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In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide–tacrolimus–mycophenolate mofetil (experimental prophylaxis) or tacrolimus–methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P=0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide–tacrolimus–mycophenolate mofetil than among those who received tacrolimus–methotrexate. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA haploidentical (haplo) donor followed by graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) results in lower relapse rates and improved DFS when compared to haplo bone marrow transplant (BMT) with PTCy. However, PBSCT leads to higher rates of GVHD. It is unknown whether the benefits of haplo PBSCT may be nullified in older patients (>60 years) by a higher susceptibility to GVHD and transplant related toxicity. Thus, we sought to determine if older patients receiving haplo PBSCT with PTCy experience significantly worse outcomes than younger patients., Methods: We evaluated 121 adult patients with hematologic malignancies treated at the Moffitt Cancer Center with allogeneic haplo PBSCT followed by PTCy and compared outcomes of patients ≥60 years (n = 55) versus patients <60 years (n = 66)., Results: The cumulative incidence of non-relapse mortality (NRM) from the competing risk regression analysis was worse for the older patient group (SHR = 4.05, 95% CI: 1.43-11.47, p = 0.008). However, there was no significant difference between groups in graft-versus-host disease (GVHD), relapse, disease-free survival (DFS), or overall survival (OS). Instead, hematopoietic comorbidity index (HCT-CI) ≥ 3 was associated with worse DFS (HR = 1.87, 95% CI: 1.04-3.34, p = 0.035) and OS (HR = 1.98, 95% CI: 1.03-3.84, p -value = 0.042). Subgroup analysis of patients ≥60 years showed a trend toward improved 2-year OS with fludarabine/cyclophosphamide/total body irradiation (Flu/Cy/TBI) versus fludarabine/busulfan: 71% versus 53% (HR = 0.47, p = 0.121). In patients over 70 years (n = 14), NRM was 8% and OS was 76% at 1 year., Conclusion: Given similar OS and DFS between patients aged >60 years and those <60, haplo PBSCT with PTCy appears to be an appropriate transplant platform for older patients.

The BMT CTN 1703 phase III trial confirmed that graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) results in superior GVHD-free, relapse-free survival (GRFS) compared with Tac/methotrexate (MTX) prophylaxis. This companion study assesses the effect of these regimens on patient-reported outcomes (PROs). Using the Lee Chronic GVHD Symptom Score and PROMIS subscales (physical function, GI symptoms, social role satisfaction) as primary end points and hemorrhagic cystitis symptoms and Lee subscales as secondary end points, responses from English and Spanish speakers were analyzed at baseline and days 100, 180, and 365 after transplant. PRO scores were compared between the arms using inverse probability weighted-independent estimating equation models. The PTCy arm had significantly lower scores on the Lee Chronic GVHD Symptom Scale ( P = .01), indicating lower GVHD symptom burden. Lee Scale nutrition and mouth subscores were also better in the PTCy arm compared with the Tac/MTX arm ( P < .01 for both). Older participants (age >65 years) reported better Lee Scale psychological subscores than younger participants ( P = .003). No significant differences were identified in hemorrhagic cystitis or in the PROMIS subscales between treatment arms. The updated clinical end points at 2 years for the parent trial confirmed that PTCy/Tac/MMF maintained a significant advantage over Tac/MTX in GRFS (42.4% v 28.8%, P = .001). In addition to improved GRFS, patients randomly assigned to the PTCy arm reported lower symptom burden during the first year after transplant.

Abstract: Our phase 1 graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib (PAC; recommended phase 2 dose: 100 mg orally twice a day on day 0 to +70) plus sirolimus and tacrolimus (SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits interleukin 6 (IL-6) receptor activity and pathogenic T helper cell 1 (Th1)/Th17 differentiation in preclinical models and the phase 1 trial. Herein, we report on our completed phase 2 trial of PAC/SIR/TAC after 8/8 human leukocyte antigen matched alloHCT. This single-arm phase 2 trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed percentage phosphorylated STAT3 (pSTAT3)+ CD4+ T cells at day +21 (primary end point: percentage pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II to IV acute GVHD by day +100. The impact of PAC/SIR/TAC on T-cell subsets, CD28 (pS6 and pH3ser10), and IL-2 receptor (pSTAT5) signal transduction was also evaluated. Eligible patients (n = 28) received alloHCT for hematologic malignancies or myeloproliferative neoplasms. Reduced or myeloablative intensity conditioning was permitted. PAC/SIR/TAC met the primary end point, reducing percentage pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of regulatory T cells to Th1 and Th17 cells with PAC/SIR/TAC at recommended phase 2 dose PAC compared with dose level 1 PAC. The cumulative incidence of grade II to IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46% vs 43%). Although PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Fludarabine (Flu) and melphalan (Mel) reduced-intensity conditioning is frequently used for allogenic hematopoietic cell transplant (allo-HCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, there is limited evidence on the impact of Mel dosing on toxicities and clinical outcomes of allo-HCT. We retrospectively compared 8/8 HLA-matched donor allo-HCT outcomes of 345 patients with AML or MDS receiving total Mel dose of 100 mg/m 2 (Mel-100, n = 62) versus 140 mg/m 2 (Mel-140, n = 283) in combination with Flu. Median age at allo-HCT was 66 years and median follow-up was 36.5 months. For Mel-100 versus Mel-140 groups, any grade gastrointestinal (GI) toxicity rates were 40.3% versus 67.8% (P < .001), day 100 grade II to IV acute graft-versus-host disease (GVHD) rates were 21.0% versus 43.1% (P = .001) and 2-year chronic GVHD rates were 17.4% versus 27.1% (P = .033). In multivariable analysis, Mel-140 resulted in higher risks of GI toxicity (HR = 1.83, P = .013), grade II to IV acute GVHD (HR=2.35, P = .003), and moderate/severe chronic GVHD (HR = 3.13, P = .007). Total Mel dose had no independent impact on oral mucositis, nonrelapse mortality, relapse, relapse-free survival, and overall survival. While independent validation of our observation is warranted, our findings support using Mel-100 in combination with Flu to minimize allo-HCT toxicities and morbidities related to GVHD., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Mycophenolate mofetil (MMF) is commonly included in post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GVHD) prophylaxis after haploidentical (haplo) hematopoietic cell transplant (HCT). In the non-PTCy setting, higher MMF dose/kg has been shown to reduce rates of acute graft-versus-host disease (GVHD). When used in conjunction with PTCy, MMF is dosed at 15 mg/kg three times daily up to a maximum dose of 3 g/day. Thus, patients who weigh ≥67 kg receive 3 g/day and a variable dose/kg of MMF. We investigated the impact of MMF dose/kg on clinical outcomes following haploidentical PBSCT with PTCy-based GVHD prophylaxis. All consecutive adult patients with hematologic malignancies receiving haploidentical T cell replete peripheral blood stem cell transplant (PBSCT) with PTCy/MMF and either tacrolimus or sirolimus at the Moffitt Cancer Center or City of Hope between April 2014-August 2020 were included. For analyses, MMF dose relative to patient actual body weight (mg/kg/day), was stratified into categories of low (<29 mg/kg/day), low intermediate (29-34 mg/kg/day), high intermediate (35-41 mg/kg/day), and high (>41 mg/kg/day). Three hundred eighty-six patients were included. Of these, 54 patients received low dose, 73 low intermediate, 137 high intermediate and 122 high dose MMF by relative weight exposure. In multivariate analysis, low MMF dose exposure was associated with reduced rates of relapse in comparison to the high dose group (HR = 0.45, 95% CI: 0.21 to 0.94, P = .03). This led to superior PFS among patients with low compared to high MMF dose exposure (HR = 0.58, 95% CI: 0.34 to 0.99, P = .045). MMF relative dose exposure was not associated with engraftment, GVHD, nonrelapse mortality, or OS. In this study of patients receiving haploidentical PBSCT with PTCy based GVHD prophylaxis, low MMF dose/kg was associated with improved rates of relapse and PFS. Future prospective studies should investigate optimal dosing strategies of MMF when given with the PTCy regimen., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Human herpesvirus 6B (HHV-6B) frequently reactivates following allogeneic stem cell transplant (alloHCT). Consensus guidelines note that haploidentical alloHCT may represent a high-risk population for which there is little evidence; this warrants further investigation., Methods: In this single-center retrospective study, we evaluated 188 consecutive adult patients receiving haploidentical alloHCT between 11/2014 and 11/2020 and compared outcomes between patients with HHV-6B reactivation receiving targeted antiviral therapy and those who were clinically observed., Results: Of the 58 included patients, 21 (36.2%) received antiviral therapy for HHV-6B reactivation with foscarnet (n = 19) or ganciclovir (n = 2). There were no differences in patient or disease characteristics between treated and observed patients. Treated patients were more likely to have high-level DNAemia (85.7% vs 40.5%; P < .001) and had higher peak viral quantitative measurements (median log 10 , 4.65 vs 3.84; P < .001). The median time to clearance from plasma (interquartile range) was 13 (7.25-20.00) days for all patients and was not significantly different between groups. There were no differences in episodes of encephalitis, grade III/IV acute graft-vs-host disease (GVHD), or time to neutrophil or platelet engraftment among treated vs observed patients. Day 100 nonrelapse mortality was not significantly different in the multivariate analysis; however, the presence of central nervous system symptoms was strongly associated with worse survival (hazard ratio, 4.11; 95% CI, 1.27-13.34; P = .018)., Conclusions: We did not observe a difference in clinical outcomes between the treated and observed groups of patients with HHV-6B reactivation following haploidentical alloHCT. With the rising use of haploidentical transplant and post-transplant cyclophosphamide GVHD prevention platforms, prospective studies are needed to further characterize the risk and outcomes associated with HHV-6B reactivation and therapy., Competing Interests: Potential conflicts of interest. G.H., Y.P., E.E., G.D., Y.P., O.K., A.B., A.J.F., F.K., A.S.M., L.O., L.P., M.N., F.P., and J.K. report no conflicts of interest. M.A. reports a consulting or advisory role with BMS and Janssen and speakers’ bureau membership with Janssen Oncology; H.E. reports a consulting or advisory role with Sanofi and Humanigen and research funding from BMS; D.K.H. reports a consulting or advisory role with BMS, Janssen, Pfizer, and Karyopharm and research funding from Janssen and Karyopharm; C.L.F. reports a consulting or advisory role with BMS, Seattle Genetics, Celgene, AbbVie, Sanofi, Incyte, Amgen, ONK Therapeutics, and Janssen and has received research funding from BMS, Janssen, and Roche/Genentech; M.D.J. reports a consultancy or advisory role for Kite/Gilead and Myeloid Therapeutics and received research funding from Kite/Gilead, Incyte, and Loxo@Lilly; F.L. reports a consulting or advisory role with Novartis, Celgene, Calibr, Alimera Sciences, Gerson Lehrman Group, EcoR1 Capital, Amgen, Bluebird Bio, BMS, Iovance Biotherapeutics, Legend Biotech, Cowen, Kite, a Gilead company, Umoja Biopharma, Takeda, Sana Biotechnology, Daiichi Sankyo/UCB Japan, Bristol Myers Squibb/Celgene, Janssen, A2 Biotherapeutics, Miltenyi Biotec, Caribou Biosciences, Takeda, and Umoja Biopharma and research funding from Kite, a Gilead company (Inst), Alimera Sciences (Inst), Novartis (Inst), Bluebird Bio (Inst), and Bristol Myers Squibb/Celgene (Inst); A.L. provides consultancy fees from, receives honoria from, and is a member of the scientific advisory board for Sanofi; H.D.L. has a membership on the board of directors of the advisory committee at BioLineRx; A.M. reports research funding from Novartis; T.N. reports research funding from Novartis and Karyopharm and is on the speakers’ bueau at Medexus Pharmaceuticals; J.P. reports a consulting and advisory board membership with Syndax, CTI Biopharma, Amgen, Regeneron, and Incyte and has received clinical trial funding from Novartis, Amgen, Takeda, Janssen, Johnson and Johnson, Pharmacyclics, AbbVie, CTI Biopharma, and BMS; O.C. reports a consulting or advisory role for Legend Biotech USA Inc. and Bristol Myers Squibb and being a member of the speakers’ bureau for Bristol Myers Squibb; N.B. provides consulting for and receives research funding from Orca Bio, CareDx Pharma, CRISPR, Sanofi, CTI BioPharma, Medexus Pharmaceuticals, and Magenta; R.F. receives research funding from Gilead., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Abstract: We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Hypomethylating agent + venetoclax is an effective frontline combination for acute myeloid leukemia, but its efficacy and safety in post-allogeneic hematopoietic cell transplant (alloHCT) relapse remain underexplored. Outcomes have been poor for this population, with no standard treatment., Patients and Methods: We retrospectively analyzed 72 Ven-naïve patients who received hypomethylating agents + venetoclax at relapse following alloHCT and aimed to evaluate the rates of complete remission with or without hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity, CR/CRi duration, and overall survival. We leveraged our larger sample to analyze the impact of cytogenetic/molecular features on the odds of CR/CRi., Results: CR/CRi was achieved among 32 of 67 (48%) patients, and MRD negativity was recorded among 10 of 12. NPM1 and IDH 1 or 2 mutations increased the odds of CR/CRi, as did increasing time from alloHCT to relapse. Fourteen patients subsequently received donor lymphocyte infusions or a second alloHCT. Responses lasted a median of 17.8 months (95% CI, 7.2 months to not reached), and responders had a greater median overall survival of 19.7 months (95% CI, 7.6-51.5 months) compared to 2.9 months among nonresponders (95% CI, 1.8-4.4 months; log-rank P < .01). Treatment was well tolerated, but prolonged cytopenias were common and most patients required reduction in the number of venetoclax days per cycle., Conclusion: These data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity., Competing Interests: Disclosures Authors reports no conflicts of interest. The study received no external funding., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) for allogeneic haploidentical donor (haplo) hematopoietic cell transplantation (HCT) results in comparable outcomes to matched unrelated donor HCT. A phase II study from the Moffitt Cancer Center substituting sirolimus (Siro) for Tac in this prophylactic regimen reported comparable rates of grade II-IV acute GVHD (aGVHD). Many centers have substituted Siro for Tac in this setting based on a preferable side effect profile, although comparative data are limited. In this study, we retrospectively compared outcomes in haplo-HCT with PTCy/Siro/MMF versus haplo-HCT with PTCy/Tac/MMF. The study cohort included all consecutive patients receiving haploidentical donor T cell-replete peripheral blood stem cell (PBSC) HCT for hematologic malignancies at Moffitt Cancer Center or the City of Hope National Medical Center between 2014 and 2019. A total of 423 patients were included, of whom 84 (20%) received PTCy/Siro/MMF and 339 (80%) received PTCy/Tac/MMF. The median age for the entire cohort was 54 years (range, 18 to 78 years), and the median follow-up was 30 months. The Siro group had a higher proportion of patients age ≥60 years (58% versus 34%; P < .01), and the groups also differed in diagnosis type, conditioning regimen, and cytomegalovirus serostatus. There were no significant differences in the rates of grade II-IV aGVHD (45% versus 47%; P = .6) at day +100 or chronic GVHD (cGVHD) (47% versus 54%; P = .79) at 2 years post-HCT. In multivariate analysis, neutrophil engraftment at day +30 was significantly better in the Tac group (odds ratio, .30; 95% confidence interval, .1 to .83; P = .02), with a median time to engraftment of 17 days versus 18 days in the Siro group, but platelet engraftment was similar in the 2 groups. Otherwise, in multivariate analysis, GVHD prophylaxis type had no significant influence on aGVHD or cGVHD, nonrelapse mortality, relapse, GVHD-free relapse-free survival, disease-free survival, or overall survival after PBSC haplo-HCT. These findings suggest that Siro is a comparable alternative to Tac in combination with PTCy/MMF for GVHD prophylaxis, with overall similar clinical outcomes despite delayed engraftment after peripheral blood stem cell haplo-HCT. Although Tac remains the standard of care, Siro may be substituted based on the side effect profile of these medications, with consideration of patient medical comorbidities at HCT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Aim: Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between CYP3A4, CYP3A5 or ABCB1 genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration. Materials & methods: We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis. Results & conclusion: The findings of the present study suggests that CYP3A5 genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.

Idecabtagene vicleucel (ide-cel) is a type of B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Currently, the incidence of cardiac events associated with ide-cel remains unclear. This was a retrospective single-center observational study of patients treated with ide-cel for RRMM. We included all consecutive patients who received standard-of-care ide-cel treatment at least 1-month follow-up. Baseline clinical risk factors, safety profile, and responses were examined based on the development of a cardiac event. A total of 78 patients were treated with ide-cel, and 11 patients (14.1%) developed cardiac events: heart failure (5.1%), atrial fibrillation (10.3%), nonsustained ventricular tachycardia (3.8%), and cardiovascular death (1.3%). Only 11 of the 78 patients had repeat echocardiogram. Baseline risk factors associated with the development of cardiac events included being female sex and having poor performance status, λ light-chain disease, and advanced Revised International Staging System stage. Baseline cardiac characteristics were not associated with cardiac events. During index hospitalization after CAR-T, higher-grade (≥grade 2) cytokine release syndrome (CRS) and immune cell-associated neurologic syndrome were associated with cardiac events. In multivariable analyses, the hazard ratio for the association of the presence of cardiac events with overall survival (OS) was 2.66 and progression-free survival (PFS) was 1.98. Ide-cel CAR-T for RRMM was associated with similar cardiac events as other types of CAR-T. Worse baseline performance status and higher-grade CRS and neurotoxicity were associated with cardiac events after BCMA-directed CAR-T-cell therapy. Our results suggest that the presence of cardiac events may confer worse PFS or OS; although because of the small sample size, the power to detect an association was limited., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Cardiovascular comorbidities increase the risk of transplant-associated complications. However, the impact of atrial fibrillation (AF) as an independent risk factor remains limited., Methods: The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases codes to identify patients admitted for allogeneic stem cell transplant (ASCT). The patients were then subclassified into with and without AF. Subsequently, a multivariate logistic regression model was constructed to account for patient demographics, comorbidities, and hospital characteristics to evaluate the impact of AF on the primary outcome of interest: all-cause mortality, and secondary outcomes of interest that included common hospitalization complications., Results: The data for 77 157 cases of ASCT were collected between 2002 and 2019. Among these 5086 (6.6%) cases had concurrent AF. Multivariate logistic regression revealed patients undergoing ASCT with AF had almost a three times higher risk of all-cause mortality (odds ratio = 2.99 [95% confidence interval: 2.73-3.28]; p < .01). AF patients also had a higher risk for cardiac arrest, cardiogenic shock, acute kidney injury, and need for hemodialysis (all p < .01)., Conclusion: AF causes a higher risk of death and cardiovascular complications among patients undergoing ASCT. This signifies the importance of pretransplant consultation and optimization for cardiovascular comorbidities to improve hospitalization outcomes., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In 2022, the US Food and Drug Administration (FDA) approved 37 novel drugs. Twenty-four of the 37 (65%) novel drug approvals were reviewed and approved through an expedited review pathway and 20 of the 37 (54%) were approved for treatment of a rare disease. This review includes a summary of the novel drugs approved by the FDA in 2022., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for blood or marrow transplantation (BMT). In this collaboration across North America, we retrospectively analyzed outcomes of first BMT using haploidentical donor and posttransplantation cyclophosphamide (PTCy) in MDS/MPN-overlap neoplasms (MDS/MPN), an otherwise incurable hematological neoplasm. We included 120 patients, 38% of non-White/Caucasian ethnicity, across 15 centers with median age at BMT 62.5 years. The median follow-up is 2.4 years. Graft failure was reported in 6% patients. At 3-years, nonrelapse mortality (NRM) was 25%, relapse 27%, grade 3-4 acute graft versus host disease (GVHD) 12%, chronic GVHD requiring systemic immunosuppression 14%, progression-free survival (PFS) 48% and overall survival (OS) 56%. On multivariable analysis, statistically significant associations included older age at BMT (per decade increment) with NRM (sdHR 3.28, 95%CI 1.30-8.25), PFS (HR 1.98, 95% 1.13-3.45) and OS (HR 2.01, 95% CI 1.11-3.63), presence of mutation in EZH2/RUNX1/SETBP1 with relapse (sdHR 2.61, 95%CI 1.06-6.44), and splenomegaly at BMT/prior splenectomy with OS (HR 2.20, 95%CI 1.04-4.65). Haploidentical donors are a viable option for BMT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Disease-related factors including splenomegaly and high-risk mutations dominate outcomes following BMT.

There is increasing recognition that pathogenic germ line variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germ line predisposition variants have different posttransplant outcomes than those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germ line variants and 34% underwent HSCT. Deleterious germ line variants in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germ line DDX41 variants had a higher incidence of severe (stage 3-4) acute graft-versus-host disease (GVHD) (38%) than recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germ line variants (9%) (P = .002). Importantly, the use of posttransplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germ line DDX41-associated myeloid neoplasms (0% vs 53%, P = .03). Based on these results, we advocate the use of posttransplant cyclophosphamide when individuals with deleterious germ line DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease-a major complication of allogeneic HCT-to enable the patient and clinician to assess management options in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.

Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patients with renal impairment (RI) are typically excluded from trials evaluating chimeric antigen receptor (CAR) T cell therapies. We evaluated the outcomes of patients with RI receiving standard of care (SOC) CAR T cell therapy for relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this retrospective, single-center cohort study of patients with R/R DLBCL treated with SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after 2 or more prior lines of therapy, renal and survival outcomes were compared based on RI and fludarabine dose reduction (DR) status. RI was defined by an estimated glomerular filtration rate <60 mL/min/1.73 m 2 as determined by the Modification of Diet in Renal Disease equation using day -5 creatinine (Cr) values. Acute kidney injury (AKI) was identified and graded using standard Kidney Disease: Improving Global Outcomes criteria. Renal recovery was considered to occur if Cr was within .2 mg/mL of baseline by day +30. Fludarabine was considered DR if given at <90% of the recommended Food and Drug Administration label dose. Among 166 patients treated with CAR T cell therapy were 17 patients (10.2%) with baseline RI and 149 (89.8%) without RI. After CAR T cell infusion, the incidence of any grade AKI was not significantly different between patients with baseline RI and those without RI (42% versus 21%; P = .08). Similarly, severe grade 2/3 AKI was seen in 1 of 17 patients (5.8%) with baseline RI and in 11 of 149 patients (7.3%) without RI (P = 1). Decreased renal perfusion (28 of 39; 72%) was the most common cause of AKI, with cytokine release syndrome (CRS) contributing to 17 of 39 AKIs (44%). Progression-free survival (PFS) and overall survival (OS) did not differ between patients with RI and those without RI or between those who received standard-dose fludarabine and those who received reduced-dose fludarabine. In contrast, patients with AKI had worse clinical outcomes than those without AKI (multivariable PFS: hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2 to 3.7; OS: HR, 3.9; 95% CI, 2.1 to 7.4). Notably, peak inflammatory cytokine levels were higher in patients who experienced AKI. Finally, we describe 2 patients with end-stage renal disease (ESRD) on dialysis who received lymphodepletion and CAR T cell therapy. Baseline renal function did not affect renal or efficacy outcomes after CAR T cell therapy in DLBCL. On the other hand, patients with AKI went on to experience worse clinical outcomes. AKI was commonly related to CRS and high peak inflammatory cytokine levels. CAR T cell therapy is feasible in patients with ESRD and requires careful planning of lymphodepletion., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

This study aimed to compare complete revascularization (CR) guided by angiography with a fractional flow reserve (FFR)-guided strategy in patients presenting with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD). CR is preferred to culprit-only revascularization for patients with STEMI and MVD. However, whether FFR-guided CR is superior to angiography-guided CR is unclear in patients presenting with STEMI who have MVD. Randomized controlled trials comparing CR with an FFR- or angiography-guided strategy to culprit-only revascularization in patients with STEMI and MVD were systematically identified. A random-effects network meta-analysis was performed comparing clinical outcomes in the 3 arms. A total of 13 studies with a total of 8,927 patients were included in our analysis. Compared with culprit-only revascularization, angiography-guided CR was associated with a significantly decreased risk of myocardial infarction (MI) (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.37 to 0.82), all-cause death (HR 0.69, 95% CI 0.49 to 0.97), and cardiovascular death (HR 0.54, 95% CI 0.34 to 0.85) but FFR-guided CR was not (MI: HR 0.77, 95% CI 0.53 to 1.12; cardiovascular death: HR 0.89, 95% CI 0.64 to 1.24; all-cause death: HR 0.93, 95% CI 0.72 to 1.18). The network meta-analysis comparison of angiography- versus FFR-guided CR showed an HR of 0.75 (95% CI 0.50 to 1.11) for all-cause death and an HR of 0.71 (95% CI 0.54 to 1.17) for MI. In conclusion, for patients with MVD presenting with STEMI, angiography-guided CR may provide additional benefits compared with FFR-guided CR., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In 2021, the US Food and Drug Administration (FDA) approved 50 novel drugs. Thirty-seven of the 50 (74%) novel drug approvals were reviewed and approved through an expedited review pathway, and 26 of the 50 (52%) were approved for treatment of a rare disease. This review includes a summary of the novel drugs approved by the FDA in 2021., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We describe outcomes after post-transplantation cyclophosphamide and nonmyeloablative conditioning-based allogeneic blood or marrow transplantation for myelofibrosis using matched or mismatched related or unrelated donors. The conditioning regimen consisted of fludarabine, cyclophosphamide, and total body irradiation. Forty-two patients were included, with a median age of 63 years, of whom 19% had Dynamic International Prognostic Scoring System (DIPSS)-plus intermediate-1 risk, 60% had intermediate-2 risk, and 21% had high-risk disease, and 60% had at least 1 high-risk somatic mutation. More than 90% of patients engrafted neutrophils, at a median of 19.5 days, and 7% experienced graft failure. At 1 year and 3 years, respectively, overall survival was 65% and 60%, relapse-free survival was 65% and 31%, relapse was 5% and 40%, and nonrelapse mortality was 30% and 30%. Acute graft-versus-host disease grade 3-4 was seen in 17% of patients at 1 year, and chronic graft-versus-host disease requiring systemic therapy in occurred in 12% patients. Spleen size ≥17 cm or prior splenectomy was associated with inferior relapse-free survival (hazard ratio [HR], 3.50; 95% confidence interval [CI], 1.18 to 10.37; P = .02) and higher relapse rate (subdistribution HR [SDHR] not calculable; P = .01). Age >60 years (SDHR, 0.26; 95% CI, 0.08 to 0.80, P = .02) and receipt of peripheral blood grafts (SDHR, 0.34; 95% CI, 0.11 to 0.99; P = .05) were associated with a lower risk of relapse. In our limited sample, the presence of a high-risk mutation was not statistically significantly associated with an inferior outcome, although ASXL1 was suggestive of inferior survival (SDHR, 2.36; 95% CI, 0.85 to 6.6; P = .09). Overall, this approach shows outcomes comparable those of to previously reported approaches and underscores the importance of spleen size in the evaluation of transplantation candidates., Competing Interests: Declaration of Competing Interest T.J. reports institutional research support from CTI Biopharma and Syneos Health, consultancy for Targeted Healthcare Communications, and advisory board participation for Care Dx, Bristol Myers Squibb, Incyte and CTI Biopharma. The other authors have no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Although tacrolimus and sirolimus (TAC/SIR) is an accepted graft-versus-host disease (GVHD) prophylaxis regimen following allogeneic hematopoietic cell transplantation (HCT), toxicity from this regimen can lead to premature discontinuation of immunosuppression. There are limited studies reporting outcomes and subsequent treatment of patients with TAC/SIR intolerance. This study was conducted to assess the outcomes of patients with TAC/SIR intolerance and guide their subsequent management. We retrospectively analyzed transplantation outcomes of consecutive adult patients at Moffitt Cancer Center who underwent allogeneic HCT with TAC/SIR as GVHD prophylaxis between 2009 and 2018. TAC/SIR intolerance was defined as discontinuation of either TAC or SIR due to toxicity before post-transplantation day +100. A total of 777 patients met the inclusion criteria. The median duration of follow-up was 22 months (range, 0.2 to 125 months). Intolerance occurred in 13% (n = 104) of the patients at a median of 30 days (range, 5 to 90 days). The most common causes of intolerance were acute kidney injury (n = 53; 51%), thrombotic microangiopathy (n = 31; 28%), and veno-occlusive disease (n = 23; 22%). The cumulative incidence of grade II-IV acute GVHD at 100 days was 50% (95% CI, 39% to 64%) in the TAC/SIR-intolerant patients and 25% (95% CI, 22% to 29%) in patients tolerant to this regimen (P < .0001). In multivariate analyses, the incidence of grade II-IV 4 acute GVHD was significantly higher in the TAC/SIR-intolerant patients (hazard ratio [HR], 2.40; 95% CI, 1.59 to 3.61; P < .0001). Similarly, in multivariate analyses, the TAC/SIR-intolerant patients had a higher incidence of chronic GVHD (HR, 1.48; 95% CI, 1.03 to 2.12; P = .03). The nonrelapse mortality (NRM) at 1 year was 47% (95% CI, 38% to 59%) in the TAC/SIR-intolerant patients and 12% (95% CI, 10% to 15%) in those tolerant to the regimen (P < .0001). The 2-year relapse-free survival was 35% (95% CI, 25% to 44%) in the TAC/SIR-intolerant patients and 60% (95% CI, 57% to 65%) in the TAC/SIR-tolerant patients (HR, 2.30; 95% CI, 1.61 to 3.28; P < .0001). Intolerance stratified by early (≤30 days) versus late (31 to 100 days) significantly affected the cumulative incidence of acute GVHD at 75% (early; 95% CI, 59% to 94%) versus 33% (late; 95% CI, 21% to 50%) (P = .001), as well as the cumulative incidence of NRM at 61% (early; 95% CI, 48% to 77%) versus 35% (late; 95% CI, 24% to 51%) (P = .006). Most patients who developed TAC/SIR intolerance were switched to an alternative 2-drug regimen (71 of 104; 68%), most commonly mycophenolate mofetil in addition to continuing TAC or SIR (68 of 71; 96%). Overall, TAC/SIR intolerance was associated with poorer outcomes. Early intolerance contributed to a higher risk of acute GVHD, increased NRM, and inferior survival. Patients with early intolerance were often switched to an alternative agent, and patients with late intolerance tended to be continued on single-drug therapy without substitution. The use of single-drug versus 2-drug regimens after intolerance did not appear to affect outcomes. Management strategies to mitigate the risks of intolerance are warranted., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report. Financial disclosure: No disclosures relevant to this work., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We report the results from a multicenter retrospective study of 69 adult patients who underwent haploidentical blood or marrow transplantation (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) for chronic phase myelofibrosis. The median age at BMT was 63 years (range, 41-74). Conditioning regimens were reduced intensity in 54% and nonmyeloablative in 39%. Peripheral blood grafts were used in 86%. The median follow-up was 23.1 months (range, 1.6-75.7). At 3 years, the overall survival, relapse-free survival (RFS), and graft-versus-host-disease (GVHD)-free-RFS were 72% (95% CI 59-81), 44% (95% CI 29-59), and 30% (95% CI 17-43). Cumulative incidences of non-relapse mortality and relapse were 23% (95% CI 14-34) and 31% (95% CI 17-47) at 3 years. Spleen size ≥22 cm or prior splenectomy (HR 6.37, 95% CI 2.02-20.1, P = 0.002), and bone marrow grafts (HR 4.92, 95% CI 1.68-14.4, P = 0.004) were associated with increased incidence of relapse. Cumulative incidence of acute GVHD grade 3-4 was 10% at 3 months and extensive chronic GVHD was 8%. Neutrophil engraftment was reported in 94% patients, at a median of 20 days (range, 14-70). In conclusion, haplo-BMT with PTCy is feasible in patients with myelofibrosis. Splenomegaly ≥22 cm and bone marrow grafts were associated with a higher incidence of relapse in this study., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Post-transplantation cyclophosphamide (PTCy) is a safe and efficacious graft-versus-host-disease (GVHD) prophylaxis following hematopoietic cell transplantation (HCT) from a haploidentical (haplo) donor. Cytokine release syndrome (CRS) is a common complication of this platform. Early fever post-haplo-HCT using bone marrow grafts is associated with higher CD3 + cell dose and CRS. However, the impact of CD3 + and CD34 + cell dose on CRS post-haplo-HCT using peripheral blood stem cell (PBSC) grafts is unknown. Our goals were to evaluate the incidence of CRS following PBSC transplantation (PBSCT) and to identify factors that can be modified to prevent the development of severe CRS in this setting. In 271 patients, we investigated factors associated with the development of CRS following haplo-PBSCT and examined the impact of CRS on clinical outcomes. Ninety-three percent of the patients developed CRS of any grade post-haplo-PBSCT. In multivariate analysis, severe CRS (grade 3-4 versus grade 0-1) was associated with higher nonrelapse mortality (hazard ratio [HR], 6.42; 95% confidence interval [CI], 2.68 to 15.39; P < .001), worse 1-year overall survival (HR, 3.40; 95% CI, 1.63 to 7.08; P = .005), and worse disease-free survival (HR, 4.02; 95% CI, 1.99 to 8.08; P < .001). Moderate to severe CRS (grade 2-4) did not impact 1-year relapse or acute GVHD (grade II-IV and III-IV) at 100 days (P = .71 and .19, respectively). Importantly, higher CD3 + cell dose, but not CD34 + cell dose, predicted a higher incidence of grade 2-4 CRS (HR, 1.20; 95% CI,1.07 to 1.36; P = .003) and grade 3-4 CRS (HR, 1.40; 95% CI, 1.05 to 1.86; P = .022). Both older age (HR, 8.57; 95% CI, 1.73 to 42.36; P < .001) and non-total body irradiation-based reduced-intensity conditioning with fludarabine/melphalan (HR, 15.38; 955 CI, 2.06 to 114.67; P < .001) were predictive of grade 3-4 CRS. Overall, we observed that severe CRS (grade 3-4) negatively affected transplantation outcome, and that higher CD3 cell dose was associated with the development of any grade CRS and severe CRS., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Randomized clinical trials offer the highest-quality data for modifying clinical practice. Results of a phase III randomized trial of nonmyeloablative transplantation for adults with high-risk hematologic malignancies with 2 umbilical cord blood (UCB) units (n = 183) or HLA-haploidentical relative bone marrow (Haplo-BM; n = 154) revealed a 2-year progression-free survival (PFS) of 41% after Haplo-BM transplantation and 35% after 2-unit UCB transplantation (P = .41), with overall survival (OS) of 57% and 46%, respectively (P = .04). We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial's prespecified 2-year outcomes. All transplantations were performed between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial would be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM with those after haploidentical peripheral blood (Haplo-PB). The trial's broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select nontrial subjects. Extended follow-up of trial subjects was obtained from this data source. Three separate analyses were performed: (1) trial subjects beyond the trial's 2-year endpoint; (2) comparison of trial subjects with a contemporaneous cohort of nontrial subjects (195 2-unit UCB, 358 Haplo-BM, and 403 Haplo-PB); and (3) comparison of nontrial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups. With longer follow-up of the trial cohorts, 5-year PFS (37% versus 29%; P = .08) and OS (42% versus 36%; P = .06) were not significantly different between the treatment groups. We then compared the trial results with outcomes of comparable real-world transplantations. Five-year OS did not differ between trial and nontrial 2-unit UCB transplantations (36% versus 41%; P = .48) or between trial and nontrial Haplo-BM transplantations (42% versus 47%; P = .80), confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in PFS. With substantially larger numbers of nontrial Haplo-BM transplantations, 5-year survival was higher after nontrial Haplo-BM compared with trial 2-unit UCB (47% versus 36%; P = .012). Nontrial patients who underwent Haplo-PB transplantation had higher 5-year survival (54%) compared with trial Haplo-BM (hazard ratio [HR], 0.76; P = .044) and nontrial Haplo-BM (HR, 0.78; P = .026). Similarly, survival was better after Haplo-PB compared with trial UCB (HR, 0.57; P < .0001) and nontrial UCB (HR, 0.63; P = .0002). When considering alternative donor low-intensity conditioning regimen transplantation, a haploidentical relative is preferred, and PB is the preferred graft source., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD.  This trial was registered at www.clinicaltrials.gov as #NCT01680965., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Myelodysplastic syndromes (MDS) are a diverse group of hematological malignancies distinguished by a combination of dysplasia in the bone marrow, cytopenias and the risk of leukemic transformation. The hallmark of MDS is bone marrow failure which occurs due to selective growth of somatically mutated clonal hematopoietic stem cells. Multiple prognostic models have been developed to help predict survival and leukemic transformation, including the international prognostic scoring system (IPSS), revised international prognostic scoring system (IPSS-R), WHO prognostic scoring system (WPSS) and MD Anderson prognostic scoring system (MDAPSS). This risk stratification informs management as low risk (LR)-MDS treatment focuses on improving quality of life and cytopenias, while the treatment of high risk (HR)-MDS focuses on delaying disease progression and improving survival. While therapies such as erythropoiesis stimulating agents (ESAs), erythroid maturation agents (EMAs), immunomodulatory imide drugs (IMIDs), and hypomethylating agents (HMAs) may provide benefit, allogeneic blood or marrow transplant (alloBMT) is the only treatment that can offer cure for MDS. However, this therapy is marred, historically, by high rates of toxicity and transplant related mortality (TRM). Because of this, alloBMT is considered in a minority of MDS patients. With modern techniques, alloBMT has become a suitable option even for patients of advanced age or with significant comorbidities, many of whom who would not have been considered for transplant in prior years. Hence, a formal transplant evaluation to weigh the complex balance of patient and disease related factors and determine the potential benefit of transplant should be considered early in the disease course for most MDS patients. Once alloBMT is recommended, timing is a crucial consideration since delaying transplant can lead to disease progression and development of other comorbidities that may preclude transplant. Despite the success of alloBMT, relapse remains a major barrier to success and novel approaches are necessary to mitigate this risk and improve long term cure rates. This review describes various factors that should be considered when choosing patients with MDS who should pursue transplant, approaches and timing of transplant, and future directions of the field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jain and Elmariah.)

Post-transplantation cyclophosphamide (PTCy) is being increasingly used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT) across various donor types. However, immune reconstitution and infection incidence after PTCy-based versus conventional GVHD prophylaxis has not been well studied. We evaluated the infection density and immune reconstitution (ie, absolute CD4 + T cell, CD8 + T cell, natural killer cell, and B cell counts) at 3 months, 6 months, and 1 year post-HCT in 583 consecutive adult patients undergoing allo-HCT with myeloablative (n = 223) or reduced-intensity (n = 360) conditioning between 2012 and 2018. Haploidentical (haplo; n = 75) and 8/8 HLA-matched unrelated (MUD; n = 08) donor types were included. GVHD prophylaxis was PTCy-based in all haplo (n = 75) and in 38 MUD allo-HCT recipients, whereas tacrolimus/methotrexate (Tac/MTX) was used in 89 and Tac/Sirolimus (Tac/Sir) was used in 381 MUD allo-HCT recipients. Clinical outcomes, including infections, nonrelapse mortality (NRM), relapse, and overall survival (OS), were compared across the 4 treatment groups. The recovery of absolute total CD4 + T-cell count was significantly lower in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups throughout 1 year post-allo-HCT (P = .025). In contrast, CD19 + B-cell counts at 6 months and thereafter were higher in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (P < .001). Total CD8 + T cell and NK cell recovery was not significantly different among the groups. Infection density analysis showed a significantly higher frequency of total infections in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (5.0 and 5.0 vs 1.8 and 2.6 per 1000-person days; P < .01) within 1 year of allo-HCT. The cumulative incidence of cytomegalovirus reactivation/infection at 1 year post-allo-HCT was higher in the haplo-PTCy group (51%) compared with the MUD-PTCy (26%), Tac/MTX (26%), or Tac/Sir (13%) groups (P < .001). The incidence of BK, human herpesvirus 6, and other viruses were also higher in the PTCy-based groups. Overall, the treatment groups had similar 2 year NRM (P = .27) and OS (P = .78) outcomes. Our data show that PTCy-based GVHD prophylaxis is associated with delayed CD4 + T cell but faster B cell immune reconstitution and a higher frequency of infections compared with conventional GVHD prophylaxis but has no impact on nonrelapse mortality or overall survival., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

In 2020, the US Food and Drug Administration approved 53 novel drugs. Thirty-six of the 53 (68%) drugs were reviewed and approved through an expedited review pathway, and 31 of the 53 (58%) were approved for treatment of a rare disease. This review includes a summary of the novel drugs approved by the US Food and Drug Administration in 2020., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

While immune checkpoint inhibitors (ICIs) have ushered in major changes in standards of care for many solid tumor malignancies, primary and acquired resistance is common. Insufficient antitumor T cells, inadequate function of these cells, and impaired formation of memory T cells all contribute to resistance mechanisms to ICI. Adoptive cellular therapy (ACT) is a form of immunotherapy that is rapidly growing in clinical investigation and has the potential to overcome these limitations by its ability to augment the number, specificity, and reactivity of T cells against tumor tissue. ACT has revolutionized the treatment of hematologic malignancies, though the use of ACT in solid tumor malignancies is still in its early stages. There are currently three major modalities of ACT: tumor-infiltrating lymphocytes (TILs), genetically engineered T-cell receptors (TCRs), and chimeric antigen receptor (CAR) T cells. TIL therapy involves expansion of a heterogeneous population of endogenous T cells found in a harvested tumor, while TCRs and CAR T cells involve expansion of a genetically engineered T-cell directed toward specific antigen targets. In this review, we explore the potential of ACT as a treatment modality against solid tumors, discuss their advantages and limitations against solid tumor malignancies, discuss the promising therapies under active investigation, and examine future directions for this rapidly growing field., Competing Interests: Competing interests: KK: Owns stock in Seattle Genetics, Oncternal Therapeutics, and Veru. HE: None. DA-D: Member of the scientific advisory board of Anixa Biosciences. He receives research funding from Intellia Therapeutics and Bluebird Bio and has been listed as inventor or coinventor in patent applications filed by Moffitt Cancer Center. CHC: Honoraria from Sanofi and Exelixis for ad hoc Scientific Advisory Board participation., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation., Patients and Methods: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC ( n = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells., Results: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4 + T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias., Conclusions: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial., (©2021 American Association for Cancer Research.)

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223., (© 2021 by The American Society of Hematology.)

European LeukemiaNet (ELN) 2017 risk stratification by genetics is prognostic of outcomes in patients with acute myeloid leukemia (AML). However, the prognostic impact of the 2017 ELN genetic risk stratification after allogeneic hematopoietic cell transplantation (alloHCT) is not well established. We examined the effect of 2017 ELN genetic risk stratification on alloHCT outcomes of AML. We included 500 adult (≥18 years) AML patients in first (n = 370) or second (n = 130) complete remission receiving alloHCT from 2005 to 2016. Patients were classified into favorable (12%), intermediate (57%), and adverse (32%) 2017 ELN risk groups. The Cox proportional hazard model was used to conduct the multivariable analyses of leukemia-free survival (LFS) and overall survival (OS). Relapse and nonrelapse mortality were analyzed by the Fine-Gray regression model. OS at 2 years was 72% in the favorable versus 60% in the intermediate versus 45% in the adverse risk groups (P < .001). In multivariable analyses, the 2017 ELN classifier was an independent predictor of OS after alloHCT with significantly higher overall mortality in the intermediate (hazard ratio [HR] = 1.68, 95% confidence interval [CI], 1.06-2.68; P = .03) and adverse (HR = 2.50, 95% CI, 1.54-4.06; P < .001) risk groups compared to the favorable risk group. Similarly, LFS was worse in the intermediate (HR = 1.63, 95%, CI 1.06-2.53; P = .03) and adverse (HR 2.23, 95% CI, 1.41-3.54; P < .001) risk groups while relapse was higher in the adverse risk group (HR = 2.36, 95% CI, 1.28-4.35; P = .006) as compared to the favorable risk group. These data highlight the prognostic impact of the 2017 ELN genetic risk stratification on the survival of AML patients after alloHCT. Patients in the adverse risk group had the highest risk of relapse and worst survival. Thus the 2017 ELN prognostic system can help identify AML patients who may benefit from clinical trials offering relapse mitigation strategies to improve transplant outcomes., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We compared outcomes in 603 patients with myelodysplastic syndrome (MDS) after HLA-haploidentical relative (n = 176) and HLA-matched unrelated (n = 427) donor hematopoietic cell transplantation (HCT) from 2012 to 2017, using the Center for International Blood and Marrow Transplant Research database. All transplantations used reduced-intensity conditioning regimens. Total-body irradiation plus cyclophosphamide and fludarabine was the predominant regimen for HLA-haploidentical relative donor HCT, and graft-versus-host disease (GVHD) prophylaxis was uniformly posttransplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate. Fludarabine with busulfan or melphalan was the predominant regimen for HLA-matched unrelated donor HCT, and GVHD prophylaxis was calcineurin inhibitor with mycophenolate or methotrexate. Results of multivariate analysis revealed higher relapse (hazard ratio [HR], 1.56; P = .0055; 2-year relapse rate, 48% vs 33%) and lower disease-free survival (DFS) rates after HLA-haploidentical relative donor HCT (HR, 1.29; P = .042; 2-year DFS, 29% vs 36%). However, overall survival (OS) rates did not differ between donor type (HR, 0.94; P = .65; 2-year OS, 46% for HLA-haploidentical and 44% for HLA-matched unrelated donor HCT) because of mortality associated with chronic GVHD. Acute grade 2 to 4 GVHD (HR, 0.44; P < .0001) and chronic GVHD (HR, 0.36; P < .0001) were lower after HLA-haploidentical relative donor HCT. By 2 years, probability of death resulting from chronic GVHD was lower after HLA-haploidentical relative compared with HLA-matched unrelated donor HCT (6% vs 21%), negating any potential survival advantage from better relapse control. Both donor types extend access to transplantation for patients with MDS; strategies for better relapse control are desirable for HLA-haploidentical relative donor HCT, and effective GVHD prophylaxis regimens are needed for unrelated donor HCT.

Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for a variety of hematologic diseases. However, this therapeutic platform is limited by an initial period when patients are profoundly immunocompromised. There is gradual immune recovery over time, that varies by transplant platform. Here, we review immune reconstitution after allogeneic HCT with a specific focus on two alternative donor platforms that have dramatically improved access to allogeneic HCT for patients who lack an HLA-matched related or unrelated donor: haploidentical and umbilical cord blood HCT. Despite challenges, interventions are available to mitigate the risks during the immunocompromised period including antimicrobial prophylaxis, modified immune suppression strategies, graft manipulation, and emerging adoptive cell therapies. Such interventions can improve the potential for long-term overall survival after allogeneic HCT.

With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative (NMA) HLA-haploidentical (haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Previous reports have shown that discontinuation of immunosuppression (IS) as early as day 60 after infusion of a bone marrow (BM) haplo allograft with PTCy is feasible. There are certain diseases in which peripheral blood (PB) may be favored over BM, but given the higher rates of GVHD with PB, excessive GVHD is of increased concern. We report a completed, prospective single-center trial of stopping IS at days 90 and 60 after NMA PB stem cell transplantation (PBSCT). Between 12/2015-7/2018, 117 consecutive patients with hematologic malignancies associated with higher rates of graft failure after NMA conditioned BMT and PTCy, received NMA PB allografts on trial. The primary objective of this study was to evaluate the safety and feasibility of reduced-duration IS (from day 5 through day 90 in the D90 cohort and through day 60 in the D60 cohort). Of the 117 patients (median age, 64 years; range, 22 to 78 years), the most common diagnoses were myelodysplastic syndrome (33%), acute myelogenous leukemia (with minimal residual disease or arising from an antecedent disorder) (32%), myeloproliferative neoplasms (19%), myeloma (9%), and chronic lymphoblastic leukemia (7%). Shortened IS was feasible in 75 patients (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 patients), followed by early relapse (11 patients), nonrelapse mortality (NRM) (7 patients), patient/ physician preference (4 patients) or graft failure (3 patients). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned, and among the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV acute GVHD was 21 days in the D90 cohort and 32 days in the D60 cohort, with almost all cases developing within 40 days. Approximately one-third of these patients resumed IS. All outcome measures were similar in the 2 cohorts and our historical outcomes with 180 days of IS. The cumulative incidence of grade III-IV acute GVHD was low, 2% in the D90 cohort and 7% in the D60 cohort. The incidence of severe chronic GVHD at 2 years was 9% in the D90 cohort and 5% in the D60 cohort. The 2-year overall survival was 67% for both the D90 and D60 cohorts. The 2-year progression-free survival was 47% for the D90 cohort and 52% for the D60 cohort, and the GVHD-free, relapse-free survival was <35% for both cohorts. These data suggest that reduced-duration IS in patients undergoing NMA PBSCT with PTCy is feasible and has an acceptable safety profile. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs). The proportion of patients who are hospitalized for irAEs and their spectrum, management, and outcomes are not well described., Methods: We report the proportion of hospitalized patients in an academic center who were treated with ICIs from May to December 2017. Patient characteristics, toxicities, management, and outcomes for confirmed irAE admissions are reported. Associations between patient features and irAE hospitalizations are examined., Results: Twenty-three percent (n = 100) of 443 patients who were admitted to an academic oncology center over 6 months had ever received ICIs. Of these patients, 41% were admitted for suspected irAEs and 23% were confirmed irAEs. IrAEs accounted for 5% of all oncology hospitalizations (n = 23). Ninety-one percent of patients with confirmed irAEs prompted a medicine subspecialist consultation, most commonly gastroenterology (22%). Fifteen patients (65%) had their irAEs improve/resolve, seven (30%) had worsening irAEs, and three (13%) died of their irAEs. The majority of patients (n = 20; 87%) discontinued ICIs after discharge. Among ICI-treated patients who required admission, an increased likelihood of irAE-related hospitalization was associated with patient age older than 65 years (odds ratio, 5.4; 95% CI, 1.6 to 17.8) and receipt of combination immunotherapy (OR, 6.8; 95% CI, 2.0 to 23.2)., Conclusion: A notable proportion of ICI-treated patients are hospitalized for irAEs, and these patients have a high demand for multidisciplinary management. Older age and combination ICI treatment were associated with an increased risk of irAE-related hospitalization. Whereas these data are from an academic center and include patients in clinical trials, with expanding use of ICIs, these data have important implications for inpatient service planning and risk stratification.

Allogeneic blood or marrow transplantation (BMT) is a curative therapy for a number of high-risk hematologic malignancies. Historically, only patients with a human leukocyte antigen (HLA)-matched sibling or unrelated donor were able to receive this therapy, thus excluding many potential transplant recipients. In recent years, partially mismatched related donor, or human leukocyte antigen-haploidentical (haplo) BMT has expanded the donor pool to nearly every patient in need of a transplant, particularly when using post-transplantation cyclophosphamide to promote immune tolerance and prevent graft-versus-host disease. With now over 15 years of clinical experience using this platform, long terms outcomes are well understood. We review the clinical literature and highlight the advantages and disadvantages of haplo BMT with post-transplantation cyclophosphamide., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose of Review: Chronic myelomonocytic leukemia (CMML) is a rare and often aggressive myeloid malignancy. Historically, prognostic markers and therapeutic paradigms have been applied from myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPNs). Interest has increased recently in developing tailored approaches for the MDS/MPN overlap syndrome of CMML., Recent Findings: Multiple prognostic scores have been validated specifically for CMML in the past 5 years. These incorporate somatic mutations, with ASXL1 mutations repeatedly correlating with poor prognosis. Accurate prognostication can guide treatment. Hypomethylating agents (HMAs) and curative allogeneic blood or marrow transplantation (BMT) remain the most available standard treatments. Recently, a number of novel approaches using unapproved therapies (i.e., lenalidomide, ruxolitinib, sotatercept, and tipifarnib) have demonstrated some efficacy in CMML. Increased recognition and interest in CMML have led to the development of a number of new prognostic models and potential treatment options. Standard treatment options remain limited and clinical trials should be strongly considered whenever available.

Outcomes of nonmyeloablative (NMA) haploidentical (haplo) blood or marrow transplant (BMT) with post-transplantation cyclophosphamide (PTCy) using non-first-degree relatives are unknown. We evaluated 33 consecutive adult patients (median age, 56 years) with hematologic malignancies who underwent NMA haplo T cell-replete BMT with PTCy at Johns Hopkins using second- or third-degree related donors. Donors consisted of 10 nieces (30%), 9 nephews (27%), 7 first cousins (21%), 5 grandchildren (15%), and 2 uncles (6%). Thirty-one patients (94%) reached full donor chimerism by day 60. The estimated cumulative incidence (CuI) of grades II to IV acute graft-versus-host disease (aGVHD) at day 180 was 24% (90% confidence interval [CI], 9% to 38%). Only 1 patient experienced grades III to IV aGVHD. At 1 year the CuI of chronic GVHD was 10% (90% CI, 0% to 21%). The CuI of nonrelapse mortality at 1 year was 5% (90% CI, 0% to 14%). At 1 year the probability of relapse was 31% (90% CI, 12% to 49%), progression-free survival 64% (90% CI, 48% to 86%), and overall survival 95% (90% CI, 87% to 100%). The 1-year probability of GVHD-free, relapse-free survival was 57% (90% CI, 41% to 79%). NMA haplo BMT with PTCy from non-first-degree relatives is an acceptably safe and effective alternative donor platform, with results similar to those seen with first-degree relatives., (Copyright © 2018. Published by Elsevier Inc.)