analysis of 92 Patients By Year of Diagnosis
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Mark R. Litzow, Stephen M. Ansell, Hassan B. Alkhateeb, William J. Hogan, Naseema Gangat, Carrie A. Thompson, Michelle A. Elliott, Thomas E. Witzig, Moussab Damlaj, Tasha Lin, Grzegorz S. Nowakowski, Aref Al-Kali, and Mrinal M. Patnaik
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Pediatrics ,medicine.medical_specialty ,business.industry ,Immunology ,Age adjustment ,Adult T Acute Lymphoblastic Leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Lymphoma ,Log-rank test ,Median follow-up ,Nelarabine ,Medicine ,Clofarabine ,business ,Survival analysis ,medicine.drug - Abstract
Background: Adult T-cell acute lymphoblastic leukemia / lymphoma (T-ALL) is an rare and aggressive hematological malignancy with overall survival (OS) according to the UKALL XII/E2993 of 48% at 5 years (Marks et al, Blood 2009). Over the last decade, the incorporation of L-asparaginase, dose intensification (similar to pediatric protocols), availability of newer agents such as clofarabine (Dec 2004) and nelarabine (Oct 2005) have been shown to improve outcomes. We carried out this study to see if the above mentioned changes in treatment have translated to an OS benefit. Methods: After due IRB approval, adults diagnosed with T-ALL from 1990-2014 at Mayo Clinic were identified. All clinical and pathologic data was retrospectively reviewed Comparative analysis was performed based on year of diagnosis before and after 2005 (Group 1, diagnosis prior to 2005, and Group 2, diagnosis post 2005). Survival was estimated using the Kaplan-Meier Method and log-rank test. Chi-square test was used to compare variables. Results: A. Patient Characteristics: Between 1990 and 2014, a total of 92 consecutive patients (pts) with T-ALL were identified. Median age at diagnosis was 33 years (range; 18-88 years) with 72% males. Distribution of pts by year of diagnosis was as follows: Group 1(n= 47) (51%), and Group 2 (n=45) (49%). Median overall survival was 97.2 months. Median follow up for Group 1 was 50 months, during which time 23 (39%) deaths were documented, and 22.8 months (0.9 - 115.4) for Group 2 at which time19 deaths (42%) were documented (p= 0.04). Pts in Group 2 were older than Group1 (median age 41 vs 27 years (p= 0.004). Apart from age, the two groups were similar in other characteristics (Table 1). B. Therapy received by patient groups: We observed a high use of L-asparaginase containing regimens in Group 1 vs Group 2 [35(74%) pts vs 19 (42%), p=0.0013]. In contrast there was an increase in use of Hyper-CVAD in Group 2; 23(51%) vs. 3 (6%) (p C. Overall outcome by patient groups: We did not observe any difference in CR, or relapse rates among the two groups. The median OS and time to relapse were also not statistically different among Group 1 and 2 [102.6 vs 61.8 months Figure A, and 7.1 vs 14.1 months respectively]. Furthermore, age adjusted survival analysis was also not statistically significant. Conclusion: In this large cohort of adult T-ALL patients, in spite of significant advances in treatment strategies over the last two decades, we observed no difference in overall and relapse free survival prior to and after 2005. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding. Witzig:Spectrum: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Valeant Pharma: Equity Ownership.
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- 2015
19. Clofarabine Based Chemotherapy in Adult Relapsed/Refractory Acute Lymphoblastic Leukemia/Lymphoma-a Single Institution Experience
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Michelle A. Elliott, Naseema Gangat, Tasha Lin, Mrinal M. Patnaik, Lisa Sproat, Aref Al-Kali, Shahrukh K. Hashmi, Moussab Damlaj, Hassan B. Alkhateeb, William J. Hogan, Mark R. Litzow, Jeffrey Betcher, and Jason N. Barreto
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Chemotherapy ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Salvage therapy ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Gastroenterology ,Donor lymphocyte infusion ,Surgery ,Regimen ,Internal medicine ,Acute lymphocytic leukemia ,Medicine ,Clofarabine ,business ,medicine.drug - Abstract
Background: Adult relapsed/refractory acute lymphoblastic leukemia/lymphoma (rALL) carries a very poor prognosis with limited options for effective salvage therapy. To date, there has been only a single retrospective report on the use of clofarabine in adult rALL demonstrating CR rate of 31% in this setting (Barba P et al. 2012). Aim: To evaluate the efficacy and toxicity of clofarabine based therapy in a relatively large cohort of adult rALL patients. Method: After IRB approval, a retrospective single institution study of all patients (pts) diagnosed with rALL treated with a clofarabine based regimen at Mayo Clinic between 2000 - 2014 was performed. Categorical variables were analyzed using Pearson's chi-squared test while continuous variables were analyzed using the Wilcoxon / Kruskal-Wallis test with P < 0.05 considered statistically significant. Survival estimates were calculated using Kaplan-Meier method and means were compared using log ranks. Results: Presenting features: We identified a total of 22 pts with a diagnosis of rALL who received clofarabine based therapy. 20 patients were evaluable and 2 were excluded (one received clofarabine as salvage for positive MRD and the other as systemic maintenance with CNS directed therapy for an isolated CNS relapse). Among evaluable pts, median age at time of Clofarabine based chemotherapy was 39 years (range 19-65) and 50% were males. Thirteen had B-ALL while 7 had T-ALL. Median leukocyte count was 6 x109 (0.2-28.7), hemoglobin 9.8 g/dL (7-12.9), platelet 65 x109 (12-493), peripheral blood blast 4% (0-88) and bone marrow blasts 80% (0-95) while five pts had extramedullary disease. Median number of prior regimens was 2 (1-7).. 8 (40%) pts were post allogeneic transplant Treatment and Response: 10 pts (50%) received clofarabine monotherapy, 7(35%) clofarabine and cytarabine, and 3 (15%) had clofarabine, etoposide and cyclophosphamide. Overall response rate (CR/CRi + PR) was 35%. Five (25%) achieved CR/CRi, and 2 achieved PR. Among those who achieved CR, 4 out 5 proceeded to further therapy; 2 to allogeneic stem cell transplant and two additional patients received donor lymphocyte infusion (DLI). One pt with PR also proceeded to allogeneic stem cell transplant. In comparative analysis, there were more males 6 (86%) vs 1(14%) in the responding arm (P = 0.014), otherwise the number of regimens prior to clofarabine, type of clofarabine regimen, transplant status, T vs B cell ALL, did not impact response. Median overall survival was 2.4 months (1.3-2.9) in non-responders vs. 12.8 months (3-27.4) in responders (P =0.0007) (Figure 1). All pts who proceeded to transplant or DLI relapsed with a median time to relapse of 6.4 (4.8-13.7) months. Toxicity: Rash/Hand Foot syndrome was observed in 3 pts (19%), Grade III-IV liver toxicity occurred in 4 (26%) with no permanent sequela. Opportunistic infection occurred in 3 pt (17%). Conclusion: Clofarabine based chemotherapy was a well-tolerated salvage regimen in heavily pretreated patients and was an effective bridge to definitive therapy in a significant proportion of cases. Prospective evaluation of these findings is warranted. Figure 1. Figure 1. Disclosures Al-Kali: Celgene: Research Funding.
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- 2015
20. Response to Hypomethylating Agents in Myelodysplastic Syndromes Based on WHO 2008 Subtypes and IPSS-R Stratification and Impact on Survival
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Moussab Damlaj, Michelle A. Elliott, Muhanad Hreh, Mrinal M. Patnaik, Hassan B. Alkhateeb, Aref Al-Kali, Mark R. Litzow, and William J. Hogan
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medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Immunology ,Azacitidine ,Decitabine ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Log-rank test ,Median follow-up ,Internal medicine ,Cohort ,medicine ,business ,Progressive disease ,Survival analysis ,medicine.drug - Abstract
Background: Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by cytopenias and a propensity to progress into acute myeloid leukemia in a subset of patients. Clinical trials which led to FDA approval of hypomethylating agents (HMAs) stratified patient's risk status per the IPSS. In 2008, WHO further categorized patients into different groups and the IPSS was revised into the IPSS-R. Therefore, there is a paucity of data regarding the response rates and clinical outcomes of HMA therapy when stratified per WHO subtype and IPSS-R. Goal: We carried this review to assess whether WHO subtypes or IPSS-R had a differential response with corresponding impact on survival. Methods: After IRB approval, all MDS pts who received hypomethylating agents (HMA) (azacitidine or decitabine) with available response data (2000-2014) were included. Clinical characteristics were obtained retrospectively. IPSS-R (Greenberg 2012) was used for risk stratification. Response assessment was based on IWGR 2006 criteria. Statistical comparisons were performed with the χ2 test for categorical variables and the Wilcoxon test for continuous variables. Survival analysis was based on the Kaplan-Meier method and log rank test. For all analyses, P ≤ 0.05 was considered statistically significant. Results: We identified 823 pt in our MDS database; among those that received HMA therapy 70 patients (pts) had evaluable response data. The median age at diagnosis was 67 years (31-85) and 49 (70%) were males. MDS subtypes per WHO 2008 classification were 31(44%) RAEB1/2, 26(37%) RCMD, 10(14%) MDS-U, 2(3%) RARS, and 1(1%) MDS 5q. Fifteen (33%) patients had secondary MDS. 23(32%) developed AML, and median time to leukemic transformation was 14 months (7.8-21). Median time to start HMA was 2.7 months (0-77). Median follow up from initial diagnosis was 20 months (3-118) at which time 22(31%) deaths were documented. A. Patient characteristics: Prior to HMA therapy median laboratory values included; Hemoglobin 9.6 g/dL (6.6-14.8), ANC 1.1 x1010 (0.01-16), Platelet 66 x1010 (4-937), peripheral blast % 0 (0-18), and bone marrow blast % 5 (0-17). IPSS-R for our cohort was as the following, 15(27%) Very high, 14(25%) high, 10(18%) intermediate 12(21%) low, and 5(9%) very low risk. B. HMA Response rates based on WHO subtype: We observed no significant difference in response (p = 0.6) when comparing response rate among different groups. Response rates per WHO subtype were as follows: i. RAEB: 7 (22%) pts achieved CR/Marrow CR, 1(3%) had HI/PR, 17(55%), and 6(20%) had stable disease (SD) and progressive disease (PD), respectively. ii. RCMD: 2 (8%) pts achieved CR/Marrow CR, 4(16%) had HI/PR, 12(46%), and 8(30%) had SD and PD, respectively. iii. MDS-U: 1 (10%) pt achieved CR/Marrow CR, 1(10%) had HI/PR, 6(60%), and 2(20%) had SD and PD, respectively. iv. MDS 5q/RARS: 1(33%) had SD, and the remaining three pts had PD. C. HMA Response rates based on IPSS-R: i. Very low: 1(20%) had HI/PR, 3(60%), and 1(20%) had SD. ii. Low: 2(17%) pts achieved CR/Marrow CR, 3(25%) had HI/PR, 4(33%), and 3(25%) had SD and PD, respectively. iii. Intermediate: 2 (20%) pts achieved CR/Marrow CR, 5(50%), and 3(30%) had SD and PD, respectively. iv. High: 2(14%) pts achieved CR/Marrow CR, 2(14%) had HI/PR, 7(50%), and 3(21%) had SD and PD, respectively. v. Very high: 1(7%) pts achieved CR/Marrow CR, 9(60%), and 5(33%) had SD and PD, respectively. Comparing responses among IPSS-R risk stratification groups, was not statistically significant (p = 0.49). We did not observe a difference in response rate when we further classified pts into low risk (very low, low & intermediate), and high risk (high, very high) (p = 0.27). D. Response effect on Survival: Overall survival was not statistically different among responders (CR/Marrow CR/HI &PR) and non-responder (SD & PD); 22.3 vs 14.7 months respectively (p = 0.21) (Figure1). Conclusion: Using contemporary MDS risk stratification and WHO classification was not predictive of response to hypomethylating agents. Responders did not seem to benefit from prolongation of survival. Given the small sample size in this cohort, this should be further explored in larger groups to identify if there are any potential subgroups that would benefit more from such therapy. Figure 1. Figure 1. Disclosures Al-Kali: Celgene: Research Funding.
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- 2015
21. The Role of Spleen Directed Therapy and Predictors of Outcomes with Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Primary Myelofibrosis and Splenomegaly
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Ruben A. Mesa, Shahrukh K. Hashmi, Mrinal M. Patnaik, Daniel K. Partain, Aref Al-Kali, Mark R. Litzow, William J. Hogan, Jeanne Palmer, Vivek Roy, James L. Slack, Moussab Damlaj, James M. Foran, Wilson I. Gonsalves, and Naseema Gangat
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medicine.medical_specialty ,Ruxolitinib ,business.industry ,medicine.medical_treatment ,Immunology ,Splenectomy ,Spleen ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Splenic artery ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Transplantation ,medicine.anatomical_structure ,medicine.artery ,Internal medicine ,medicine ,Myelofibrosis ,business ,Survival analysis ,medicine.drug - Abstract
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for primary myelofibrosis (PMF). Reduced intensity conditioning (RIC) allows otherwise ineligible patients to proceed with HSCT. Host factors in PMF such as bone marrow (BM) fibrosis, massive splenomegaly, and transfusion related allo-immunization increase the risk of engraftment failure, especially with RIC. Spleen directed therapy (SDT) is often used in PMF patients with splenomegaly to help with engraftment, however little data exists supporting this practice. This study was carried out to investigate the role for SDT and the predictors of outcomes with RIC HSCT for PMF. Methods :After IRB approval, the Mayo Clinic HSCT registry was queried for patients with PMF that underwent RIC allo-HSCT from 2005-2014. Disease and transplant related data were retrospectively abstracted and analyzed for HSCT related outcomes. SDT was defined as a therapeutic strategy with specific intent to overcome an enlarged spleen prior to HSCT and included splenectomy, splenic artery embolization, splenic irradiation, or JAK inhibitor therapy that was stopped Results :51 patients (67% males) with WHO defined PMF with palpable splenomegaly that underwent RIC allo-HSCT were included in the study; median age 57 years (range, 35-68). The median follow-up was 12.2 months, and at last follow up, 19 deaths (37%) and 4 relapses (8%) were documented. The median OS for the group was not reached (mean 34.2 months); 88% at 100 days and 60% at 2 years. 17 deaths were attributed to non-relapse mortality (NRM). There were 3 engraftment failures (6%). 32 patients (63%) developed acute GVHD (grades II-IV) and 24 patients (47%) developed chronic GVHD (all grades). Twenty-one patients (41%) received SDT; 10 (48%) splenectomy, 2 (9%) splenic irradiation, and 9 (43%) JAK inhibitor therapy (ruxolitinib). The SDT group had a median spleen size of 14.5 cm (range, 1-29 cm) below the left costal margin (LCM) and 13 patients (62%) with spleen size >10 cm below LCM, while the no SDT group had a median spleen size of 7 cm (range, 1-19 cm) and 12 patients (40%) with spleen size >10 cm below LCM; p = 0.01. Seven (64%) of 11 patients receiving splenic irradiation (n = 1) or JAK inhibitor therapy (n = 6) were eligible for IWG-MRT spleen response, and 2 (29%) responded (both in JAK inhibitor group). Of the remaining 5 patients, 2 had a response not meeting IWG-MRT criteria. There were no differences in age (p = 0.09), gender (p = 1.0), DIPSS + score (p = 0.35), or HCT-CI (p = 0.61) between the two groups. There was a statistically significant difference in engraftment failure, with all 3 engraftment failures occurring in the SDT group (2 splenectomy patients, 1 splenic irradiation patient; p = 0.02). Engraftment failures were not attributable to insufficient cell dose, donor specific antibodies, or identifiable host factors. The patient with engraftment failure who underwent splenic irradiation had persistent massive splenomegaly. There were similar outcomes with regards to relapse rates, NRM, and acute and chronic GVHD. In the SDT group, the median OS was 13.3 months; 81% at 100 days and 33% at 2 years. In the no SDT group, the median OS was not reached; 94% at 100 days and 68% at 2 years; p=0.13. In a univariate survival analysis that included age, gender, SDT, DIPSS+ score, HCT-CI, CMV status, ABO status, HLA matching, donor source, graft source, engraftment status, and acute and chronic GVHD, predictors of survival were engraftment failure (p = 0.02) and major/bidirectional ABO incompatibility (p = 0.02). Similar results were obtained when JAK inhibitor therapy was considered separately from other forms of SDT. In a multivariate analysis, engraftment failure (HR 8.2, 1.8-27.2; p = 0.01) and major/bidirectional ABO incompatibility (HR 4.1, 1.4-10.9; p = 0.009) retained independent prognostic significance. Discussion:In patients with PMF and splenomegaly, there was no demonstrable benefit from SDT. Predictors of post-HSCT survival included engraftment failure and major/bidirectional ABO incompatibility. These findings need validation in a larger cohort of patients. Disclosures Al-Kali: Celgene: Research Funding. Mesa:Gilead: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding.
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- 2015
22. A Case Of Refractory Autoimmune Hemolytic Anemia In a Patient With Digeorge Syndrome Treated Successfully With Plasma Exchange
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Chantal Séguin and Moussab Damlaj
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Hemolytic anemia ,medicine.medical_specialty ,Romiplostim ,business.industry ,Reticulocytosis ,medicine.medical_treatment ,Immunology ,Splenectomy ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Internal medicine ,medicine ,Rituximab ,Fresh frozen plasma ,medicine.symptom ,Autoimmune hemolytic anemia ,business ,Packed red blood cells ,medicine.drug - Abstract
Background warm auto-immune hemolytic anemia (AIHA) results from targeted antibodies towards the RBCs and can be secondary to certain diseases (auto-immune disease or malignancy), drugs, infections or may be idiopathic in nature. Patients with DiGeorge syndrome are vulnerable to auto-immune conditions secondary to thymic hypoplasia with an estimated incidence in one series of 8.5% (Tison, Nicholas et al. 2011). First line therapy of AIHA consists of corticosteroids with an anticipated response rate of 80% (Lechner and Jager 2010). Relapses are not uncommon and are treated with splenectomy or rituximab. Case we describe an unusual case of an 18 year old female with DiGeorge syndrome who presented with AIHA refractory to usual modes of therapy. In this case, she was diagnosed with immune thrombocytopenia purpura (ITP) at age 13 with multiple relapses following successful standard therapy. Eventually, she was managed with monthly IVIG (intravenous immune globulin) infusions and thrombopoietin analogue romiplostim, maintaining her platelet count between 50 - 100 x 10 9/L. At 18 years of age she presented with severe anemia (Hb 55 g/L), positive hemolytic markers and a positive direct Coombs (3+ IgG and negative C3). A diagnosis of AIHA was established, and patient was started on prednisone (1-1.5 mg/kg) with transfusion support. Due to lack of response, high dose IVIG was administered followed by weekly rituximab 375 mg/m2. Due to hemodynamic instability, Rituximab was interrupted after the second dose. The finding of ineffective erythropoiesis evident by inappropriately low reticulocytosis prompted a bone marrow aspirate and biopsy. Aside from erythroid hyperplasia (M:E ratio of 1:4) with a left shift, no other anomaly was noted. PNH and G6PD screen was negative. The refractory nature of her AIHA required that the patient undergo a splenectomy. Hemolytic markers transiently improved however, within a few days, her hemolytic picture worsened and patient remained transfusion dependent. Given deterioration of her clinical status, decision was made to proceed with plasma exchange (PE) daily for 5 sessions with fresh frozen plasma fluid replacement. 24 hours following her first exchange session, there was a steady improvement of her hemolytic markers and patient became transfusion independent (Fig 1). Hb normalized eight days following the last exchange session. Additionally, platelets normalized following the splenectomy and she no longer required romiplostim. At her last follow up, 280 days following her last session of PE, Her Hb is within normal limits and hemolytic markers continue to be negative. During her admission, she required 42 bags of PRBCs (Fig 2). Conclusion This is the first reported case of a DiGeorge syndrome presenting with refractory AIHA successfully treated with PE. We conclude in this case that the combination of splenectomy followed by PE successfully controlled her hemolysis. Thus, we hope this report will give an additional insight on the use of PE as a therapeutic modality in refractory cases. Disclosures: No relevant conflicts of interest to declare.
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- 2013
23. Impact Of Dedicated CML Clinic On The Outcome Of Patients With Newly Diagnosed CML: Experience Of a Single Canadian Center
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Moussab Damlaj, Yury Monczak, and Sarit Assouline
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Pediatrics ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Discontinuation ,Log-rank test ,Clinical trial ,Imatinib mesylate ,Median follow-up ,Cohort ,Medicine ,Medical history ,business ,Sokal Score - Abstract
Background The outcome of patients with CML has improved significantly since the introduction of imatinib (O’Brien et al 2003). In the landmark IRIS trial, the rate of complete cytogenetic response (CCyR) was 69% by 12 months and 87% by 60 months and 7% of patients progressed to accelerated or blast crisis (Druker et al 2006). Multiple studies show that bcr-abl transcript level at 3 months can predict outcome and can be used to guide therapeutic strategies (Marin et al 2012). Additionally, patients achieving CCyR within 2 years on imatinib were projected to have a normal life expectancy (Gambacorti-Passerini et al 2011). Surprisingly, a survey of the CML World Registry involving over 1800 patients revealed that only 10% and 15% of patients had cytogenetic and molecular evaluation at 3 months, respectively. At our institution, we have a dedicated, multidisciplinary CML clinic with RT-PCR assay in house. We sought to determine how the outcome of our CP-CML patients, followed every 3 months and according to the ELN (European Leukemia Network) guidelines compares to clinical trial results. Methods Patients with CP-CML treated with imatinib first line between January 2004 and December 2012 were included in this retrospective chart review. Diagnosis was based on bone marrow aspirate with blast count and cytogenetic and/or FISH, and bcr/abl transcript RT-PCR using the IS method. Patients presenting in AP or BP, or those having previous lines of therapy except hydroxyurea or anagrelide were excluded. Baseline demographic, medical history, Sokal score at presentation and monitoring frequency for hematologic, cytogenetic and molecular responses were extracted. Definitions of cytogenetic and molecular responses were in accordance with the ELN guidelines. Cumulative rates of cytogenetic and molecular responses were estimated using the Kaplan–Meier method. Data for patients not achieving an adequate response were censored at the last follow up visit. Differences between groups were calculated by log rank test. The study received IRB approval at our institution. Results 55 eligible patients were identified. Median age was 53 years (17-92) and 33 (60%) were male. Distribution of Sokal score was low in 28 (50.9%), intermediate in 22 (40%) and high in 5 (9%). Median follow up duration was 53 months (range 3-106). Seven patients (12.7%) required switching to second line TKI, six for inadequate response, one for intolerance and one patient required switch to third line TKI for inadequate response. Molecular testing at 3 and 18 months post start of imatinib was performed in 48 pts (87.3%) and 53 (96.4%), respectively. At 12 months, 49 (89.1%) had cytogenetic evaluation. Estimated rates of CCyR at 6 months, 12 months, 18 months and 24 months were 46.6%, 69.2%, 78.7% and 88.2%, respectively. Estimated rates of MMR at 6 months, 12 months, 18 months and 24 months were 23.9%, 41.2%, 58.8% and 70.6%, respectively. When stratified by Sokal score, rate of CCyR at 12 months was 82.1%, 72.7% and 60% (p 0.8840) for low, intermediate and high scores, respectively. Conclusions CP-CML patients followed in a dedicated CML clinic receive more rigorous follow-up and monitoring and achieve response rates similar to that of clinical trials. Additionally, in this small cohort of patients, discontinuation rate of imatinib was substantially lower than previously reported. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
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