Coexistence of Light Chain and Transthyretin Cardiac Amyloidosis.

Although most patients with cardiac amyloidosis are diagnosed with either light chain (AL) or transthyretin (ATTR) disease, coexisting amyloid subtypes can occur. We present three cases of coexisting AL and ATTR cardiac amyloidosis and demonstrate the importance of clinical history and endomyocardial biopsy in diagnosis of this rare entity.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Alternative donor BMT with posttransplant cyclophosphamide as initial therapy for acquired severe aplastic anemia.

Severe aplastic anemia (SAA) is a marrow failure disorder with high morbidity and mortality. It is treated with bone marrow transplantation (BMT) for those with fully matched donors, or immunosuppressive therapy (IST) for those who lack such a donor, which is often the case for underrepresented minorities. We conducted a prospective phase 2 trial of reduced-intensity conditioning HLA-haploidentical BMT and posttransplantation cyclophosphamide (PTCy)-based graft-versus-host (GVHD) prophylaxis as initial therapy for patients with SAA. The median patient age was 25 years (range, 3-63 years), and the median follow-up time was 40.9 months (95% confidence interval [CI], 29.4-55.7). More than 35% of enrollment was from underrepresented racial/ethnic groups. The cumulative incidence of grade 2 or 4 acute GVHD on day 100 was 7% (95% CI, not applicable [NA]-17), and chronic GVHD at 2 years was 4% (95% CI, NA-11). The overall survival of 27 patients was 92% (95% CI, 83-100) at 1, 2, and 3 years. The first 7 patients received lower dose total body irradiation (200 vs 400 cGy), but these patients were more likely to have graft failure (3 of 7) compared with 0 of 20 patients in the higher dose group (P = .01; Fisher exact test). HLA-haploidentical BMT with PTCy using 400 cGy total body irradiation resulted in 100% overall survival with minimal GVHD in 20 consecutive patients. Not only does this approach avoid any adverse ramifications of IST and its low failure-free survival, but the use of haploidentical donors also expands access to BMT across all populations. This trial was registered at www.clinicaltrials.gov as NCT02833805.

Systemic Light Chain Amyloidosis, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

Allogeneic Blood or Marrow Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Age ≥55 Years.

Patients age ≥55 years with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy, with a 5-year overall survival (OS) of ∼20%. Tyrosine kinase inhibitors and novel B cell-targeted therapies can improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (alloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplantations with low rates of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD). The transplantation database at Johns Hopkins was queried for patients age ≥55 years who underwent alloBMT for ALL using PTCy. The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first complete remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% confidence interval [CI], 34% to 57%) and 49% (95% CI, 37% to 60%), respectively. Grade III-IV acute GVHD occurred in only 3% of patients, and chronic GVHD occurred in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (hazard ratio [HR], 4.65; P = .001), whereas transplantation in CR1 (HR, .30; P = .004) and transplantation for Philadelphia chromosome-positive (Ph+) ALL versus T-ALL (HR, .29; P = .03) were associated with improved RFS. Of the 54 patients who underwent RIC alloBMT in CR1 for B-ALL, the 5-year RFS and OS were 62% (95% CI, 47% to 74%) and 65% (95% CI, 51% to 77%), respectively, with a 5-year relapse incidence of 16% (95% CI, 7% to 27%) and an NRM of 24% (95% CI, 13% to 36%). RIC alloBMT with PTCy in CR1 represents a promising consolidation strategy for B-ALL patients age ≥55 years.

Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide for Peripheral T Cell Lymphoma: The Importance of Graft Source.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus host-disease (GVHD) prophylaxis has revolutionized allogeneic blood or marrow transplantation (alloBMT), but there is limited published experience in peripheral T cell lymphoma (PTCL). We sought to assess outcomes in patients with PTCL who underwent alloBMT with PTCy. We reviewed the charts of all adult patients age ≥18 years who underwent alloBMT with nonmyeloablative conditioning and PTCy-based GVHD prophylaxis at the Sidney Kimmel Comprehensive Cancer Center between January 2004 and December 2020. Sixty-five patients were identified. The median age was 59 years (range, 24 to 75 years). Lymphoma histology included PTCL not otherwise specified (n = 24), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 14), angioimmunoblastic T cell lymphoma (n = 7), enteropathy-associated T cell lymphoma (n = 6), hepatosplenic T cell lymphoma (n = 4), and others (n = 10). Eleven patients were in first complete remission (17%); the remaining patients were in first partial remission or underwent salvage therapy to at least PR prior to transplantation. Forty-eight patients underwent alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (11%). All patients received fludarabine, cyclophosphamide, and total body irradiation (TBI). The graft source was bone marrow (BM) in 46 patients (71%) and peripheral blood (PB) in 19 patients (29%); all patients in the BM cohort received 200 cGy TBI, and most patients in the PB cohort (15 of 19) received 400 cGy TBI. GVHD prophylaxis comprised PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow-up of 2.8 years (range, 290 days to 14.2 years), the 2-year progression-free survival (PFS) for the entire cohort was 49% (95% confidence interval [CI], 38% to 64%), and the 2-year overall survival (OS) was 55% (95% CI, 44% to 69%). Outcomes were significantly improved in those receiving PB compared to those receiving BM, including a 2-year PFS of 79% (95% CI 63% to 100%) versus 39% (95% CI, 27% to 56%), 2-year OS of 84% (95% CI, 69% to 100%) versus 46% (95% CI, 33% to 63%), and 1-year cumulative incidence of relapse of 5% (95% CI, 0 to 16%) versus 33% (95% CI, 19% to 46%), with no difference in GVHD and nonrelapse mortality. AlloBMT with PTCy is safe and well-tolerated in patients with PTCL. Our data suggest that increasing the TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings.

Combination Therapy With Casirivimab/Imdevimab and Remdesivir for Protracted SARS-CoV-2 Infection in B-cell-Depleted Patients.

Profoundly B-cell-depleted patients can have prolonged severe acute respiratory syndrome coronavirus 2 infections with evidence of active viral replication, due to inability to mount an adequate humoral response to clear the virus. We present 3 B-cell-depleted patients with prolonged coronavirus disease 2019 infection who were successfully treated with a combination of casirivimab/imdevimab and remdesivir.

Post-Transplantation Cyclophosphamide-Based Graft- versus-Host Disease Prophylaxis with Nonmyeloablative Conditioning for Blood or Marrow Transplantation for Myelofibrosis.

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.

NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Nonmyeloablative Allogeneic Transplantation With Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia With IDH Mutations: A Single Center Experience.

INTRODUCTION: Mutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes. PATIENTS AND METHODS: In this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML. RESULTS: Patients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15). CONCLUSION: Among patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).

An Allogeneic Multiple Myeloma GM-CSF-Secreting Vaccine with Lenalidomide Induces Long-term Immunity and Durable Clinical Responses in Patients in Near Complete Remission.

PURPOSE: This proof-of-principle clinical trial evaluated whether an allogeneic multiple myeloma GM-CSF-secreting vaccine (MM-GVAX) in combination with lenalidomide could deepen the clinical response in patients with multiple myeloma in sustained near complete remission (nCR). PATIENTS AND METHODS: Fifteen patients on lenalidomide were treated with MM-GVAX and pneumococcal conjugate vaccine (PCV; Prevnar) at 1, 2, 3, and 6 months. RESULTS: Eight patients (53.3%) achieved a true CR. With a median follow-up of 5 years, the median progression-free survival had not been reached, and the median overall survival was 7.8 years from enrollment. MM-GVAX induced clonal T-cell expansion and measurable cytokine responses that persisted up to 7 years in all patients. At baseline, a higher minimal residual disease was predictive of early relapse. After vaccination, a lack of both CD27-DNAM1-CD8+ T cells and antigen-presenting cells was associated with disease progression. CONCLUSIONS: MM-GVAX, along with lenalidomide, effectively primed durable immunity and resulted in long-term disease control, as suggested by the reappearance of a detectable, fluctuating M-spike without meeting the criteria for clinical relapse. For patients in a nCR, MM-GVAX administration was safe and resulted in prolonged clinical responses.

Nonmyeloablative, HLA-Mismatched Unrelated Peripheral Blood Transplantation with High-Dose Post-Transplantation Cyclophosphamide.

High-dose post-transplantation cyclophosphamide (PTCy) is an effective platform for prevention of severe graft-versus-host disease (GVHD) after allogeneic bone marrow (BM) transplantation with mismatched unrelated donors (mMUDs). Previous studies evaluating PTCy with mMUDs favored BM allografts over peripheral blood stem cell transplantation (PBSCT) due to concerns that PBSCT may be associated with an increased risk of acute and chronic GVHD. In addition, haploidentical PBSCT is associated with high rates of cytokine release syndrome (CRS), which is another concern with mMUD PBSCT. This study was conducted to determine the feasibility and safety of using mMUD PBSCT with PTCy as GVHD prophylaxis. Patients who received mMUD PBSCT using a PTCy-based GVHD prophylaxis at Johns Hopkins Hospital as part of a prospective clinical trial of mMUD and non-first-degree relative haploidentical transplantation with PTCy (ClinicalTrials.gov identifier NCT01203722) were included. All patients underwent T cell-replete PBSCT between November 2012 and August 2020. Statistical analyses were performed using the Kaplan-Meier method and proportional subdistribution hazard regression model for competing risks. The 29 patients in the study had a median age of 54 years, with 10 patients (34%) age ≥60 years. Nineteen grafts (66%) were matched for 9/10 HLA loci, 6 (21%) were match for 8/10, and 4 (14%) were matched for 7/10. No primary or secondary graft failure occurred. The median time to neutrophil recovery (≥500/µL) was 17 days, and that to platelet recovery (≥20,000/µL) was 28 days. Full donor chimerism was achieved in all patients by day +60. The cumulative incidence (CuI) of grade II-IV acute GVHD at 180 days was 15% (90% confidence interval [CI], 3% to 26%). There were no cases of severe chronic GVHD, 3 cases of mild chronic GVHD, and 1 case of moderate chronic GVHD. The CuI of nonrelapse mortality (NRM) was 7% (90% CI, NA to 18%) at 1 year. Eighteen patients (62%) experienced mild CRS (grade 1-2), and 1 patient (3%) experienced severe CRS (grade 3-5). At 1 year, the CuI of relapse was 29% (90% CI, 8% to 50%), overall survival was 93% (90% CI, 85% to 100%), progression-free survival was 64% (90% CI, 46% to 88%), GVHD-free relapse-free survival was 41% (90% CI, 23% to 73%), and chronic GVHD-free relapse-free survival was 64% (90% CI, 46% to 88%). Our data indicate that mMUD PBSCT using PTCy-based GVHD prophylaxis is safe and feasible. All patients engrafted, and rates of NRM (7%) and acute GVHD (15%) at 1 year were low. There was only 1 case (3%) of severe CRS. Compared with previously published outcomes, mMUD PBSCT using PTCy-based GVHD prophylaxis has a safety and efficacy profile that may not be different from that of PBSCT from matched donors. These results further solidify that all patients who require blood or BM transplantation should be able to find an acceptable donor.

Allogeneic Blood or Marrow Transplantation with Nonmyeloablative Conditioning and High-Dose Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis for Secondary Central Nervous System Lymphoma.

Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplantation (alloBMT) is widely used in patients with relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. We reviewed outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with nonmyeloablative conditioning using fludarabine, cyclophosphamide, and 200 cGy total body irradiation. For graft-versus-host disease prophylaxis, all patients received post-transplantation cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI], 5.3 months to not reached). The cumulative incidence of relapse was 25% (95% CI, 5% to 45%), and nonrelapse mortality was 30% (95% CI, 5% to 54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS/systemic. The use of alloBMT in CNS lymphoma merits further investigation.

Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide.

Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.

Thrombotic Microangiopathy after Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis.

Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.

Shortened-Duration Immunosuppressive Therapy after Nonmyeloablative, Related HLA-Haploidentical or Unrelated Peripheral Blood Grafts and Post-Transplantation Cyclophosphamide.

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.