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A key step towards setting a benchmark for tackling transplant-associated thrombotic microangiopathy Improvements in allogeneic haematopoietic cell transplantation (allo-HCT) techniques and supportive care strategies over the last several decades have resulted in a marked reduction in non-relapse mortality (NRM) due to fewer serious complications. This is especially relevant given the advent of novel complement pathway inhibitors and agents aimed at restoring endothelial integrity (Sicre De Fontbrune I et al. i , [31]; De Fontbrune I et al. i , [9]; Yeates I et al. i , [33]; Khaled I et al. i , [18]). Among the 23 665 paediatric and adult and allo-HCT recipients, they found 661 cases of TA-TMA resulting in a 3-year cumulative incidence estimate of 3%, which is considerably lower than what has been reported in recent studies (Jodele I et al. i , [16]; Dvorak I et al. i , [11]). [Extracted from the article]

• Long-term follow-up of auto-auto versus auto-allo in newly diagnosed multiple myeloma patients confirms significant and durable reduction in risk of relapse with the auto-allo approach. • Auto-allo transplant is associated with better 6-year PFS for high-risk patients. • Patients who relapsed after auto-allo had longer postrelapse survival than patients who relapsed after auto-auto transplant. Allogeneic hematopoietic cell transplant (HCT) may improve long-term multiple myeloma (MM) control through the graft-versus-myeloma effect. The Blood and Marrow Transplant Clinical Trials Network 0102 trial was a biologic assignment trial comparing tandem autologous transplant (auto-auto) versus autologous followed by reduced-intensity allogeneic (auto-allo) transplant in patients with newly diagnosed MM with standard-risk (n = 625) or high-risk (n = 85; β 2 -microglobulin at diagnosis ≥ 4 mg/dL or deletion of chromosome 13 by conventional karyotyping) disease. Although the initial 3-year analysis showed no difference in progression-free survival (PFS) between arms in either risk group, we hypothesized that long-term follow-up may better capture the impact of the graft-versus-myeloma effect. Median follow-up of survivors was over 10 years. Among standard-risk patients there was no difference in PFS (hazard ratio [HR], 1.11; 95% confidence interval [CI],.93 to 1.35; P =.25) or OS (HR, 1.03; 95% CI,.82 to 1.28; P =.82). The 6-year PFS was 25% in the auto-auto arm versus 22% in the auto-allo arm (P =.32), and 6-year overall survival (OS) was 60% and 59%, respectively (P =.85). In the high-risk group, although there was no statistically significant difference in PFS (HR,.66; 95% CI,.41 to 1.07; P =.07) and OS (HR, 1.01; 95% CI,.60 to 1.71; P =.96), a reduction in 6-year risk of relapse of 77% versus 47% (P =.005) was reflected in better PFS of 13% versus 31% (P =.05) but similar OS, at 47% versus 51% (P =.69). Allogeneic HCT can lead to long-term disease control in patients with high-risk MM and needs to be explored in the context of modern therapy. [ABSTRACT FROM AUTHOR]

Objective To evaluate acupuncture as a nonpharmacologic intervention for pain management in patients undergoing hematopoietic stem cell transplantation (HSCT). Methods Adult patients with multiple myeloma undergoing high-dose melphalan chemotherapy and autologous peripheral blood HSCT were randomized to receive either true (TA) or sham acupuncture (SA) once daily for five days starting on the day after chemotherapy. Use of pain medications and pain scores were assessed at baseline and at days 5, 15, and 30 after transplantation. Results Among 60 evaluable subjects, the SA group (vs TA) had greater than five times odds of increasing pain medication use from baseline. Among patients who were opioid nonusers at baseline, all 15 patients in the TA group remained free from opioid use at the end of the study. In contrast, 20% of those in the SA group (four of the 20 patients) started to use opioids after chemotherapy and stem cell infusion (day 5) and 40% (eight of the 20) had become opioid users by day 30 after HSCT (Fisher exact test P  = 0.006). Among patients who were taking opioids at baseline, 14% in the TA group vs 10% in the SA group increased opioid intake at day 5, and 21% (TA) vs 30% (SA) at day 30 (P  = 0.86). Conclusions Acupuncture appears to significantly reduce the need for pain medications during HSCT and the number of post-HSCT opioid users among baseline opioid nonusers. It warrants further studies as an opioid-sparing intervention for pain in HSCT patients. [ABSTRACT FROM AUTHOR]

Purpose: Hematopoietic stem cell transplantation (HCT) is potentially curative for a number of hematologic malignancies, but is associated with high symptom burden. We conducted a randomized sham-controlled trial (RCT) to evaluate efficacy and safety of acupuncture as an integrative treatment for managing common symptoms during HCT.Methods: Adult patients with multiple myeloma undergoing high-dose melphalan followed by autologous HCT (AHCT) were randomized to receive either true or sham acupuncture once daily for 5 days starting the day after chemotherapy. Patients and clinical evaluators, but not acupuncturists, were blinded to group assignment. Symptom burden, the primary outcome was assessed with the MD Anderson Symptom Inventory (MDASI) at baseline, during transplantation, and at 15 and 30 days post transplantation.Results: Among 60 participants, true acupuncture produced nonsignificant reductions in overall MDASI core symptom scores and symptom interference scores during transplantation (P = .4 and .3, respectively), at 15 days (P = .10 and .3), and at 30 days posttransplantation (P = .2 and .4) relative to sham. However, true acupuncture was significantly more efficacious in reducing nausea, lack of appetite, and drowsiness at 15 days (P = .042, .025, and .010, respectively). Patients receiving sham acupuncture were more likely to increase pain medication use posttransplantation (odds ratio 5.31, P = .017).Conclusions: Acupuncture was well tolerated with few attributable adverse events. True acupuncture may prevent escalation of symptoms including nausea, lack of appetite, and drowsiness experienced by patients undergoing AHCT, and reduce the use of pain medications. These findings need to be confirmed in a future definitive study.Trial Registration: NCT01811862. [ABSTRACT FROM AUTHOR]

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), can develop in a subset of patients, primarily after myeloablative hematopoietic stem cell transplantation, but it also may occur after reduced-intensity conditioning. Severe VOD/SOS, typically characterized by multiorgan failure, has been associated with a mortality rate greater than 80%. Therefore, an accurate and prompt diagnosis of VOD/SOS is essential for early initiation of appropriate therapy to improve clinical outcomes. Moreover, some studies have support the use of prophylaxis for patients who are at high risk of developing VOD/SOS. This review summarizes risk factors associated with development of VOD/SOS, including pretransplantation patient characteristics and factors related to stem cell transplantation, that can facilitate patient stratification according to risk. The incidence of VOD/SOS, clinical features, and diagnostic criteria are reviewed. Data on emerging treatment strategies for patients with VOD/SOS are discussed in the context of recent treatment guidelines. Additionally, options for prophylaxis in individuals who are at increased risk are presented. Although historically only those patients with moderate to severe VOD/SOS have been treated, early therapy and prophylaxis may be appropriate for many patients and may have the potential to improve patients' outcomes and survival, including for those with nonsevere disease. [ABSTRACT FROM AUTHOR]

In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to “best non-HCT” therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy. [ABSTRACT FROM AUTHOR]

High-dose chemotherapy (HDT) followed by autologous peripheral blood progenitor cell transplant (PBPCT) has become a standard intervention in certain clinical settings of hematologic malignancies, particularly multiple myeloma and relapsed/refractory lymphoma. While the minimal required PBPCs infused, as defined by number of CD34 + cells, has been relatively well delineated for adequate hematopoietic recovery post-HDT, optimal PBPC dose has not been clearly defined. This is particularly relevant in the context of retrospective data suggesting improved survival outcomes with increased PBPC doses. The potential confounding of these data as they relate to disease risk is discussed within this review. Additionally, other retrospective data have suggested that enhanced quantitative lymphocyte subset reconstitution post-HDT-PBPCT may confer progression-free and overall survival advantage. These reported series herein reviewed may inform discussion of future, prospective clinical trials with the intent of defining optimal autologous PBPC dose following HDT, especially as it may relate to metrics beyond hematopoietic recovery. [ABSTRACT FROM AUTHOR]

The Patient Protection and Affordable Care Act requires that health care insurers cover routine patient costs associated with participating in clinical trials for cancer and other life-threatening diseases. There is a need to better define routine costs within the context of hematopoietic stem cell transplantation (HSCT) clinical trials. This white paper presents guidance on behalf of the American Society for Blood and Marrow Transplantation for defining a standard HSCT episode and delineates components that may be considered as routine patient costs versus research costs. The guidelines will assist investigators, trial sponsors, and transplantation centers in planning for clinical trials that are conducted as a part of the HSCT episode and will inform payers who provide coverage for transplantation. [ABSTRACT FROM AUTHOR]

In the article, the author discusses issues in the use of allogeneic hematopoietic cell transplantation (HCT) as a curative therapy for myelodysplastic syndromes (MDS) in the U.S. as of September 2016. Also cited are the decision by the U.S. Centers for Medicare & Medicaid Services to allow Medicare coverage to allogeneic hematopoietic stem cell transplantation (HSCT) for MDS, and the importance of clinical trials in MDS.

Autologous stem cell transplantation (ASCT) has long been considered frontline therapy for newly diagnosed myeloma patients. This Spotlight examines the role of ASCT in the era of novel drugs and argues that ASCT should continue to be considered for eligible patients. A combination of novel drugs with ASCT in a sequential treatment approach can attain long-term survival and perhaps cure a subset of patients. ASCT will likely remain an important platform to develop curative strategies in the foreseeable future. [ABSTRACT FROM AUTHOR]

Abstract: Autologous hematopoietic stem cell transplantation (aHSCT) is a well-established treatment for malignancies such as multiple myeloma (MM) and lymphomas. Various changes in the field over the past decade, including the frequent use of tandem aHSCT in MM, the advent of novel therapies for the treatment of MM and lymphoma, and the addition of new stem cell mobilization techniques, have led to the need to reassess current stem cell mobilization strategies. Mobilization failures with traditional strategies are common and result in delays in treatment and increased cost and resource utilization. Recently, plerixafor-containing strategies have been shown to significantly reduce mobilization failure rates, but the ideal method to maximize stem cell yields and minimize costs associated with collection has not yet been determined. A panel of experts convened to discuss the currently available data on autologous hematopoietic stem cell mobilization and transplantation and to devise guidelines to optimize mobilization strategies. Herein is a summary of their discussion and consensus. [Copyright &y& Elsevier]

High-dose melphalan with autologous stem cell support has been an integral part of myeloma therapy for more than 25 years either as salvage therapy or as consolidation of an initial remission. Although multiple phase III trials have demonstrated that this therapy results in higher response rates and longer remission duration than conventional chemotherapy the use of thalidomide, lenalidomide and bortezomib as induction therapy have limited the clinical relevance of these trials. In this manuscript, we will summarize the results of ongoing and recently published clinical trials and describe how they have impacted current transplant recommendations, and their relevance to the treatment of myeloma patients in developing countries. [ABSTRACT FROM AUTHOR]

The article provides information on a study which determined the efficacy of low-dose azacitidine in reducing recurrence rates in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) following allogeneic transplantation. A review of the related literature on treatment of AML patients with allogenic hematopoietic stem cell transplantation (HSCT) is offered. It describes the methods utilized by the research authors. The findings of the study are discussed in detail.

Background: Despite the unquestionable importance of clinically oriented research designed to test the safety and efficacy of new therapies in patients with malignant disease, there is limited information regarding strategies to evaluate the quality of such efforts at academic institutions. Methods: To address this issue, a committee of senior faculty at the University of Texas M.D. Anderson Cancer Center established specific criteria by which investigators from all departments engaged in clinical research could be formally evaluated. Scoring criteria were established and revised based on the results of a pilot study. Beginning in January 2004, the committee evaluated all faculty involved in clinical research within 35 departments. Scores for individual faculty members were assigned on a scale of 1 (outstanding) to 5; a score of 3 was set as the standard for the institution. Each department also received a score. The results of the evaluation were shared with departmental chairs and the Chief Academic Officer. Results: 392 faculty were evaluated. The median score was 3. Full professors more frequently received a score of 1, but all faculty ranks received scores of 4 and 5. As a group, tenure/tenure track faculty achieved superior scores compared to nontenure track faculty. Conclusions: Based on our experience, we believe it is possible to conduct a rigorous consensus-based evaluation of the quality of clinical cancer research being conducted at an academic medical center. It is reasonable to suggest such evaluations can be used as a management tool and may lead to higher-quality clinical research. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Several letters to the editor are presented regarding the meta-analysis of tandem versus single autologous hematopoietic cell transplantation (HCT) for multiple myeloma patients by A. Kumar and colleagues.

The article discusses the efficacy of hypomethylating agent 5-azacitidine in treating patients with acute leukemia. The authors claim that low doses of 5-azacitidine may maximize the graft-versus-leukemia effect and may be tolerated well after allogeneic transplantation (HSCT). They add that it may induce durable remissions for patients who develop disease recurrence after HSCT.

Abstract: To determine the long-term outcome of patients undergoing unrelated donor transplantation (URD) after a reduced intensity conditioning (RIC) regimen, we performed a retrospective analysis of the transplant outcomes of the first 5 years of RIC experience as reported to the National Marrow Donor Program (NMDP). Patients were included if they were older than 18 years and had undergone a URD transplant procured through the NMDP from January 1, 1996 until May 31, 2001, with an RIC regimen for a hematologic malignancy. The number of URDs performed using an RIC increased from 59 during 1996 to 1999, to 149 in the year 2000. RIC recipients were older (53 vs. 33 years) and had a higher likelihood of having advanced disease (81% vs. 51%) when compared to patients undergoing a myeloablative conditioning regimen during the same time period. The 5-year survival rate is 23% (95% confidence interval [CI]; 18, 28), whereas the 5 year incidence of progression/relapse is 43.4% (95% CI; 37,49). Prognostic factors for better overall survival on multivariate analysis were earlier disease stage, longer time to transplant from diagnosis, better HLA match, ≥90% performance score, and use of peripheral blood stem cells. This analysis demonstrates that long-term survival and disease control can be obtained with URD progenitor cell transplantation after RIC conditioning. However, only prospective trials will define the optimal role of this therapy in patients with hematologic malignancies. Therefore, URD transplantation with RIC should continue to be explored in the context of clinical trials. [Copyright &y& Elsevier]

The discovery and approval of imatinib drastically changed the therapeutic algorithm for chronic myeloid leukaemia (CML). Imatinib is now considered the therapy of choice for patients with newly diagnosed CML, including those previously considered candidates for allogeneic haematopoietic cell transplantation (HCT). We compared numbers and types of allogeneic HCTs performed for CML in North America before and after the introduction of imatinib, and publication of the International Randomized Trial of Interferon and STI571 (IRIS) using transplants reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The number of HCTs for CML registered with the CIBMTR in 1998 was 617; 62% were performed in first chronic phase (CP1). Only 1% of patients had received imatinib prior to transplantation. In 2003, the number of HCTs reported was 223; 44% were performed in CP1 and 77% of patients received imatinib prior to transplantation. The introduction of imatinib therapy has had a profound impact on the use of allogeneic transplantation for CML, with a marked decrease in the number of transplants for CML and an accompanying decrease in the proportion done in CP1. Most patients now receive a trial of imatinib before proceeding to HCT. [ABSTRACT FROM AUTHOR]

Abstract: Reduced-intensity conditioning has extended the use of allogeneic hematopoietic stem cell transplantation (HSCT) to patients otherwise not eligible for this treatment due to older age or frailty. One hundred twelve acute myelogenous leukemia/myelodysplastic syndromes patients received fludarabine and melphalan (FM) conditioning with allogeneic HSCT. Most patients (73%) were not in remission. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate. Median age was 55 years (range, 22-74). Donors were related (53%) and unrelated (47%). Median follow-up of surviving patients (n = 43) was 29.4 months (range, 13.1-87.7). The complete remission (CR) rate was 82%. Estimates of 2-year survival were 66%, 40%, and 23% for patients in CR, with active disease without and with circulating blasts at HSCT, respectively. In multivariate analysis, survival was negatively influenced by active disease at HSCT and development of grade II-IV acute GVHD. Presence of circulating blasts at HSCT negatively influenced freedom from disease progression. Incidence of nonrelapse mortality (NRM) was significantly higher for patients with active disease, but was not influenced by patient age. Patients in CR had a day-100 and 2-year NRM of 0% and 20%, respectively. Use of unrelated donors increased the risk of NRM only among patients with active disease. FM and HSCT elicited long-term disease control in a significant fraction of this high-risk cohort. [Copyright &y& Elsevier]

Abstract: With the increasing use of progenitor cell transplantation in older patients defining predictors of outcomes in this patient population will be important to guarantee the appropriate use of this procedure. Comorbidity assessments are not sufficiently sensitive in determining outcomes, functional assessment tools such as those used in rehabilitation medicine could be useful not only in predicting outcomes, but as another dimension of quality of life. These tools have rarely been used in the setting of hematopoietic progenitor cell transplantation. In this session we will review current trends in predicting transplant outcomes, the use of functional assesment tools in predicting morbidity post medical interventions, as well as potential strategies of improving functional status using growth hormone agonists. [Copyright &y& Elsevier]

Summary Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR‐T) with non‐negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19‐directed CAR‐T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post‐CAR‐T, we compiled a retrospective single‐centre cohort of non‐Hodgkin lymphoma patients. Only commercial CAR‐T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR‐T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67–5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post‐CAR‐T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co‐occurred with cytokine release syndrome and were associated with higher post‐CAR‐T infusion peak levels of IL‐10, TNF‐alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39–19.6]) and using CAR‐T product with a CD28‐costimulatory domain (OR = 5.17 [1.72–18.6]). Atrial arrhythmias following CD19‐CAR‐T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR‐T product with a CD28 costimulatory domain. [ABSTRACT FROM AUTHOR]

Abstract: Despite advances in hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies, relapse remains the leading cause of death after transplant. Biologic and clinical investigations are needed to combat this primary cause of death after transplantation. The National Cancer Institute held international workshops in 2009 and 2012 to help address this problem. Three major initiatives for coordinated research were proposed: 1) To establish multicenter networks for basic, translational, epidemiologic and clinical research; 2) To establish a network of biorepositories for the collection of samples before and after HSCT to aid in laboratory and clinical studies; and 3) To refine, implement and study proposed definitions for disease-specific response and relapse and for monitoring of minimal residual disease. The workshop in 2012 also featured nine presentations, summaries of which follow in three manuscripts. [Copyright &y& Elsevier]

With the increasing efficacy of induction therapy in multiple myeloma (MM), primary induction failure (i.e. less than a partial response) is an extremely rare phenomenon. However, those results are most likely not relevant to modern induction therapy since patients did not receive modern induction therapy with a proteasome inhibitor (PI) or an immunomodulator drug (IMID). Thus delaying high dose melphalan therapy may not be in the patient's best interest and post ASCT consolidation is likely to be more effective in patients responding to high dose melphalan. [Extracted from the article]

Abstract: During the 2006 BMT Tandem Meetings, a workshop was convened by the Center for International Blood and Marrow Transplant Research (CIBMTR) to discuss conditioning regimen intensity and define boundaries of reduced-intensity conditioning (RIC) before hematopoietic cell transplantation (HCT). The goal of the workshop was to determine the acceptance of available RIC definitions in the transplant community. Participants were surveyed regarding their opinions on specific statements on conditioning regimen intensity. Questions covered the “Champlin criteria,” as well as operational definitions used in registry studies, exemplified in clinical vignettes. A total of 56 participants, including transplantation physicians, transplant center directors, and transplantation nurses, with a median of 12 years of experience in HCT, answered the survey. Of these, 67% agreed that a RIC regimen should cause reversible myelosuppression when administered without stem cell support, result in low nonhematologic toxicity, and, after transplantation, result in mixed donor–recipient chimerism at the time of first assessment in most patients. Likewise, the majority (71%) agreed or strongly agreed that regimens including < 500 cGy of total body irradiation as a single fraction or 800 cGy in fractionated doses, busulfan dose < 9 mg/kg, melphalan dose <140 mg/m2, or thiotepa dose < 10 mg/kg should be considered RIC regimens. However, only 32% agreed or strongly agreed that the combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) should be considered a RIC regimen. These results demonstrate that although HCT professionals have not reached a consensus on what constitutes a RIC regimen, most accept currently used criteria and operational definitions. These results support the continued use of current criteria for RIC regimens until a consensus statement can be developed. [Copyright &y& Elsevier]

In this article, the author reflects upon the FDA's approval of Tisagenlecleucel, a drug used to treat cancer. Topics discussed include how the drug has been approved to treat acute lymphoblastic leukemia, how a one-time infusion of the drug costs $475,000 and details relating to the drug's black box warning as its use can cause hypotension, multiorgan failure and even death. Details relating to revenue outlooks for pharmaceutical companies including Novartis and Gilead are also offered.

Summary: Autologous haematopoietic cell transplantation (autoHCT) and continuous post‐transplant maintenance therapy are the standard of care in transplant‐eligible multiple myeloma (MM) patients. We sought to describe symptom burden and identify symptom clusters occurring in MM patients after autoHCT using data from the BMT CTN 0702 randomized controlled trial comparing the outcomes of three treatment interventions after an autoHCT in 758 MM patients. We analysed individual transplant‐related symptoms assessed via the FACT‐BMT questionnaire at enrolment and annually for 4‐year post‐autoHCT. We also described the effect the individual symptoms and symptom clusters have on quality of life (QoL). We identified three stable symptom clusters: malaise symptom cluster (lack of energy, feeling ill, having pain, experiencing nausea, loss of appetite), physical symptom cluster (having skin problems, tremors, worsening eyesight, change in taste, shortness of breath, frequent colds) and emotional symptom cluster (feeling sad, being nervous, experiencing sleep problems). Malaise and emotional symptom clusters have a greater impact on QoL than the physical symptoms cluster. Identifying these symptoms warrant additional support in terms of psychosocial support, in addition to treatment of the physical symptoms themselves. [ABSTRACT FROM AUTHOR]

Background: Pulmonary complications are common among hematologic stem cell transplant (HSCT) recipients. Their evaluation can be pursued through bronchoscopy with bronchoalveolar lavage (BAL) and a variety of available noninvasive studies, which include newer molecular markers for detecting a variety of infectious agents. Objective: The objective of this study is to evaluate the diagnostic yield of BAL among HSCT patients relative to the yield of noninvasive testing. Method: This is a retrospective analysis of HSCT recipients who underwent both BAL and noninvasive testing at a cancer center in 2013 and 2014. Results: There were 210 diagnostic results among 98 HSCT recipients. There were 84 unique findings on noninvasive testing that were not evident on BAL, and 36 unique findings on BAL that were not evident on noninvasive testing. Noninvasive testing tended to yield bacterial and viral infections more commonly, while BAL yielded mycobacterial isolates more commonly. Conclusion: While both noninvasive testing and BAL are helpful in this population, each appeared more precise than the other with individual lung diseases. Bronchoscopy with BAL and noninvasive testing should be considered complementary strategies in the workup of pulmonary complications among HSCT patients. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the predictive value of routine pulmonary function testing (PFT) at the 12-month mark post-autologous hematopoietic cell transplant (AHCT) in identifying clinically significant lung disease in lymphoma survivors. In 247 patients, 173 (70%) received BEAM (carmustine, etoposide, cytarabine, melphalan), and 49 (20%) received TBC (thiotepa, busulfan, cyclophosphamide) conditioning regimens. Abnormal baseline PFT was noted in 149 patients (60%). Thirty-four patients had a significant decline (reduction of >/= 20% in DLCO or FEV1 or FVC) in post-AHCT PFT, with the highest incidence in the CNS lymphoma group (39%). The incidence of clinically significant lung disease post-transplant was low at 2% and there was no association between abnormal pre- and 1-year post-transplant PFTs with the development of clinical lung disease. While this study illustrates the impact of treatment regimens on PFT changes, it did not demonstrate a predictive value of scheduled PFTs in identifying clinically significant post-AHCT lung disease. [ABSTRACT FROM AUTHOR]

Summary: Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo‐HCT) is essential for estimating non‐relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high‐yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34‐selected allo‐HCT. Here, we evaluated the SCI in a single‐centre cohort of 327 patients receiving reduced‐intensity conditioning followed by unmanipulated allografts from HLA‐matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0–1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3‐year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all‐cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1‐, 2‐ and 3‐year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo‐HCT from HLA‐matched donors after reduced‐intensity conditioning. [ABSTRACT FROM AUTHOR]

Despite ongoing therapeutic advances, multiple myeloma (MM) remains largely incurable, and outcomes in patients who develop resistance to immunomodulatory drugs or proteasome inhibitors remain grim. Allogeneic hematopoietic cell transplantation (alloHCT) is an alternative option that may offer potential for cure. Although rates of transplantation-related morbidity and mortality have decreased in recent years, weighing this approach's potential benefits against nontransplantation therapies demands a thoroughly informed pre-alloHCT assessment. Here we assess the impact of pre-alloHCT variables on important clinical outcomes in a large cohort of relapsed refractory MM (RRMM) CD34+-selected alloHCT recipients. We included all patients with MM who underwent CD34+-selected alloHCT at our center between June 2010 and December 2015. Patients were conditioned with busulfan (0.8 mg/kg × 10), melphalan (70 mg/m2 × 2), and fludarabine (25 mg/m2 × 5), followed by infusion of a CD34+-selected peripheral blood stem cell graft, without post-alloHCT graft-versus-host disease (GVHD) prophylaxis. The 73-patient cohort had a median age of 55 years (range, 37 to 66 years). Overall survival (OS) and progression-free survival (PFS) rates were 70% and 53%, respectively, at 1 year (95% confidence interval [CI], 58% to 79% and 41% to 64%) and 50% and 30%, respectively, at 3 years (95% CI, 38% to 62% and 19% to 41%). The cumulative incidence of relapse was 25% at 1 year (95% CI, 15% to 35%) and 47% at 3 years (95% CI, 35% to 58%). Nonrelapse mortality at 1 year was 22% (95% CI, 13% to 32%). The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 7% at 100 days (95% CI, 3% to 14%), and that of any chronic GVHD (cGVHD) was 8% at 1 year (95% CI, 3% to 16%). International Staging System (ISS) stage II-III assessed before salvage therapy was associated with poorer 3-year OS (30% versus 54%; P =.037) and 3-year PFS (9% versus 33%; P =.013), and increased 3-year relapse incidence (72% versus 39%; P =.004). Older age and GVHD before 6 months (aGVHD grade II-IV or cGVHD of any grade) were also associated with poorer OS, and a greater number of pre-alloHCT lines of therapy was also associated with increased relapse incidence. Our findings reinforce that CD34+-selected alloHCT can achieve prolonged disease control and long-term survival in high- risk, heavily treated refractory MM populations. We also identified numerous pre-alloHCT variables associated with OS, PFS, and relapse. Amongst these, presalvage ISS stage II-III was consistently associated with poorer survival and relapse outcomes. Given the lack of established alternate therapies for patients with RRMM, we advocate the identification of adverse pre-alloHCT variables to inform alloHCT decision making rather than to exclude patient cohorts from this potentially curative treatment option. [ABSTRACT FROM AUTHOR]

Simple Summary: We studied cognitive (thinking) abilities and brain structure and function in older adults with multiple myeloma—a cancer of plasma cells—treated with high-dose chemotherapy and a stem cell transplant. The initial results suggested that after the chemotherapy and transplant, functional connectivity was diminished in regions involving the frontal and parietal lobes of the brain, while brain structure and cognitive function remained relatively stable. We also found increases in markers of inflammation after the transplant. The findings provide supporting evidence for the vulnerability of frontal and parietal brain regions to the side effects of chemotherapy. These preliminary findings would support the design of large future studies with the goal of developing therapeutic interventions. There is a paucity of research on treatment-related neurotoxicity in older adults with multiple myeloma (MM) treated with high-dose chemotherapy (HDC) and autologous SCT (HDC/ASCT), despite the increasing use of this regimen. We examined resting state functional connectivity (RSFC), gray matter (GM) volume, neurocognitive function (NF), and proinflammatory cytokines (PCy) in older patients with MM pre- and post-HDC/ASCT. Eighteen patients underwent MRI, NF tests, and serum PCy measurements prior to HDC/ASCT, and fifteen patients completed a follow up five-months post-HDC/ASCT. There were significant decreases in RSFC post-HDC/ASCT in (1) the central executive network (CEN) involving the left dorsolateral prefrontal cortex and right posterior parietal cortex (p = 0.022) and (2) the CEN involving the right posterior parietal cortex and the salience network involving the right dorsal anterior cingulate cortex (p = 0.029). There were no significant changes in GM or NF, except for improvements in attention (Digit Span Backward, p = 0.03). There were significant increases in several PCy post-HDC/ASCT (p ≤ 0.05). In conclusion, RSFC decreased in frontal, parietal, and cingulate cortices post-HDC/ASCT, NF was relatively stable, and several PCy increased. These findings are congruent with other studies in cancer patients and provide supporting evidence for the vulnerability of frontoparietal regions to chemotherapy's adverse effects. [ABSTRACT FROM AUTHOR]

In this article, the author discusses the topic on the use of nonspecific immunotherapy for the medication of secondary disease after allogeneic transplantation. It mentions the application of antithymocyte globulin (ATG) as prophylaxis of acute graft versus host disease (GVHD). The result of reduced intensity conditioning (RIC) is also examined.

Acute hypertensive crisis during autologous hematopoietic progenitor cell (HPC) infusions using DMSO is widely reported, but the literature is silent regarding this event during infusions of HPC from matched unrelated donors (MUD). MUD-HPC infusions are often given by evening nursing staff when there is less clinical support in the hospital, and treatment varies with physician preference. Identification of predictive factors, and of optimal treatment may lead to improved outcomes. To identify predictive factors for the development of acute hypertensive crisis and to develop best treatment pathways. A retrospective chart review of 97 adult patients receiving MUD-HPC infusions from October 2003 - September 2004 was done. A retrospective chart review of 97 consecutive patients receiving MUD HPC infusions was completed. Demographic, clinical and laboratory factors were evaluated for the occurrence of hypertensive crisis using regression analysis. This analysis was limited to patients receiving HPC-marrow because only 2 of 20 cases occurred among patients receiving peripheral blood stem cell infusions. Hypertension crisis was defined as SBP >160, DBP >100 or a symptomatic increases in BP of 20 mm HG > baseline On univariate analysis, volume infused (adjusted for weight), elevated creatinine (>1.0mg/dl) and BUN levels above the median (>15mg/dl) were significant predictors. Because of high correlation between BUN and creatinine, only BUN was considered in multivariate analysis (higher precision associated with the estimate). Patients receiving high volume infusions with an elevated BUN were at the greatest risk (62%), followed by patients receiving high volume infusions and low BUN (28%), and then by patients receiving low volume and high BUN (17%). There were no cases of hypertension among the 18 patients who received low volumes and had a low BUN. Medical treatment during hypertensive episodes varied by best responses was seen with combined use of IV antihypertensive agents and diuretics. These findings suggest that volume reduction of HPC-M may decrease the incidence of acute hypertensive crisis during MUD infusions. [ABSTRACT FROM AUTHOR]

BACKGROUND. Refractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT). METHODS. In phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject’s HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted. RESULTS. T cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses. CONCLUSIONS. Recipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine the utility of a patient-reported outcome (PRO) as it relates to patient performed testing (PPT) for measuring functional status in multiple myeloma patients after autologous hematopoietic stem cell transplantation (auto-HCT).Methods: Symptom interference on walking (a PRO) was measured by the MD Anderson Symptom Inventory (MDASI). PPT was assessed via 6-min walk test (6MWT). Mixed effects modeling was used to examine (1) the longitudinal relationship between the MDASI score and 6MWT distance and (2) the MDASI scores between patients who did or did not complete the 6WMT. Receiver operating characteristic (ROC) curve analysis was performed to quantify the construct validity of the PRO by differentiating performance status.Results: Seventy-nine patients were included. Mean 6MWT distance significantly correlated with MDASI-walking interference score (PRO) over the first month of auto-HCT (est = 6.09, p = 0.006). There was a significantly higher completion rate for MDASI versus 6MWT at each time point (p < 0.01). Patients who completed the 6MWT reported less interference on walking during the study period (est = 1.61, p < 0.0001). Finally, the PRO demonstrated significant construct validity for measuring functioning status with MDASI-walking against ECOG-PS as the anchor (AUC = 0.77, 95% CI 0.60-0.94, p = 0.003).Conclusion: The PRO of MDASI-walking interference is a valid physical functioning measure, correlating with an objective functional measure (6MWT) in MM patients undergoing auto-HCT. As patients with poorer functional status during therapy are less likely to complete PPT, this PRO may offer a more practical quantitative measure of functioning in patients. [ABSTRACT FROM AUTHOR]

Abstract: High-dose chemotherapy and autologous stem-cell transplantation (HDT-ASCT) is standard therapy for younger patients with multiple myeloma (MM) who are physically fit enough to undergo the treatment. Nevertheless, MM remains incurable and strategies to prevent or delay relapse after HDT-ASCT are needed. A continuous therapy approach using maintenance therapy may provide sustained control of minimal residual disease after HDT-ASCT. Alternatively, extending treatment with novel induction regimens may delay the need for HDT-ASCT. Although there is some clinical evidence to support the use of these strategies, their efficacy has not been proven definitively in clinical trials; ongoing studies should help determine their merit in transplant-eligible patients with MM. [Copyright &y& Elsevier]

At last follow-up, 5 (50%) patients remained on maintenance lenalidomide, and 5 (50%) patients received a subsequent line of therapy (note: three patients, in the absence of PD, continued on daratumumab beyond the six cycles). It is plausible that in standard-risk patients there may be a stable MRD clone without clinical consequence, leading to clinician and patient preferences to avoid interventions in the absence of a clinical relapse. Despite the improved complete response (CR) rates in multiple myeloma with newer therapies, most patients still relapse [[1]]. Although there was a third patient that converted to bone marrow MRD-negativity, this patient had serologic progressive disease (PD) at the time of response assessment and was deemed not to have achieved the primary end point. [Extracted from the article]

Background Cytomegalovirus (CMV)–seropositive (R+) hematopoietic cell transplant (HCT) recipients have a survival disparity compared with CMV-seronegative recipient/donor (R–D–) pairs. We hypothesized that primary letermovir prophylaxis (LET) may abrogate this disparity. We investigated the relationship between LET and mortality at 1 year post-HCT. Methods In this retrospective cohort study, we included adult R–D– or R+ patients who received HCT pre-LET (between 1 January 2013 through 15 December 2017) and post-LET (between 16 December 2017 through December 2019). R+ were categorized by LET receipt as R+/LET or R+/no-LET. Cox proportional hazard models were used to estimate the association of LET with all-cause mortality at 1 year after transplantation. Results Of 848 patients analyzed, 305 were R–D–, 364 R+/no-LET, and 160 R+/LET. Because of similar mortality (adjusted hazard ratio [aHR], 1.29 [95% confidence interval {CI},.76–2.18]; P  = .353]) between pre-LET/R–D– and post-LET/R–D–, R–D– were combined into 1 group. Compared with R–D–, the aHR for mortality was 1.40 (95% CI, 1.01–1.93) for R+/no-LET and 0.89 (95% CI,.57–1.41) for R+/LET. Among R+, LET was associated with decreased risk of death (aHR, 0.62 [95% CI,.40–.98]); when conventional HCT and T-cell depleted HCT were analyzed separately, the aHR was 0.86 (95% CI,.51–1.43) and 0.21 (95% CI,.07–.65), respectively. Conclusions At 1 year post-HCT, LET was associated with closing the mortality disparity between R–D– and R+. Among all R+, LET was associated with decreased mortality, driven by 79% reduced incidence of death in T-cell depleted HCT. [ABSTRACT FROM AUTHOR]

Although upfront autologous stem cell transplantation (ASCT) generally improves progression-free survival (PFS) in newly diagnosed multiple myeloma (NDMM), the overall survival (OS) benefit and optimal timing of ASCT are not well established. Patients with early response may be able to safely continue induction and avoid ASCT without compromised outcomes. We report an extended follow-up analysis of a phase 2 trial that randomized transplant-eligible patients with NDMM who responded to induction (50/65 patients) to continued induction or ASCT; median follow-up was 8.0 years. Patients had similar 8-year PFS (55% vs. 43%), 8-year OS (83% vs. 72%), and rates of at least very good partial response (72% vs. 84%) whether continuing induction of lenalidomide and dexamethasone (Ld arm) or receiving ASCT (Ld + ASCT arm) (p = 0.5). Notably, over 50% of patients receiving continuous Ld had PFS of 5–10 years. These results suggest the need for prospective trials incorporating response-adapted therapeutic approaches to NDMM. Presented in abstract form (interim analysis) at the 56th annual meeting of the American Society of Hematology (San Francisco, CA, 6 December 2014) and at the 57th annual meeting of the American Society of Hematology (Orlando, FL, 3 December 2015). [ABSTRACT FROM AUTHOR]

A response by Sergio Giralt and colleagues to several letters to the editor about their article on the treatment of leukemia in relapse after bone marrow transplantation in the September 9, 1993 issue is presented.

Background: Patients whose leukemia relapses after allogeneic bone marrow transplantation have a poor prognosis; few respond to further chemotherapy, and almost none survive over the long term. We present preliminary observations on the use of filgrastim (granulocyte colony-stimulating factor) for relapse after transplantation. Methods: Seven female patients with leukemia (one with chronic myelogenous leukemia, five with acute myelogenous leukemia, and one with a myelodysplastic syndrome that transformed into acute myelogenous leukemia) whose disease relapsed within 360 days after allogeneic bone marrow transplantation received filgrastim (5 μg per kilogram of body weight per day by subcutaneous injection) to reinduce remission by stimulating residual donor marrow cells. Cytogenetic analysis of bone marrow, fluorescence in situ hybridization, and determination of restriction-fragment-length polymorphisms were used to assess response and chimerism. Results: Three of the seven patients had a complete hematologic and cytogenetic remission, with reestablishment of hematopoiesis of donor origin. Mild chronic graft-versus-host disease developed in one patient, and acute graft-versus-host disease in none. One patient had a relapse 12 months after treatment, and two others remained in remission after 10 and 11 months. In two of the patients with a response, fluorescence in situ hybridization demonstrated stimulation of donor cells without differentiation of the leukemic clone. Conclusions: Filgrastim may be effective in selected cases of leukemic relapse after allogeneic bone marrow transplantation. (N Engl J Med 1993;329:757-61.) [ABSTRACT FROM AUTHOR]