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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

Cord blood transplantation (CBT) can be complicated by a high incidence of clinically significant cytomegalovirus infection (csCMVi). We have investigated the efficacy of extended letermovir prophylaxis in seropositive adult CBT recipients. The aim was to continue prophylaxis for ≥6 months (insurance permitting). By day 100, the incidence of csCMVi was 0% in 28 patients who received letermovir prophylaxis. Moreover, of 24 patients alive at day 100, none had csCMVi by day 180, having continued prophylaxis for all (n = 20) or part (n = 4) of that period. Overall, 20 patients stopped letermovir at a median of 354 days (range, 119-455 days) posttransplant, with only 5 requiring 1 (n = 4) or 2 (n = 1) courses of valganciclovir (median total duration, 58 days; range, 12-67 days) for postprophylaxis viremia, with no subsequent csCMVi. There were no toxicities attributable to letermovir. Of the 62 historic control subjects who received acyclovir only, 51 developed csCMVi (median onset, 34 days; range, 5-74 days), for a day 100 incidence of 82% (95% confidence interval, 73-92). Seven patients developed proven/probable CMV disease, and 6 died before day 100 (3 with proven/probable CMV pneumonia). Forty-five patients required extended therapy during the first 6 months for 1 (n = 10), 2 (n = 14), or 3/persistent (n = 21) csCMVi, with 43 (84%) of 51 developing significant treatment toxicities. Letermovir is a highly effective, well-tolerated prophylaxis that mitigates CMV infection, CMV-related mortality, and antiviral therapy toxicities in CBT recipients. Our data support prophylaxis duration of at least 6 months after CBT.

Following allogeneic hematopoietic cell transplantation (allo-HCT), the gastrointestinal (GI) tract is frequently affected by acute graft-versus-host disease (aGVHD), the pathophysiology of which is associated with a dysbiotic microbiome. Since microbial composition varies along the length of the GI tract, the authors hypothesized that microbiome features correlate with the pattern of organ involvement after allo-HCT. We evaluated 266 allo-HCT recipients from whom 1303 stool samples were profiled by 16S ribosomal gene sequencing. Patients were classified according to which organs were affected by aGVHD. In the 20 days prior to disease onset, GVHD patients had lower abundances of members of the class Clostridia, lower counts of butyrate producers, and lower ratios of strict-to-facultative (S/F) anaerobic bacteria compared with allograft recipients who were free of GVHD. GI GVHD patients showed significant reduction in microbial diversity preonset. Patients with lower GI aGVHD had lower S/F anaerobe ratios compared with those with isolated upper GI aGVHD. In the 20 days after disease onset, dysbiosis was observed only in GVHD patients with GI involvement, particularly those with lower-tract disease. Importantly, Clostridial and butyrate-producer abundance as well as S/F anaerobe ratio were predictors of longer overall survival; higher abundance of butyrate producers and higher S/F anaerobe ratio were associated with decreased risk of GVHD-related death. These findings suggest that the intestinal microbiome can serve as a biomarker for outcomes of allo-HCT patients with GVHD.

Endothelial activation and stress index (EASIX) predicts nonrelapse mortality (NRM) when assessed before hematopoietic cell transplantation (HCT). We sought to determine whether changes in EASIX after HCT may be an informative marker of NRM. We evaluated 509 adults who underwent reduced intensity, unmodified (N = 149, 29%), or myeloablative ex vivo CD34+-selected allogeneic HCT (allo-HCT) (N = 306, 71%) between 2008 and 2016. Patients who underwent unmodified allo-HCT received tacrolimus-based graft-versus-host disease (GVHD) prophylaxis, whereas CD34+-selected patients received no planned immunosuppression. EASIX (lactate dehydrogenase × creatinine/platelet count) was calculated continuously until 1-year after HCT. Log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. In total, 360 patients (71%) received CD34+-selected and 149 (29%) unmodified allo-HCT. Among all patients, EASIX scores increased rapidly, peaked at day +8, then declined rapidly until day +33. Thereafter, scores declined gradually but remained above the pre-HCT baseline. In unmodified HCT, scores appeared higher over time than in CD34+-selected patients. EASIX discrimination of NRM was highest around day +180 (concordance index = 0.85) in both platforms, but the prognostic impact of EASIX across time points differed between the 2 platforms. Mean EASIX scores were higher in men (mean log2 +0.52) and in patients who developed grade 2 to 4 GVHD (+0.81) and lower in patients who received matched vs mismatched donors (−0.81, all P < .01). EASIX scores are dynamic and variably concordant with NRM when analyzed longitudinally, and patterns differ between HCT platforms. Compared to pre-HCT evaluation, post-HCT EASIX scores may better predict risk of NRM as patients acquire additional endothelial injury and toxicities.

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.

Purpose: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. Experimental Design: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. Results: We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. Conclusions: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.

Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti–SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20–directed therapies, and anti-CD38/B-cell maturation antigen–directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not.Significance:Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population.See related article by Tamari et al., p. 577.This article is highlighted in the In This Issue feature, p. 549

3A: Anti-SARS-CoV-2 spike IgG titers by different cutoffs Supplemental Table 3B: Neutralization Ab >30% threshold when using different cutoffs of anti-SARS-CoV-2 spike IgG response

50 Anti-SARS-CoV-2 spike IgG, 30 Neutralizing antibodies

Cellular therapies including allogeneic hematopoietic cell transplant (allo-HCT) and autologous hematopoietic cell transplant (auto-HCT) and chimeric antigen receptor (CAR) T-cell therapy render patients severely immunocompromised for extended periods after therapy, and data on responses to COVID-19 vaccines are limited. We analyzed anti–SARS-CoV-2 spike IgG Ab (spike Ab) titers and neutralizing Ab among 217 recipients of cellular treatments (allo-HCT, n = 149; auto-HCT, n = 61; CAR T-cell therapy, n = 7). At 3 months after vaccination, 188 patients (87%) had positive spike Ab levels and 139 (77%) had positive neutralization activity compared with 100% for both in 54 concurrent healthy controls. Time from cellular therapy to vaccination and immune recovery post–cellular therapy were associated with response. Vaccination against COVID-19 is an important component of post–cellular therapy care, and predictors of quantitative and qualitative response are critical in informing clinical decisions about optimal timing of vaccines and the requirement for booster doses.Significance:Identifying predictors of response to vaccination against SARS-CoV-2 in patients following cellular therapy is critical to managing this highly vulnerable patient population. To date, this is the most comprehensive study evaluating quantitative and qualitative responses to vaccination, providing parameters most predictive of response and potentially informing booster vaccination strategies.See related article by Chung et al., p. 568.This article is highlighted in the In This Issue feature, p. 549

2A- MVA for the whole cohort 2B-MVA for patients who underwent allo-HCT only

Purpose:The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT.Experimental Design:This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity.Results:We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus.Conclusions:Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.

Supplementary Data

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.

PURPOSE 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.

Many clinical trials incorporate stopping rules to terminate early if the clinical question under study can be answered with a high degree of confidence. While common in later-stage trials, these rules are rarely implemented in dose escalation studies, due in part to the relatively smaller sample size of these designs. However, even with a small sample size, this paper shows that easily implementable stopping rules can terminate dose-escalation early with minimal loss to the accuracy of maximum tolerated dose estimation. These stopping rules are developed when the goal is to identify one or two dose levels, as the maximum tolerated dose and co-maximum tolerated dose. In oncology, this latter goal is frequently considered when the study includes dose-expansion cohorts, which are used to further estimate and compare the safety and efficacy of one or two dose levels. As study protocols do not typically halt accrual between escalation and expansion, early termination is of clinical importance as it either allows for additional patients to be treated as part of the dose expansion cohort to obtain more precise estimates of the study endpoints or allows for an overall reduction in the total sample size.

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.

In studies of survival and its association with treatment and other prognostic variables, elapsed time alone will often show itself to be among the strongest, if not the strongest, of the predictor variables. Kaplan-Meier curves will show the overall survival of each group and the general differences between groups due to treatment. However, the time-dependent nature of treatment effects is not always immediately transparent from these curves. More sophisticated tools are needed to spotlight the treatment effects. An important tool in this context is the treatment effect process. This tool can be potent in revealing the complex myriad of ways in which treatment can affect survival time. We look at a recently published study in which the outcome was relapse-free survival, and we illustrate how the use of the treatment effect process can provide a much deeper understanding of the relationship between time and treatment in this trial.

Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti–SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20–directed therapies, and anti-CD38/B-cell maturation antigen–directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not.Significance:Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population.See related article by Tamari et al., p. 577.This article is highlighted in the In This Issue feature, p. 549

Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter’s transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution.

The post-transplant scoring system (PTSS), developed by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, is based on three independent post-transplant risk factors: grade of acute graft-versus-host disease, lack of platelet recovery before day 100, and relapse before day 100; discriminating low- (0), intermediate- (1–3), and high-risk (4–8) patients. We investigated the prognostic value of the PTSS in a cohort of patients with MDS who underwent myeloablative CD34-selected TCD transplants. From 2008 to 2018, 109 patients underwent a first TCD-HCT for MDS at our center. We used Cox proportional hazards models and different landmark analyses to evaluate the association of categorized PTSS score risk groups with overall survival (OS). Patients with an intermediate/ high risk PTSS score had decreased OS at day 180 (univariate HR 3.25 [95% CI 1.60, 6.60], p = 0.001) and at day 365 (univariate HR 5.42 [95% CI 2.21, 13.3], p

BACKGROUND: B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein–coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×10(6) CAR T cells. At the 450×10(6) CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×10(6) to 150×10(6) cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×10(6) to 150×10(6) cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×10(6) to 150×10(6) cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.)

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.

We develop three approaches to phase I dose finding designs for engineered T cells in oncology. Our goal is to address a very particular difficulty in this clinical setting: an inability to fully administer the dose allocated to some patients. Current designs can be biased as a result of this incomplete information being ignored or discarded from the analysis. The performance of the three proposed solutions is largely similar, and all offer an advantage over the currently used design. One of the three methods is supported by theoretical study, and we provide some new results on this approach.

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.

Despite a detailed understanding of the genes mutated in myelodysplastic syndromes (MDS), diagnostic and treatment decisions for patients with MDS rely primarily on clinical and cytogenetic variables as considered by the Revised International Prognostic Scoring System (IPSS-R). Here we describe the recently developed Molecular IPSS (IPSS-M), a clinico-genomic risk stratification system that considers clinical, cytogenetic and genetic parameters; the implementation of a web portal to facilitate its adoption, a strategy to handle missing variables, and the worldwide utilization of the web calculator as a clinical support tool. The IPSS-M was trained on 2,957 clinically annotated diagnostic MDS samples profiled for mutations in 156 driver genes. To maximize the clinical applicability of the IPSS-M and account for missing genetic data (i.e genes missing from a sequencing panel), we implemented a strategy to calculate a risk score under three scenarios: best, worst and average. Last, we developed an online calculator as a standalone single-page web application using VueJs, and D3Js for the interactive visualizations, deployed through a CI/CD pipeline on AWS, where collection of anonymous usage analytics allows to track adoption and usability of the new proposed model. The model incorporates clinical, morphological, genetic variables informed by cytogenetics and constructed from the presence of oncogenic mutations in 31 genes. It delivers a unique risk score for each individual patient, as well as an assignment to one of six IPSS-M risk strata. Compared to the IPSS-R the IPSS-M re-stratified 46% of MDS patients. The model was validated in an external dataset of 754 MDS patients. We released an open-access IPSS-M web calculator available at https://mds-risk-model.com. By specifying the patient clinical and molecular profiles, the tool returns the patient-specific IPSS-M risk score and category, and the probability estimates over time for three clinical endpoints, i.e. leukemia free survival (LFS), overall survival, and incidence of leukemic transformation. Since its launch in June 2022, the calculator has been used by >6000 users in >75 countries, reaching a daily average of 100 users per day. Risks have been calculated for >45,000 patient profiles. 99.28% of the sessions initiated reach an IPSS-M score, suggesting that the calculator is intuitive and easy to use. We trained and validated the IPSS-M on 3,711 patients, a patient tailored risk stratification tool for patients with MDS that considers clinical, morphological and genetic variables inclusive of cytogenetics and mutations in one of 31 genes. The development of a web based tool was instrumental to the global dissemination of the model, enabling non-expert users to leverage the power of molecular biomarkers in risk stratification for patients with MDS. Citation Format: Elsa Bernard, Juan E. Arango Ossa, Heinz Tuechler, Peter L. Greenberg, Robert P. Hasserjian, Yasuhito Nannya, Sean M. Devlin, Maria Creignou, Philippe Pinel, Lily Monier, Juan S. Medina-Martinez, Dylan Domenico, Martin Jädersten, Ulrich Germing, Guillermo Sanz, Arjan A. van de Loosdrecht, Olivier Kosmider, Matilde Y. Follo, Felicitas Thol, Lurdes Zamora, Ronald F. Pinheiro, Andrea Pellagatti, Detlef Haase, Pierre Fenaux, Monika Belickova, Michael R. Savona, Virginia M. Klimek, Fabio P. Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Solé, Uwe Platzbecker, Michael Heuser, Peter Valent, Kazuma Ohyashiki, Carlo Finelli, Maria Teresa Voso, Lee-Yung Shih, Michaela Fontenay, Joop H. Jansen, José Cervera, Norbert Gattermann, Benjamin L. Ebert, Rafael Bejar, Luca Malcovati, Mario Cazzola, Seishi Ogawa, Eva Hellström-Lindberg, Elli Papaemmanuil. Implementation and adoption of a web tool to support precision diagnostic and treatment decisions for patient with myelodysplastic syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6168.

High-dose chemotherapy and autologous hematopoietic cell transplantation is an effective consolidation therapy in lymphoma; however, its use in elderly patients has been limited because of concerns for greater toxicity in this group. We investigated the toxicities of carmustine, etoposide, cytarabine, and melphalan (BEAM) and autologous hematopoietic cell transplantation (AHCT) in 346 patients in 2 age groups: 279 patients aged 60 to 69 years and 67 patients aged ≥70 years. The majority developed severe toxicities; the most common were febrile neutropenia, gastrointestinal, infections, and cardiovascular. Older patients were at higher risk for grade ≥3 cardiovascular toxicities (hazard ratio [HR], 3.36; 95% confidence interval [CI], 2.25-5.00; P < .001) and skin toxicities (HR, 2.45; 95% CI, 1.08-5.54, P = .032). In the older group, nonrelapse mortality at 100 days and at 2 years was 2.99% (95% CI, 0.55-9.32) and 6.2% (95% CI, 1.97-13.95), respectively, vs 1.79% (95% CI, 0.68-3.92) and 2.91% (95% CI, 1.37-5.42), respectively, in the younger group. When adjusting for the number of grade ≥3 toxicities within the first 100 days, older patients had a 1.71-fold (95% CI, 1.08-2.71) increased risk for progression or death relative to younger patients. Although BEAM followed by AHCT is effective, it is associated with significant organ toxicities, especially in patients aged ≥70 years. Interventions to mitigate toxicities while maintaining efficacy are much needed.