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There are no standard treatments to prevent or hasten the recovery from severe conditioning-regimen–induced thrombocytopenia occurring after autologous hematopoietic cell transplantation (auto-HCT). We conducted an open-label, single-arm pilot study of romiplostim, a thrombopoietin receptor agonist, to enhance platelet recovery in patients with multiple myeloma or lymphoma undergoing auto-HCT. All patients were treated weekly with romiplostim starting day +1 after auto-HCT until the platelet count was >50 × 109/L without transfusion. Compared with contemporary retrospective data from romiplostim-naïve patients (N = 853), romiplostim-treated patients (N = 59) had a similar median number of days of grade 4 thrombocytopenia or days requiring transfusions, time to platelet engraftment, and number of platelets transfusions during the auto-HCT. However, romiplostim-treated patients had enhanced platelet recovery to normal values beginning at approximately day +15. In matched cohort multivariable analyses, romiplostim treatment was associated with higher platelet counts by an average of 40 × 109/L (95% confidence interval (CI) (14, 67), P = .003) and 118 × 109/L (95% CI [84, 152], P

Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57–69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6–11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10–4.72]), lack of response to CAR-T (2.33 [1.02–5.29]), age >65 years (HR 2.65 [1.49–4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61–5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.

Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. MATERIALS AND METHODS: Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre–CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. RESULTS: We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type (P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. CONCLUSION: TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.

CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough for patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) inducing sustained remissions in these patients. However, CAR T-cells can result in significant toxicities. Pre-infusion disease burden is associated with toxicities and outcomes after CAR T-cell therapy. We identified 33 patients with R/R DLBCL treated at 8 academic centers who had no detectable disease at the time of CAR T-cell therapy. The median time from leukapheresis to CAR T-cell infusion was 48 (19-193) days. Nine patients received axicabtagene ciloleucel and 24 received tisagenlecleucel. There was no severe (grade≥3) cytokine release syndrome and only 1 patient developed severe neurotoxicity (grade 4). After a median follow-up of 16 months, 13 patients relapsed (39.4%) and 6 died (18.1%). One-year event-free survival and overall survival were 59.6% and 81.3%, respectively. Our findings suggest that, in patients with R/R DLBCL who have an indication for CAR T-cell therapy, treating patients in complete remission at time of infusion is feasible, safe, and associated with favorable disease control. Further exploration in a larger clinical trial setting is warranted.

While alternative donors extend transplant access, whether recipient ancestry impacts the time to allogeneic transplant is not established. We analyzed the likelihood of clinically significant delays to allograft by patient ancestry in 313 transplanted adult acute myelogenous leukemia (AML) patients. Non-European ancestry patients (n = 99) were more likely than Europeans (n = 214) to receive HLA-mismatched donor allografts (45% versus 24%, p < 0.001). Overall, the median time from transplant indication to allograft was 127 days (range 57-1,683). In multivariable analysis, non-Europeans had an increased risk of prolonged indication-transplant time > 180 days (OR 2.1, 95%CI:1.4-5.6, p = 0.012) due to significant delays in indication-consult > 90 days (OR 2.8, 95%CI:1.3-4.5, p = 0.005) and consult-transplant > 120 days (OR 2.4, 95%CI:1.2-3.7, p = 0.005). Compared to recipients of HLA-matched unrelated donors (URD), HLA-mismatched adult donor recipients were at increased risk of delayed indication-transplant whereas matched sibling and cord blood recipients were at lower risk. Sub-analysis showed more indication-transplant delays in non-European versus European 8/8 URD recipients (44% versus 19% > 180 days, p = 0.004). Finally, the pandemic further exacerbated delays for non-Europeans. In summary, while non-European AML patients are less likely to receive 8/8 URDs as expected, if they do their transplants are delayed. HLA-identical siblings and cord blood facilitate the fastest transplants regardless of patient ancestry whereas other adult donor transplants are delayed. Strategies to mitigate referral barriers, hasten donor evaluation, and utilize all alternative donor sources are critical to ensure timely transplantation for AML patients.

Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy has transformed the care of patients with relapsed/refractory large B cell lymphoma (LBCL). However, approximately 60% of CAR-T recipients ultimately will experience disease recurrence or progression. Salvage therapies after CAR-T treatment failures are of limited efficacy and have a short duration of response. The objective of the present study was to evaluate the role of allogeneic hematopoietic cell transplantation (allo-HCT) after CAR-T therapy in LBCL patients. This was a multicenter observational study reporting the outcome of 39 adult LBCL patients who underwent allo-HCT following anti-CD19 CAR-T therapy. The median patient age was 47 years (range, 20 to 68 years). HLA-matched sibling, HLA-matched unrelated, and alternative donors were used in 36%, 36%, and 28% of transplantations, respectively. Conditioning regimens were primarily of low or intermediate intensity. Disease status at allo-HCT was complete response in 41%, partial response in 38%, and progressive disease in 21%. Allo-HCT was performed at a median of 127 days (range, 82 to 206 days) after CAR-T therapy. A high incidence of hepatic toxicity (28%), including sinusoidal obstruction syndrome (15.4%; 95% confidence interval; [CI], 6.2% to 28.5%), was observed. The 1-year cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) was 38.5% (95% CI, 23.2% to 53.6%) and 15.4% (95% CI, 6.1% to 28.5%), respectively. The 2-year cumulative incidence of moderate-severe chronic GVHD was 11.1% (95% CI, 3.3% to 24.3%). Overall, 2-year nonrelapse mortality and relapse/progression incidence were 26% (95% CI, 13% to 41%) and 43% (95% CI, 27% to 59%), respectively. With a median follow-up of 32 months, the 2-year overall survival (OS) and progression-free survival (PFS) were 45% (95% CI, 31% to 66%) and 31% (95% CI, 19% to 50%), respectively. In multivariable analyses, pre-HCT elevated lactate dehydrogenase level and transformed lymphoma were predictive of OS and PFS, respectively. Our data suggest that allo-HCT after anti-CD19 CAR-T treatment failure is feasible with a relatively promising efficacy but possibly high toxicity rate.

Introduction: Older adults with hematologic malignancies such as AML and MDS increasingly undergo allogeneic hematopoietic cell transplantation (alloHCT). The impact of the aging host environment, especially cellular senescence, remains unexplored, however. Objectives: We hypothesize that pre-transplant senescence-associated secretary phenotype (SASP) is associated with alloHCT outcomes among older patients and tested it in this biomarker correlative study. Methods: We measured ten SASP-related cytokines (IFNγ, IL1β, IL2, IL4, IL6, IL8, IL10, IL12, IL13, and TNFα, and C-reactive protein (CRP) from pre-transplant plasma samples of 155 patients (>50 years) who had undergone alloHCT at MSKCC from 2011 to 2019 for acute leukemias and other myeloid malignancies. Expression of aging biomarker p16 was measured on a subset of patients by immunohistochemistry. Results and Discussion: The median age was 64.1 years (IQR 58.3 – 67.8). Diseases included 57% acute leukemias (AML and ALL) and 43% MDS/MPN. KPS was 3 in 53% of patients. With median follow-up of 61 months for survivors, the 5-year OS and PFS is 50% and 46%, respectively. The 2-year cumulative incidence of non-relapse mortality (NRM) and relapse is 18% and 31%, respectively. At the baseline, these SASP-related cytokines have variable degree of association with KPS, chronologic age, and disease risk. IL2 trended toward significant positive association with OS (HR 1.19, 95% CI 1-1.43, p=0.052) and was significantly associated with PFS (HR 1.21, 95% CI 1.02-1.44, p=0025) in univariate analysis, but not in multivariate analysis after adjusting for clinical characteristics. No cytokine was associated with NRM. IL2 and IL4 were associated with relapse in univariate but not multivariate analysis. Several cytokines including IL12 p70, IL13, IL4, and TNFα were associated with 100d grade II-IV acute GVHD in patients who received CNI-based GVHD prophylaxis. In summary, we found potential association of SASP-related cytokines with patient characteristics and transplant outcomes. We aim to validate these findings and examine their therapeutic potential to improve alloHCT outcomes. Citation Format: Richard J Lin, Phillip Wong, Jessica R Flynn, Erika R Ritter, Caleb Ho, Josel D Ruiz, Ann A Jakubowski, Esperanza B Papadopoulos, Brian C Shaffer, Hugo R Castro-Malaspina, Christina J Cho, Doris R Ponce, Juliet N Barker, Roni Tamari, Craig S Sauter, Boglarka Gyurkocza, Marcel van den Brink, James W Young, Miguel-Angel Perales, Sean M Devlin, Sergio A Giralt. Aging-related, Senescence-associated Secretory Phenotype and Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A48.

High-dose melphalan is one of the main cytotoxic DNA alkylating agents and is used in many transplantation conditioning regimens. Studies have shown a wide range of drug exposure when a traditional weight-based dose of melphalan is used. The optimal melphalan dose in BEAM (carmustine, etoposide, cytarabine, and melphalan), which results in maximum efficacy with acceptable toxicity, is unknown. In this pharmacokinetic (PK) analysis of 105 patients with lymphoma undergoing treatment with BEAM and autologous hematopoietic cell transplantation, we initially estimated melphalan exposure as area under the curve (AUC) by a noncompartmental analysis and subsequently compared it with a newly developed 2-compartment population-PK model. The 2 models correlated closely with each other. We found that the traditional fixed weight-based dosing of propylene glycol-free (captisol-enabled) melphalan in BEAM results in a wide variation in exposure as estimated by both models. Higher melphalan exposure was significantly associated with increased metabolic toxicities but did not seem to impact progression-free survival. Although our study suggests a melphalan AUC of 8 mg·h/L as a potential target in BEAM, larger prospective studies using personalized PK-directed melphalan dosing are needed to determine the optimal melphalan exposure in lymphomas.