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We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome-positive (Ph(+)) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.

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]

PURPOSE: Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown. METHODS: Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died. RESULTS: Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P =.022) and decreased OS (3-year OS, 55% v 79%, P =.045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P =.003) and RFS was lower (3-year RFS, 13% v 49%; P =.003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication. CONCLUSION: This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk. [ABSTRACT FROM AUTHOR]

Traditionally, hematopoietic cell transplant-comorbidity index (HCT-CI) and pre-transplant Karnofsky Performance Scale (KPS) assessed by clinicians are used to determine the overall fitness of an older patient [[5]]. In order to better utilize geriatrics resource, we have since prospectively tested a patient self-reported, electronic rapid fitness assessment tool (eRFA), originally developed for older preoperative cancer patients [[11]], as a screening instrument for older transplant patients and are now reporting results from this pilot study. 1 HCT: Hematopoietic cell transplant; AML/MDS: Acute myeloid leukemia/Myelodysplastic syndrome; NHL: Non-Hodgkin Lymphoma; HL: Hodgkin Lymphoma; CR/VGPR/PR: Complete response/Very good partial response/Partial response; HCT-CI: Hematopoietic cell transplant-comorbidity index; KPS: Karnofsky Performance Scale; RIC/NMA: Reduced-intensity/non-myeloablative conditioning. Despite these limitations, we have shown here prospectively that adopting a patient-reported, electronic geriatric impairment screening instrument is entirely feasible in our transplant population and may help triage patients appropriately for in-depth geriatrics evaluation and management. [Extracted from the article]

Summary: TP53 alterations portend extremely poor prognosis in patients with mantle cell lymphoma treated with standard treatment modalities. We reviewed outcomes of 42 patients with available TP53 status who had received a reduced‐intensity or non‐myeloablative allogeneic haematopoietic cell transplant at our institution. We demonstrated a 2‐year overall survival and progression‐free survival of 78% [95% confidence interval (CI) 60–88] and 61% (95% CI 43–75), respectively. The 2‐year cumulative incidences of relapse and non‐relapse mortality were 19% and 20%, respectively. Importantly, there is no significant difference among patients with and without TP53 alterations, suggesting for the first time a beneficial treatment modality for these high‐risk patients. [ABSTRACT FROM AUTHOR]

While recent progress has been made in the management of multiple myeloma, it remains a highly fatal malignancy especially among patients with relapsed-refractory disease. Immunotherapy with adoptive T cells targeting myeloma-associated antigens are at various stages of development and have brought about a new hope for cure. This is a review on the emerging field of adoptively transferred engineered T cell based approaches, with an in-depth focus on chimeric antigen receptors (CAR) targeting multiple myeloma. The recent results from CAR T cells targeting B cell maturation antigen are encouraging but eventual resistance to the CAR T cell therapies remain problematic. With newer approaches in therapies for multiple myeloma, the role of transplantation is evolved to form a platform for T cell therapies. [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 article discusses research being done on symptom burden among 64 patients with myeloma who underwent autologous stem cell transplantation (ASCT). It references a study by Erica Campagnaro et al, published in the 2008 issue of "Cancer." It was found that M. D. Anderson Symptom Inventory (MDASI) scores increased significantly throughout transplantation, with most patients returning to baseline by Day 30 after the procedure.

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: 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]

High-dose chemotherapy and autologous peripheral blood progenitor cell transplantation is an effective treatment for multiple myeloma. Progenitor cells are generally mobilised into the peripheral blood by administration of filgrastim. Pegfilgrastim is a covalent conjugate of filgrastim with a longer half-life. The results of a phase II study of pegfilgrastim, administered as a single injection to mobilise autologous peripheral blood progenitor cells in patients with multiple myeloma, is reported. All patients ( n = 19) received 12 mg of pegfilgrastim. Leukaphaeresis was started when the peripheral blood CD34+ count was >0·015 × 109/l. Daily, leukaphaeresis was performed until the target progenitor cell dose was obtained. The median number of leukaphaeresis procedures required to collect the target CD34+ cell dose was 2 (range 1–5). A median of 8·4 × 106 CD34+ cells/kg (range 4·1–15·8) was collected. The most common toxicity was bone pain/myalgia. Sustained haematological recovery occurred in all the patients who underwent high-dose chemotherapy followed by autologous peripheral blood progenitor cell transplantation with pegfilgrastim-mobilised cells. A single fixed dose of pegfilgrastim was effective in mobilising adequate peripheral blood progenitor cells in patients with multiple myeloma. The efficacy and toxicity profile was similar to that described with filgrastim treatment. [ABSTRACT FROM AUTHOR]

Summary. Neurotoxicity is a significant complication of the use of tacrolimus. From April 1998 to December 2001, we identified 10 patients (six women, four men) who developed 11 episodes of tacrolimus-associated posterior reversible encephalopathy syndrome (PRES) after allogeneic haematopoietic stem cell transplantation for haematological malignancies. The diagnosis was made by characteristic clinical findings (mental status changes, seizures, neurological deficits) with the exclusion of other causes and characteristic imaging findings. The median age was 35·5 years (range 19–57 years). Seven patients received a matched-unrelated donor transplant and three received a cord blood transplant. The overall incidence of PRES was 1·6%, while the incidence in matched-unrelated, mismatched-related and cord blood transplants was 3·5%, 4·9% and 7·1% respectively. Mental status changes, cognitive deficits, seizures and lethargy were the most common clinical findings. Eight of 10 patients had characteristic findings of hyperintensity of the white matter on T2-weighted images and FLAIR (fluid-attenuated inversion recovery) sequence on magnetic resonance imaging of the brain. Serum tacrolimus levels were within the therapeutic range in most patients. Tacrolimus treatment was continued (n = 4) or temporarily withheld (n = 7) for 1–14 d. One patient was changed to cyclosporine. In most patients, subsequent treatment with tacrolimus was well tolerated without recurrence of neurotoxicity. [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]

Cytomegalovirus (CMV) is associated with significant morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) patients. We evaluated the efficacy of letermovir as primary and secondary prophylaxis in 53 CMV‐seropositive hematopoietic stem cell transplant recipients. 70% of patients were at high risk for CMV reactivation and disease (primarily ex vivo T‐cell–depleted HCT [n = 18; 34%] or haploidentical T‐replete HCT [n = 12; 23%]). This was a retrospective, single‐center study which identified patients transplanted between January 2018 and June 2018. Patients were followed through September 2018. The primary outcome was the incidence of clinically significant CMV infection (CMV viremia requiring preemptive treatment or CMV disease). Primary letermovir prophylaxis started at a median of 7 days (range, 7‐40) after allo‐HCT. The median duration of primary letermovir prophylaxis was 116 days (range, 12‐221). With primary prophylaxis in 39 patients, the observed CMV reactivation rate was 5.1%. Twenty‐nine patients continued primary prophylaxis beyond 14 weeks with a reactivation rate of 3.4%. No recurrent reactivation was seen with secondary prophylaxis of an additional 14 patients. Our experience demonstrates the efficacy of letermovir in a real‐world setting for CMV prevention for the first 14 weeks and continued efficacy when given longer than 14 weeks after allogeneic stem cell transplantation or as secondary prophylaxis. [ABSTRACT FROM AUTHOR]

Background Letermovir (LTV) is approved for the prevention of CMV infection in CMV seropositive (R+) HCT recipients. Low rates of CMV breakthrough viremia have been reported with LTV prophylaxis. We studied the kinetics of CMV reactivation up to day (D) +100 in patients (patients) receiving LTV prophylaxis and compared them to historical controls not receiving LTV. Methods Retrospective cohort study of CMV R+ recipients of peripheral blood or marrow allografts at MSKCC during 2017–2018. Routine LTV prophylaxis was implemented in MSKCC in December 2017. Patients were categorized based on LTV prophylaxis to LTV group (LTV prophylaxis) and no LTV group [managed with preemptive therapy (PET)]. Routine CMV monitoring was performed weekly by a qPCR assay in plasma from D +14 through D +100. CMV viremia was defined as any detectable CMV viral load (VL). Clinically significant CMV viremia (csCMV) was defined as any CMV VL treated preemptively. CMV end-organ disease (EOD) was assessed by standard criteria. LTV resistance was tested at Viracor-Eurofins Laboratories after May 2018. Results Of 193 R+ HCT, 98 (50.8%) were in the LTV and 95 (49.2%) in the no LTV group. CMV viremia occurred in 43 (43.9%) patients in LTV and 63 (66.3%) in no LTV (Figure 1). CMV viremia occurred earlier in LTV compared with no LTV (median, 19 vs. 26 days post HCT, respectively, P = 0.009). The duration of CMV viremia was shorter in LTV compared with no LTV (median 16 days vs. 35 days, respectively; P < 0.0001). The peak CMV VL was lower in LTV compared with no LTV (median, 137 IU/mL vs. 578 IU/mL, respectively); P < 0.0001. Rates of csCMV viremia were significantly lower in LTV compared with no LTV (5.1% vs. 54%, respectively); P < 0.0001 (Figure 2). LTV group received a total of 134 PET-days and no LTV group received 2,160 PET-days by D +100. No patient in LTV developed CMV EOD, while two patients in no LTV developed CMV duodenitis. LTV resistance was documented in 2 patients (2% of the LTV group). Overall survival by D +100 was similar between LTV and no LTV groups. Conclusion Implementation of LTV prophylaxis significantly reduced rates of csCMV infection and resulted in 93.8% reduction in total PET days. Among patients with csCMV viremia, LTV group had a shorter duration of viremia and lower peak CMV VL compared with no LTV. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background: Graft-versus-host disease (GVHD) is one of the leading causes of non-relapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HCT). Methods: We evaluated the outcomes of two well-established strategies used for GVHD prevention: in vivo T cell depletion using antithymocyte globulin (ATG) and ex vivo T cell depletion using a CD34-selected (CD34+) graft. A total of 525 adult patients (363 ATG, 162 CD34+) with intermediate or high-risk cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1) were included. Patients underwent myeloablative allo-HCT using matched related or unrelated donors. Results: Two-year overall survival estimate was 69.9% (95% CI, 58.5–69.4) in the ATG group and 67.6% (95% CI, 60.3–74.9) in the CD34+ group (p = 0.31). The cumulative incidence of grade II–IV acute GVHD and chronic GVHD was higher in the ATG cohort [HR 2.0 (95% CI 1.1–3.7), p = 0.02; HR 15.1 (95% CI 5.3–42.2), p < 0.0001]. Parameters associated with a lower GVHD-free relapse-free survival (GRFS) were ATG [HR 1.6 (95% CI 1.1–2.2), p = 0.006], adverse cytogenetic [HR 1.7 (95% CI 1.3–2.2), p = 0.0004], and the use of an unrelated donor [HR 1.4 (95% CI 1.0–1.9), p = 0.02]. There were no statistical differences between ATG and CD34+ in terms of relapse [HR 1.52 (95% CI 0.96–2.42), p = 0.07], non-relapse mortality [HR 0.96 (95% CI 0.54–1.74), p = 0.90], overall survival [HR 1.43 (95% CI 0.97–2.11), p = 0.07], and leukemia-free survival [HR 1.25 (95% CI 0.88–1.78), p = 0.21]. Significantly, more deaths related to infection occurred in the CD34+ group (16/52 vs. 19/112, p = 0.04). Conclusions: These data suggest that both ex vivo CD34-selected and in vivo ATG T cell depletion are associated with a rather high OS and should be compared in a prospective randomized trial. [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]

With the advent of reduced-intensity conditioning regimens and improvements in supportive care, hematopoietic cell transplantation (HCT) has become increasingly available to older adults and medically vulnerable populations with hematologic diseases. However, adverse outcomes including long-term treatment-related distress, disability (frailty), and death remain important concerns in this population. In other areas of oncology, comprehensive geriatric assessments have been used to stratify patients for treatment-related risk, and patient-reported outcomes (PROs) have helped in understanding treatment-related toxicity from a patient perspective. However, these powerful tools have not yet become widely used in HCT. Here, we review the theories and available data that support the development of pretreatment functional assessments and longitudinal PRO sampling in HCT. We discuss the potential for these techniques to improve transplantation outcomes through risk stratification, interventional studies, and predictive models that incorporate genetic and biomarker data. Predicting and understanding long-term transplantation-related toxicity through functional assessments and PROs will be critical to calculating the risk/benefit ratio of aggressive therapies in older patient populations, and we contend that functional assessments and PRO sampling should become standard parts of the routine evaluation of HCT patients. [ABSTRACT FROM AUTHOR]

BACKGROUNDUnderstanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations.METHODSWe retrospectively investigated patients diagnosed between March 15, 2020, and May 7, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available.RESULTSWe identified 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days; IQR, 354-1611 days). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of nonrebreather or higher oxygen requirement and death (n events = 25 of 77) included number of comorbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host disease was not identified among Allo recipients. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients.CONCLUSIONIn this series of Allo, Auto, and CAR T recipients, we report overall favorable clinical outcomes for patients with COVID-19 without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the antiviral response and immune reconstitution.FUNDINGNIH grant P01 CA23766 and NIH/National Cancer Institute grant P30 CA008748. [ABSTRACT FROM AUTHOR]

• Time to relapse after T cell-depleted hematopoietic cell transplantation defines distinct postrelapse outcomes. • Relapse with extramedullary disease is common and associated with dismal prognosis. • Donor lymphocyte infusion for relapse prevention improves postrelapse survival. Allogeneic hematopoietic cell transplantation (alloHCT) for multiple myeloma (MM), with its underlying graft-versus-tumor capacity, is a potentially curative approach for high-risk patients. Relapse is the main cause of treatment failure, but predictors for postrelapse survival are not well characterized. We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival (OS) in 60 MM patients who progressed after myeloablative T cell-depleted alloHCT. The median patient age was 56 years, and 82% had high-risk cytogenetics. Patients received a median of 4 lines of therapy pre-HCT, and 88% achieved at least a partial response (PR) before alloHCT. Of the 38% who received preemptive post-HCT therapy, 13 received donor lymphocyte infusions (DLIs) and 10 received other interventions. Relapse was defined as very early (<6 months; 28%), early (6 to 24 months; 50%), or late (>24 months; 22%). At relapse, 27% presented with extramedullary disease (EMD). The median postrelapse overall survival (OS) by time to relapse was 4 months for the very early relapse group, 17 months for the early relapse group, and 72 months for the late relapse group (P =.002). Older age, relapse with EMD,

• We assessed toxicities by day 100 associated with preemptive therapy (PET) in a cohort of cytomegalovirus-seropositive hematopoietic cell transplantation recipients. • Neutropenia occurred in 41.8% of PET versus 28.6% of no PET patients (P =.0009). • Acute kidney injury (AKI) occurred in 10.2% of PET versus 7.8% of no PET patients (P =.19). • In multivariate models, PET increased the risk of neutropenia and AKI by 1.8- and 2.8-fold, respectively. (Val)ganciclovir (vGCV) or foscarnet (FCN) as preemptive therapy (PET) for cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT) is associated with myelosuppression and nephrotoxicity, respectively. We analyzed a cohort of CMV-seropositive (R+) HCT recipients managed preemptively at a single center. The objectives of our study were to (1) quantify the frequencies of neutropenia and acute kidney injury (AKI) through day +100 (D100) post-HCT and at PET discontinuation and (2) assess the impact of PET on neutropenia and AKI in multivariate models. This was a retrospective cohort study of adult CMV R+ recipients who underwent allo-HCT at Memorial Sloan Kettering Cancer Center from March 18, 2013, through December 31, 2017, and were managed with PET. Patients were grouped by receipt of PET (PET and no PET). Neutropenia and AKI were defined by Common Terminology Criteria for Adverse Events version 4. Frequencies of toxicities by D100 were compared between relevant groups. The impact of PET on toxicities was examined in univariate and multivariate Poisson/negative binomial regression models. Of 368 CMV R+ HCT recipients, 208 (56.5%) received PET. Neutropenia by D100 occurred in 41.8% and 28.6% patients in PET and no PET, respectively (P =.0009). PET increased the risk of neutropenia (adjusted relative risk = 1.81; 95% confidence interval [CI], 1.48 to 2.21; P <.0001) in multivariate analyses. AKI by D100 occurred in 12.0% and 7.8% patients in PET and no PET, respectively (P =.19). PET increased the risk of AKI by 2.75-fold (95% CI, 1.71 to 4.42; P <.0001). When PET recipients were grouped by first antiviral, neutropenia by D100 occurred in 34.8% and 48.9% of vGCV and FCN recipients, respectively, (P =.08), and AKI occurred in 13.0% and 34.0% of vGCV and FCN recipients, respectively (P =.001). At discontinuation of vGCV or FCN, neutropenia was present in 11.2% versus 2.1% patients, respectively (P =.08), and AKI was present in 1.9% of versus 12.8% patients respectively (P =.005). Preemptive therapy for CMV increased the risk of neutropenia and AKI in the first 100 days post-HCT by 1.8-fold and 2.8-fold, respectively. Our results underscore the need for safer antivirals for CMV management in HCT recipients. [ABSTRACT FROM AUTHOR]

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years the field has not only seen an improvement in transplantation technology, thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells, including chimeric antigen receptor T cells and engineered T-cell receptors, has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established a multiple stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on indications for HCT and IECT. This article presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but have been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exists but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early-phase clinical studies show HCT/IECT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available. [ABSTRACT FROM AUTHOR]

• Isavuconazole as primary antifungal prophylaxis after allogeneic HCT was safe and effective in our study cohort. • Seven patients (7.4%) stopped prophylaxis due to treatment emergent toxicity. • Three patients (3.1%) developed breakthrough candidemia while on isavuconazole therapy. Isavuconazole is a broad-spectrum triazole approved for treatment of invasive fungal infections (IFIs). In this open-label, single-arm study, we evaluated isavuconazole for antifungal prophylaxis after allogeneic hematopoietic cell transplantation (HCT). Adult patients admitted for first HCT received micafungin 150 mg i.v. daily from admission through day +7 (D+7) post-transplantation (±2 days) followed by isavuconazole prophylaxis (i.v./p.o. 372 mg every 8 hours for 6 doses and then 372 mg daily) through maximum D+98 post-HCT. Patients were followed through D+182. The primary endpoint was prophylaxis failure, defined as discontinuation of prophylaxis for proven/probable IFI; systemic antifungal therapy for >14 days for suspected IFI; toxicity leading to discontinuation; or an adverse event. Between June 2017 and October 2018, 99 patients were enrolled in the study, of whom 95 were included in our analysis. The median patient age was 57 years (interquartile range [IQR], 50 to 66 years). Sixty-four (67%) patients received peripheral blood, 17(18%) received bone marrow, and 14 (15%) received a cord blood allograft for acute leukemia (55%), lymphoma (17%), myelodysplastic syndrome (16%), or another hematologic disease (14%). One-third (n = 31; 33%) of patients underwent CD34+-selected HCT. Isavuconazole prophylaxis was given for a median of 90 days (IQR, 87 to 91 days). Ten patients (10.7%) met the primary endpoint. Candidemia occurred in 3 patients (3.1%), 1 of whom had grade III skin acute graft-versus-host disease (GVHD). Toxicity leading to discontinuation occurred in 7 patients (7.4%). The most common toxicity was liver function abnormalities in 5 patients, including grade 1 transaminitis in 2 patients and grade 3 hyperbilirubinemia in 3 patients. Four patients (4.2%) had early discontinuation of isavuconazole for reasons not meeting the primary study endpoint. Six patients died during the study period, including 3 during prophylaxis and 3 during follow-up. No deaths were attributed to isavuconazole. The majority (85%) of allogeneic HCT recipients completed isavuconazole prophylaxis according to protocol. The rate of breakthrough candidemia was 3.1%, and there were no invasive mold infections. Our data support the utility of isavuconazole for antifungal prophylaxis after HCT. [ABSTRACT FROM AUTHOR]

• Antithymocyte globulin (ATG) is given with the patient in a lymphodepleted state before ex vivo CD34+ selected allogeneic hematopoietic cell transplantation. • Standard weight-based ATG dosing results in heavier patients receiving high total ATG doses. • High total ATG doses results in higher nonrelapse mortality and inferior disease-free survival and overall survival. Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was.0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P =.029), disease-free survival (DFS) rates were 37% and 61%, respectively (P =.003), and OS rates were 40% and 67%, respectively (P =.001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P =.01), shorter DFS (HR, 2.0; P =.03), and inferior OS (HR, 2.1; P =.01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG. [ABSTRACT FROM AUTHOR]

• In this retrospective analysis, high-risk molecular mutations were found to not affect outcomes of patients with myelofibrosis (MF) undergoing allogeneic hematopoietic cell transplantation (HCT). • The presence of U2AF1 mutations was associated with worsened overall survival and relapse-free survival in patients undergoing allo-HCT for MF. • Further studies with larger cohorts are needed to further assess the role of molecular mutations in the field of MF and allo-HCT. Mutational profiling has demonstrated utility in predicting the likelihood of disease progression in patients with myelofibrosis (MF). However, there is limited data regarding the prognostic utility of genetic profiling in MF patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We performed high-throughput sequencing of 585 genes on pre-transplant samples from 101 patients with MF who underwent allo-HCT and evaluated the association of mutations and clinical variables with transplantation outcomes. Overall survival (OS) at 5 years post-transplantation was 52%, and relapse-free survival (RFS) was 51.1 % for this cohort. Nonrelapse mortality (NRM) accounted for most deaths. Patient's age, donor's age, donor type, and Dynamic International Prognostic Scoring System score at diagnosis did not predict for outcomes. Mutations known to be associated with increased risk of disease progression, such as ASXL1, SRSF2, IDH1/2, EZH2 , and TP53 , did not impact OS or RFS. The presence of U2AF1 (P =.007) or DNMT3A (P =.034) mutations was associated with worse OS. A Mutation-Enhanced International Prognostic Scoring System 70 score was available for 80 patients (79%), and there were no differences in outcomes between patients with high risk scores and those with intermediate and low risk scores. Collectively, these data identify mutational predictors of outcome in MF patients undergoing allo-HCT. These genetic biomarkers in conjunction with clinical variables may have important utility in guiding transplantation decision making. [ABSTRACT FROM AUTHOR]

• Immune cytopenia rates appears similar for ex vivo CD34+-selected and unmodified allo-HCT. • Reduced donor T cell immunity does not appear to increase risk of IC in allograft recipients. • IC is associated with a higher relapse risk after ex vivo CD34+-selected allo-HCT. Immune-mediated cytopenias (ICs), such as immune thrombocytopenia and immune hemolytic anemia, are among the adverse events after allogeneic hematopoietic cell transplantation (allo-HCT). Previous reports suggest that in vivo T cell depletion may increase the incidence of IC after allo-HCT. We evaluated whether a strategy that reduces functional donor T cells via ex vivo CD34+-selection associates with the development of IC in a cohort of 408 patients who underwent allo-HCT for hematologic malignancy. The cumulative incidence of IC at 6, 12, and 36 months after the 30-day landmark post-HCT was 3.4%, 4.9%, and 5.8%, respectively. Among 23 patients who developed IC, 7 died of relapse-related mortality and 4 of nonrelapse mortality. A median 2 types of treatment (range, 1 to 5) was required to resolve IC, and there was considerable heterogeneity in the therapies used. In univariable analyses, a hematologic malignancy Disease Risk Index (DRI) score of 3 was significantly associated with an increased risk of IC compared with a DRI of 1 or 2 (hazard ratio [HR], 4.12; P =.003), and IC (HR, 2.4; P =.03) was associated with increased risk of relapse. In a multivariable analysis that included DRI, IC remained significantly associated with increased risk of relapse (HR, 2.4; P =.03). Our findings show that IC events occur with relatively similar frequency in patients after ex vivo CD34+-selected allo-HCT compared with unmodified allo-HCT, suggesting that reduced donor T cell immunity is not causative of IC. Moreover, we noted a possible link between its development and/or treatment and increased risk of relapse. [ABSTRACT FROM AUTHOR]

Highlights • CMV viremia was associated with substantial PET use and hospitalizations. • PET use was 3-fold higher in CD34-selected compared with conventional HCT. • CMV viremia increased the number and length of stay of readmissions in CD34-selected HCT. • One-third of readmissions among CD34-selected HCT were for CMV management. Abstract We quantified cytomegalovirus (CMV) antiviral use and hospital length of stay (LOS) associated with CMV infection in a contemporary cohort of conventional (CONV) and CD34-selected (T cell–depleted) hematopoietic cell transplantation (HCT) recipients managed by preemptive therapy (PET) in a single US center. Adults who received first allogeneic HCT at Memorial Sloan Kettering Cancer Center from June 2010 through December 2014 were analyzed. Days on PET, number of readmissions, and readmission LOS by day 180 post-HCT were summarized. Estimated unit value (EUV) was defined as the expected number of PET days for a cohort of 100 HCT with characteristics as the analyzed cohort. Standardized incidence ratio was calculated as the ratio of observed outcomes of patients with CMV viremia over the outcomes of patients without CMV viremia. Of 318 patients, 88 received CONV and 230 CD34-selected HCT. Rates of CMV viremia were 26.3% for CONV and 41.9% for CD34-selected (P =.003). Among patients with viremia 68.2% CONV and 97.9% CD34-selected received PET. EUV for PET was 852 days and 2821 days for CONV and CD34-selected, respectively. The standardized incidence ratios for number of readmission and readmission LOS were 1.7 (95% confidence interval [CI], 1.4 to 2.1) and 1.2 (95% CI, 1.1 to 1.3), respectively, for CONV HCT and 1.7 (95% CI, 1.3 to 2.1) and 1.6 (95% CI, 1.5 to 1.7), respectively, for CD34-selected HCT. Overall survival was similar between patients with and without CMV viremia by HCT type. CMV end-organ disease was associated with lower overall survival only in CD34-selected HCT (P =.0007). CMV infection managed by PET requires substantial antiviral use and is associated with longer readmission LOS more, particularly among CD34-selected HCT. [ABSTRACT FROM AUTHOR]

• Telehealth use for follow-up care delivery is feasible across different hematopoietic cell transplantation types. • Patients report greater satisfaction with telehealth use compared with providers. • Feedback is essential to optimize telehealth usability and provider satisfaction. Telehealth involves the use of telecommunication and information technology for the delivery of clinical care and may be a mechanism to alleviate the burden of visits faced by patients undergoing hematopoietic cell transplantation (HCT). Few studies have evaluated the feasibility and acceptability of telehealth visits in the care of HCT patients. We conducted 27 telehealth visits with 25 patients undergoing HCT using a videoconferencing system that allows for real-time, 2-way interactions and administered satisfaction surveys to patients and providers. Of the 25 patients included in the study, 20 (80%) and 5 (20%) were undergoing autologous and allogeneic HCT, respectively. The telehealth visits were distributed as follows: 3 inpatient visits upon admission for HCT; 11 inpatient visits between 2 and 14 days post-HCT; 4 inpatient visits prior to discharge after HCT; 8 outpatient, post-HCT follow-up visits; and 1 handoff to a community oncologist. Out of a total of 54 provider assessments, 7 providers (13%) were unable to complete some part of the physical examination, but no provider reported being unable to manage patients' symptoms through telehealth. Eighty-one percent of patients were either satisfied or very satisfied with the telemedicine session. Overall satisfaction was higher among patients than providers (mean scores 4.12 versus 2.64; scale 1 to 5, with 1 = very poor to 5 = excellent). Technological barriers resulting in delays and suboptimal physical examination were largely responsible for provider dissatisfaction. The use of telehealth to deliver comprehensive follow-up care to HCT patients is feasible across different HCT types but is dependent upon quality of data streaming and videoconferencing technologies. [ABSTRACT FROM AUTHOR]

Ex vivo CD34 + selection before allogeneic hematopoietic stem cell transplantation (allo-HCT) reduces graft-versus-host disease without increasing relapse but usually requires myeloablative conditioning. We aimed to identify toxicity patterns in older patients and the association with overall survival (OS) and nonrelapse mortality (NRM). We conducted a retrospective analysis of 200 patients who underwent CD34 + selection allo-HCT using the ClinicMACS® system between 2006 and 2012. All grade 3 to 5 toxicities by CTCAE v4.0 were collected. Eighty patients aged ≥ 60 years with a median age of 64 (range, 60 to 73) were compared with 120 patients aged < 60 years. Median follow-up in survivors was 48.2 months. OS and NRM were similar between ages ≥ 60 and <60, with 1-year OS 70% versus 78% ( P  = .07) and 1-year NRM 23% versus 13% ( P  = .38), respectively. In patients aged ≥ 60 the most common toxicities by day 100 were metabolic, with a cumulative incidence of 88% (95% CI, 78% to 93%), infectious 84% (95% CI, 73% to 90%), hematologic 80% (95% CI, 69% to 87%), oral/gastrointestinal (GI) 48% (95% CI, 36% to 58%), cardiovascular (CV) 35% (95% CI, 25% to 46%), and hepatic 25% (95% CI, 16% to 35%). Patients aged ≥ 60 had a higher risk of neurologic (HR, 2.63 [95% CI, 1.45 to 4.78]; P  = .001) and CV (HR, 1.65 [95% CI, 1.04 to 2.63]; P  = .03) toxicities but a lower risk of oral/GI (HR, .58 [95% CI, .41 to .83]; P  = .003) compared with those aged < 60. CV, hepatic, neurologic, pulmonary, and renal toxicities remained independent risk factors for the risk of death and NRM in separate multivariate models adjusting for age and hematopoietic cell transplantation–specific comorbidity index. Overall, the toxicity of a more intense regimen is potentially balanced by the absence of toxicity related to methotrexate and calcineurin inhibitors in older patients. Prospective study of toxicities after allo-HCT in older patients is essential. [ABSTRACT FROM AUTHOR]

We retrospectively analyzed the outcomes of all acute myelogenous leukemia (AML) patients in first remission (n = 44; median age = 48 years; high-risk cytogenetics = 59%) who received unrelated donor hematopoietic cell transplantation (HCT) with myeloablative conditioning regimen of i.v. busulfan, fludarabine, and antithymocyte globulin (ATG) between January 2002 and November 2009 at our institution. Donor-recipient pairs were matched by high-resolution HLA-A, -B, -C, -DRB1, and -DQB1 typing (10/10 matches, n = 41; 9/10 matches, n = 3). With a median follow-up of 34 months, actuarial 3-year event-free survival (EFS) and overall survival (OS) is 70% and 78%, respectively. The 3-year EFS and OS in patients with and without poor risk cytogenetics is similar (63% versus 82%, P = 0.43 and 78% versus 82%, P = .89, respectively). The 3-year EFS and OS is also similar in patients above age 55 year versus patients age 55 year or younger (80% versus 67%, P = .47 and 80% versus 78%, P = .81, respectively). The 100-day and 3-year cumulative incidence of transplant-related mortality is 5% and 15%, respectively. Six patients have relapsed, and 3 of them are alive and in remission after salvage therapy, with a median follow-up of 23 months. These results indicate that the majority of AML patients eligible for this treatment can achieve long-term disease control. [Copyright &y& Elsevier]

Abstract: Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced-intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% confidence interval [CI] 10%-21%) and 33% (95% CI 25%-41%), respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and the Karnofsky Performance Scale (KPS) <90 were significant risk factors for TRM, PFS, and OS, whereas chemosensitivity at transplantation was not. Dose intensity of the conditioning regimen (RIC versus NST) did not impact outcomes. Unrelated donor HCT with RIC/NST can salvage some patients with relapsed/refractory HL, but relapse remains a common reason for treatment failure. Clinical studies should be aimed at reducing the incidence of acute graft-versus-host disease (GVHD) and relapse. [Copyright &y& Elsevier]

Abstract: We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with i.v. busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. Sixty-seven patients received BuCy2, and subsequently, 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these nonrandomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 versus 39 years, P < .01), more often had unrelated donors (47.3% versus 20.9%, P < .0003), and had shorter median follow-up (39.7 versus 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome (“period” effects), 78 acute myelogenous leukemia (AML) patients receiving Melphalan-Flu (MF), treated in parallel during this time (1997-2004) were used to estimate the period effect. The MF patients'' outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in the first complete remission (CR1) had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, whereas CR1 patients younger than age 41 had a 3-year EFS of 83%. These results support replacing BuCy ± ATG with Bu-Flu ± rabbit-antithymocyte globulin (ATG), and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1. [Copyright &y& Elsevier]

Abstract: The treatment of steroid-refractory acute graft-versus-host disease (aGVHD) remains a clinical challenge, for which no standard therapy exists. Alemtuzumab is a humanized anti-CD52 monoclonal antibody (mAb) that has been successfully used as part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) to prevent GVHD. The purpose of this study was to evaluate the safety and efficacy of alemtuzumab in treating steroid-refractory aGVHD (≥grade II) following HSCT. Eighteen patients received subcutaneous alemtuzumab 10 mg daily on 5 consecutive days. Response was assessed at day 28 following initiation of alemtuzumab. Eight patients had grade II aGVHD, 8 had grade III, and 2 had grade IV. The main organ involved was the liver in 4 patients, gastrointestinal (GI) tract in 5, skin in 3, skin and liver in 3, and skin and GI tract in 3. Fifteen patients (83%) responded to alemtuzumab, including 6 (33%) with complete response. All 3 unresponsive patients died of GVHD. Ten of 15 responders are alive at median follow-up of 11 months (range: 3-24). Infections occurred in 14 patients, including cytomegalovirus (CMV) reactivation in 11. Grade 3 neutropenia and thrombocytopenia occurred in 6 and 4 patients, respectively. Alemtuzumab was well tolerated, and induces promising response rates in steroid-refractory aGVHD. [Copyright &y& Elsevier]

Endothelial Activation and Stress Index (EASIX), a surrogate of endothelial dysfunction, is a powerful tool for predicting non-relapse mortality (NRM) when evaluated prior to allogeneic hematopoietic cell transplantation (allo-HCT) and at specific landmarks post-HCT. We sought to determine if changes in EASIX over time may also be an informative marker of NRM. We evaluated 509 adults who underwent RIC/NMA unmodified or MAC ex-vivo CD34+-selected allo-HCT between 2008-2016. Unmodified allo-HCT patients (pts) received a GVHD prophylaxis of sirolimus/tacrolimus and low-dose methotrexate. CD34+-selected pts received no planned immunosuppression. EASIX scores (LDH x creatinine/platelet count) were calculated continuously until 1-year post-HCT. A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A 1-unit increase in log2 EASIX is associated with a doubling of EASIX on the original scale. Disease relapse or death were considered competing risks for NRM. 360 pts (71%) received a CD34+-selected and 149 (29%) an unmodified allo-HCT. HLA matched donors were used in 435 (86%) and mismatched in 74 (14%) pts. HCT-CI was 0 in 24% of pts, 1-2 in 32%, and ≥ 3 in 44%. Median age was 56 (range 19-78) and 59% were males. Most unmodified allo-HCTs were done for non-Hodgkin lymphoma (69%), and most CD34+-selected allo-HCTs were done for acute leukemia (61%). Among all patients, EASIX scores increased rapidly, peaked at day +8, then declined until day +40. Thereafter, scores decreased but remained above pre-HCT baseline for the first year (Figure 1a). In unmodified pts, EASIX scores appeared higher over time than in CD34+-selected pts, whose scores rapidly decreased by 2 months post-HCT (Figure 1b). EASIX's ability to discriminate NRM in the subsequent 180 days was similar when analyzed as a categorical variable at landmark timepoints and as change from pre-HCT. EASIX discrimination of NRM was highest between day +180 to +210 (concordance index=0.85) (Figure 2). At this landmark, pts with log EASIX >2 died of infection (14%), GVHD (29%), relapse (33%), and other causes (25%) in the subsequent 180 days. Mean EASIX scores at this landmark were higher in men (mean log2 +0.52) and in pts who developed grade 2-4 GVHD by day +180 (+0.81), lower in pts who received matched unrelated versus mismatched donors (-0.81, all P<0.01), and did not differ based on disease. After day +30, pts who did not die of NRM had consistently lower EASIX scores compared to pts who died of NRM in the subsequent 180 days (Figure 3). EASIX scores are dynamic and variably concordant with NRM when analyzed longitudinally post-HCT, and patterns differ between allo-HCT platforms. Compared to pre-HCT evaluation, dynamic EASIX scores may better predict risk of NRM over time as pts acquire additional endothelial injury and toxicities along the allo-HCT journey. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (allo-HCT) allows for the possibility of cure in patients (pts) with Non-Hodgkin Lymphoma (NHL) as it provides an immunologic graft-versus-lymphoma effect. Non-relapse mortality (NRM) was prohibitive in myeloablative regimens, but technical advances with the advent of reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) regimens have decreased these rates. RIC regimens are generally associated with more toxicity and higher NRM than NMA regimens. Though studies showed both approaches are safe and effective, there is lack of direct comparison between these different intensities in NHL. This retrospective study identified pts aged ≥ 18 years who underwent allo-HCT for relapsed/refractory NHL between 3/2008-6/2017 at our center. Outcomes were compared between pts who received NMA and RIC conditioning, with intensity defined per CIBMTR. Progression-free survival (PFS) was the primary outcome. Secondary outcomes included overall survival (OS) and non-relapse mortality (NRM). Additional outcomes included rates of acute GVHD at Day 100, chronic GVHD, and CMV reactivation at Day 100. Regimen intensity and other variables significant by univariate analysis were included in the multivariate analysis For the 144 pts identified, median age was 56 years (range, 19-79). More pts received NMA regimens (n=80, 56%) and most did not undergo prior autologous HCT (n=103, 72%). NMA regimens were given more frequently to pts with indolent B-cell lymphoma and were more likely to receive ATG and/or rituximab (p = 0.008, p < 0.001, and p < 0.001, respectively). At a median overall follow-up of 57.8 months (range 49 - 75.1) neither median PFS or OS were reached. In univariate analysis, NMA conditioning was associated with a longer PFS than RIC [HR 1.9 (1.11-3.24), p = 0.019). No difference was found in OS [HR 1.56 (0.85-2.85), p = 0.15). There was an increase in all grades of aGVHD [HR 3.68 (2.16, 6.28), p < 0.001)] with RIC regimens, but only 12 events of grade III/IV aGVHD overall. In multivariate analyses (with histology and ATG as covariates) NMA with rituximab had improved PFS compared to RIC without rituximab [HR 0.43 (95% CI 0.22, 0.81; p=0.009)]. However, PFS was similar comparing NMA and RIC groups [HR 0.72 (95% CI 0.37, 1.41; p=0.3)]. Similarly, aGVHD (any grade) risk was lower in NMA pts receiving rituximab compared to RIC pts who did not [HR 0.15 (0.07-0.32), p < 0.001). No significant differences were noted in NRM or CMV reactivation between groups. Our study suggests that there are comparable and favorable outcomes between RIC and NMA regimens in allo-HCT for NHL with careful patient and regimen selection. Further studies are needed to better define criteria in choosing between NMA and RIC allo-HCT regimens for pts with NHL. [ABSTRACT FROM AUTHOR]

Retrospective studies indicate that the use of unrelated hematopoietic stem cell donors with Killer Ig-like Receptor (KIR) genotypes resulting in low inhibitory interactions with recipient HLA are associated with lower relapse and higher survival in patients with myeloid neoplasia undergoing allogeneic hematopoietic cell transplantation (allo HCT). To validate these findings in a prospective fashion and to determine if advantageous KIR donors can readily be identified for patients with myeloid neoplasia, we prospectively KIR genotyped and provided KIR/HLA-based ranking for unrelated donors (URD) evaluated for patients with a diagnosis of acute myeloid leukemia or myelodysplastic syndrome undergoing workup at our center for allo HCT. Donors were prioritized first to minimize inhibitory KIR3DL1 - HLA-Bw4 interactions, followed by prioritization of donors with non-tolerized activating KIR2DS1, and finally prioritizing donors homozygous for the centromeric B haplotype. We evaluated 2,079 donors for 527 patients (median 4 donors per patient), among whom 263 ultimately underwent allo HCT. In a multivariate analysis adjusting for age, HCT-CI, and conditioning intensity, we found that the use of a KIR3DL1-low-inhibition donor was associated with an improved hazard for survival (HR = 0.58 (95% confidence interval (CI): 0.35 – 0.96), P = 0.035) and event-free survival (HR = 0.61 (95% CI: 0.39 – 0.93), P = 0.023) due to a decreased hazard for relapse (HR = 0.52, 95% CI: 0.30 – 0.90, P = 0.021) without increased non-relapse mortality when compared to KIR3DL1-non-interacting or -high-inhibition donors. Donor KIR2DS1/HLA-C1 status and centromeric haplotype B content were not predictive of relapse or survival in this cohort. Among 339 HLA-Bw4+ patients evaluated for transplant, 242 (71.4%) had an available KIR3DL1-low-inhibition donor and 205 (60.5%) had a mixture of KIR3DL1-low-inhibition with either -high-inhibition or -non-interacting donors facilitating a choice using donor KIR3DL1 genotyping. Evaluating greater numbers of donors associated with an increased probability of identifying an advantageous donor based on inhibitory KIR3DL1 interactions (P < 0.0001). We found that acquisition of a KIR3DL1-low-inhibition donor did not increase the time from formalized URD search to transplantation when compared to KIR3DL1-Neutral/Disadvantageous donors (mean 147 vs. 119 days, respectively, P = 0.34). Donor age and CMV serostatus were similar among KIR3DL1-Advantageous versus non-advantageous donors. In summary, this single center study demonstrates that donor KIR typing and prioritization of low inhibition KIR3DL1 donors is feasible and favors protection from relapse in patients with myeloid neoplasia. [ABSTRACT FROM AUTHOR]

We recently showed that empiric weight-based ATG dosing in heavier patients (pts) prior to ex vivo CD34-selected allogeneic hematopoietic cell transplantation (allo-HCT) is associated with high non-relapse mortality (NRM) and poor survival. A more precise method is to assess the relationship between ATG pharmacokinetic (PK) exposure and outcomes. Therefore, we estimated ATG exposure using a population PK model and hypothesized that peri-HCT ATG overexposure would similarly result in unfavorable outcomes secondary to poorer immune reconstitution (IR). We studied 415 consecutive adult pts who underwent first myeloablative ex vivo CD34-selected allo-HCT with ATG (Thymoglobulin) between 2006 and 2017. We estimated pre-/post-HCT and total ATG area under the curve (AUC, in mg*d/L) for all pts using an established PK model (Admiraal et al., Lancet Hematol 2017). We evaluated the association between ATG exposure and outcomes using a nonparametric estimate of median relapse-free survival (RFS) by ATG exposure to define an optimal ATG AUC cut point (highest RFS) that was used to estimate RFS and NRM. We also evaluated how CD4+ T cell IR related to NRM in a subgroup of 232 pts with sufficient data. IR was defined according to prior studies as absolute CD4+ ≥ 50 at ≥ 2 time points before day +100 and 1 subsequent time point within 60 days. Among all pts, median age was 55 (range, 19-73), 228 (55%) were male, 204 (49%) had AML, 105 (25%) MDS, 50 (12%) ALL, and 56 (14%) other hematologic diseases. HCT-CI was 0 in 85 (20%), 1-2 in 146 (35%), and ≥ 3 in 184 (45%) of pts. Allografts were HLA matched related in 150 (36%), matched unrelated in 202 (49), and mismatched in 63 (15%). CMV serostatus was positive in 251 (60%). Conditioning regimens were chemotherapy based in 279 (67%) and TBI based in 136 (33%). All but 2 pts, who were inevaluable given early deaths, engrafted. All pts received 1-3 doses of ATG 2.5 mg/kg between days -4 and -1: 361 (87%) received 2 doses, 47 (11%) 3 doses, and 7 (2%) 1 dose. Among all pts, median estimated ATG AUC values were: pre-HCT 19 (range, 9-36), post-HCT 48 (range, 17-101), and total 66 (29-125). Median follow-up among survivors was 3.9 years (range, 0.7-12). A post-HCT ATG AUC of >60 was associated with poorer median predicted RFS (Figure 1). Pts with an estimated post-HCT ATG AUC of >60 and <60, respectively, had 5-year RFS of 31% and 55%, p=0.008 and higher 5-year NRM of 51% and 22%, p<0.001 (Figure 2). Pts who did not have or had IR, respectively, by day +100 post-HCT had higher 5-year NRM, 34% versus 8%, p<0.001 (Figure 3). Population PK modeling confirms that post-HCT ATG overexposure in certain pts undergoing ex vivo CD34-selected allo-HCT leads to inferior RFS and markedly higher NRM possibly due to poor IR. Identifying the optimal ATG exposure and individualizing ATG dosing may improve early CD4+ IR and ultimately improve survival in these pts. [ABSTRACT FROM AUTHOR]

Co-morbidities are essential for risk-stratification before allogeneic hematopoietic stem cell transplantation (HCT). We hypothesized that only certain components of the co-morbidity index (HCT-CI) are predictive of outcomes, and that their impact is conditioning-regimen dependent. This retrospective single-center analysis included 580 adult patients who underwent HCT with ex-vivo CD34+ selection following myeloablative conditioning between 2008 and 2018. Chemotherapy and total body irradiation (TBI)-based conditioning were given to 75% and 25% of patients, respectively. Common co-morbidities in the population included mild/severe hepatic dysfunction (25%), moderate and severe pulmonary disease (32% and 11%, respectively), prior malignancy (14%), and psychiatric disorders (13%). The median HCT-CI was 2 (IQR 1-3). Among co-morbidities meeting statistical criteria for analysis (prevalence >5% and association with at least 5 outcome events), only severe and moderate pulmonary dysfunction (Figure 1) were associated with decreased overall survival (OS) and increased non-relapse mortality (NRM; HR 1.37, p.023; HR 1.94 p<.001, respectively) in a multivariable Cox model. Using cubic splines, we found that the increase in mortality was mainly attributed to hemoglobin-adjusted DLCO, with an linear increase in mortality risk as DLCO decreases from 80. There was a trend towards poorer OS in the univariate analyses of cardiac disease (p.085) and obesity (p.068). While hepatic dysfunction, defined as either mild or more severe hepatic comorbidity, was not associated with decreased OS in the complete cohort, there was an increased risk in patients conditioned with TBI (HR 2.361, p.004), but not with chemotherapy (HR 0.81, p.234) (Figure 2). Among patients with moderate pulmonary disease, the HR for overall mortality was 1.49 (p.007) in the TBI group and 1.11 (p.170) in the chemotherapy group. Our findings suggest that, in CD34+ selected HCT, only certain co-morbidities included in the HCT-CI are likely to contribute to the prognostic assessment of transplantation candidates. Reevaluation of the additive role of co-morbidities in this setting is warranted. In addition, the hazard of co-morbidities may be regimen-dependent, introducing another consideration when selecting the conditioning modality. [ABSTRACT FROM AUTHOR]