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Background: One proposed mechanism of extracorporeal photopheresis (ECP) in reducing chronic graft-versus-host disease (cGVHD) is alteration in numbers of circulating dendritic cells (DCs). This hypothesis was tested by correlating numbers of DC precursors and T cells in the blood before and during ECP therapy with response of cGVHD.Study Design and Methods: Twenty-five patients with cGVHD were treated with ECP. Data were collected with emphasis on blood cellular markers, clinical response to ECP, and overall survival.Results: Fourteen patients (56%) responded and had better 2-year survival than nonresponders (88% vs. 18%, p=0.003). Responders had higher baseline circulating myeloid DC (mDC) and plasmacytoid DC precursors and CD4+ and CD8+ T cells compared with nonresponders. Receiver operating characteristic curve analyses showed that the best baseline cutoff values to predict response to ECP were mDC counts of 3.7 cells/µL (79% sensitivity, 82% specificity) and CD4+ T-cell counts of 104 cells/µL (71% sensitivity, 82% specificity). CD4+ T cells declined in responders over time, but not in nonresponders, and no significant changes were seen in CD8 T-cell or DC numbers over a 12-month period in responder or nonresponder groups.Conclusions: Higher baseline numbers of circulating DCs and T cells may predict clinical response to ECP in patients with cGVHD. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the safety and efficacy of allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning in patients with severe systemic sclerosis (SSc). METHODS: Eligibility criteria for the study included SSc patients with features indicative of a poor prognosis. The myeloablative conditioning regimen included busulfan, cyclophosphamide, and antithymocyte globulin. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and methotrexate. Bone marrow was transplanted from HLA-identical siblings. RESULTS: Two patients with diffuse cutaneous SSc and lung involvement who were refractory to conventional immunosuppressive treatment were enrolled in the study. In patient 1, there were no complications related to the conditioning regimen, and GVHD did not develop after transplantation. At 5 years after HCT, there was nearly complete resolution of the scleroderma and marked improvement in physical functioning. Internal organ function improved (lung) or remained stable. On examination of serial skin biopsy samples, there was resolution of the dermal fibrosis. Patient 2 experienced skin toxicity from the conditioning regimen and hypertensive crisis that was likely related to high-dose corticosteroids given for treatment of GVHD. Although this patient experienced an improvement in scleroderma and overall functioning, a fatal opportunistic infection developed 17 months after HCT. CONCLUSION: Allogeneic HCT may result in sustained remission of SSc. GVHD and opportunistic infections are the major risks associated with allogeneic HCT for SSc, as for allogeneic HCT in general. [ABSTRACT FROM AUTHOR]

Background: Increasing indications for cellular therapy collections have stressed our healthcare system, with autologous collections having a longer than desired wait time until apheresis collection. This quality improvement initiative was undertaken to accommodate more patients within existing resources., Study Design and Methods: Patients with multiple myeloma who underwent autologous peripheral blood stem cell collection from October 2022 to April 2023 were included. Demographic, mobilization, laboratory, and apheresis data were retrospectively collected from the medical record., Results: This cohort included 120 patients (49.2% male), with a median age of 60 years. All received G-CSF and 95% received pre-emptive Plerixafor approximately 18 hours pre-collection. Most (79%) had collection goals of at least 8 × 10 6 /kg CD34 cells, with 63% over 70 years old having this high collection goal (despite 20 years of institutional data showing <1% over 70 years old have a second transplant). With collection efficiencies of 55.9%, 44% of patients achieved their collection goal in a single day apheresis collection. A platelet count <150 × 10 3 /μL on the day of collection was a predictor for poor mobilization; among 27 patients with a low baseline platelet count, 17 did not achieve the collection goal and 2 failed to collect a transplantable dose., Conclusions: With minor collection goal adjustments, 15% of all collection appointments could have been avoided over this 6-month period. Other strategies to accommodate more patients include mobilization modifications (Plerixafor timing or substituting a longer acting drug), utilizing platelet counts to predict mobilization, and modifying apheresis collection volumes or schedule templates., (© 2024 Wiley Periodicals LLC.)

Background: Hospital acquired infections pose a significant risk for patients undergoing hematopoietic stem cell transplantation. Horizontal transfer of antimicrobial resistance genes contributes to prevalence of multidrug-resistant infections in this patient population., Methods: At an academic bone marrow transplantation center, we performed whole genome DNA sequencing (WGS) on commonly used physician items, including badges, stethoscopes, soles of shoes, and smart phones from 6 physicians. Data were analyzed to determine antimicrobial resistance and virulence factor genes., Results: A total of 1,126 unique bacterial species, 495 distinct bacteriophages, 91 unique DNA viruses, and 175 fungal species were observed. Every item contained bacteria with antibiotic and/or antiseptic resistance genes. Stethoscopes contained greatest frequency of antibiotic resistance and more plasmid-carriage of antibiotic resistance., Discussion and Conclusions: These data indicate that physician examination tools and personal items possess potentially pathogenic microbes. Infection prevention policies must consider availability of resources to clean physical examination tools as well as provider awareness when enacting hospital policies. Additionally, the prevalence of antimicrobial resistance genes (eg, encoding resistance to aminoglycosides, β-lactams, and quinolones) reinforces need for antimicrobial stewardship, including for immunocompromised patients. Further research is needed to assess whether minute quantities of microbes on physician objects detectable by WGS represents clinically significant inoculums for immunocompromised patients., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

Purpose: Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths., Methods: In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place., Results: Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%., Conclusion: Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes., Competing Interests: Conflicts of Interest Statement:Accepted on September 22, 2020. Martha L. ArellanoConsulting or Advisory Role: Gilead SciencesResearch Funding: Cephalon (Inst) Manila GaddhConsulting or Advisory Role: Agios, PfizerResearch Funding: MedImmune (Inst), Apellis Pharmaceuticals (Inst), Celgene (Inst), Janssen Pharmaceuticals (Inst), Daiichi Sankyo (Inst)Travel, Accommodations, Expenses: Agios, Pfizer Amy A. LangstonResearch Funding: Chimerix (Inst), Astellas Pharma (Inst), Incyte (Inst), Takeda Pharmaceuticals (Inst), Jazz Pharmaceuticals (Inst), Kadmon (Inst), Novartis (Inst) Leonard T. HeffnerSpeakers’ Bureau: Kite PharmaResearch Funding: Pharmacyclics (Inst), Genentech (Inst), Kite Pharma (Inst), ADC Therapeutics (Inst), Astex Pharmaceuticals (Inst) Elliott F. WintonResearch Funding: Incyte, Sierra Oncology, Samus Therapeutics, Blueprint Medicines Asim PatiHonoraria: Aptitude Health, ITA Group, AstraZeneca, Bristol Myers Squibb, BeiGene Michael R. GrunwaldStock and Other Ownership Interests: MedtronicHonoraria: OncLive, Med Learning Group, Physicians’ Education ResourceConsulting or Advisory Role: Incyte, Cardinal Health, Pfizer, Agios, AbbVie, Trovagene, Daiichi Sankyo, Bristol-Myers Squibb, Premier, Astellas PharmaResearch Funding: Janssen Pharmaceuticals (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Genentech (Inst), Roche (Inst)Travel, Accommodations, Expenses: Amgen, Incyte Jonathan M. GerberPatents, Royalties, Other Intellectual Property: US Patent No. 9,012,215, US Patent No. 10,222,376 Jorge CortesConsulting or Advisory Role: Bristol Myers Squibb, BioLineRx, Novartis, Pfizer, Amphivena Therapeutics, Daiichi Sankyo, Bio-Path Holdings, Astellas Pharma, Takeda Pharmaceuticals, Jazz PharmaceuticalsResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Immunogen (Inst), Sun Pharma (Inst), Takeda Pharmaceuticals (Inst), Merus (Inst), Daiichi Sankyo (Inst), Tolero Pharmaceuticals (Inst), Trovagene (Inst), Jazz Pharmaceuticals (Inst) Robert K. StuartConsulting or Advisory Role: Ono PharmaceuticalResearch Funding: Ono Pharmaceutical, Agios, Astellas Pharma Vamsi K. KotaConsulting or Advisory Role: Pfizer, Novartis, AbbVieNo other potential conflicts of interest were reported.

The oncology community is concerned that patients with cancer will be unfairly classified in pandemic allocation guidance. Past guidance either excluded patients with metastatic cancer from consideration or categorized them as having a survival of less than 1 year. Given recent improvements in treatments, we recommend that the prognosis of an individual patient with cancer be determined with input from a cancer specialist or, if this is impractical, that the presence of active metastatic solid cancer or relapsed hematologic malignancy is graded as a major comorbidity, with a likelihood that survival will be less than 5 years; severe limitation in physical functioning (3 or 4 on the Eastern Cooperative Oncology Group performance status) would define a patient with advanced cancer as having a severe comorbidity, with a likelihood of less than 1 year of survival. Cancer may be the "Emperor of all Maladies," but it is no longer a certain death sentence., (© 2020 AlphaMed Press.)

Background: Both gemcitabine and bendamustine have been evaluated in patients with recurrent/refractory Hodgkin lymphoma but to the authors' knowledge not as a doublet. The authors completed a phase 1/2 trial to identify the optimal dose and frequency of administration and to assess the efficacy of this combination in patients with recurrent/refractory Hodgkin lymphoma., Methods: Patients were treated up to a maximum dose of gemcitabine (1000 mg/m 2 on day 1) and bendamustine (120 mg/m 2 on days 1 and 2), which was determined to be the recommended phase 2 dose, administered every 21 days for up to 6 cycles. Patients could discontinue study therapy after 2 cycles to proceed with autologous or allogeneic stem cell transplantation., Results: No dose-limiting toxicities were identified, but 4 patients experienced grade 3 to 5 pulmonary adverse events (toxicity was graded according to Common Terminology Criteria for Adverse Events [version 4]). A total of 26 patients were enrolled having completed a median of 4 prior lines of therapy (range, 1-7 lines), including 13 patients at the recommended phase 2 dose, in whom the overall response rate was 69% and the complete response rate was 46%. The median progression-free survival for the phase 2 patients was 11 months (95% CI, 3 months to not reached), and the median overall survival for this group had not been reached at the time of last follow-up (95% CI, 4 months to not reached)., Conclusions: This doublet was found to be tolerable and effective, but patients must be monitored closely for pulmonary toxicity. The authors currently are evaluating this doublet in combination with nivolumab., (© 2019 American Cancer Society.)

Relapse of chronic lymphocytic leukemia (CLL) after allogeneic hematopoietic cell transplantation (HCT) remains a clinical challenge. We studied in a phase II trial whether the addition of peri-transplant rituximab would reduce the relapse risk compared with historical controls (n = 157). Patients (n = 55) received fludarabine and low-dose total body irradiation combined with rituximab on days -3, + 10, + 24, + 36. Relapse rate at 3 years was significantly lower among rituximab-treated patients versus controls (17% versus 31%; P = 0.04). Overall survival (OS), progression-free survival (PFS) and nonrelapse mortality (NRM) were statistically similar: (53% versus 50%; P = 0.8), (44% versus 42%; P = 0.63), and (38% versus 28%; P = 0.2), respectively. In multivariate analysis, rituximab treatment was associated with lower relapse rates both in the overall cohort [hazard ratio (HR): 0.34, P = 0.006] and in patients with high-risk cytogenetics (HR: 0.21, P = 0.0003). Patients with no comorbidities who received rituximab conditioning had an OS rate of 100% and 75% at 1 and 3 years, respectively, with no NRM. Peri-transplant rituximab reduced relapse rates regardless of high-risk cytogenetics. HCT is associated with minimal NRM in patients without comorbidities and is a viable option for patients with high-risk CLL. Clinical trial information: NCT00867529.

Background: Acute graft-versus-host-disease (GVHD) after non-myeloablative human leucocyte antigen (HLA)-matched, unrelated donor, allogeneic haemopoietic stem cell transplantation (HSCT) is associated with considerable morbidity and mortality. This trial aimed to evaluate the efficacy of adding sirolimus to the standard cyclosporine and mycophenolate mofetil prophylaxis therapy for preventing acute GVHD in this setting., Methods: This multicentre, randomised, phase 3 trial took place at nine HSCT centres based in the USA, Denmark, and Germany. Eligible patients were diagnosed with advanced haematological malignancies treatable by allogeneic HSCT, had a Karnofsky score greater than or equal to 60, were aged older than 50 years, or if they were aged 50 years or younger, were considered at high risk of regimen-related toxicity associated with a high-dose pre-transplantation conditioning regimen. Patients were randomly allocated by an adaptive randomisation scheme stratified by transplantation centre to receive either the standard GVHD prophylaxis regimen (cyclosporine and mycophenolate mofetil) or the triple-drug combination regimen (cyclosporine, mycophenolate mofetil, and sirolimus). Patients and physicians were not masked to treatment. All patients were prepared for HSCT with fludarabine (30 mg/m 2 per day) 4, 3, and 2 days before receiving 2 or 3 Gy total body irradiation on the day of HSCT (day 0). In both study groups, 5·0 mg/kg of cyclosporine was administered orally twice daily starting 3 days before HSCT, and (in the absence of GVHD) tapered from day 96 through to day 150. In the standard GVHD prophylaxis group, 15 mg/kg of mycophenolate mofetil was given orally three times daily from day 0 until day 30, then twice daily until day 150, and (in the absence of GVHD) tapered off by day 180. In the triple-drug group, mycophenolate mofetil doses were the same as in the standard group, but the drug was discontinued on day 40. Sirolimus was started 3 days before HSCT, taken orally at 2 mg once daily and adjusted to maintain trough concentrations between 3-12 ng/mL through to day 150, and (in the absence of GVHD) tapered off by day 180. The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD at day 100 post-transplantation. Secondary endpoints were non-relapse mortality, overall survival, progression-free survival, cumulative incidence of grade 3-4 acute GVHD, and cumulative incidence of chronic GVHD. Efficacy and safety analyses were per protocol, including all patients who received conditioning treatment and underwent transplantation. Toxic effects were measured according to the Common Terminology Criteria for Adverse Events (CTCAE). The current study was closed prematurely by recommendation of the Data and Safety Monitoring Board on July 27, 2016, after 168 patients received the allocated intervention, based on the results of a prespecified interim analysis for futility. This study is registered with ClinicalTrials.gov, number NCT01231412., Findings: Participants were recruited between Nov 1, 2010, and July 27, 2016. Of 180 patients enrolled in the study, 167 received the complete study intervention and were included in safety and efficacy analyses: 77 patients in the standard GVHD prophylaxis group and 90 in the triple-drug group. At the time of analysis, median follow-up was 48 months (IQR 31-60). The cumulative incidence of grade 2-4 acute GVHD at day 100 was lower in the triple-drug group compared with the standard GVHD prophylaxis group (26% [95% CI 17-35] in the triple-drug group vs 52% [41-63] in the standard group; HR 0·45 [95% CI 0·28-0·73]; p=0·0013). After 1 and 4 years, non-relapse mortality increased to 4% (95% CI 0-9) and 16% (8-24) in the triple-drug group and 16% (8-24) and 32% (21-43) in the standard group (HR 0·48 [0·26-0·90]; p=0·021). Overall survival at 1 year was 86% (95% CI 78-93) in the triple-drug group and 70% in the standard group (60-80) and at 4 years it was 64% in the triple-drug group (54-75) and 46% in the standard group (34-57%; HR 0·62 [0·40-0·97]; p=0·035). Progression-free survival at 1 year was 77% (95% CI 68-85) in the triple-drug group and 64% (53-74) in the standard drug group, and at 4 years it was 59% in the triple-drug group (49-70) and 41% in the standard group (30-53%; HR 0·64 [0·42-0·99]; p=0·045). We observed no difference in the cumulative incidence of grade 3-4 acute GVHD (2% [0-5] in the triple-drug group vs 8% [2-14] in the standard group; HR 0·55 [0·16-1·96]; p=0·36) and chronic GVHD (49% [39-59] in triple-drug group vs 50% [39-61] in the standard group; HR 0·94 [0·62-1·40]; p=0·74). In both groups the most common CTCAE grade 4 or higher toxic effects were pulmonary., Interpretation: Adding sirolimus to cyclosporine and mycophenolate mofetil resulted in a significantly lower proportion of patients developing acute GVHD compared with patients treated with cyclosporine and mycophenolate mofetil alone. Based on these results, the combination of cyclosporine, mycophenolate mofetil, and sirolimus has become the new standard GVHD prophylaxis regimen for patients treated with non-myeloablative conditioning and HLA-matched unrelated HSCT at the Fred Hutchinson Cancer Research Center., Funding: National Institutes of Health., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

With the exception of the minority of patients with acute myelocytic leukemia who are considered potentially cured by chemotherapy, hematopoietic cell transplantation (HCT) has traditionally been the recommended approach for those patients achieving complete remission who meet the criteria for HCT and have an appropriate stem-cell donor. This decision has become more complex with the discovery of new risk factors, such as genomic abnormalities and minimal residual disease, especially in younger populations. Patients younger than age 60 years who are considered fit and who do not harbor poor prognostic features are felt still to have a high likelihood of cure without having to undergo HCT. Here, we discuss the role that these emerging risk factors play in the decision to undergo transplantation, but emphasize that this remains a decision made jointly by the patient, the treating hematologist, and the transplant physician.

Background: Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains., Methods: Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs)., Results: From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57-75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses., Conclusions: Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified., Clinical Trials Registration: NCT01611974., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are established components in the treatment of multiple myeloma; however, undergoing transplantation usually requires hematopoietic support, which poses a challenge among patients who are unwilling to receive blood products. Most transplant centers decline HDT/ASCT to these patients because of safety concerns. Here, the authors' institutional data on safety, engraftment parameters, and survival outcomes after bloodless ASCT (BL-ASCT) are examined among patients with myeloma. This retrospective case-control study included patients who underwent BL-ASCT and Transfusion-supported ASCT (TS-ASCT) at Emory University Hospital between August 2006 and August 2016. In total, 24 patients who underwent BL-ASCT and 70 who underwent TS-ASCT were included. The median time for neutrophil engraftment, platelet engraftment and the median length of hospital stay all were equivalent for both groups. There were no transplant-related cardiovascular complications or mortality in either the BL-ASCT group or the TS-ASCT group. The median progression-free survival was 36 months and 44 months in the BL-ASCT and TS-ASCT groups, respectively (P = .277), and the median OS was not reached in either group at a median follow-up of 59 months after ASCT (P = .627). There was no transplant-related mortality at the 100-day or 1-year mark in either group. BL-ASCT is safe and feasible; transplant-related mortality, cardiovascular and hematologic complications are similar to those associated with TS-ASCT. Furthermore, BL-ASCT can yield similar engraftment and survival parameters comparable to those observed with TS-ASCT., (© 2018 American Cancer Society.)

Purpose: To provide an updated joint ASCO/Infectious Diseases Society of America (IDSA) guideline on antimicrobial prophylaxis for adult patients with immunosuppression associated with cancer and its treatment., Methods: ASCO and IDSA convened an update Expert Panel and conducted a systematic review of relevant studies from May 2011 to November 2016. The guideline recommendations were based on the review of evidence by the Expert Panel., Results: Six new or updated meta-analyses and six new primary studies were added to the updated systematic review., Recommendations: Antibacterial and antifungal prophylaxis is recommended for patients who are at high risk of infection, including patients who are expected to have profound, protracted neutropenia, which is defined as < 100 neutrophils/µL for > 7 days or other risk factors. Herpes simplex virus-seropositive patients undergoing allogeneic hematopoietic stem-cell transplantation or leukemia induction therapy should receive nucleoside analog-based antiviral prophylaxis, such as acyclovir. Pneumocystis jirovecii prophylaxis is recommended for patients receiving chemotherapy regimens that are associated with a > 3.5% risk for pneumonia as a result of this organism (eg, those with ≥ 20 mg prednisone equivalents daily for ≥ 1 month or on the basis of purine analog usage). Treatment with a nucleoside reverse transcription inhibitor (eg, entecavir or tenofovir) is recommended for patients at high risk of hepatitis B virus reactivation. Recommendations for vaccination and avoidance of prolonged contact with environments that have high concentrations of airborne fungal spores are also provided within the updated guideline. Additional information is available at www.asco.org/supportive-care-guidelines .

Inhibition of the Janus-associated kinases (JAK) with ruxolitinib (RUX) reduces graft-versus-host disease (GVHD) in preclinical and clinical models. In total 19 allograft recipients with moderate/severe steroid-dependent chronic GVHD received RUX as ≥2nd line salvage. RUX was well tolerated, and led to complete/partial resolution of oral (92/7%), cutaneous (82/0%), hepatic (71/28%), gastro-intestinal (75/17%), musculoskeletal (33/67%), pulmonary (0/80%), scleroderma (0/75%), vaginal (0/75%), and ocular (0/100%) chronic GVHD. Overall 18 achieved partial response and 1 complete response according to NIH Consensus Criteria. Responses occurred early and were sustained which enabled discontinuation (68%) or reduction of steroids to physiologic doses (21%). We conclude that RUX is an effective steroid-sparing agent in chronic GVHD.

Purpose To provide an updated joint ASCO/Infectious Diseases Society of American (IDSA) guideline on outpatient management of fever and neutropenia in patients with cancer. Methods ASCO and IDSA convened an Update Expert Panel and conducted a systematic review of relevant studies. The guideline recommendations were based on the review of evidence by the Expert Panel. Results Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. Recommendation Clinical judgment is recommended when determining which patients are candidates for outpatient management, using clinical criteria or a validated tool such as the Multinational Association of Support Care in Cancer risk index. In addition, psychosocial and logistic considerations are outlined within the guideline. The panel continued to endorse consensus recommendations from the previous version of this guideline that patients with febrile neutropenia receive initial doses of empirical antibacterial therapy within 1 hour of triage and be monitored for ≥ 4 hours before discharge. An oral fluoroquinolone plus amoxicillin/clavulanate (or clindamycin, if penicillin allergic) is recommended as empirical outpatient therapy, unless fluoroquinolone prophylaxis was used before fever developed. Patients who do not defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen should be re-evaluated and considered as candidates for inpatient treatment. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

More than 90% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receive red blood cell (RBC) or platelet transfusions in the peritransplantation period. We tested the hypothesis that transfusions are associated with the development of severe (grade III-IV) acute graft-versus-host disease (aGVHD) or mortality after allo-HSCT in a retrospective study of 322 consecutive patients receiving an allogeneic bone marrow or granulocyte colony-stimulating factor-mobilized blood stem cell graft for a hematologic malignancy. Counting transfused RBC and platelet units between day -7 pretransplantation and day +27 post-transplantation, but excluding transfusions administered after a diagnosis of aGVHD, yielded medians of 5 RBC units and 2 platelet units transfused. Sixty-three patients (20%) developed a maximal grade III-IV aGVHD with onset up to day +150 post-transplantation (median aGVHD onset of 28 days). HLA mismatch (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7; P = .01), and transfusion of more than the median number of RBC units (HR, 2.1; 95% CI, 1.1 to 3.7; P = .02) were independently associated with greater risk of grade III-IV aGVHD in a multivariable analysis model. Disease risk strata (HR, 1.7; 95% CI, 1.2 to 2.4 for high risk versus low risk; P = .005) and transfusion of more than the median number of RBC units (HR, 1.4; 95% CI, 1.0 to 2.0; P = .054) were independently associated with inferior overall survival. These data support our hypothesis that peritransplantation RBC transfusions are associated with the risk of developing severe aGVHD and worse overall survival following allo-HSCT, and suggest that strategies to reduce routine RBC transfusion may favorably reduce the incidence and severity of GVHD., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: To the authors' knowledge, the optimal frequency of monitoring after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) has not been established. Data regarding the discontinuation of second-generation TKIs used in first-line treatment or after the failure of first-line treatment with TKIs are limited. Herein, the authors report real-world experience with "reduced frequency" molecular monitoring in patients with CML in all phases who discontinued treatment with imatinib, dasatinib, or bosutinib., Methods: The records of patients who discontinued TKIs were reviewed. Patients who discontinued TKIs were monitored prospectively on an intended schedule of monthly blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 for 3 months, quarterly for 12 months, and every 6 months thereafter until loss of major molecular response (MMR). After loss of MMR, the TKI that previously was discontinued was reinitiated., Results: Between January 2010 and September 2015, a total of 24 patients in chronic (21 patients), accelerated (2 patients), and lymphoid blast (1 patient) phase discontinued imatinib (16 patients), dasatinib (5 patients), or bosutinib (3 patients) used in the front-line treatment or beyond. Blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 was performed 1.3 ± 0.7 times within the first 3 months (24 patients) and 2.7 ± 1.4 times in the following 12 months (18 patients). With a median follow-up of 36.5 months (range, 3.2-67.4 months), the probabilities of treatment-free remission at 1 year and 2 years were 65.7% (95% confidence interval, 55.8%-75.6%) and 59.7% (95% confidence interval, 49.1%-70.3%), respectively. Loss of MMR was observed in 9 patients at a median of 2.8 months (range, 1.8-14.2 months) after discontinuation of TKIs., Conclusions: With the limitations of a small sample size, the results of the current study demonstrate that less frequent monitoring of BCR-ABL1 does not appear to affect outcomes, and that discontinuation of TKIs used as first-line treatment or beyond after resistance or intolerance to first-line treatment appears feasible. Cancer 2017;123:2482-88. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Mantle cell lymphoma is a relatively rare malignancy, comprising fewer than 10% of all non-Hodgkin lymphomas. It is a heterogeneous disease, and although most patients experience an aggressive clinical course, some have a more indolent disease and may not require immediate therapy. There are currently few reliable prognostic markers, making it difficult to accurately predict which patients require early intensive treatment. We argue that consolidative autologous stem cell transplantation in first remission remains the standard of care for the young and fit patient population, based on long-term data from phase II and III trials demonstrating that early transplantation extends both progression-free and overall survival. Novel targeted agents are currently being investigated in both the upfront and relapse settings, but to date there are few data to suggest durable treatment responses that compare favorably with results of transplantation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Hematopoietic stem cell transplant (HSCT) recipients represent a high-risk group for developing Clostridium difficile (CD) infection (CDI). We aimed to identify specific risk factors for CDI in an HSCT patient population during the peritransplant period., Methods: We performed a case-control study within a cohort of HSCT patients who received a transplant from November 2010 to March 2013. Cases had a clinical presentation compatible with CDI and a positive stool sample Xpert ® C. difficile test. Controls were CDI negative and matched on age, gender, and transplant type. Peritransplant period was defined as -30 days or time of stem cell mobilization maneuver to 30 days post transplant in autologous SCT or 90 days post transplant in allogeneic SCT., Results: Of 781 HSCTs performed during the study period, 650 (83.2%) had a stool sample submitted for CD testing. Eight-six (13.2%) cases with CDI were identified. Most of the cases were diagnosed within a week after transplantation (median of 5 days). In adjusted analysis, prior hospitalization (odds ratio [OR]: 2.01, 95% confidence interval [CI] 1.2-3.36), prior cephalosporin administration (OR 2.72, 95% CI: 1.54-4.83), and prior chemotherapy (OR: 3.26, 95% CI: 1.92-5.5) were significantly associated with CDI., Conclusions: Hospitalization, and prior antibiotic and chemotherapy use are risk factors that are not easily modifiable, which emphasizes the need to start investigating preventive or prophylactic strategies in this high-risk population., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: The effect of post-transplant maintenance tyrosine kinase inhibitors (TKIs) on the outcomes of allogeneic hematopoietic stem cell transplantation in high-risk Philadelphia chromosome-positive (Ph(+)) leukemia remains unknown., Patients and Methods: A retrospective analysis that included allograft recipients with accelerated phase and blast phase chronic myeloid leukemia or Ph(+) acute lymphoblastic leukemia who had received post-transplant maintenance TKI therapy from 2004 to 2014., Results: A total of 26 patients, 9 with accelerated phase/blast phase CML and 17 with Ph(+) acute lymphoblastic leukemia, received maintenance post-transplant therapy with imatinib, dasatinib, nilotinib, or ponatinib. The TKI was selected according to the pretransplantation TKI response, anticipated toxicities, and ABL1 domain mutations, when present. Newer generation TKIs were initiated at a ≥ 50% dose reduction from the standard pretransplantation dosing to limit the toxicities and avoid therapy interruptions. TKIs were started a median of 100 days (range, 28-238 days) after transplantation and were administered for a median of 16 months (range, 8 days to 105 months). Eight patients discontinued therapy because of adverse events. With a median follow-up of 3.6 years (range, 4 months to 8.7 years), the 5-year relapse-free survival rate was 61%. All 3 patients who developed a relapse underwent successful salvage treatment and remained disease-free. The 5-year overall survival rate was 78%., Conclusion: Maintenance TKI therapy after transplantation is feasible and might reduce the incidence of relapses and improve outcomes after allogeneic hematopoietic stem cell transplantation for patients with high-risk Ph(+) leukemia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Infection is a major complication of hematopoietic cell transplantation. Prolonged neutropenia and graft-versus-host disease are the 2 major complications with an associated risk for infection, and these complications differ according to the graft source. A phase 3, multicenter, randomized trial (Blood and Marrow Transplant Clinical Trials Network [BMT CTN] 0201) of transplantation of bone marrow (BM) versus peripheral blood stem cells (PBSC) from unrelated donors showed no significant differences in 2-year survival between these graft sources. In an effort to provide data regarding whether BM or PBSC could be used as a preferential graft source for transplantation, we report a detailed analysis of the infectious complications for 2 years after transplantation from the BMT CTN 0201 trial. A total of 499 patients in this study had full audits of infection data. A total of 1347 infection episodes of moderate or greater severity were documented in 384 (77%) patients; 201 of 249 (81%) of the evaluable patients had received a BM graft and 183 of 250 (73%) had received a PBSC graft. Of 1347 infection episodes, 373 were severe and 123 were life-threatening and/or fatal; 710 (53%) of these episodes occurred on the BM arm and 637 (47%) on the PBSC arm, resulting in a 2-year cumulative incidence 84.7% (95% confidence interval [CI], 79.6 to 89.8) for BM versus 79.7% (95% CI, 73.9 to 85.5) for PBSC, P = .013. The majority of these episodes, 810 (60%), were due to bacteria, with a 2-year cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively (P = .003). The cumulative incidence of bloodstream bacterial infections during the first 100 days was 44.8% (95% CI, 38.5 to 51.1) for BM versus 35.0% (95% CI, 28.9 to 41.1) for PBSC (P = .027). The total infection density (number of infection events/100 patient days at risk) was .67 for BM and .60 for PBSC. The overall infection density for bacterial infections was .4 in both arms; for viral infections, it was .2 in both arms; and for fungal/parasitic infections, it was .04 and .05 for BM and PBSC, respectively. The cumulative incidence of infection before engraftment was 47.9% (95% CI, 41.5 to 53.9) for BM versus 32.8% (95% CI, 27.1 to 38.7) for PBSC (P = .002), possibly related to quicker neutrophil engraftment using PBSC. Infections remain frequent after unrelated donor hematopoietic cell transplantation, particularly after BM grafts., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Disparities in clinical care have been described for patients with limited insurance coverage or social support. We hypothesized that patients with relapsed Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM) treated at an urban county hospital serving indigent and under-insured patients would face barriers for referral to a private academic transplant center for autologous stem cell transplantation (ASCT). Charts of patients with HL, NHL, or MM treated at Grady Memorial Hospital between 2007 and 2013 were reviewed, and 215 patients with diagnosis of HD (n=40), NHL (n=96), and MM (n=79). 55 patients were referred for ASCT consults and 160 patients were not referred. Reasons for transplant non-referral included established clinical criteria (64% of cases), poor performance status (13%), refusal (4%), moved/lost-to-follow-up (4%), medical non-compliance (3%), death (3%), or referral to another hospital (1%). Non-referral based upon socio-economic criteria included: lack of legal immigration status/insurance (2%), and lack of social support/substance abuse (2%). Among the 55 referred patients, 27 patients (49%) underwent ASCT. Median follow-up for all referred patients from the time of diagnosis was 3.9 [0.7-22.7] years. 5-year survival from the date of diagnosis for patients who received ASCT was 80.2% versus 65.7% for non-transplanted patients (log-rank test, p-value=0.11). While the referral process did not demonstrate significant barriers based upon insurance or social status, further evaluation is needed to identify modifiable factors that can improve referral and assess the impact of the Affordable Care Act on access to ASCT.

Bortezomib-containing combinations are active in non-Hodgkin lymphoma (NHL) although peripheral neuropathy can limit their dose intensity. Based on our phase I findings, we conducted a phase II trial of bortezomib in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with a modified dose of vincristine. Patients with untreated indolent NHL received bortezomib (1·6 mg/m(2) ) on days 1 and 8 of a 21-day cycle for up to 8 cycles and R-CHOP with a 1·5 mg cap of vincristine. Patients achieving a complete response (CR) received maintenance rituximab, and remaining patients received maintenance rituximab and bortezomib. The primary endpoint was CR rate; secondary survival analyses were evaluated using the Kaplan-Meier method. Among 29 eligible patients, NHL morphologies included follicular (n = 20), marginal zone (n = 5) and small lymphocytic lymphoma (n = 4). Nineteen patients had CR (66%) and 10 had partial response (34%), yielding a 100% overall response rate. With a median follow-up of 48·7 months, the 4-year progression-free and overall survivals were 83% and 93%. Twenty-two patients experienced peripheral neuropathy of any grade, and two had grade 3 neuropathy. The combination of bortezomib with R-CHOP is effective for indolent NHL, and we plan to evaluate therapies incorporating novel proteasome inhibitors in future studies in NHL., (© 2015 John Wiley & Sons Ltd.)

Background: Previously, early results were reported for allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab in 33 patients with mantle cell lymphoma (MCL)., Methods: This study examined the outcomes of 70 patients with MCL and included extended follow-up (median, 10 years) for the 33 initial patients. Grafts were obtained from human leukocyte antigen (HLA)-matched, related donors (47%), unrelated donors (41%), and HLA antigen-mismatched donors (11%)., Results: The 5-year incidence of nonrelapse mortality was 28%. The relapse rate was 26%. The 5-year rates of overall survival (OS) and progression-free survival (PFS) were 55% and 46%, respectively. The 10-year rates of OS and PFS were 44% and 41%, respectively. Eighty percent of surviving patients were off immunosuppression at the last follow-up. The presence of relapsed or refractory disease at the time of HCT predicted a higher rate of relapse (hazard ratio [HR], 2.94; P = .05). Despite this, OS rates at 5 (51% vs 58%) and 10 years (43% vs 45%) were comparable between those with relapsed/refractory disease and those undergoing transplantation with partial or complete remission. A high-risk cytomegalovirus (CMV) status was the only independent predictor of worse OS (HR, 2.32; P = .02). A high-risk CMV status and a low CD3 dose predicted PFS (HR, 2.22; P = .03)., Conclusions: Nonmyeloablative allogeneic HCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses., (© 2015 American Cancer Society.)

Background: Granulocyte-monocyte colony stimulating factor (GM-CSF) is a hematopoietic cytokine with immunomodulatory activity that has preclinical evidence for enhancement of antitumor immunity when administered in combination with chemotherapy. We evaluated the utility of GM-CSF with chemoimmunotherapy in patients with indolent non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) in a pilot study., Patients and Methods: Patients with previously untreated, relapsed, or refractory indolent NHL or CLL were treated with GM-CSF, rituximab, fludarabine, and cyclophosphamide or mitoxantrone for a maximum of 6 cycles., Results: Sixteen patients were enrolled, including 1 patient who did not receive study therapy. Of the 15 remaining patients, 6 received cyclophosphamide and 9 received mitoxantrone in combination with fludarabine, rituximab, and GM-CSF. The overall response rate for all patients was 87%. Nine patients have subsequently had relapse of their disease, and 6 remained in remission at last study contact. There were no toxic deaths during the study., Conclusion: GM-CSF-based chemoimmunotherapy was well-tolerated and resulted in a high response rate and warrants evaluation in larger studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001)., (Copyright© Ferrata Storti Foundation.)

Purpose: Hematopoietic stem cell transplantation (HSCT) is the mainstay of treatment for adults with acute leukemia. Total body irradiation (TBI) remains an important part of the conditioning regimen for HCST. For those patients unable to tolerate myeloablative TBI (mTBI), reduced intensity TBI (riTBI) is commonly used. In this study we compared outcomes of patients undergoing mTBI with those of patients undergoing riTBI in our institution., Methods and Materials: We performed a retrospective review of all patients with acute leukemia who underwent TBI-based conditioning, using a prospectively acquired database of HSCT patients treated at our institution. Patient data including details of the transplantation procedure, disease status, Karnofsky performance status (KPS), response rates, toxicity, survival time, and time to progression were extracted. Patient outcomes for various radiation therapy regimens were examined. Descriptive statistical analysis was performed., Results: Between June 1985 and July 2012, 226 patients with acute leukemia underwent TBI as conditioning for HSCT. Of those patients, 180 had full radiation therapy data available; 83 had acute lymphoblastic leukemia and 94 had acute myelogenous leukemia; 45 patients received riTBI, and 135 received mTBI. Median overall survival (OS) was 13.7 months. Median relapse-free survival (RFS) for all patients was 10.2 months. Controlling for age, sex, KPS, disease status, and diagnosis, there were no significant differences in OS or RFS between patients who underwent riTBI and those who underwent mTBI (P=.402, P=.499, respectively). Median length of hospital stay was shorter for patients who received riTBI than for those who received mTBI (16 days vs 23 days, respectively; P<.001), and intensive care unit admissions were less frequent following riTBI than mTBI (2.22% vs 12.69%, respectively, P=.043). Nonrelapse survival rates were also similar (P=.186)., Conclusions: No differences in OS or RFS were seen between all patients undergoing riTBI and those undergoing mTBI, despite older age and potential increased comorbidity of riTBI patients. riTBI regimens were associated with shorter length of hospital stay, fewer intensive care unit admissions, and similar rates of nonrelapse survival, which may reflect reduced toxicity. Prospective trials comparing riTBI and mTBI are warranted., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Reduced-intensity conditioning (RIC) permits allogeneic hematopoietic progenitor cell transplantation in patients who would not be considered candidates for transplantation using a myeloablative preparative regimen because of age, comorbidities or prior therapy. In the setting of myeloablative transplantation, use of antithymocyte globulin (ATG) can reduce the risk of GVHD without negatively affecting transplant outcomes; however, limited data exist on the impact of ATG in the setting of RIC, particularly when there is HLA-mismatch. We performed a retrospective analysis of 85 patients who received unrelated donor transplants at our institution for hematologic malignancies following conditioning with fludarabine and melphalan (FluMel), with or without rabbit ATG (6 mg/kg). ATG was targeted to patients receiving HLA-mismatched grafts. With a median follow-up of 36 months, those receiving ATG and a mismatched graft had similar rates of acute and chronic GVHD, relapse, and similar OS compared with those receiving HLA-matched grafts without ATG. In a multivariate analysis, HLA-mismatched donor was not associated with a decrement in OS. We conclude that this intermediate dose of ATG is effective in preventing severe GVHD in the setting of HLA-mismatch, without undue compromise of the graft versus tumor effects on which RIC transplants depend.

Background: Despite prophylactic platelet transfusions, bleeding remains a significant problem in thrombocytopenic patients., Methods: The antifibrinolytic agent epsilon aminocaproic acid (EACA) was administered to 44 chronically (median duration, 273 days) and severely (platelet count, 8 × 10(9)/L; range, 1 × 10(9)/L-19 × 10(9)/L) thrombocytopenic patients with hematological malignancies. Prophylactic EACA at a dose of 1 g twice daily was orally administered for a median duration of 47 days (range, 7 days-209 days) until the platelet count recovered to > 30; × 10(9) /L. Platelets were only transfused if bleeding occurred., Results: While receiving EACA, 59% of the patients did not bleed, 25% had 19 episodes of spontaneously resolving minor bleeding that did not require platelet transfusion, and 16% received a median of 4 platelet transfusions (range, 1 transfusion-8 transfusions) for 1 major traumatic and 9 spontaneous grade 2 to grade 3 bleeding (based on the World Health Organization classification of idiopathic thrombocytopenic purpura). No EACA toxicities were noted, and venous thromboses were not observed., Conclusions: EACA is well tolerated and is associated with a low risk of major bleeding in patients with hematological malignancies who are experiencing chronic severe thrombocytopenia., (© 2013 American Cancer Society.)

We performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days -1, +5, +14, +28 post-HCT. The feasibility of adding abatacept, its pharmacokinetics, pharmacodynamics, and its impact on aGVHD, infection, relapse, and transplantation-related mortality (TRM) were assessed. All patients received the planned abatacept doses, and no infusion reactions were noted. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4(+) T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4(+) Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (P < .01). The ABA patients demonstrated a low rate of aGVHD, despite robust immune reconstitution, with 2 of 10 patients diagnosed with grade II-IV aGVHD before day +100, no deaths from infection, no day +100 TRM, and with 7 of 10 evaluable patients surviving (median follow-up, 16 months). These results suggest that costimulation blockade with abatacept can significantly affect CD4(+) T cell proliferation and activation post-transplantation, and may be an important adjunct to standard immunoprophylaxis for aGVHD in patients undergoing unrelated-donor HCT., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Plerixafor with granulocyte colony-stimulating factor (G-CSF) is effective for hematopoietic stem cell (HSC) mobilization in patients with non-Hodgkin Lymphoma and myeloma; however, labeling requires dosing 11 hours before apheresis. Pharmacodynamic studies show peak blood CD34(+) cell counts at 10 to 14 hours; limited data are available for later time points. To address the effect of afternoon plerixafor dosing on CD34(+) cell yields, we conducted a prospective clinical trial in myeloma patients undergoing stem cell collection. Thirty-one patients received plerixafor 17 hours before apheresis; blood CD34(+) cells were measured before the first plerixafor dose and 1, 3, and 17 ± 1 hours after treatment. The target HSC number (≥10 × 106 CD34(+) cells/kg) was collected from 22 subjects (73%) in 1 day and from all subjects within 3 days. Hematopoietic engraftment after transplantation and adverse events were similar to previous studies. Plerixafor given 17 hours before apheresis yields desired HSC collection efficiencies after induction treatment in myeloma patients., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, after non-Hodgkin lymphoma. Family pedigree analyses of high-risk families, case-control studies and racial disparities in disease incidence all point to a potential inherited predisposition to MM. Genome-wide association studies (GWASs) have identified susceptibility loci in a number of cancers and such studies are currently underway in MM. To date, GWASs in MM have identified several potential regions of interest for further study on chromosomes 3p22, 7p15.3, 8q24 and 2p23.3. In addition, several targets of paraproteins (so called 'paratargs') in MM have been identified. Hyperphosphorylation of the paratarg protein, which is inherited in an autosomal dominant manner, appears a common mechanism underlying the antigenicity of these proteins. One particular protein, hyperphosphorylated paratarg-7 (pP-7) is a common target in persons with myeloma and has also been identified in affected members of several high-risk MM families. It appears that the frequency of pP-7 as an antigenic target may be particularly high in African American patients with MM, which could be part of the explanation for observed racial disparities in the incidence of MM. In this review we focus on available data in the area of inherited predisposition to MM, and highlight future research directions.