Faculty Bibliography

We compared outcomes of patients ≥ 70 years old undergoing allogeneic stem cell transplantation (alloSCT) with graft-vs-host disease (GvHD) prophylaxis regimens either including post-transplant cyclophosphamide (PTCy) or without cyclophosphamide (non-Cy). The primary endpoint was GvHD-free, relapse-free survival (GRFS) at one and five years; secondary endpoints included clinically significant acute (grade III-IV) and chronic (extensive) GvHD, relapse, overall survival (OS), and non-relapse mortality (NRM). Among 61 patients, 41 received PTCy and 20 received non-Cy prophylaxis. Unrelated donors accounted for 80 % of allografts; all non-Cy patients had 10/10 HLA matches, while PTCy patients had 64 % matched, 29 % haploidentical, and 7 % mismatched unrelated donors. Acute GvHD occurred in 5 % of PTCy vs 15 % of non-Cy patients (p = ns). One-year chronic GvHD incidence was lower with PTCy (12 % vs 30 %, p = 0.03). One-year GRFS was similar (34 % PTCy, 35 % non-Cy; p = ns). At five years, OS was 20 % vs 30 % and GRFS 21 % vs 15 % for PTCy and non-Cy, respectively (p = ns). We observed similar outcomes among patients receiving GvHD prophylaxis with PTCy compared to non-Cy. Importantly, non-Cy patients had HLA-matched donors, whereas mismatched donors were possible for the PTCy group. In this way, PTCy seems to have equalized outcomes for fully matched and mismatched alloSCT by yielding similar one and five-year GRFS. We also found no significant difference in relapse rate, NRM, OS, and five-year GRFS between patients aged 70-74 and ages 75 + , showing that numerical age should not be a contraindication to alloSCT.

OBJECTIVE:To evaluate the safety and efficacy of CD19 chimeric antigen receptor (CAR) T cell therapy in a patient with refractory lupus nephritis who experienced severe disease flare during immunosuppressive washout, and to assess whether pulse corticosteroid intervention affects CAR T cell therapeutic outcomes. METHODS:We report a single case of a 22-year-old woman with SLE and lupus podocytopathy refractory to multiple therapies including rituximab, belimumab and obinutuzumab. The patient was treated under single-patient IND (#30146) with autologous CD19 CAR T cells (KYV-101). During the preinfusion washout period, she developed severe lupus flare requiring pulse intravenous methylprednisolone. Clinical outcomes, CAR T cell expansion, B cell depletion and laboratory parameters were monitored before and after therapy. RESULTS:Despite experiencing severe lupus flare (fever, rash, arthritis, anti-dsDNA elevation, hypocomplementaemia) during washout, pulse methylprednisolone (250 mg intravenous, rapidly tapered) successfully controlled symptoms without compromising subsequent CAR T cell expansion (peak 15.5 cells/µL on day 7). The patient achieved sustained clinical remission with SLE Disease Activity Index Score decreasing from 17 prior to leukapheresis to 4 by week 17. At 12 months postinfusion, she remained in drug-free remission with stable kidney function and had returned to full-time work. CONCLUSION/CONCLUSIONS:This case report illustrates that targeted pulse corticosteroids during CAR T cell therapy washout can effectively manage severe lupus flares without impairing therapeutic efficacy.

BACKGROUND:The prolonged turnaround time for next-generation sequencing (NGS) results may be a barrier to the timely selection of therapeutics in myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) with mutated TP53. Biomarker validation for early detection of TP53 mutation may have a significant impact on clinical decision-making. METHODS:In this study, p53 immunohistochemistry (IHC) (index test) and TP53 NGS (referent test) were performed on 145 bone marrow specimens from 82 unique patients with TP53-mutant MDS or AML to validate IHC as an early surrogate for NGS, and to assess the prognostic relevance of IHC. RESULTS:p53 IHC testing was able to correctly identify 95.5% of patients with TP53-mutant MDS and 100% of patients with TP53-mutant AML in this cohort. The mean p53 stain positivity was higher for AML compared to MDS (28% ± 3.67% vs. 8.8% ± 1.61%; p < .001), as well as for multihit TP53 compared to monoallelic TP53. Bootstrap analysis with 2000 iterations showed that a p53 IHC of 7% was the threshold best associated with multihit TP53. False-negative results were obtained with IHC in all TP53 sole nonsense or frameshift mutations. IHC positivity was inversely correlated with overall survival (OS), with the highest quintile of p53 positivity showing a median OS of just 2.53 months. CONCLUSIONS:IHC is a useful biomarker for the early detection of TP53-mutant MDS or AML and for prediction of TP53 allelic state. The results suggest a role for IHC across global markets, especially in geographic areas with inaccessibility to NGS testing.

BACKGROUND:The prognostic impact of cohesin mutations in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is controversial. METHODS:In patients with AML and MDS who underwent next-generation sequencing at the authors' center during 2017-2023, the authors assessed the landscape of cohesin mutations and the impact of co-occurring mutations on overall survival (OS) and compared outcomes between patients with cohesin mutations and those with wild-type (WT) cohesin genes. RESULTS:The study included 83 patients, 36 with cohesin mutations (STAG2, n = 28; SMC1A, n = 7; SMC3, n = 3; co-expression of cohesin mutations, n = 2) and 47 with WT cohesin genes. Of the 36 patients with cohesin mutations, 17 (47%) had AML (six de novo and 11 secondary), and 19 (53%) had MDS. Patients who had STAG2 mutations had better median OS than patients who had only SMC1A and SMC3 mutations (26 vs. 10 months; p = .043). SRSF2 mutation was the most frequent co-occurring mutation (n = 12; 33%) and was associated with worse median OS than WT SRSF2 (13 vs. 43 months; p = .016). Seven patients (19%) with cohesin mutations underwent hematopoietic transplantation; their median OS was 70 months. Compared with the WT cohesin group, patients who had cohesin mutations were more likely to have adverse-risk AML (82% vs. 53%). The median OS was similar among patients with adverse-risk AML in the cohesin-mutation and WT cohesin groups (10 vs. 14 months, respectively; p = .9). CONCLUSIONS:The current study provides insight into the prognostic impact of cohesin mutations and co-occurring mutations in patients with myeloid malignancies.

Using haploidentical donors for allogeneic hematopoietic cell transplantation (HCT) broadens transplant accessibility to a growing number of patients with hematologic disorders. Moreover, haploidentical HCT with post-transplant cyclophosphamide (PTCy) has become widespread practice due to accumulating evidence demonstrating favorable rates of survival and graft-versus-host disease (GvHD). Most studies comparing outcomes by donor sources have been confounded by variability in conditioning regimens, graft type (peripheral blood [PB] or bone marrow), and post-transplant GvHD prophylaxis (PTCy or non-PTCy), making it difficult to define the effect of donor source on outcomes. Levine Cancer Institute started a transplant and cellular therapy program in 2014, with both haploidentical and matched related donor (MRD) transplants initially performed using a uniform reduced-intensity conditioning (RIC) regimen, PB grafts, and PTCy-based GvHD prophylaxis. This retrospective observational study was conducted to compare the clinical outcomes associated with RIC haploidentical HCT and MRD HCT in patients receiving identical conditioning regimens, graft types, and supportive care. Our transplant database was queried to evaluate demographic characteristics, clinical features, and outcomes of RIC HCT for consecutive patients with hematologic malignancies who received haploidentical or MRD grafts between March 2014 and December 2017. An MRD was the preferred donor source; when unavailable, a haploidentical donor was used. Sixty-seven patients underwent haploidentical HCT and 25 MRD HCT. Overall, characteristics of transplant recipients were similar for the haploidentical and MRD groups; however, haploidentical donors were younger than MRDs (median 36 yr versus 57 yr, P < .0001). Results of univariable analysis showed similar overall survival (OS) for haploidentical and MRD HCT (hazard ratio [HR], 1.15; 95% CI, 0.61 to 2.15; P = .669). One-year, 1-yr, and 5-yr OS were 80.2%, 54.7%, and 41.2% for haploidentical HCT and 76.0%, 55.7%, and 51.1% for MRD HCT, respectively. With a median follow-up of 81.90 months, results of multivariable analysis revealed that donor source (haploidentical versus MRD) was not significantly associated with OS (HR, 0.97; 95% CI, 0.51 to 1.87; P = .933), relapse-free survival (HR, 0.75; 95% CI, 0.42 to 1.35; P = .337), cumulative incidence of relapse (HR, 0.81; 95% CI, 0.39 to 1.70; P = .579), or non-relapse mortality (HR, 1.12; 95% CI, 0.40 to 3.14; P = .827). Cumulative incidences of acute GvHD (aGvHD) and chronic GvHD (cGvHD) were not significantly different for haploidentical and MRD HCT (grades II to IV aGvHD: HR, 1.78; 95% CI, 0.72 to 4.37; P = .210; grades III to IV aGvHD: HR, 2.84; 95% CI, 0.34 to 23.63; P = .335; cGvHD: HR, 1.00; 95% CI 0.36 to 2.76; P = .995). With care that was homogenous in terms of conditioning regimens, graft type, GvHD prophylaxis, and supportive care, 92 patients who were biologically randomized to either haploidentical HCT or MRD HCT after RIC with PTCy had comparable outcomes.

INTRODUCTION/UNASSIGNED:In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety. METHODS/UNASSIGNED:A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites. RESULTS/UNASSIGNED:We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites. CONCLUSION/UNASSIGNED:The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.