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Abstract Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma. [ABSTRACT FROM AUTHOR]

Treatment options for newly diagnosed aplastic anemia (AA) patient includes upfront allogeneic hematopoietic stem cell transplant (HSCT) or immunosuppressive therapy (IST). With recent advances in supportive care, conditioning regimens and post-transplant immunosuppression the overall survival for HSCT approaches 70–90%. Transplant eligibility needs to be assessed considering age, comorbidities, donor availability and probability of response to immunosuppressive therapy (IST). Upfront HSCT should be offered to children and young adults with matched related donor (MRD). Upfront HSCT may also be offered to children and young adults with rapidly available matched unrelated donor (MUD) who require urgent HSCT. Bone marrow (BM) graft source and cyclosporine (CsA) plus methotrexate (MTX) as graft versus host disease (GVHD) prophylaxis are preferable when using anti-thymocyte globulin (ATG) based conditioning regimens. Alemtuzumab is an acceptable alternative to ATG and is used with CsA alone and with either BM or peripheral blood stem cells (PBSC). Cyclophosphamide (CY) plus ATG conditioning is preferable for patients receiving MRD transplant, while Fludarabine (Flu) based conditioning is reserved for older adults, those with risk factors of graft failure and those receiving MUD HSCT. For haploidentical transplant, use of low dose radiotherapy and post-transplant cyclophosphamide has resulted in a marked reduction in graft failure and GVHD. • Transplant outcomes for aplastic anemia continues to improve with time, overall survival after MUD and Haploidentical transplant is now approaching MRD HSCT. • Bone marrow graft source and cyclosporine plus methotrexate GVHD prophylaxis are preferable. • Cyclophosphamide plus ATG conditioning is preferable for younger patients receiving MRD transplant, while Fludarabine based conditioning is reserved for older adults, with risk factors for graft failure and those receiving MUD HSCT. [ABSTRACT FROM AUTHOR]

The practice of choosing the next best therapy for patients with relapsed and/or refractory multiple myeloma (RRMM) is becoming increasingly complex. There is no clear consensus regarding the best treatment sequence for RRMM. With the approval of novel proteasome inhibitors (ixazomib and carfilzomib), immunomodulatory agents (pomalidomide), monoclonal antibodies (daratumumab and elotuzumab), and other targeted therapies, multiple combination regimens utilizing these agents are being studied with the goal of enhancing disease control, prolonging progression-free survival, and improving overall survival. We, herein, describe a review of FDA-approved regimens for RRMM patients and offer a paradigm in selecting subsequent treatment regimens, focusing on patient specific morbidity, treatment toxicity, and disease-specific characteristics. [ABSTRACT FROM AUTHOR]

Background: Acquired thrombocytopenia (aTP) is associated with a high frequency of bleeding and ischemic complications in patients undergoing percutaneous coronary intervention (PCI). Herein, we report a meta-analysis evaluating the adverse effects of aTP on cardiovascular outcomes and mortality post-PCI.Methods: A literature search was performed using PubMed, Embase, Cochrane and, clinicaltrials.gov from the inception of these databases through October 2019. Patients were divided into two groups: 1) No Thrombocytopenia (nTP) and 2) Acquired Thrombocytopenia (aTP) after PCI. Primary endpoints were in-hospital, 30-day and all-cause mortality rates at the longest follow-up. The main summary estimate was random effects Risk ratio (RR) with 95% confidence intervals (CIs).Results: Seven studies involving 57,247 participants were included. There was significantly increased in-hospital all-cause mortality (HR 10.73 [6.82-16.88]), MACE (HR 2.96 [2.24-3.94]), major bleeding (HR 4.78 [3.54-6.47]), and target vessel revascularization (TVR) (HR 7.53 [2.8-20.2]), in the aTP group compared to the nTP group. Similarly, aTP group had a statistically significant increased incidence of 30-day all-cause mortality (HR 6.08), MACE (HR 2.77), post-PCI MI (HR 1.98), TVR (HR 5.2), and major bleeding (HR 12.73). Outcomes at longest follow-up showed increased incidence of all-cause mortality (HR 3.98 [1.53-10.33]) and MACE (HR 1.24 [0.99-1.54]) in aTP group, while there was no significant difference for post-PCI MI (HR 0.94 [0.37-2.39]) and TVR (HR 0.96 [0.69-1.32]) between both groups.Conclusions: Acquired Thrombocytopenia after PCI is associated with increased morbidity, mortality, adverse bleeding events and the need for in-hospital and 30-day TVR. [ABSTRACT FROM AUTHOR]

• Graft-versus-host disease (GVHD) often leads to post-transplant morbidity and mortality and can severely compromise quality of life. • Cyclosporine combined with short-course methotrexate is considered standard-of-care GVHD prophylaxis for patients with severe aplastic anemia who undergo transplantation using cyclophosphamide (Cy) plus anti-thymocyte globulin (ATG) conditioning. • Single-agent cyclosporine is a feasible option for GVHD prophylaxis in matched related donor hematopoietic stem cell transplantation using fludarabine-Cy-ATG conditioning and is associated with very low rates of acute and chronic GVHD. Cyclosporine (CsA) combined with short-course methotrexate is considered standard-of-care graft-versus-host disease (GVHD) prophylaxis for patients with severe aplastic anemia (AA) who undergo transplantation using cyclophosphamide (Cy) plus anti-thymocyte globulin (ATG) conditioning. However, there is no consensus on optimal post-transplant GVHD prophylaxis for patients undergoing matched related donor (MRD) transplantation using fludarabine (Flu)-based conditioning. We conducted a single-center retrospective analysis of patients with acquired AA (n = 106) undergoing MRD transplantation from July 2007 through January 2019. All patients received Flu-Cy-ATG conditioning and single-agent CsA as GVHD prophylaxis. Median age of the study cohort was 20 years (range, 3 to 52) and male to female ratio was 3.8:1. Median time from diagnosis to transplant was 11.5 months (range, 2.8 to 62). Graft source was bone marrow harvest in 71 (68%), combined bone marrow and peripheral blood stem cells in 34 (31%), and peripheral blood alone in 1 (1%) patient. Cumulative incidence of neutrophil engraftment at day 28 was 93.4% (95% confidence interval [CI], 87.3% to 97.1%) while that of platelet engraftment at day 100 was 90.5% (95% CI, 84% to 96%). Cumulative incidence of primary graft failure at day 28 was 6.6% (95% CI, 4% to 8%) while secondary graft failure occurred at a median of 190 days (range, 90 to 415) at a cumulative incidence of 3.7% (95% CI, 2% to 5%). Cumulative incidence of grade II to IV acute GVHD at day 100 was 3.8% (95% CI, 1.4% to 9.9%), while a 1-year probability of chronic GVHD was calculated as 7.5% (95% CI, 2.6% to 15%). Median follow-up post-transplant was 61 months (range, 6 to 144). Overall survival was 84.9%, disease-free survival was 80.2%, and GVHD-free relapse-free survival was 76.3%. This study indicates that single-agent cyclosporine is a feasible option for GVHD prophylaxis in MRD hematopoietic stem cell transplantation using Flu-Cy-ATG conditioning and is associated with very low rates of acute and chronic GVHD. [ABSTRACT FROM AUTHOR]

Relapse after stem cell transplantation for Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) remains a significant challenge. In this systematic review, we compare survival outcomes of second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib with first-generation TKI imatinib when these agents are used after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Ph+ ALL. In addition, we review the literature on TKI use to prevent relapse in patients who proceed to allo-HSCT beyond first complete response (>CR1). We performed database searches (inception to January 2018) using PubMed, Cochrane Library, and Embase. After exclusions, 17 articles were included in this analysis. Imatinib was used post-transplant either prophylactically or preemptively in 12 studies, 7 prospective studies and 5 retrospective studies. Overall survival (OS) for most prospective studies at 1.5 to 3 and 5 years ranged between 62% to 92% and 74.5% to 86.7%. Disease-free survival at 1.5 to 5 years was 60.4% to 92%. Additionally, imatinib failed to show survival benefit in patients who were >CR1 at the time of allo-HSCT. The cumulative OS for most retrospective studies using imatinib at 1 to 2 and 3 to 5 years was 42% to 100% and 33% to 40% respectively. Event-free survival at 1 to 2 and 3 to 5 years was 33.3% to 67% and 20% to 31% respectively. Dasatinib was used as maintenance treatment in 3 retrospective studies (n = 34). The OS for patients with Ph+ ALL using dasatinib as maintenance regimen after allo-HSCT at 1.4 to 3 years was 87% to 100% and disease-free survival at 1.4 to 3 years was 89% to 100%. Ninety-three percent of patients with minimal residual disease (MRD) positive status after allo-HSCT became MRD negative. Three prospective studies used nilotinib. In 2 studies where investigators studied patients with advanced chronic myeloid leukemia and Ph+ ALL, the cumulative OS and event-free survival at 7.5 months to 2 years were 69% to 84% and 56% to 84%, respectively. In the third study (n = 5) in patients with Ph+ ALL, nilotinib use resulted in OS at 5 years of 60%. Our review showed that use of TKIs (all generations) after allo-HSCT for patients in CR1 improved OS when given as a prophylactic or preemptive regimen. Limited data suggest that second-generation TKIs (ie, dasatinib) have a better OS, especially in patients with MRD-positive status. Imatinib did not improve OS in patients who were >CR1 at the time of allo-HSCT; for this population, no data were available with newer generation TKIs. The evaluation of survival benefit with newer generation TKIs and their efficacy in patients in >CR1 needs further study in large randomized clinical trials. [ABSTRACT FROM AUTHOR]

• Transplant donors and recipients should be current on their vaccination schedule. • Post-transplant vaccination is crucial to prevent infections. • Transplant recipients should be vaccinated again endemic diseases before travel. • Live vaccines should be avoided in those in close contact with transplant patients. Vaccination is an effective strategy to prevent infections in immunocompromised hematopoietic stem cell transplant recipients. Pretransplant vaccination of influenza, pneumococcus, Haemophilus influenza type b, diphtheria, tetanus, and hepatitis B, both in donors and transplant recipients, produces high antibody titers in patients compared with recipient vaccination only. Because transplant recipients are immunocompromised, live vaccines should be avoided with few exceptions. Transplant recipients should get inactive vaccinations when possible to prevent infection. This includes vaccination against influenza, pneumococcus, H. influenza type b, diphtheria, tetanus, pertussis, meningococcus, measles, mumps, rubella, polio, hepatitis A, human papillomavirus, and hepatitis B. Close contacts of transplant recipients can safely get vaccinations (inactive and few live vaccines) as per their need and schedule. Transplant recipients who wish to travel may need to get vaccinated against endemic diseases that are prevalent in such areas. There is paucity of data on the role of vaccinations for patients receiving novel immunotherapy such as bispecific antibodies and chimeric antigen receptor T cells despite data on prolonged B cell depletion and higher risk of opportunistic infections. [ABSTRACT FROM AUTHOR]

• High-risk aplastic anemia (AA) is associated with inferior overall survival (OS) and disease-free survival (DFS) when conventional cyclophosphamide-based conditioning is used. • Fludarabine-based conditioning is well tolerated, with lower rates of rejection and excellent long-term survival in these high-risk aplastic anemia patients. • High-risk factors identified in our study were prior hematopoietic stem cell transplant (HSCT), age ≥ 20 years, disease duration > 3 months, RBC transfusions > 20, and random platelet transfusions > 50. • Cyclosporine alone as GVHD prophylaxis and marrow source stem cells as graft source are preferable options. • A randomized trial of fludarabine-based versus conventional cyclophosphamide-containing conditioning would be helpful in establishing a standard of care conditioning regimen in high-risk AA patients. Despite excellent transplant outcomes of aplastic anemia (AA) in developed countries, management in developing countries is challenging because of delay in the diagnosis, use of family donors for transfusions, and higher infection risk pretransplant. These factors can lead to allo-immunization, increased risk of graft failure, graft-versus-host disease (GVHD), and transplant-related mortality, leading to unfavorable outcomes. Conventional cyclophosphamide (Cy) and antithymocyte globulin (ATG) are associated with inferior overall survival in such high-risk patients. We conducted single-center retrospective analysis of high-risk AA patients (N = 147) enrolled consecutively and undergoing matched related donor transplant from March 2002 through October 2018. We included high-risk AA patients receiving fludarabine (Flu)-based conditioning. Median patient age was 20 years (range, 3 to 52). The median time from diagnosis to transplant was 11 months (range, 3 to 63). High-risk features included age ≥ 20 years in 55.8% of patients (n = 82), disease duration more than 3 months in 95 % (n = 140), RBC concentrates transfusions > 20 in 79.6% (n = 117), random donor platelet transfusion > 50 in 64.6% of patients (n = 95), and second hematopoietic stem cell transplant (HSCT) in 7.4% (11). We divided patients into 2 groups based on different conditioning regimens. Flu group 1 (Flu1) received Flu 120 to 150 mg/m2, Cy 120 to 200 mg/kg, and ATG 20 mg/kg, and Flu group 2 (Flu2) was given Flu 150 mg/m2, Cy 300 mg/m2, and ATG 20 mg/kg. Bone marrow stem cells were used as graft source in 97% of patients (n = 144) (alone in 52% and with peripheral blood stem cells in 45%). Cyclosporine alone was used for GVHD prophylaxis in 75% (n = 110) and cyclosporine plus methotrexate in 25% (n = 37). Median total nucleated cell dose was 5 × 108/kg. Median days for neutrophil engraftment was 13 (range, 10 to 20) and platelet engraftment 20 (range, 14 to 43). Day 100 mortality was 7.5% (n = 11). Sustained successful engraftment was achieved in 87.8% of patients (n = 129). Most graft failures (40%) occurred in Flu2 conditioning (P =.000) and in patients with >2 risk factors (P =.000). Overall incidence of acute and chronic GVHD was 11.6% (n = 17) and 12.9% (n = 19), respectively, in Flu1 and Flu2 groups. Overall survival (OS), disease-free survival (DFS), and GVHD-free relapse-free survival (GRFS) was 83.7%, 78.2%, and 70.7%, respectively. A trend toward improved OS was observed in patients receiving Flu1 conditioning but was statistically nonsignificant (P =.256), whereas DFS and GRFS were significantly better in Flu1 versus Flu2 (P =.004 and.001, respectively). When stratified per number of risk factors (age > 20, RBC concentrate > 20 or platelet > 50 random, duration > 3 months, previous HSCT), OS and DFS decreased significantly with increasing number of risk factors (P =.000 and.001, respectively). Patients are able to tolerate Flu-based conditioning well with lower rates of rejection and excellent long-term survival in high-risk AA patients. Cyclosporine alone as GVHD prophylaxis and marrow source stem cells as graft source are preferable options. Use of Flu plus low-dose Cy conditioning is associated with inferior survival outcomes. A randomized trial of Flu-based versus conventional Cy-containing conditioning would be helpful in establishing a standard of care conditioning regimen in high-risk AA patients. [ABSTRACT FROM AUTHOR]

Background Conditional survival (CS) is defined as the probability of surviving an additional x years given a patient has already survived y years since diagnosis or a time-point of interest. Although there are readily available overall survival (OS) estimates in multiple myeloma (MM) from the time of diagnosis or autologous stem cell transplantation (ASCT), data on CS in those who had already survived a landmark time since ASCT are lacking. Our objective was to investigate 5-year CS rate and standardized mortality ratio (SMR) in 1-, 3- and 5-year survivors after front-line ASCT in MM. Method We reviewed the institutional transplant database at Cleveland Clinic to identify 340 patients who underwent frontline ASCT (≤18 months from diagnosis) for MM between 1996 and 2013. OS was estimated by the Kaplan-Meier method. Relapse mortality (RM) and non-relapse mortality (NRM) were estimated with cumulative incidence. SMR was defined as the ratio of number of deaths in the study patients to that in an age, sex and race-matched healthy population. Estimates of outcomes and SMR are presented with 95% confidence intervals (CI). Results We identified 309 survivors at 1 year, 246 at 3 years, and 178 at 5 years from ASCT. The median age at ASCT was 56 years (range, 22-76) in all 3 cohorts. The median time from diagnosis to ASCT was 7.9 months in 1- and 3-year and 8.2 months in 5-year survivors. Approximately 40%, 35%, and 25% of patients had ISS stage I, II and III disease respectively at diagnosis in all cohorts. Median follow-up from ASCT in surviving patients was 88 months, 90 months and 100 months in 1-, 3- and 5-year survivors respectively. Estimated 5-year CS was 59% (53-64) in 1-year survivors, 60% (53-67) in 3-year survivors and 62% (53-70) in 5-year survivors. The respective cumulative incidence of 5-year conditional RM was 34% (28-39), 29% (23-35) and 25% (18-33) and that of NRM was 7% (5-11), 11% (7-16) and 13% (8-19). The SMR of 1-year, 3-year and 5-year survivors was 6.9 (5.8-8.2), 6.1 (5.0-7.5) and 5.6 (4.3-7.3) respectively, indicating significantly worse survival compared to demographically-matched healthy population irrespective of the duration of survival after ASCT. Survival curves for the 3 cohorts are shown in Figure I. Conclusion The probability of surviving an additional 5 years in patients with MM undergoing front-line ASCT does not improve with time, as shown in 1-, 3- and 5-year survivors, with estimated 5-year CS staying constant at around 60%. However, a decrease in the magnitude of SMR was observed with increase in the number of years already survived after ASCT. Information on CS and SMR is a pragmatic resource for long-term survivorship and beneficial at an individual level for counselling patients. [ABSTRACT FROM AUTHOR]

Highlights • The use of checkpoint inhibitors (CPIs) in hematologic malignancies before allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with high rates of hyperacute (7%), acute (56%), and chronic (29%) graft-versus-host disease (GVHD). • The use of CPIs in hematologic malignancies after allo-HSCT shows high efficacy but also increases the risk of GVHD (14% acute, 9% chronic). ABSTRACT Investigators are using checkpoint inhibitors (CPIs) to treat aggressive hematologic malignancies in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and in some patients with relapsed disease after allo-HSCT. CTLA-4 inhibitors and PD-1 inhibitors are 2 main types of CPIs, which work through activation of the immune system. On one hand, CPIs can achieve graft-versus-tumor effect, and on the other hand, there is a risk of graft-versus-host disease (GVHD). After a comprehensive literature review, we included data (n = 283) from 24 studies (11 original manuscripts and 13 case reports or case series) and evaluated the results to assess the safety and efficacy of CPI use in conjunction with allo-HSCT. Among the 283 patients, 107 received CPI before allo-HSCT, and 176 received CPI after allo-HSCT. The most common indication for CPI use was for Hodgkin lymphoma. The CPIs used in various studies included ipilimumab, nivolumab, and pembrolizumab. Among the patients exposed to CPI before allo-HSCT, 56% developed acute GVHD and 29% developed chronic GVHD. Investigators reported 20 deaths, 60% of which were GVHD-related. The overall mortality risk with GVHD is 11%. In this group, investigators noted an objective response rate (ORR) in 68% of patients, with complete remission (CR) in 47%, partial remission (PR) in 21%, and stable disease in 11%. Among the patients who received a CPI after allo-HSCT for disease relapse, 14% developed acute GVHD and 9% developed chronic GVHD. Investigators reported 40 deaths, 28% of which were GVHD-related. The mortality risk with GVHD is approximately 7%. Investigators reported ORR in 54% of patients, with CR in 33%, PR in 21%, and disease stabilization in 5%. After careful evaluation of collective data, we found that CPI use both before and after allo-HSCT can be highly effective, but exposure can lead to a significantly increased risk of GVHD-related morbidity and mortality in this patient population. Despite limited availability of data, there is need for extreme caution while making decisions regarding the use of CPIs. Detailed discussions and prospective well-designed clinical trials are needed to explore this issue further. [ABSTRACT FROM AUTHOR]

Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) are at a very high risk of hepatitis B virus reactivation (HBVr). Lamivudine is commonly used as prophylaxis against HBVr in high-risk patients undergoing allo-HSCT. Unfortunately, its efficacy is diminishing due to the development of HBV mutant drug-resistant strains. With the availability of newer antiviral agents such as entecavir, telbivudine, adefovir, and tenofovir, it is important to assess their role in HBVr prophylaxis. A comprehensive search of 7 databases was performed to evaluate efficacy of antiviral prophylaxis against HBVr in allo-HSCT patients (PubMed/Medline, Embase, Scopus, Cochrane Library, Web of Science, CINAHL, and ClinicalTrials.gov (June 21, 2017)). We identified 10 studies, with 2067 patients undergoing allo-HSCT; these primarily evaluated the use of lamivudine and entecavir as prophylaxis against HBVr in patients undergoing allo-HSCT because there were little or no data about adefovir, telbivudine, or tenofovir as prophylaxis in this specific patient population. Thus, included studies were categorized into 2 main prophylaxis groups: lamivudine and entecavir. Results of our meta-analysis suggest that entecavir is very effective against HBVr, although further clinical trials are required to test efficacy of new antivirals and explore the emerging threat of drug resistance. [ABSTRACT FROM AUTHOR]

High grade B-cell lymphoma (HGBCL) by WHO 2016 classification requires rearrangements of MYC and BCL2 and/or BCL6, practically covering the so called “double-hit” or “triple hit” lymphomas. We report a case of HGBCL “triple-hit” lymphoma in a 64-year old female. Cytogenetic and fluorescence in situ hybridization (FISH) studies revealed complex karyotype including rearrangement of MYC to a novel, non- IG partner on chromosome 18, and rearrangement of BCL2, BCL6 and IGH as well as ins(3)(q21q27.3q25.1) among other abnormalities. FISH studies showed five copies of MYC and 3–8 copies of BCL2 . Gene expression analysis by RNA sequencing showed that MYC, BCL2 and MECOM genes were overexpressed whereas BCL6 was under-expressed. BCL 6 was fused to MBNL1 gene due to complex structural rearrangement. MYC was expressed in >70% of cells and BCL2 was diffusely but highly expressed by immunohistochemistry. No pathogenic mutations were identified by sequencing a 26-gene panel including TP53. The patient has unexpectedly been in complete remission for 12 months after diagnosis after intensive chemotherapy including DA-EPOCH regimen despite having HGBCL. The prognostication of HGBCL patients may further be improved by the sub-categorization of these lymphomas on the basis of more detailed genomic markers than merely the WHO 2016 classification. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a hematological malignancy due to anomalous differentiation and proliferation of hematopoietic stem cells with myeloid blast buildup. Induction chemotherapy is considered the first line of treatment in most patients with AML. However, targeted therapy in the form of FLT-3, IDH, BCL-2, and immune checkpoint inhibitors, can be considered as the first line depending on their molecular profile, resistance to chemotherapy, comorbidities, etc. This review aims to assess the tolerability and efficacy of isocitrate dehydrogenase (IDH) inhibitors in AML. We searched Medline, WOS, Embase, and clinicaltrials.gov. PRISMA guidelines were followed in this systematic review. 3327 articles were screened, and 9 clinical trials (N = 1119) were included. In randomized clinical trials (RCTs), objective response (OR) was reported in 63–74% of the patients with IDH inhibitors + azacitidine as compared to 19–36 % of the patients with azacitidine monotherapy in newly diagnosed (ND) medically unfit patients. Survival rates were significantly improved with the use of ivosidenib. OR was reported in 39.1–46 % of the patients who relapsed/refractory to chemotherapy. ≥Grade 3 IDH differentiation syndrome and QT prolongation were reported in 3.9–10 % and 2–10 % of the patients, respectively. IDH inhibitors (ivosidenib for IDH-1 and enasidenib for IDH-2) are safe and effective in treating ND medically unfit or relapsed refractory patients with IDH mutation. However, no survival benefit was reported with enasidenib. More randomized multicenter double-blinded clinical studies are needed to confirm these results and compare them with other targeting agents. [Display omitted] • IDH inhibitors were well tolerated by AML patients. • Ivosidenib significantly improved response rates and survival. • Enasidenib significantly improved response rates without survival benefit. • Among newer agents, olusidenib was effective in AML patients. [ABSTRACT FROM AUTHOR]

Background Brentuximab vedotin (BV) is an antibody-drug conjucate (ADC) comprising a CD30-directed antibody, conjugated to the microtubule-disrupting agent MMAE via a protease cleavable linker. BV is FDA approved for use in relapsed classical Hodgkin lymphoma (HL) and relapsed systemic anaplastic large cell lymphoma (sALCL). There are multiple publications for its utility in other malignancies such as diffuse large B-cell lymphoma (DLBCL), mycosis fungoides (MF), Sézary syndrome (SS), T-cell lymphomas (TCL), primary mediastinal lymphoma (PMBL), and post-transplant lymphoproliferative disorders (PTLD). We believe that BV could potentially provide a strong additional treatment option for patients suffering from NHL. Objective Perform a systematic review on the use of BV in non-Hodgkin lymphoma (NHL) and other CD30 + malignancies in humans. Data sources We searched various databases including PubMed (1946–2015), EMBASE (1947–2015), and Cochrane Central Register of Controlled Trials (1898–2015). Eligibility criteria Inclusion criteria specified all studies and case reports of NHLs in which BV therapy was administered. Included studies A total of 28 articles met these criteria and are summarized in this manuscript. Conclusion Our findings indicate that BV induces a variety of responses, largely positive in nature and variable between NHL subtypes. With additional, properly powered prospective studies, BV may prove to be a strong candidate in the treatment of various CD30 + malignancies. [ABSTRACT FROM AUTHOR]

Significant uncertainty exists in regard to the efficacy of maintenance therapy after high-dose chemotherapy (HDC) as well as autologous stem cell transplantation (ASCT) for the treatment of patients with aggressive lymphoma. A systematic review was performed to evaluate the effectiveness of post-ASCT maintenance therapy in patients with relapsed/refractory lymphoma. A comprehensive literature search yielded 4476 studies and a total of 42 studies (11 randomized controlled trials [RCT], 9 retrospective comparative studies, and 22 single-arm studies) were included in the systematic review. There was significant heterogeneity in study design, chemotherapeutic regimens, post-ASCT maintenance strategies, patient enrollment criteria, and study endpoints. Our findings suggest that post-ASCT maintenance immune-targeting strategies, including PD-1/PD-L1 blocking antibodies, rituximab, and brentuximab, may improve progression-free survival but not overall survival. Collectively, the results indicate a need for testing new strategies with well-designed and adequately powered RCTs to better address the role of post-ASCT maintenance in relapsed/refractory lymphomas. [ABSTRACT FROM AUTHOR]

Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). While transplant-related mortality has decreased substantially over the last few decades, little progress has been made in outcomes and no standard of care exists for patients (pts) with post-alloHCT relapse. In the recent era, several new therapies, including targeted agents, have been approved for ALL, AML, and MDS. We conducted a study to evaluate outcomes of pts with these diseases who relapse after alloHCT in the contemporary period with routine availability of these newer therapeutic agents. We performed a single-institution retrospective cohort study to review treatment strategies and outcomes of relapse post-alloHCT. We identified 420 adults who received their first alloHCT in 2010-2018 using any conditioning regimen or donor source. Overall, 115 (27%) pts experienced relapse (ALL=17/64 [27%], AML=67/242 [28%], MDS=31/114 [27%]) and were included in the analysis. Myeloablative (54%) matched-unrelated donor grafts (50%) were the most common types of HCTs. Peripheral blood stem cell graft (49%) and bone marrow graft (48%) were used the most. Median time from alloHCT to relapse was 5 (range 1-65) months, and 83% of relapses occurred within the first year. Only 24% and 11% of pts experienced grade II-IV acute and any chronic graft-versus-host disease (GVHD) prior to relapse, respectively. Seven of 17 pts had Ph+ ALL. Mutation panel was tested in 56% of AML and MDS. Median follow-up period after relapse was 19 (range 6-80) months. The estimated survival after relapse is shown in figure 1. Table 1 summarizes the treatments used for relapse after alloHCT. Targeted therapy was associated with a trend towards better survival compared to other therapies (Fig 2, HR 0.65, 95% CI 0.41-1.03, p=0.06). Matched unrelated (vs. matched sibling, HR 1.70, p=0.027) or haploidentical donor grafts (HR 2.69, p=0.003), presence of grade II-IV acute GVHD before relapse (HR 2.46, p<0.001), and <12 months from HCT to relapse (<6 vs. >12 months, HR 6.34, p<0.001; 6-12 vs. >12 months, HR 3.16, p=0.005) were adverse prognostic features with survival after relapse post-alloHCT (Table 2). Outcomes of pts with ALL, AML, and MDS who relapse following alloHCT remain poor in the contemporary era when several newer therapies, including targeted agents, are available for their treatment. Targeted agents were used only in a minority of post-alloHCT relapses likely due to the combination of pt status, absence of the target mutation, the agents' availability, and other factors. Pts who developed grade II-IV acute GVHD and had shorter "disease-free" duration from unrelated or haploidentical donor grafts had the significantly shorter survival following relapse. More innovative treatment strategies to prevent and treat relapse post-alloHCT are needed. [ABSTRACT FROM AUTHOR]

PROs are increasingly used in HCT to capture symptoms, quality of life, and functional status. At the Cleveland Clinic, PROs are systematically collected prior to ambulatory visits and used in routine clinical care to identify patients (pts) with distress in real-time through a data capture initiative called the "Knowledge Program." Instruments include the Patient Health Questionnaire (PHQ-9), National Comprehensive Cancer Network Distress Thermometer (DT), and Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Health (PH) and Mental Health (MH) assessments. There are limited data on the use of these instruments in the HCT population. We evaluated these PRO measures in HCT recipients and their association with post-HCT outcomes. We identified 292 adult pts undergoing first allogeneic HCT from 2015-2018. Of those, 257 had at least one PRO assessment and were included in this analysis. Time intervals evaluated were: pre-HCT (within 3 months [mos]), 0-6 mos, 6-12 mos, 1-2 years (yrs), and 2-5 yrs post HCT. PHQ-9 assesses depression and categorized as minimal (score 0-4), mild (5-9), moderate (10-14), moderately severe (15-19), and severe (20-27). Higher DT scores indicate more distress and categorized as mild (0-3), moderate (4-7), severe (8-10). Lower scores on PROMIS indicate poorer PH or MH respectively. We evaluated PRO data descriptively for each time interval. Pre-HCT scores were analyzed for association with grade 2-4 acute graft-versus-host disease (GVHD), relapse, non-relapse mortality (NRM), and survival. Figure 1 shows boxplots for mean PHQ-9 and DT scores pre- and post-HCT. Mean scores for the PHQ-9 ranged from 1.1 ± 2.4 (SD) occurring >2 yrs post-HCT to 2.4 ± 3.0 pre-HCT. Mean DT scores were overall low, with highest distress (2.0 ± 2.2) seen pre-HCT. Mean scores for PH and MH were similar at each time intervals, with means ranging 47-48 for PH and 49-51 for MH. Higher PHQ-9 pre-HCT was associated with higher NRM (HR 1.21, 95% CI 1.09-1.34, P<0.001) and worse overall mortality (HR 1.12, 95% CI 1.02-1.23, P=0.016). Higher PROMIS PH and MH scores were associated with lower NRM (HR 0.49, 95% CI 0.26-0.94, P=0.031 and HR 0.28, 95% CI 0.14-0.56, P<0.001), respectively. DT scores had no associations with any outcome. Pts who developed acute GVHD had significantly higher PHQ-9 scores (mean 2.8 vs 1.9, P=0.014), PROMIS-PH (mean 45 vs 49, P=0.029) and MH scores (mean 47 vs 52, P=0.011) relative to those who did not have acute GVHD. PROs such as the PHQ-9, DT, and PROMIS have important clinical utility in allogeneic HCT recipients. Routine clinical use of these assessments not only help identify pts with high levels of distress or depression in real-time, they also demonstrate prognostic value for post-HCT survival outcomes. [ABSTRACT FROM AUTHOR]

Busulfan (Bu) based conditioning regimens are associated with serious toxicities including myelosuppression, hepatotoxicity, and sinusoidal obstructive syndrome (SOS). Previous literature reports increased risk of toxicities when the daily AUC concentrations exceed 6000 uM-minute. Bu TDM has also been associated with improved overall and progression free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We implemented real time pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of Bu for myeloablative conditioning (MAC) regimens. Compare toxicity of IV Bu before and after implementation of TDM. The primary endpoint was incidence of hepatotoxicity, defined as days of elevation of AST or ALT > 3 times the upper limit of normal (ULN) or total bilirubin >1.5 times ULN. Secondary outcomes included time to neutrophil and platelet engraftment, duration of IV opioid administration, breakthrough antiemetic use, incidence of SOS, hospital length of stay (LOS), incidence of Bu dose adjustment, and repeat Bu PK. A Bu PK-guided TDM program was implemented in April 2018 for patients receiving busulfan/ cyclophosphamide (BuCy) MAC regimens for allo-HSCT. Medical records were retrospectively reviewed with weight-based dose (WBD) BuCy conditioning from August 2017 through March 2018 (N=14) and TDM from April 2018 through December 2018 (N=22). Bu was given at a fixed dose of 0.8 mg/kg/dose every 6 hours for 16 doses on days -8 to -4 for WBD patients. For TDM patients, after a WBD of 3.2 mg/kg/dose on day -7 (Bu 1), serial plasma Bu concentrations were used to calculate Bu area under the curve (AUC) for subsequent dose adjustment on days -6 to -4 to target a daily AUC of 5000 μM-minute. If the AUC actual /AUC target exceeded 1.2 or was less than 0.8, the second dose of Bu (Bu 2) was changed by no more than ± 20%, repeat PK samples were drawn, and the process was repeated for TDM for the third dose of Bu. Recipients of Bu TDM were younger than those receiving WBD (median 45 vs. 58 years, p=0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between TDM and WBD (median 1 vs. 0 days, p=0.40), time to neutrophil (median 17 vs. 17 days, P=0.18) or platelet engraftment (median 29 vs. 25 days, p=0.75), IV opioid administration (median 4 vs. 4 days, p=0.83), breakthrough antiemetic use (median 59 vs. 58 doses, p=0.99), SOS (4.5 vs. 7.1%, p=1.0), or LOS (median 28 vs. 27 days, p=0.95). In the TDM group, 45% of patients had increases and 41% had decreases in Bu dose after Bu 1. 32% of patients required repeat PK after Bu 2. A PK dose monitoring program for MAC IV Bu regimens may be considered a safe practice in allo-HSCT recipients. The majority of patients receiving PK-guided TDM required dose changes, and TDM patients had no significant difference in toxicity compared to those receiving WBD. [ABSTRACT FROM AUTHOR]

Use of Axi-cel in patients with refractory and relapsed (R/R) large B-cell lymphoma (BCL) is associated with significant inpatient and outpatient resource utilization, which has not been systematically evaluated. We characterized resources used around Axi-cel infusion and identified factors that lead to longer hospitalization during the first 100 days of therapy. We reviewed medical records of consecutive adult patients with R/R large BCL treated with Axi-cel at our center from May 2018 to June 2019. Resource utilization data were collected across 3 time points and sorted into categories that reflect inpatient and outpatient resources (Table 1). We evaluated the number of "days alive and out-of-hospital through Day 100 from cell infusion" (DAOH 100), as a surrogate for institutional resource utilization and to identify factors leading to prolonged hospitalization. Axi-cel was used in 27 patients with R/R BCL; 18 were male (67%) with median age 63 years (IQR 48-68), median IPI 2 (IQR 2-3), 20 (74%) had ECOG PS < 2 and 24 (89%) had stage ≥ 3 disease. Median number of prior therapies was 3 (IQR 3-5) and HCT-CI score was 2 (IQR 0-3). The median length of stay for the initial hospitalization was 13 days (IQR 9-16) and through Day 100 was 16 days (IQR 12-30). Eight (30%) patients required ICU admission for a median of 2.5 days (IQR 1-9.8), while vasopressors, mechanical ventilation and dialysis were used in 6 (22%), 3 (11%) and 2 (7%) patients respectively. Patients had a median of 5 (IQR 3-7) outpatient clinic visits through Day 100. The median number of radiological studies and cardiac/neurological evaluation through Day 100 were 6 (IQR 4-11) and 1 (IQR 0-6) respectively. Pharmaceutical resources are summarized in Table 1. Cytokine release syndrome (CRS) and CAR-related encephalopathy syndrome (CRES) were seen in 22 (82%) and 20 (74%) patients, with ≥ Grade 2 CRS (Lee, et al) and CRES (CARTOX-10) in 16 (59%) and 13 (48%) patients respectively. By Day 100, 24 (89%) patients were alive and 4 (15%) had disease progression. The median DAOH 100 were 84 days (IQR 69-88). DAOH 100 were higher in patients with favorable ECOG PS (< 2) compared to unfavorable (≥ 2) (median DAOH 100 86 vs 70 days, P=0.04). Patients with no or mild CRES (< grade 2) had higher DAOH 100 compared to those with moderate to severe CRES (≥ grade 2) (median DAOH 100 86 vs 70 days, P=0.01). DAOH 100 did not differ with respect to age, HCT-CI score, IPI, number of prior therapies or CRS grade (Table 2). In this single institutional experience of using Axi-cel therapy for R/R BCL, we demonstrated utilization of substantial resources in terms of hospitalization, ICU stay, diagnostic studies and pharmaceutical products. Patients with favorable PS and no or minimal CRES spend a higher number of days at home (alive and out-of-hospital), in first 100 days of Axi-cel therapy. [ABSTRACT FROM AUTHOR]

Pharmacists are increasingly identified as vital members of the HSCT multidisciplinary team. At our institution, pharmacists recently established roles providing clinical pharmacy services in the outpatient setting focused on performing interventions during the pre-HSCT clinic visit. The primary objective was to evaluate the number of medication discrepancies identified during pre-HSCT clinic visits performed by pharmacists, defined as addition, removal, or dose adjustment of current medications. Secondary objectives were to evaluate the number of interventions made by pharmacists for drug interactions, chemotherapy dose adjustments, and other medication recommendations for all patients prior to HSCT. A retrospective review of all patients admitted for HSCT from August 2018 to 2019 was performed. Patients are seen by their HSCT provider about 1 week prior to HSCT. At this visit, oncology trained pharmacists specializing in HSCT meet with the patient and provide services such as medication reconciliation, screening for drug interactions, screening for pertinent medication allergies/ intolerances and identifying alternatives, assessing medication adherence, evaluating need for chemotherapy dose adjustments, and identifying barriers to medication access. Patients that are unable to be seen by the pharmacist receive extensive chart review prior to admission to identify medication interventions. HSCT pharmacists performed 150 pre-HSCT clinic visits for 88 (59%) autologous, 46 (31%) allogeneic, and 16 (11%) Chimeric Antigen Receptor Therapy (CAR- T) recipients. A total of 511 medication discrepancies were identified in 128 (85%) patients seen (Figure 1). In addition to the 150 patients seen, 88 patient charts were reviewed by a pharmacist. A total of 66 significant drug interactions requiring intervention were identified in 52 (22%) patients and 30 chemotherapy dose adjustments were implemented in 29 (12%) patients. Other medication recommendations were made to the provider for 109 (46%) patients. Examples of these interventions include stopping oral chemotherapy prior to HSCT, modifying supportive care medications to reflect patient preference and prior response, modifying hydration due to cardiac history, coordinating steroid tapers before haploidentical HSCT or CAR-T, adjusting prophylactic antimicrobials due to allergies or to meet institutional standards, coordinating refills, and developing a plan for non-formulary medications. Pharmacists play a crucial role in providing safe and effective care to HSCT patients, and their involvement in the multidisciplinary team can lead to significant clinical interventions. Future directions include expansion of the role of HSCT pharmacists through Pharmacy Consult Agreements, focusing on HSCT patients post-transplant and within a Survivorship Clinic. [ABSTRACT FROM AUTHOR]

Background The nearly universal donor accessibility afforded by haploidentical bone marrow transplantation (haplo-BMT) is salient for our program, as half of the patients undergoing hematopoietic cell transplantation (HCT) are ethnic or racial minorities. This highlights the need for effective haplo-BMT regimens and improvements in graft-versus-host disease (GvHD) prophylaxis. Balancing GvHD prevention with the maintenance of graft-versus-leukemia (GvL) is an ongoing challenge in the field of HCT. We have previously shown in mice that bendamustine (BEN) can safely replace cyclophosphamide (CY) as post-transplant (PT) GvHD prophylaxis following haplo-BMT, with comparable protection from GvHD and superior GvL effects. Based on our preclinical data, we have initiated a Phase I/II study to replace PT-CY (given on days +3 and +4) with PT-BEN following haplo-BMT. Methods Phase I is a standard 3 + 3 dose escalation design with six dose level cohorts. The first three cohorts (1-3) consist of a combination of sequentially reduced doses of CY and increased doses of BEN on day +4 post-BMT with the dose of CY on day +3 remaining unchanged. The next three cohorts (4-6) will involve progressive substitution of CY with BEN on day +3. We are enrolling patients ages 8-60 years with a diagnosis of acute leukemia, chronic myeloid leukemia, myelodysplastic syndrome, Hodgkin's or non-Hodgkin's lymphoma who do not have a readily available HLA-matched (10/10) donor. Myeloablative busulfan, fludarabine, and melphalan or TBI and fludarabine are used as conditioning regimens. Engraftment, immune reconstitution, T-cell receptor β (TRB) diversity, GvHD, infections, relapse, non-relapse mortality (NRM), event-free survival (EFS) and overall survival (OS) are monitored. Patients undergoing haplo-BMT (using the same conditioning regimens) who do not wish to receive PT-BEN are consented as PT-CY controls for the clinical endpoints and immune reconstitution studies. Results We have enrolled through Cohort 2 with no dose-limiting toxicities. Cohort 2 of PT-BEN had significantly earlier neutrophil engraftment than PT-CY controls (median day +13 compared to +17), with >5-fold higher neutrophil to lymphocyte ratios through day +100. PT-BEN patients displayed higher CD4 to CD8 ratio and demonstrated significantly greater TRB diversity than PT-CY only patients through 1 year following transplant. Patients receiving PT-BEN had a trend toward a lower incidence of CMV reactivation, 33% compared to 100% in PT-CY controls. No PT-BEN patient has developed grade III-IV acute GvHD or chronic GvHD. Conclusions PT-BEN has been well-tolerated, with patients demonstrating early engraftment. Preliminary data with PT-BEN indicate potential differences in immune reconstitution and TRB diversity. This may be advantageous in viral control, as well as in GvHD and GvL responses. [ABSTRACT FROM AUTHOR]