DNA Sequencing to Detect Residual Disease in Adults With Acute Myeloid Leukemia Prior to Hematopoietic Cell Transplant.

Importance: Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized. Objective: To determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants. Design, Setting, and Participants: In this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research. Exposure: Centralized DNA sequencing of banked pretransplant remission blood samples. Main Outcomes and Measures: The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models. Results: Of 1075 patients tested, 822 had FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3-ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3-ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P < .001) and decreased survival at 3 years (39% vs 63%; difference, -24% [2-sided 95% CI, -39% to -9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P < .001). Conclusions and Relevance: Among patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.

Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide.

The intensive and prolonged immunosuppressive therapy required to prevent or treat graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) puts patients at substantial risk for life-threatening infections, organ toxicity, and disease relapse. Posttransplantation cyclophosphamide (PTCy) can function as single-agent GVHD prophylaxis after myeloablative, HLA-matched related (MRD), or HLA-matched unrelated (MUD) donor T-cell-replete bone marrow allografting, obviating the need for additional prophylactic immunosuppression. However, patients who develop GVHD require supplemental treatment. We assessed the longitudinal requirement for immunosuppressive therapy in 339 patients treated with this transplantation platform: 247 receiving busulfan/cyclophosphamide (BuCy) conditioning (data collected retrospectively) and 92 receiving busulfan/fludarabine (BuFlu) conditioning (data collected prospectively). Approximately 50% of MRD patients and 30% of MUD patients never required immunosuppression beyond PTCy. In patients requiring further immunosuppression, typically only 1 to 2 agents were required, and the median durations of systemic pharmacologic immunosuppression for the BuCy MRD, BuFlu MRD, BuCy MUD, and BuFlu MUD groups all were 4.5 to 5 months. For these 4 groups, 1-year probabilities of being alive and off all systemic immunosuppression were 61%, 53%, 53%, and 51% and 3-year probabilities were 53%, 48%, 49%, and 56%, respectively. These data suggest that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched alloBMT.

Organ sparing of linac-based targeted marrow irradiation over total body irradiation.

PURPOSE: Targeted marrow irradiation (TMI) is an alternative conditioning regimen to total body irradiation (TBI) before bone marrow transplantation in hematologic malignancies. Intensity-modulation methods of external beam radiation therapy are intended to permit significant organ sparing while maintaining adequate target coverage, improving the therapeutic ratio. This study directly compares the dose distributions to targets and organs at risk from TMI and TBI, both modalities conducted by general-use medical linacs at our institution. METHODS: TMI treatments were planned for 10 patients using multi-isocentric feathered volumetric arc therapy (VMAT) plans, delivered by 6 MV photon beams of Elekta Synergy linacs. The computed tomography (CT) datasets used to obtain these plans were also used to generate dose distributions of TBI treatments given in the AP/PA extended-field method. We compared dose distributions normalized to the same prescription for both plan types. The generalized equivalent uniform dose (gEUD) of Niemierko for organs and target volumes was used to quantify effective whole structure dose and dose savings. RESULTS: For the clinical target volume (CTV), no significant differences were found in mean dose or gEUD, although the radical dose homogeneity index (minimum dose divided by maximum dose) was 31.7% lower (P = 0.002) and the standard deviation of dose was 28.0% greater (P = 0.027) in the TMI plans than in the TBI plans. For the TMI plans, gEUD to the lungs, brain, kidneys, and liver was significantly lower (P < 0.001) by 47.8%, 33.3%, 55.4%, and 51.0%, respectively. CONCLUSION: TMI is capable of maintaining CTV coverage as compared to that achieved in TBI, while significantly sparing organs at risk. Improvement on sparing organs at risk permits a higher prescribed dose to the target or the maximum number of times marrow conditioning may be delivered to a patient while maintaining similar typical tissue complication rates.

Impact of HLA Alleles on Outcomes of Allogeneic Transplantation for B Cell Non-Hodgkin Lymphomas: A Center for International Blood and Marrow Transplant Research Analysis.

Even in the modern era of targeted therapies, allogeneic hematopoietic stem cell transplantation (allo-HCT) can offer a chance of extended survival in B cell non-Hodgkin lymphoma (B-NHL) patients who relapse after or are deemed ineligible for autologous transplantation. A better understanding of the factors influencing the graft-versus-lymphoma (GVL) response would be useful in identifying B-NHL patients who may benefit from allo-HCT. Based on prior single-center reports, we hypothesized that certain HLA alleles, or haplotypes, may be associated with superior GVL compared with others after allo-HCT. To test this possibility we retrospectively evaluated whether the presence of HLA-A2, HLA-C1C1, HLA-DRB1*01:01, or HLA-DRB1*13 alleles or the presence of HLA-A1+, HLA-A2-, and HLA-B44- haplotypes is associated with outcomes in a cohort of 1314 HLA-8/8 matched sibling or unrelated donor HCT for relapsed/refractory B-NHL. We observed no significant association between any HLA allele or haplotype and overall survival or any of the secondary endpoints. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-NHL patients based on HLA type. Identification of other variables will be required to delineate the immunologic impact of donor-host interactions on outcomes of allo-HCT for B-NHL.

Dual institution experience of nodal marginal zone lymphoma reveals excellent long-term outcomes in the rituximab era.

Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin lymphoma that arises from mature B-cells. We delineate outcomes, prognostic factors and treatment trends among a large cohort of patients with NMZL in the rituximab era. We identified 56 such patients treated at our institutions. The majority presented with advanced stage disease (78·6%). Over a median follow-up of 38·2 months, median progression-free survival (PFS) was 42·4 months and median overall survival (OS) was not reached. Kaplan-Meier estimates of OS at 120 months after diagnosis was 71·9%. High-risk follicular lymphoma international prognostic index (FLIPI) was associated with inferior PFS. Age >60 years and elevated serum lactate dehydrogenase (LDH) were associated with inferior OS. Transformation to diffuse large B-cell lymphoma occurred in 7 patients, 6 of who presented with advanced disease. OS was comparable to our previously reported extranodal MZL cohort. FLIPI score predicted for inferior PFS and OS when both cohorts were analysed together (n = 267). In summary, outcomes in NMZL are favourable with a large majority of patients surviving at 120 months. High risk FLIPI, age >60 years, and elevated serum LDH were associated with inferior outcomes.

Dual institution experience of extranodal marginal zone lymphoma reveals excellent long-term outcomes.

Extranodal marginal zone lymphoma (EMZL) is a B-cell lymphoma arising from mucosa-associated lymphoid tissue (MALT). The disease characteristics, clinical course and treatment vary considerably based on site of involvement. Because long-term outcome data for EMZL are limited, we sought to describe the clinical details of a large number of patients with EMZL evaluated at the Case Comprehensive Cancer Center over a 12-year period to identify prognostic markers including the impact of site of involvement. We identified 211 cases of EMZL involving the stomach (30%), ocular adnexa (19%), lungs (16%) and intestines (9%). Initial treatment included antibiotics (18%), radiation (21%), rituximab (20%), chemotherapy (3%), rituximab + chemotherapy (7%), surgery (17%) or observation (8%). After a median follow-up of 44·3 months (range 2·2-214·9), median progression-free survival (PFS) was 68·2 months (95% confidence interval [CI] 54·5-111·3) and median overall survival (OS) has not been reached. Age >60 years, elevated lactate dehydrogenase level (LDH), ≥4 lymph node groups involvement, and high follicular lymphoma international prognostic index (FLIPI) were associated with inferior PFS/OS. In summary, patients with EMZL have excellent prognosis with median OS in excess of 10 years. Age, elevated LDH, advanced disease, and high FLIPI score are associated with worse outcomes.

Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research.

We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients.

Allotransplantation for patients age ≥40 years with non-Hodgkin lymphoma: encouraging progression-free survival.

Non-Hodgkin lymphoma (NHL) disproportionately affects older patients, who do not often undergo allogeneic hematopoietic cell transplantation (HCT). We analyzed Center for International Blood and Marrow Transplant Research data on 1248 patients age ≥40 years receiving reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT for aggressive (n = 668) or indolent (n = 580) NHL. Aggressive lymphoma was more frequent in the oldest cohort 49% for age 40 to 54 versus 57% for age 55 to 64 versus 67% for age ≥65; P = .0008). Fewer patients aged ≥65 had previous autografting (26% versus 24% versus 9%; P = .002). Rates of relapse, acute and chronic GVHD, and nonrelapse mortality (NRM) at 1 year post-HCT were similar in the 3 age cohorts (22% [95% confidence interval (CI), 19% to 26%] for age 40 to 54, 27% [95% CI, 23% to 31%] for age 55 to 64, and 34% [95% CI, 24% to 44%] for age ≥65. Progression-free survival (PFS) and overall survival (OS) at 3 years was slightly lower in the older cohorts (OS: 54% [95% CI, 50% to 58%] for age 40 to 54; 40% [95% CI, 36% to 44%] for age 55 to 64, and 39% [95% CI, 28% to 50%] for age ≥65; P < .0001). Multivariate analysis revealed no significant effect of age on the incidence of acute or chronic GVHD or relapse. Age ≥55 years, Karnofsky Performance Status <80, and HLA mismatch adversely affected NRM, PFS, and OS. Disease status at HCT, but not histological subtype, was associated with worse NRM, relapse, PFS, and OS. Even for patients age ≥55 years, OS still approached 40% at 3 years, suggesting that HCT affects long-term remission and remains underused in qualified older patients with NHL.

Low rate of infusional toxicity after expanded cord blood transplantation.

BACKGROUND AIMS: Umbilical cord blood (CB) is used with increasing frequency to restore hematopoiesis in patients with bone marrow transplant who lack a suitable human leukocyte antigen-matched donor. CB transplantation is limited by low cell doses and delays in neutrophil and platelet engraftment. CB progenitors expanded ex vivo before transplantation provide more rapid hematopoietic and immune reconstitution as well as less engraftment failure compared with unmanipulated CB. However, the safety of infusing double and ex vivo-expanded CB has not been systematically examined. METHODS: We reviewed the immediate adverse events (AE) associated with the infusion of CB occurring within 24 hours in 137 patients enrolled in clinical CB transplant trials at the MD Anderson Cancer Center from February 2004 to May 2010. All patients received an unmanipulated CB unit followed by infusion of a second unmanipulated CB unit or a second CB unit expanded ex vivo with the use of cytokines in a liquid culture system or in mesenchymal stromal cell co-cultures. RESULTS: A total of three grade 2 and two grade 3 infusion reactions occurred within 24 hours of CB transplantation. This resulted in an AE rate of 3.7%. The majority of AEs manifested as signs of hypertension. No association with patient age, sex, disease status, premedication, ABO compatibility or total infusion volume was observed. In summary, the incidence of infusion-related toxicities in patients who receive unmanipulated and ex vivo-expanded double CB transplantation is low. CONCLUSIONS: We conclude that the infusion of unmanipulated followed by expanded CB products is a safe procedure associated with a low probability of inducing severe reactions.

Flow cytometry of DNMT1 as a biomarker of hypomethylating therapies.

The 5-azacytidine (AZA) and decitabine (DEC) are noncytotoxic, differentiation-inducing therapies approved for treatment of myelodysplastic syndrome, acute myeloid leukemias (AML), and under evaluation as maintenance therapy for AML postallogeneic hematopoietic stem cell transplant and to treat hemoglobinapathies. Malignant cell cytoreduction is thought to occur by S-phase specific depletion of the key epigenetic regulator, DNA methyltransferase 1 (DNMT1) that, in the case of cancers, thereby releases terminal-differentiation programs. DNMT1-targeting can also elevate expression of immune function genes (HLA-DR, MICA, MICB) to stimulate graft versus leukemia effects. In vivo, there is a large inter-individual variability in DEC and 5-AZA activity because of pharmacogenetic factors, and an assay to quantify the molecular pharmacodynamic effect of DNMT1-depletion is a logical step toward individualized or personalized therapy. We developed and analytically validated a flow cytometric assay for DNMT1 epitope levels in blood and bone marrow cell subpopulations defined by immunophenotype and cell cycle state. Wild type (WT) and DNMT1 knock out (DKO) HC116 cells were used to select and optimize a highly specific DNMT1 monoclonal antibody. Methodologic validation of the assay consisted of cytometry and matching immunoblots of HC116-WT and -DKO cells and peripheral blood mononuclear cells; flow cytometry of H116-WT treated with DEC, and patient samples before and after treatment with 5-AZA. Analysis of patient samples demonstrated assay reproducibility, variation in patient DNMT1 levels prior to treatment, and DNMT1 depletion posttherapy. A flow-cytometry assay has been developed that in the research setting of clinical trials can inform studies of DEC or 5-AZA treatment to achieve targeted molecular pharmacodynamic effects and better understand treatment-resistance/failure.

Siltuximab for Chimeric Antigen Receptor T-Cell Therapy Related CRS and ICANS - A Multicenter Retrospective Analysis.

Chimeric Antigen Receptor T-Cell therapies (CAR-T) are effective in many hematologic malignancies; however, adverse events including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can affect a significant number of patients. Those who develop refractory CRS or ICANS have few treatment options. Siltuximab, a monoclonal antibody binding circulating IL-6, has been proposed to have clinical activity in both CRS and ICANS. We conducted a multi-center retrospective analysis of siltuximab treatment for CRS and ICANS following CAR-T cell therapy in a real-world cohort from six academic centers. Fifty-four patients were evaluated. Sixteen patients had CRS previously treated with tocilizumab and 17 patients had ICANS previously treated with steroids. Of the all the patients with CRS at the time of siltuximab, 75% had improvement in CRS grade. Of the all the patients with ICANS at the time of siltuximab, 60% had improvement in ICANS grade. To our knowledge, this is the largest cohort of patients treated with siltuximab for CRS and/or ICANS following CAR-T. Siltuximab appeared to be effective for both CRS and ICANS, including previously treated toxicities. These data support the use of siltuximab in CRS and ICANS as well as provide rationale for future prospective studies.

Measurable residual mutated IDH2 before allogeneic transplant for acute myeloid leukemia.

Routine genetic profiling of acute myeloid leukemia (AML) at initial diagnosis has allowed subgroup specific prognostication, drug development, and clinical management strategies. The optimal approach for treatment response assessment for AML subgroups has not yet however been determined. A nationwide cohort of 257 adult patients in first remission (CR1) from AML associated with an IDH2 mutation (IDH2m) undergoing allogeneic transplant during the period 2013-2019 in the United States had rates of relapse and survival three years after transplantation of 24% and 71%, respectively. Pre-transplant clinical flow cytometry assessment was not useful in stratifying patients based on risk of post-transplant relapse or death. DNA-sequencing was performed on CR1 blood collected within 100 days before transplant. Persistent detection of IDH2m was common (51%) and associated with increased relapse and death compared to testing negative. Co-mutation at initial diagnosis with mutated NPM1 and/or FLT3-ITD was common in this cohort (41%) and use of these validated MRD markers provided superior stratification compared to IDH2m testing. Patients testing negative for IDH2m prior to transplant had low relapse-related death, regardless of conditioning intensity. Post-transplant relapse rates for those with persistently detectable IDH2m in pre-transplant remission were lower after the FDA approval of enasidenib in August 2017.

Measurable Residual FLT3 Internal Tandem Duplication Before Allogeneic Transplant for Acute Myeloid Leukemia.

Importance: Persistence of FLT3 internal tandem duplication (ITD) in adults with acute myeloid leukemia (AML) in first complete remission (CR) prior to allogeneic hematopoietic cell transplant (HCT) is associated with increased relapse and death after transplant, but the association between the level of measurable residual disease (MRD) detected and clinical outcome is unknown. Objective: To examine the association between pre-allogeneic HCT MRD level with relapse and death posttransplant in adults with AML in first CR. Design, Setting, and Participants: In this cohort study, DNA sequencing was performed on first CR blood from patients with FLT3-ITD AML transplanted from March 2013 to February 2019. Clinical follow-up was through May 2022. Data were analyzed from October 2022 to December 2023. Exposure: Centralized DNA sequencing for FLT3-ITD in pre-allogeneic HCT first CR blood using a commercially available kit. Main Outcomes and Measures: The primary outcomes were overall survival and cumulative incidence of relapse, with non-relapse-associated mortality as a competing risk post-allogeneic HCT. Kaplan-Meier estimations (log-rank tests), Cox proportional hazards models, and Fine-Gray models were used to estimate the end points. Results: Of 537 included patients with FLT3-ITD AML from the Pre-MEASURE study, 296 (55.1%) were female, and the median (IQR) age was 55.6 (42.9-64.1) years. Using the variant allele fraction (VAF) threshold of 0.01% or greater for MRD positivity, the results closely aligned with those previously reported. With no VAF threshold applied (VAF greater than 0%), 263 FLT3-ITD variants (median [range] VAF, 0.005% [0.0002%-44%]), and 177 patients (33.0%) with positive findings were identified. Multivariable analyses showed that residual FLT3-ITD was the variable most associated with relapse and overall survival, with a dose-dependent correlation. Patients receiving reduced-intensity conditioning without melphalan or nonmyeloablative conditioning had increased risk of relapse and death at any given level of MRD compared with those receiving reduced-intensity conditioning with melphalan or myeloablative conditioning. Conclusions and Relevance: This study provides generalizable and clinically applicable evidence that the detection of residual FLT3-ITD in the blood of adults in first CR from AML prior to allogeneic HCT is associated with an increased risk of relapse and death, particularly for those with a VAF of 0.01% or greater. While transplant conditioning intensification, an intervention not available to all, may help mitigate some of this risk, alternative approaches will be necessary for this high-risk population of patients who are underserved by the current standard of care.

High-dose chemotherapy and autologous stem cell transplantation for nodular lymphocyte-predominant Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct subtype of Hodgkin lymphoma that is characterized by unique clinical presentation, histological appearance, and indolent disease course. The recurrent nature of disease provides an opportunity to examine the role of stem cell transplantation in its management. We report here a single-center experience of 26 patients with relapsed NLPHL treated with high-dose chemotherapy and autologous stem cell transplantation between 1990 and 2008. With a median follow-up of 50 months (range, 2-138 months), the 5-year overall and event-free survival were 76% (SE 10%) and 69% (SE 10%), respectively. Our data suggest that high-dose chemotherapy and autologous transplantation should be considered as an option for patients with relapsed NLPHL.

Incidence and natural history of pure red cell aplasia in major ABO-mismatched haematopoietic cell transplantation.

Major ABO mismatching is not considered a contraindication to allogeneic haematopoietic stem cell transplantation (HSCT). Modern reduced-intensity conditioning and reduced-toxicity regimens cause much less myeloablation than conventional myeloablative regimens, such as cyclophosphamide with busulfan or total body irradiation, which may affect the incidence of pure red cell aplasia (PRCA). We estimated the incidence and described the natural history of PRCA in patients with major ABO-mismatched donor stem cells. Between 2007 and 2008, 161 (27% of all patients undergoing HSCT) underwent allogeneic HSCT with major ABO-mismatched stem cells and 12 (7·5%) of these patients developed PRCA. Thirty and ninety day T-cell and myeloid cell chimerism and neutrophil and platelet engraftment did not differ between patients who developed PRCA and those who did not. The only risk factor associated with PRCA was the use of a fludarabine/busulfan conditioning regimen. All patients with PRCA needed red cell transfusion for several months after HSCT resulting in significant iron overload. Pure red cell aplasia resolved spontaneously in the majority (seven patients) but only resolved after stopping tacrolimus in three patients. Hence, after major ABO-mismatched HSCT, the incidence of PRCA was 7·5% and it resolved spontaneously or after withdrawal of immunosuppression in the majority of patients.

Promises and challenges of a decentralized CAR T-cell manufacturing model.

Autologous chimeric antigen receptor-modified T-cell (CAR T) products have demonstrated un-precedent efficacy in treating many relapsed/refractory B-cell and plasma cell malignancies, leading to multiple commercial products now in routine clinical use. These positive responses to CAR T therapy have spurred biotech and big pharma companies to evaluate innovative production methods to increase patient access while maintaining adequate quality control and profitability. Autologous cellular therapies are, by definition, manufactured as single patient batches, and demand has soared for manufacturing facilities compliant with current Good Manufacturing Practice (cGMP) regulations. The use of a centralized production model is straining finite resources even in developed countries in North America and the European Union, and patient access is not feasible for most of the developing world. The idea of having a more uniform availability of these cell therapy products promoted the concept of point-of-care (POC) manufacturing or decentralized in-house production. While this strategy can potentially decrease the cost of manufacturing, the challenge comes in maintaining the same quality as currently available centrally manufactured products due to the lack of standardized manufacturing techniques amongst institutions. However, academic medical institutions and biotech companies alike have forged ahead innovating and adopting new technologies to launch clinical trials of CAR T products produced exclusively in-house. Here we discuss POC production of CAR T products.

Measurable Residual IDH1 before Allogeneic Transplant for Acute Myeloid Leukemia.

Measurable residual disease (MRD) in adults with acute myeloid leukemia (AML) in complete remission is an important prognostic marker, but detection methodology requires optimization. The persistence of mutated NPM1 or FLT3-ITD in the blood of adult patients with AML in first complete remission (CR1) prior to allogeneic hematopoetic cell transplant (alloHCT) has been established as associated with increased relapse and death after transplant. The prognostic implications of persistence of other common AML-associated mutations, such as IDH1, at this treatment landmark however remains incompletely defined. We performed testing for residual IDH1 variants (IDH1m) in pre-transplant CR1 blood of 148 adult patients undergoing alloHCT for IDH1-mutated AML at a CIBMTR site between 2013-2019. No post-transplant differences were observed between those testing IDH1m positive (n=53, 36%) and negative pre-transplant (overall survival: p = 0.4; relapse: p = 0.5). For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD or increased post-transplant relapse risk.

Adherence of stem cell transplant recipients receiving glucocorticoid therapy to an exercise-based rehabilitation program.

The high acuity of hematopoietic stem cell transplant (HSCT) recipients receiving glucocorticoid (GC) therapy for acute graft vs. host disease (aGVHD) may limit their adherence to an exercise-based rehabilitation program and hence, slow their recovery. To make this determination, the medical records of 59 subacute outpatient stem cell transplant recipients receiving methylprednisolone (MP) were reviewed for demographic, anthropometric and medical information. Performance on the repeated sit-to-stand, 50-ft walk and 6-min walk tests were determined before and after completing a 4-week progressive exercise rehabilitation program and outcomes were compared by a paired t-test (P < 0.05). Thirty-two patients (54%) finished a treatment plan (adherent group), completing 80% of the prescribed sessions and were reevaluated. Twenty-seven patients (46%) did not complete the rehabilitation program (nonadherent group), primarily because of readmission to the hospital (18 patients, 62%). The adherent group did not significantly improve their physical performance (p > 0.05). However, a subgroup of 40% of these patients did experience clinically significant improvements in their physical performance.These findings 1) support the feasibility of having HSCT recipients receiving GC therapy to participate in an exercise-based rehabilitation program and 2) suggest that to do so can result in clinically significant improvements in functional capacity.

Assessment of Pretreatment and Posttreatment Evolution of Neurofilament Light Chain Levels in Patients Who Develop Immune Effector Cell-Associated Neurotoxicity Syndrome.

Importance: Determining whether neurofilament light chain (NfL) elevations in patients who develop immune effector cell-associated neurotoxicity syndrome (ICANS) occur before or after infusion of cellular product is important to identify high-risk patients and inform whether neuroaxonal injury is latent or a consequence of treatment. Objective: To quantify serial NfL levels in patients undergoing cellular therapy. Design, Setting, and Participants: This retrospective 2-center study examined plasma NfL levels in 30 patients with detailed medical and treatment history, including all major pretreatment and posttreatment risk factors. Exclusion criteria included dementia and severe, symptomatic central nervous system (CNS) involvement. Main Outcomes and Measures: Patients' NfL levels were measured at 7 time points: baseline (prelymphodepletion), during lymphodepletion, postinfusion day (D) 1, D3, D7, D14, and D30. Prediction accuracy for the development of ICANS was next modeled using receiver operating characteristic (ROC) classification. Finally, univariate and multivariate modeling examined the association between NfL levels, ICANS, and potential risk factors including demographic (age, sex), oncologic (tumor burden, history of CNS involvement), neurologic (history of nononcologic CNS disease or neuropathy), and neurotoxic exposure histories (vincristine, cytarabine, methotrexate, or CNS radiotherapy). Results: A total of 30 patients (median [range] age, 64 [22-80] years; 12 women [40%] and 18 men [60%]) were included. Individuals who developed ICANS had elevations in NfL prior to lymphodepletion and chimeric antigen receptor T-cell infusion compared with those who did not develop ICANS (no ICANS: 29.4 pg/mL, vs any ICANS: 87.6 pg/mL; P < .001). Baseline NfL levels further predicted ICANS development with high accuracy (area under the ROC curve, 0.96), sensitivity (0.91), and specificity (0.95). Levels of NfL remained elevated across all time points, up to 30 days postinfusion. Baseline NfL levels correlated with ICANS severity but not demographic factors, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies. Conclusions and Relevance: In a subset of patients in this cross-sectional study, the risk of developing ICANS was associated with preexisting neuroaxonal injury that was quantifiable with plasma NfL level. This latent neuroaxonal injury was present prior to drug administration but was not associated with historic neurotoxic therapies or nononcologic neurologic disease. Preinfusion NfL may further permit early screening and identification of patients most at risk for ICANS. Additional studies are needed to determine NfL's utility as a predictive biomarker for early (preemptive or prophylactic) intervention and to delineate the origin of this underlying neural injury.

Platelet recovery before allogeneic stem cell transplantation predicts posttransplantation outcomes in patients with acute myelogenous leukemia and myelodysplastic syndrome.

Complete remission (CR) is the gold standard for assessing outcomes following chemotherapy for acute myelogenous leukemia (AML). "CRp," a response criterion defined as fulfillment of all criteria for CR except platelet count recovery to ≥100 × 10(9)/L, is associated with inferior outcomes following chemotherapy. The prognostic importance of CRp before allogeneic stem cell transplantation (allo-SCT) remains unknown. We analyzed a cohort of AML (n = 334) and myelodysplastic syndrome (MDS; n = 10) patients to determine the prognostic significance of achieving CR versus CRp before allo-SCT. At time of transplantation, 266 patients were in CR (CR1 and ≥CR2) and 78 in CRp (CR1p and ≥CR2p). Median follow-up was 38 months (3-131 months). Overall survival, progression-free survival, and nonrelapse mortality (NRM) were most favorable in patients transplanted in CR (CR1 or ≥CR2) compared with CRp (CR1p or ≥CR2p). Achieving CR is therefore associated with improved posttransplantation outcomes compared with achieving CRp and is a significant prognostic factor that needs to be considered when evaluating AML/MDS patients for clinical trials and allo-SCT.