Prior Stem Cell Transplant Research Articles

Doxorubicin, Paclitaxel, and Cisplatin (ATP) for Relapsed/Refractory Germ Cell Tumors

Patients with relapsed/refractory germ cell tumors (GCT) have limited treatment options and poor survival outcomes. We describe our institutional experience with doxorubicin, paclitaxel, and cisplatin (ATP) as an outpatient regimen for 35 patients with relapsed/refractory GCT between 2017 and 2022. Twenty-four patients received nonpalliative intent ATP, with a median of 2 lines of prior therapy, 23 (96%) having received at least 1 cisplatin-based regimen and 1 (4%) with a prior stem cell transplant. The objective response rate for the nonpalliative intent cohort was 37.5% (1 complete response and 8 partial responses). Post-ATP, 12 patients underwent stem cell transplant, 7 patients had surgical resections, and 4 patients received radiation. The median PFS was 4.3 months (95% CI: 3.8, 32.7) and median OS of 13.1 months (95% CI: 10.7, NA) for the nonpalliative intent cohort. Eleven patients received palliative intent ATP, with a median of 4 lines of prior therapy, all having received at least 1 cisplatin-based regimen, and 7 (64%) having received prior stem cell transplants. Within the palliative intent cohort, the objective response rate was 9% (1 partial response). Patients who received palliative intent ATP had a median PFS of 0.92 months (95% CI 0.46, NA) and median OS of 5.2 months (95% CI 3.3, NA). Treatment toxicities occurred in 5 (14%) patients who required dose reductions and 5 (14%) patients who were admitted for treatment related toxicities, most commonly for myelosuppression. Our results support the use of ATP in a primarily anthracycline naïve patient population and show the safety of continued cisplatin use in patients who have previously received cisplatin-based regimens. Therefore, ATP is a feasible and well tolerated chemotherapy regimen in the salvage setting and can serve as a bridge to other treatments for patients with relapsed/refractory GCT.

Real-world (RW) antiemetic use and its association with duration of oral azacitidine (Oral-AZA) maintenance in patients (pts) with acute myeloid leukemia (AML) in the United States (US).

e23259 Background : Oral-AZA was approved in the US in Sep 2020 for maintenance treatment of transplant-ineligible pts with AML in remission following intensive chemotherapy. Approval was based on the QUAZAR trial (NCT01757535), which showed that Oral-AZA was associated with longer survival outcomes than placebo in this pt population. Both the prescribing information and clinical guidelines recommend antiemetic prophylaxis with Oral-AZA for at least the first 2 cycles to prevent the most common adverse events, nausea and vomiting. However, the extent to which antiemetics are being used with Oral-AZA in the real world is not yet well understood. This study aimed to examine the use of antiemetics among pts with AML receiving Oral-AZA in RW clinical practice and to determine whether this has any association with duration of therapy (DoT). Methods : This was a retrospective, observational study using Flatiron Health electronic health record data from Jan 2014 to Apr 2023. Eligible pts were ≥18 years and had a diagnosis of AML and ≥1 order for Oral-AZA on or after Sep 1, 2020. The index date was date of Oral-AZA initiation. Pts were followed until death, loss to follow-up, or the end of the study. Pt characteristics were assessed on the index date; antiemetic use was assessed at index and over the follow-up period. For each pt, each 28-day cycle of Oral-AZA was denoted as “covered” or “not covered” by antiemetics according to whether the pt had ≥14 days of antiemetics available during the cycle. Total DoT was measured for Oral-AZA using cumulative incidence curves and compared between pts with their first 2 cycles covered and those without. Results: 189 pts with AML were included. Mean age was 66 years, 52% were female, 56% had evidence of prior cytarabine use, and 10% had a prior stem cell transplant. 152 pts had ≥2 cycles of Oral-AZA. Overall, less than half of pts (48%) had a claim for an antiemetic on the index date. 16% never initiated an antiemetic between index and the end of follow-up; in the remaining 84%, the mean time from the index date to antiemetic initiation was 57 days and 29% had a time to antiemetic initiation of > 56 days. Only 9% (14/152) of pts had both their first 2 Oral-AZA cycles covered by antiemetics. Overall, pts had a median of 5 Oral-AZA cycles. Pts with antiemetic coverage of their first 2 cycles had a median of 8.5 Oral-AZA cycles versus 6 in those without. The median DoT was longer for pts with antiemetic coverage of cycles 1 and 2 than those without (258 days vs 154 days). Conclusions: These findings suggest that antiemetics are not currently widely utilized with Oral-AZA in RW US clinical practice. This may reduce DoT and could potentially impact the likelihood of observing RW efficacy outcomes like those in the QUAZAR trial. Further studies are required to examine the association between guideline-recommended antiemetic use and clinical outcomes.

Safety and efficacy of olutasidenib treatment in elderly patients with relapsed/refractory mIDH1 acute myeloid leukemia.

6527 Background: Elderly patients with relapsed/refractory (R/R AML) are a special population that may elevate safety concerns, which must be balanced with clinical benefit. Olutasidenib (OLU), a targeted therapy for m IDH1 AML, was well tolerated in a registrational, Ph2, open-label, multicenter trial and, in the pivotal cohort, demonstrated complete remission (CR) or CR with partial hematologic recovery (CRh) in 35% of patients (age 32-87 years, y) for a median duration of 25.9 months. We evaluated safety and efficacy of OLU in the elderly subgroup (≥75y) with m IDH1 AML. Methods: In the Phase 2 trial, the pivotal cohort enrolled adults with R/R m IDH1AML. OLU was administered at 150 mg BID. Adverse events (AE) and lab values were collected at least monthly and graded based on the NCI CTCAE Version 4.03. Efficacy was based on response criteria of the International Working Group in AML (2003). Results: 153 patients received OLU monotherapy, 147 had centrally-confirmed mIDH1 AML, , and 45 were ≥75y (range 75-87) at study entry. Of the 45 elderly patients, 27 (60%) were male, 51% had ECOG=1, 16% had ECOG =2, 71% were relapsed, 29% had refractory AML, 58% had prior HMA, 11% received prior venetoclax, and none had prior stem cell transplant. Median bone marrow blasts were 43% (5-93). Genetic co-mutations included FLT3 in 9%, NPM1 in 20%, and TP53 in 2%. Grade 3 or 4 adverse events were reported in 45.8% of elderly patients; the most common were decreases in red blood cells (31%), platelets (13%) and neutrophils (10%) as well as febrile neutropenia (15%). AEs were consistent with published pivotal Phase 2 results, with no new safety signals. Deaths occurred in 19 patients due to disease progression (9), pneumonia (2), sepsis (2), GI haemorrhage (1), aortic stenosis (1), atrioventricular block (1), cardiac failure congestive (1), acute kidney injury (1) and other (1). The response to OLU therapy is summarized in the table. 31% of patients ≥75 y achieved CR/CRh; median time to CR/CRh was 1.5 mos (0.9-5.6) and median duration of CR/CRh was 25.9 mos (95%CI 7.4, not reached). Conclusions: Olutasidenib was generally well tolerated in elderly patients with R/R m IDH1AML and induced durable remissions. Despite the challenges of treating elderly patients who had already failed prior AML treatment, the results suggest that elderly patients can benefit from therapy with olutasidenib. Clinical trial information: NCT02719574 . [Table: see text]

FLAG-IDA + venetoclax in newly diagnosed (ND) or relapsed/refractory (RR) AML.

6519 Background: We report the outcomes of a phase 2 study of FLAG-IDA+VEN in AML. Methods: Pts ≥18 with ND or RR AML / MDS-EB2 fit for intensive chemotherapy were eligible. Induction comprised fludarabine 30mg/m2 D2–6, cytarabine 1.5g/m2 D2–6, idarubicin 8 (6 if RR) mg/m2 D4–6 & filgrastim 5mcg/kg D1–7. VEN 400mg was administered D1–14 with CYP3A inhibitor dose adjustment until Jul 2023; following a protocol modification, VEN is now administered D1–7. The primary outcome was ORR (CR + CRh + CRi + MLFS + PR). Secondary outcomes were CRc (CR + CRh + CRi), overall survival (OS), event-free survival (EFS) & duration of response (DOR). Measurable residual disease (MRD) was assessed by flow cytometry. Results: As of Jan 2024, 134 pts have enrolled, 127 (68 ND & 59 RR) evaluable at data cut. Median age was 45 (18 – 73); 19 (15%) age ≥60. 13 (19%), 22 (32%) & 33 (49%) ND pts were ELN22 favorable, intermediate & adverse respectively. There were 7 (10%) secondary (s), including 4 hypomethylating agent failure, & 7 (10%) therapy-related (t) AML. In RR pts, 40 (68%) were in salvage 1 (S1), of whom 32 (54%) were TP53WT. 20 (34%) had prior stem cell transplant (SCT). Median of 2 cycles were given. In ND pts, ORR was 99%, (96% CRc, of whom 89% MRD negative [Table]). Similar responses were seen across ELN groups & s/tAML. At median follow-up (mFU) of 30 months (mo), the mOS, mEFS & mDOR were not reached. The 2yr OS, EFS & DOR were 75% (64 – 88), 68% (56 – 81) & 71% (59 – 85) respectively, with no differences among ELN groups. 57% went to SCT in CR1. 4/4 pts with TP53mut became CRc MRD–, but mDOR was only 8.2 mo (95% CI, 2.2 – NE), resulting in poor mOS (13.5 mo, 95% CI, 8.6 – NE). In RR pts, ORR was 70% (66% CRc, of whom 79% MRD negative [Table]). At mFU 27 mo, the mOS, mEFS & mDOR were 12 (7 – 33), 7 (4 – 23) & 21 (8 – NE) mo respectively. The 2yr OS, EFS & DOR were 40% (28 – 55), 34% (23 – 49) & 49% (35 – 68) respectively. 58% went to SCT. S1+ TP53WT pts had mOS of 34 mo (12 – NE), with 72% going to SCT. 30d & 60d mortality were 0% & 3%. Of the 4 deaths within 60d, 1 was sepsis-related in CR in a ND pt while 3 were disease-related in NR RR pts. The most frequent adverse event was infection. Grade ≥3 infections, gastrointestinal toxicities & bleeding occurred in 102 (80%), 20 (16%) & 9 (7%) pts respectively. The median time to neutrophil >1x109/L & platelet >50x109/L were 27d & 28d for C1, 39d & 67d for C2 & 35d & 50d for C3 respectively. Conclusions: FLAG-IDA+VEN results in high MRD negative response rates, leading to impressive survival outcomes across ELN risk groups in ND AML. It is an effective salvage regimen for RR AML, especially for S1+ TP53WT pts. Clinical trial information: NCT03214562 . [Table: see text]

Exploring T cell subsets as predictors of response to BCMA targeting bispecific antibody therapy in multiple myeloma.

7567 Background: BCMA targeting bispecific Antibody (bsAb) therapy has shown unprecedented response and survival rates in patients with relapsed/refractory multiple myeloma (MM). The clinical activity of bsAb therapy has been shown to depend on T-cell function, yet clinical parameters, such as absolute lymphocyte count (ALC) have not been found to be associated with response to bsAbs. The aim of the present study was to elucidate whether distinct T cell subsets, such as CD4 and CD8 counts as well as their proportion within the ALC are associated with outcome of BCMA targeting bsAb therapy. Methods: We retrospectively collected data on 79 patients who had been treated with at least one full dose of a BCMA targeting bsAb. T cell subsets, including ALC, total CD3, CD4 and CD8, were measured from peripheral blood within 7 days prior to bsAb therapy initiation. Statistical analysis was performed with SAS version 9.4 using univariate and multivariate logistic regression models. Results: Median age of the patient cohort was 72 (31-84) years with 40/79 (51%) being male and 15/79 (19%) being African American. Median lines of therapy was 5 (2-12) with 78/79 (99%) patients being triple class refractory and 50/79 (63%) being penta-drug refractory. 59/79 (75%) of patients had at least one prior stem cell transplant (SCT) with 35/79 (44%) having had at least two SCTs. 26/79 (33%) patients had prior exposure to BCMA targeting therapy, with 18/79 (23%) and 8/79 (10%) previously having received belantamab mafodotin or BCMA targeting Car-T cell therapy respectively. Cytokine release syndrome (CRS) occurred in 38/79 (48%) of patients with the majority (92%) being grade 1 with the remainder being grade 2. Median ALC was 1.02 (0.25-5) x103/mL, median CD4 count was 0.27 (0.04-1.13) x103/mL while median CD8 count was 0.5 (0.07-2.97) x103/mL. Overall response (OR) rate of the whole cohort was 82% (69/79) with best responders (³very good partial response) comprising 51% (40/79). While total ALC, CD4 and CD8 counts did not appear to impact response to BCMA targeting bsAb therapy, the ratio of CD4 to ALC proved to be significantly associated with OR (univariate p=0.04) and best response (univariate p= 0.004, multivariate p=0.01) . The CD8 to ALC ratio had no significant impact in this patient population. The only other factor to show a significant association with response was the number of prior lines of therapy with higher numbers being associated with worse response (p=0.046). Conclusions: Our study suggests that an increased proportion of CD4 cells within the ALC is significantly associated with better response to BCMA targeting bsAb. While future studies are needed to elaborate on CD4 function in bsAB therapy, our findings imply that therapeutic strategies to increase the CD4 proportion could lead to improved bsAb therapy effectiveness.

COVID-19 Outcomes in Patients with Hematologic Malignancies in the Era of COVID-19 Vaccination and the Omicron Variant.

A greater understanding of clinical trends in COVID-19 outcomes among patients with hematologic malignancies (HM) over the course of the pandemic, particularly the Omicron era, is needed. This ongoing, observational, and registry-based study with prospective data collection evaluated COVID-19 clinical severity and mortality in 1818 adult HM patients diagnosed with COVID-19 between 27 February 2020 and 1 October 2022, at 31 centers in the Madrid region of Spain. Of these, 1281 (70.5%) and 537 (29.5%) were reported in the pre-Omicron and Omicron periods, respectively. Overall, patients aged ≥70 years (odds ratio 2.16, 95% CI 1.64-2.87), with >1 comorbidity (2.44, 1.85-3.21), or with an underlying HM of chronic lymphocytic leukemia (1.64, 1.19-2.27), had greater odds of severe/critical COVID-19; odds were lower during the Omicron BA.1/BA.2 (0.28, 0.2-0.37) or BA.4/BA.5 (0.13, 0.08-0.19) periods and among patients vaccinated with one or two (0.51, 0.34-0.75) or three or four (0.22, 0.16-0.29) doses. The hospitalization rate (75.3% [963/1279], 35.7% [191/535]), rate of intensive care admission (30.0% [289/963], 14.7% [28/191]), and mortality rate overall (31.9% [409/1281], 9.9% [53/536]) and in hospitalized patients (41.3% [398/963], 22.0% [42/191]) decreased from the pre-Omicron to Omicron period. Age ≥70 years was the only factor associated with higher mortality risk in both the pre-Omicron (hazard ratio 2.57, 95% CI 2.03-3.25) and Omicron (3.19, 95% CI 1.59-6.42) periods. Receipt of prior stem cell transplantation, COVID-19 vaccination(s), and treatment with nirmatrelvir/ritonavir or remdesivir were associated with greater survival rates. In conclusion, COVID-19 mortality in HM patients has decreased considerably in the Omicron period; however, mortality in hospitalized HM patients remains high. Specific studies should be undertaken to test new treatments and preventive interventions in HM patients.

Chimeric Antigen Receptor T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma: A Multicenter Study

Background: Anti-CD19 chimeric antigen receptor T-cell (CART) therapy is a standard of care in patients (pts) with relapsed or refractory (RR) large B-cell lymphoma (LBCL). However, it remains underutilized in elderly pts due to limited efficacy and safety data. We therefore evaluated real world outcomes of CART in such pts. Methods: Seven academic centers participated in this retrospective study. Pts aged ≥65 years with RR LBCL who received a commercial CART product were included. Baseline characteristics, treatment data, CART toxicity, and clinical outcomes were collected. Progression-free survival (PFS; time from infusion to disease progression or death) and overall survival (OS; time from infusion to death from any cause) were analyzed using Kaplan-Meier method. Cumulative incidences of non-relapse mortality (NRM) and disease relapse/progression were estimated accounting for competing risks. Statistical analyses were performed in JMP v15 and XLSTAT v2022.1.2. Results: 209 pts were identified. Baseline characteristics and treatment pattern are shown in Table. Median age at infusion was 71 years (range 65-89), and 25 (12%) were ≥80 years. 131 (63%) were male, 188 (90%) were white, and 27 (13%) had ECOG PS of ≥2. The median HCT-CI was 1 (range 0-6), and 39 (22%) pts had a score of ≥3. 165 (84%) had stage III-IV disease, 131 (70%) had extranodal involvement, 24 (18%) had bulky disease, and 24 (11%) had high grade B-cell lymphoma (HGBL; double- or triple-hit lymphoma, n=15; HGBL, NOS, n=9). The median number of prior lines of therapy was 2 (range 1-8), and 99 (48%) pts had ≥3 prior lines of therapy, 45 (22%) had prior bendamustine, and 44 (21%) had prior stem cell transplant (SCT; auto-SCT, n=41; allo-SCT, n=2; both auto- and allo-SCT, n=1). Bridging therapy was given to 100 (52%) pts; among those, 57 had chemotherapy, 20 had radiotherapy, 6 had both chemotherapy and radiotherapy, 10 had lenalidomide-based regimen, and 7 had CD20 antibody and/or corticosteroids. Axicabtagene ciloleucel (axi-cel) was most frequently used (63%, n=131), followed by lisocabtagene maraleucel (liso-cel) (24%, n=49) and tisagenlecleucel (tisa-cel) (13%, n=27). Cytokine release syndrome (CRS) occurred in 75% of pts, and a minority (6%) had grade ≥3. Immune effector cell associated neurotoxicity syndrome (ICANS) occurred in 55%, and 29% had grade ≥3. The management of CRS and ICANS included corticosteroids in 101 (49%) pts, tocilizumab in 116 (56%) pts, and other biologic agents (anakinra, siltuximab, basiliximab) in 8 (4%) pts. Day 30 response was evaluable in 195 pts with an objective response rate (ORR) of 84%, and a complete response rate (CR) of 52%. 82% of the responders continued to have a response at 3 month follow up. The ORR/CR rates were 86%/53% for axi-cel, 64%/44% for tisa-cel, and 89%/52% for liso-cel, respectively. At a median follow up of 19.1 months (95% CI 16.1-23.6) after infusion, the median PFS was 6.7 months (95% CI 5.1-11.5), with 6- and 12-month PFS rates of 54% (95% CI 47-61) and 43% (95% CI 35-50), respectively. The median OS was 16.5 months (95% CI 13.2-26.7), and the 6-and 12-month OS rates were 70% (95% CI 64-77) and 61% (95% CI 54-68), respectively. The NRM rate was 17% (95% CI 11-24) at 1 year, primarily due to infections including 5 COVID-19 related deaths. In univariate analysis, ECOG PS ≥2, bulky disease, elevated LDH, and the need for bridging therapy were associated with inferior PFS and OS. No significant difference in PFS and OS was seen based on age at infusion with a median PFS of 6.4 vs 9.6 vs 6.4 vs 6.0 months ( P=0.93) (Figure) and OS of 16.4 vs 19.2 vs 28.5 vs 12.7 months ( P=0.85) in age groups ≥65-69 vs ≥70-74 vs ≥75-79 vs ≥80-89. In addition, there was no statistically significant difference in PFS and OS based on type of CART with a median PFS of 6.4 vs 5.6 vs 12.7 months ( P=0.16) and OS of 15.1 vs vs 16.1 vs NR months ( P=0.24) in pts treated with axi-cel vs tisa-cel vs liso-cel. Conclusions: In this large multicenter study of elderly pts with RR LBCL, CART therapy demonstrated favorable efficacy and safety profile comparable to that in pivotal registration trials. Survival outcomes appeared similar regardless of patient age, including those aged ≥80 years, and type of CART product used. Similar to younger pts, high tumor burden and poor performance status at CART infusion were associated with inferior survival. This analysis confirms that older pts should not be excluded from receiving CART therapy solely due to chronological age.

Nivolumab and Ibrutinib for Treatment of Patients with Refractory or Relapsed Central Nervous System Lymphoma

Background: Central Nervous System (CNS) lymphoma is a distinct entity of large B-cell lymphoma (LBCL) with a unique genomic profile with similarities to the activated B-cell (ABC) subtype, which may offer potential targets for therapy. These aberrancies commonly include MYD88 mutations, which enhances sensitivity to Bruton's tyrosine kinase (BTK) inhibitors, and translocation or copy number alterations of 9p24, which may associate with sensitivity with programmed death (PD)-targeted therapies. Expression of PD-L1 is common in CNS lymphoma and tumor infiltrating lymphocytes, and the majority of CNS lymphomas have a copy gain of 9p24.1. This suggests an attenuated immune response against CNS lymphoma. Ibrutinib in combination with nivolumab has shown safety and clinical activity in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia in a phase 1/2 trial, and therefore we hypothesized that this combination may be active in CNS lymphoma. Methods: We conducted an investigator-initiated, open label, single center, phase 2 clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Adult patients were eligible if they had CNS lymphoma (primary or secondary) refractory to or relapsed after at least 1 prior CNS directed therapy, with adequate organ and bone marrow function, without prior ibrutinib or PD1 inhibitor therapy, and did not require persistent high dose steroids. The trial had two sequentially enrolled cohorts: Cohort A included ibrutinib 560mg oral daily for one cycle (28-days per cycle), followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B included ibrutinib and nivolumab during the first cycle. Patients with a partial response or greater after 6 cycles of combined ibrutinib and nivolumab could continue therapy for up to 2 years or until progression of disease or unacceptable toxicity occurs. The primary objective was to determine the best overall response rate (ORR) of ibrutinib and nivolumab. Secondary objectives included the ORR of ibrutinib as a lead in prior to the combination, best complete response (CR) rate, landmark survival outcomes, and the safety of the combination. The trial planned to enroll 20 patients in both cohort A and B, but closed early due to slow accrual, due in part to the COVID19 pandemic. Results: The trial accrued 18 patients from February 2019 to June 2022, with all patients evaluable for response. The median age was 63 years (range 43-88), 33% were >70 years, and 78% were female. 89% had primary CNS lymphoma, 50% had non-GCB, 22% had GCB, and 28% were unable to be classified due to missing components of the Hans algorithm. The median number of prior lines of therapy was 2 (range, 1-4), 55% had refractory disease, 17% had prior stem cell transplant, and 11% had prior CAR T-cell therapy. 10 patients were enrolled to Cohort A (ibrutinib lead in), and 8 patients were enrolled to Cohort B (initial combination therapy). Adverse events included 50% with fatigue, 33% with nausea, and 28% with mucositis. For both cohorts, the best ORR was 77.8% (95% CI: 52~94%) and the best CR rate was 50% (95% CI: 26-74%). In cohort A, the ORR of ibrutinib as a lead in after 1 cycle was 90% (95% CI: 55.5-99.7%), and the CR rate was 60%. In GCB patients (n = 4), the ORR and CR rates were 25%. In non-GCB patients (n =9), the ORR and CR rates were 100% and 56%, respectively. With a median follow up time of 34.6 months, the median overall survival (OS) was 25.4 months (95% CI 12.5-NR), and the OS rate at 12 months was 70%. The median progression free survival (PFS) was 6.6 months (95% CI: 2.9 - NR), and the PFS rate at 18 months was 47%. 4 patients withdrew from protocol therapy in CR, including 2 who proceeded to stem cell transplant consolidation, and 2 who stopped due to fatigue. 3 patients withdrew from protocol therapy in PR, 2 due to mucositis and 1 due to arthralgias. 1 patient died of COVID19 infection with a CR after 4 cycles of therapy. Conclusion: Ibrutinib and Nivolumab resulted in significant clinical activity in patients with refractory/relapsed CNS lymphoma. Our trial is limited by small patient numbers but suggests the potential for targeted therapy combinations in future larger clinical studies.

Project Evolve, Evaluation of Lineage Switch (LS), an International Initiative: Preliminary Results Reveal Dismal Outcomes in Patients with LS

Introduction: Lineage switch (LS) refers to the transformation of acute leukemia from one cell lineage to another (e.g., lymphoid (ALL) to myeloid (AML)). This rare phenomenon, distinct from treatment induced malignancy (i.e., t-AML) and mixed phenotype acute leukemia (MPAL), is increasingly being observed following cell surface antigen targeting. Given challenges in the diagnosis and treatment of LS, Project EVOLVE was developed to globally identify cases of LS following immunotherapy. Methods: A protocol and data collection form for this IRB exempt study was widely disseminated to capture deidentified LS case information across multiple centers and cancer consortia. This included collection of data from published reports of LS, with authors contacted to obtain additional information. For this analysis, LS was defined by the emergence of cell-surface markers warranting reclassification of the original leukemia as a different lineage derivation based on the immunophenotype, including cases of AML emerging alongside the original ALL. “Confirmed” LS cases included those where retention of original cytogenetic or molecular aberrations and/or the clonal immunoglobulin rearrangement patterns were verified to confirm the clonal relationship. “Suspected” LS cases included those where samples to confirm clonality marker retention could not be obtained, but the clinical presentation was consistent with LS. The term “transition” was applied when immunophenotypic shifts were transient. Cases with new cytogenetic abnormalities unrelated to the original diagnosis and compatible with t-AML were excluded. Statistical analysis was primarily descriptive. Data cut-off was July 26, 2023. Results: A total of 58 cases were identified, including 19 cases referenced in prior publications. Of the 58, 11 cases were excluded from this initial analysis, including: 4 cases of t-AML, 2 cases of T-ALL to AML, and 5 “transition” cases. Collectively, 47 cases of LS (43 “confirmed”; 4 “suspected”), spanning across 3 continents and 8 countries, were analyzed. (Fig. 1A) Cases included transition from B-ALL to AML in 36 (76.6%) and to MPAL/biphenotypic/ambiguous lineage in 11 (23.4%). Two likely had MPAL at diagnosis and a third with chronic myeloid leukemia. The median age at initial diagnosis was 8.4 years (range, 1 day-76.5 years); median age at LS presentation was 11.0 years (range 0.4-77.3 years). Twenty-three (48.9%) were male and 19 (40.4%) had prior stem cell transplant (SCT). Baseline cytogenetics showed KMT2A rearrangement in 27 (57.4%). Baseline myeloid antigen co-expression was seen in 22 of 23 patients with submitted data, but variation in degree of expression across patients and antigens was substantial. The most proximal immunotherapy prior to development of LS was CAR T-cells in 23 (48.9%) and blinatumomab in 24 (51.1%). The median time from the most proximal immunotherapy to development of LS was 1.6 months (range, 7 days-36.5 months). In 7 (29.2%) patients receiving blinatumomab, LS developed during the infusion. LS presented as isolated marrow relapse in 27 (57.4%), isolated CNS in 2 (4.3%), isolated non-CNS extramedullary disease in 3 (6.4%), combined relapse in 14 (29.8%) and unreported in 1. First line treatment for LS was chemotherapy induction in 31 (66.0%), palliative care/no therapy in 8 (17.0%), and alternative therapies in the remaining 8 (17.0%). In 35 (74.5%) patients, remission induction was the goal of first line therapy. Fifteen (31.9%) achieved a complete remission (CR) of whom 2 were treated with palliative intent. Across all patients, 8 (17.0%) are alive in remission, the longest being 4.7 years from LS diagnosis; 2 (4.3%) are alive with active LS and 37 (78.7%) died from LS, their original disease, or complications of treatment of LS (Fig 1B). For those alive in CR (n=8), 7 (87.5%) proceeded to a consolidative SCT for treatment of LS and 1 patient, an octogenarian remains in remission after AML directed therapy. Conclusions: LS is emerging as an important mechanism of immune escape following immunotherapy. Project EVOLVE provides the largest dataset of patients with LS to date. This systematic, international effort reveals substantial complexity and variability in diagnosing and managing LS. Unfortunately, outcomes following LS are grim, underscoring the critical need to identify risk factors of and optimal therapies for this leukemia transformation.

A Novel Prognostic Model for Patients with Acute Myeloid Leukemia in First Relapse with Improved Prognostic Accuracy

Introduction Despite high rates of complete remission (CR) after intensive induction chemotherapy in newly diagnosed AML, relapse is frequent and associated with poor outcome with a median overall survival (OS) of 3-5 months. While cytogenetic and molecular markers are associated with outcome in newly diagnosed patients, the prognostic value in the relapsed setting is unclear, even though it may facilitate therapeutic decision making. Genetic data was only limitedly available when earlier models for relapsed patients were developed, such as reported by HOVON-SAKK (Breems, JCO 2005) and GOELAMS (Chevallier, Leukemia, 2011). Therefore, a comprehensive analysis of clinical, cytogenetic and molecular variables in a prognostic model for outcome after relapse is needed. We set out to evaluate the impact of these variables on outcome after first relapse in the current therapeutic era, and develop a new prognostic model and compare that model with earlier models. Methods A total of 946 (44%) relapsing patients out of 2127 newly diagnosed AML patients who participated in prospective HOVON-SAKK trials of intensive induction chemotherapy between 2000-2018 were included in this analysis. A random survival forest machine learning algorithm was used to identify top markers impacting 1 year survival after relapse among 45 candidate predictors, including 7 clinical parameters, and 9 cytogenetic and 29 molecular abnormalities present at diagnosis. Cox regression with backward selection was performed to obtain hazard ratios (HRs) from relevant predictors identified by the random survival forest algorithm. A clinical prognostic tool was developed with points assigned to each marker based on the rounded logarithm of HR. Four groups were defined based on quartiles of the individual predictions. Prognostic accuracy of risk models was assessed using Harrel's C-index. Results The median age of relapsed patients was 58 years (range: 18-81), with 56% being male. Adverse risk AML according to ELN2022 risk was found in 48% of patients, whereas favorable and intermediate risk were classified in 22% and 31%, respectively. Prior allogeneic stem cell transplantation (SCT) in first CR was performed in 33% of patients, while 14% received autologous SCT. The median time between CR and relapse was 14 months (range: 0-124). The median follow-up time after relapse for patients alive was 49 months (range: 0-124). The random survival forest identified 16 parameters that were associated with 1 year OS based on variable importance, including: age at relapse ≥60 years, relapse-free interval ≤1 year, white blood cell count ≥10 x 10e9/L at diagnosis, prior allogeneic SCT, absence of t(8;21)/inv16, and presence of complex or monosomal karyotype (CK/MK), -5 or del(5q), -7, t(v;11q23), chromosome 17 alterations (-17, del(17p) or abn(17p)), FLT3-ITD, and mutations found in either TP53 with VAF ≥10%, DNMT3A, EZH2, NPM1, or NRAS. From these parameters, nine remained significant with Cox regression: age (HR 1.48, p<0.01), relapse free interval ≤1 year (HR 1.74, p<0.01), white blood cell count ≥10 x 10e9/L at diagnosis (HR 1.23, p=0.02), prior allogeneic SCT (HR 1.58, p<0.01), CK/MK (HR 1.53, p<0.01), no t(8;21)/inv(16) (HR 2.34, p<0.01), t(v;11q23) (HR 1.51, p=0.02), mutated TP53 with VAF ≥10% (HR 1.70, p<0.01), FLT3-ITD (HR 1.32, p<0.01). Next, weights were assigned to these variables based on the multivariate HRs (Figure 1A). Scores were calculated for individual patients and four groups were defined. OS at 1 year estimated 54±3% in the favorable risk group (≤5 points), 35±3% in the intermediate group (6-7 points), 18±3% in the high risk group (8-9 points), and 8±2% in the very high risk group (≥10 points) (Figure 1B). The prognostic accuracy for 1 year OS as measured by the C-index was 0.70. In contrast, in this cohort C-indices for the HOVON-SAKK and GOELAMS models were 0.65 and 0.64, respectively. In addition, comparing the earlier models with the new model, 50% of patients in the adverse group of the HOVON-SAKK model were classified to the favorable (14%) and intermediate group (36%) in the new model. In the GOELAMS model, 42% of intermediate risk patients were considered high (10%) or very high risk (32%) in the new model. Conclusion Analysis of clinical, cytogenetic and molecular variables identified nine variables for a new prognostic model which was associated with distinct OS at 1 year after first AML relapse and improved prognostic accuracy.

Bendamustine Plus Brentuximab Has Superior Efficacy to Brentuximab Monotherapy As Third-Line Treatment for Classical Hodgkin Lymphoma: A Real-World, Multicentre UK Analysis

Purpose: The introduction of targeted agents has been a major advance in the treatment of classical Hodgkin lymphoma (HL) but the optimal application and sequencing of these agents is unclear. The CD30-targeted antibody-drug conjugate brentuximab vedotin (BV) is licensed for treatment of relapsed and refractory (R/R) HL as monotherapy and is available in the United Kingdom as third-line (3L) therapy for HL. BV has been evaluated in combination with chemotherapy in single-arm trials with very promising results, but randomised data are lacking. The aim of this analysis was to compare the efficacy of BV monotherapy with BV plus bendamustine (BVB) as 3L treatment of HL in a real-world UK cohort. Methods: Data were retrospectively collectively for consecutive patients receiving treatment for R/R HL with intent to consolidate with stem cell transplant (SCT) between 01/2015 and 12/2019 at 11 UK centres. Use of BVB was principally determined by availability, due to regional differences in BV funding in the UK, rather than patient disposition. Response was assessed by PET according to the Lugano Classification. Most analyses use descriptive statistics. Time-to-event analyses are measured from the start of 3L treatment until the first event (death for overall survival and death or further therapy for treatment failure) with groups compared using Kaplan Meier survival analysis and Cox regression. Results: 96 patients received BV and 30 received BVB. Baseline demographics are provided in the Table. Patients receiving BVB were slightly younger in age at diagnosis (p=0.031), but a slightly higher proportion had primary refractory disease (p=0.16) and failed to respond to second-line therapy (p=0.034). Numerically fewer patients in the BVB arm had received prior SCT (p=0.16). Patients received a median of 4 cycles of BV monotherapy (range 3 - 5). Patients treated with BVB received a median of 3 cycles of bendamustine (IQR 2 - 4) and 4 cycles of BV (IQR 3 - 5); 2 patients discontinued bendamustine after 1 cycle due to adverse reactions. Complete metabolic response was achieved in 34 patients (37.4%) with BV and 22 patients (73.3%) with BVB, with overall response rates of 57.3% and 93.3%, respectively (OR 9.2; 95% CI: 2.06 - 40.86; p=0.004). SCT consolidation was performed after 3L treatment in 33 patients (34.4%) following BV (26 autologous, 7 allogeneic) and 22 patients (73.3%) after BVB (17 autologous, 5 allogeneic). Median follow-up was 30.1 months after BV (IQR: 15.3 - 46.8) and 18.1 months after BVB (15.4 - 29.8). Freedom-from-treatment-failure (FFTF) rates at 18 months were 41.5% (95% CI: 30.8 - 51.8) after BV and 62.9% (39.3 - 79.4) after BVB (HR 0.45, 95% CI 0.23 - 0.88; p=0.019; see Figure). Overall survival rates at 18 months were 76.9% (66.0 - 84.7) after BV and 88.4% (68.1 - 96.1) after BVB (HR 0.37, 95% CI 11 - 1.23; p=0.11. There were 29 deaths following BV, including 17 (17.7%) due to HL, 6 (6.3%) due to toxicity of SCT or subsequent treatment and 6 (6.3%) due to other causes/unknown. There were 3 deaths following BVB, all due to toxicity of SCT or subsequent treatment (10%). Eight patients received single-agent bendamustine after failure of BV monotherapy, at a median of 2.4 months after commencing BV. The median number of bendamustine cycles delivered was 2 (range 1 - 6). The overall response rates was 62.5%. Two patients (25%) achieved complete metabolic response; both underwent subsequent SCT. Conclusion: In this retrospective analysis, use of BVB as 3L treatment for R/R HL was associated with higher response rates, transplant rates and FFTF compared with BV monotherapy. Although toxicity data were not available, our results are otherwise consistent with phase 2 trial data with BVB as second-line therapy (LaCasce, Blood 2018;132:40, Broccoli, Blood Cancer Journal 2019;9:100). These data demonstrate that BVB is a highly effective regimen in R/R HL, and support its use in transplant-fit patients.

Clinical Outcomes in Real-World Patients (RW) with Triple-Class Exposed (TCE) Relapsed/Refractory Multiple Myeloma (RRMM): A Retrospective Study Using Electronic Health Records from Flatiron Health and COTA Vantage Databases

Introduction: With rapid treatment advances in multiple myeloma (MM), more patients receive the 3 main classes of MM treatments (immunomodulatory imide drug [IMiD] agents, proteasome inhibitors [PIs], and anti-CD38 monoclonal antibodies [mAbs]) in earlier lines of therapy and become TCE. This is a prerequisite for subsequent treatment with some novel therapies eg, anti-B-cell maturation antigen (BCMA) agents. Published evidence of RW clinical outcomes in patients with TCE MM is scarce in the evolving RRMM treatment landscape. The objective of this study was to assess RW clinical outcomes in patients with TCE RRMM who received treatment post-TCE. Methods: In this observational study, we analyzed de-identified patient data derived from electronic health records (EHRs) from 2 key United States (US) MM longitudinal databases (Flatiron Health MM [FHMM] and COTA Vantage MM [CVMM]). We identified patients who became TCE between November 2015 and March 2021 and received a subsequent treatment post-TCE; the earliest available end date of the 3rd treatment class was considered the date patients became TCE. The start date of the 1st treatment post-TCE (index treatment) was defined as the index date. We analyzed patient demographics, disease characteristics, prior treatment exposure, refractory status, and index treatments patterns/classes. Clinical endpoints assessed were response rates (overall and complete), overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Results: The FHMM and CVMM databases included 1,319 and 1,118 TCE patients, respectively, of whom 897 and 795 received an index treatment post-TCE. Median (range) follow-up for patients who received an index treatment was 18.1 (0.1-82.0) and 15.5 (0.03-72.3) months for FHMM and CVMM cohorts, respectively. Median age for both RW cohorts was 68 years, more than half of patients were men and the majority were White. Patients received a median of 3 lines of prior treatment (range, 1-14 and 1-12 for FHMM and CVMM cohorts, respectively). In both RW cohorts, >75% of patients who received an index treatment were triple-class refractory and approximately 10% were penta-refractory, having received treatment with 2 IMiD agents, 2 PIs, and an anti-CD38 mAb. Approximately 67% and 79% of patients in the FHMM and CVMM cohorts, respectively, had ECOG performance status 0 or 1. Approximately 54% and 61% had received prior stem cell transplantation. IMiD agents either alone or in combination with a PI and/or anti-CD38 mAb constituted the main regimens for index-treated patients. In the CVMM cohort, the overall and complete response rates were 15.2% and 1.7%, respectively; response data were not available in the FHMM cohort. Median OS (22.3 and 20.4 months), median PFS (4.8 and 4.9 months), and median TTP (5.9 and 5.9 months) were comparable for both FHMM and CVMM cohorts. Conclusions: In this observational cohort study of 2 US RW EHR databases, patients became TCE with a median of 3 prior lines of therapy. Post-TCE, most patients with RRMM still received the same 3 treatment classes with poor response and survival outcomes on their treatments. Despite advances in MM management, this study highlights the need for more efficacious novel treatments for patients with TCE MM and serves as a RW benchmark in the literature for appraising emerging data from novel agents in patients with RRMM.

Real-World Outcomes of CD19CAR T Cell Therapy in Adult Patients with Relapsed Refractory Transformed Indolent Lymphoma

Introduction Transformation of indolent lymphomas to diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes, particularly for patients (pts) with relapsed or refractory (r/r) disease. While chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of r/r DLBCL and is approved for transformed indolent lymphoma (TIL), patients with TIL were largely underrepresented in the pivotal trials leading to the approval of CD19CAR T. In this study, we evaluate the safety and efficacy of standard of care (SOC) CD19CAR T in TIL relative to de novo DLBCL (dDLBCL). Methods We performed a multi-center retrospective study to evaluate safety and efficacy of SOC CD19CAR T in adults with r/r TIL and dDLBCL treated at 5 centers. Eligibility criteria included age ≥ 18 years old, diagnosis of DLBCL (de novo or transformed), r/r disease, and receipt of SOC CD19CAR T. Pts who received CAR T on clinical trials were excluded. We defined TIL as DLBCL transformed from follicular lymphoma (FL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM). Pts with Richter's syndrome were excluded. Safety endpoints: incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Response was assessed using 2014 Lugano Criteria. Efficacy endpoints include best overall response rate (ORR) (proportion of patients achieving a complete or partial response), complete response (CR) rate, progression/relapse-free survival (PFS) and overall survival (OS). Results A total of 788 pts were included (212 (27%) TIL, 576 (73%) dDLBCL) with the CAR T infusion date ranging from 12/2017 to 03/2023. In the TIL cohort, 192 (91%) pts transformed from FL, 14 (7%) MZL, 5 (2%) WM, and 1 indolent lymphoma NOS. In TIL and dDLBCL cohorts, respectively, the median age at infusion was 64 (range 33-85)/64 (21-85) yrs, 37%/36% were female, pts received a median of 3 (range: 1-11)/ 3 (1-13) prior lines of therapy, and 11%/13% had ECOG ≥2 at time of lymphodepletion. In TIL cohort, 44 (21%) pts received prior stem cell transplantation (41 autologous, 3 allogeneic, and none both), while in dDLBCL cohort, 135 (23%) received prior SCT (122 autologous, 9 allogeneic, and 4 both). In TIL and dDLBCL cohorts, 76%/73% received axicabtagene ciloleucel, 17%/18% tisagenlecleucel, and 7%/10% lisocabtagene maraleucel, respectively. Similar toxicities were observed in both cohorts. Any grade CRS/grade ≥ 3 CRS were observed in 76% (95% CI: 70-82%)/ 5% (3-9%) of TIL pts and 81% (78-84%)/ 6% (4-8%) of dDLBCL pts, respectively. Any grade ICANS/grade ≥ 3 ICANS rate were observed in 37% (95%CI: 31-44%)/ 16% (11-21%) of TIL pts and 49% (45-53%)/ 23% (20-27%) of dDLBCL pts, respectively. In TIL and dDLBCL cohorts, respectively, 49%/59% of pts received tocilizumab for CRS and 41%/51% received steroids for CRS or ICANS. Efficacy outcomes were comparable. The best ORR/ CR rate were 78% (95%CI: 72-83%)/ 63% (56-70%) in the TIL cohort and 77% (73-80%)/ 55% (51-59%) in the dDLBCL cohort. Among responders, the median time from infusion to best response was 33 days (IQR: 29-69) and 34 days (IQR: 29-85), respectively. With a median overall follow-up of 13.4 (0.03-63.1) months (mons), the median PFS was 11.2 mons (95%CI: 6.3-20.8) in the TIL and 7.9 mons (95%CI: 6.1-12.2) in the dDLBCL cohort, with a 24-month PFS of 39.4% (95%CI: 32.2-46.5%) and 39.7% (95%CI: 35.5-44.0%) respectively (logrank p=0.45). Median OS was 41.7 mons (95%CI: 24.9-not reached) and 29.7 mons (95%CI: 22.1-not reached) with a 24-month OS of 57.8% (95%CI: 50.1-64.7%) and 53.2% (95%CI: 48.4-57.7%) in TIL and dDLBCL cohorts, respectively (logrank p=0.49). There was no statistically significant difference between the survival outcomes of the TIL and dDLBCL cohorts. 41% (86/212) and 42% (241/576) pts died in the TIL and dDLBCL cohorts respectively, with similar rates of CAR T cell related deaths (9.3% vs 7.1%). Conclusion This study represents the largest evaluation to date of outcomes of CD19CAR T in TIL. The results indicate that CD19CAR T is tolerable and active in pts with r/r TIL with safety and efficacy outcomes similar to that observed in pts with dDLBCL. Our findings suggest CD19CAR T cell therapy may be able to overcome the historically poor prognosis associated with r/r TIL.

CD33 CAR T-Cells (CD33CART) for Children and Young Adults with Relapsed/Refractory AML: Dose-Escalation Results from a Phase I/II Multicenter Trial

Introduction: Current therapies for patients with acute myeloid leukemia (AML) push the limits of chemotherapy intensity but cure only 30% of adults and 70% of children. Recently developed antibody-based therapies and molecularly-targeted agents only modestly improve outcomes for select patient subsets. Thus, new approaches are needed. Given the success of chimeric antigen receptor (CAR) T-cell therapies for acute lymphoblastic leukemia (ALL), we developed and optimized a novel CD33 CAR T-cell (CD33CART) construct for clinical testing in a multicenter Phase I/II clinical trial in children, adolescents, and young adults (AYA) with relapsed/refractory (r/r) AML. ( Qin H, et al. JITC 2021) We report interim results following completion of the dose-escalation phase. Methods: This multicenter phase I/II clinical trial (NCT03971799) was conducted as a 3+3 dose escalation study through the Pediatric Transplantation and Cell Therapy Consortium with National Marrow Donor Program sponsorship and managed by CIBMTR CRO. Autologous CD33CART product were centrally manufactured on a ClinicMACS Prodigy® by the Biopharmaceutical Development Program at the Frederick National Laboratory for Cancer Research (NCI). Eligibility criteria were r/r AML in subjects < 35 years old with adequate organ/performance status and an identified allogeneic stem cell transplant (SCT) donor. Bone marrow assessment was used for standard morphologic evaluation and central flow cytometric minimal residual disease (MRD) quantification. All subjects received pre-CD33CART lymphodepleting chemotherapy (LD) with fludarabine (75-120 mg/m 2) and cyclophosphamide (900-1000 mg/m 2). CD33CART doses levels (DLs) were: DL1: 3 x 10 5 CD33 CAR+ T-cells/kg; DL2: 1 x 10 6/kg; DL3: 3 x 10 6/kg and DL4: 1 x 10 7/kg. Adverse event grading used CTCAE v5 with incorporation of ASTCT consensus definitions for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Dose-limiting toxicities (DLTs) included > grade 3 CRS, > grade 3 ICANS, and persistent > grade 3 non-hematologic toxicity that did not resolve < grade 2 in 72 hours. CD33CART persistence was assessed via flow cytometric evaluation of the blood and bone marrow. Data cut-off was June 1, 2023. Results: A total of 24 subjects (median age of 16 years, range 1-34 years), were enrolled, 12 (50%) of whom underwent a prior SCT. CD33CART products were successfully manufactured for 23 subjects and infused into 19. In 4 non-infused subjects with manufactured products, 1 died from progressive disease (PD) prior to LD, 2 transitioned to palliative care and 1 withdrew consent to seek alternative therapy. Manufacturing was not performed in one subject due to death from PD after enrollment. One morbidly obese subject (BMI=49.3) enrolled at DL4 but received treatment at DL3 due to weight-based manufacturing limitations. The median time from enrollment to infusion was 47 days (range, 24-242). (Table) Three subjects each were infused at DL1 and DL2 without DLTs. At DL3, 1 subject experienced DLT (grade 4 CRS) prompting expansion at this dose level, and no subsequent DLTs were observed. At DL4, 1 subject experienced a prolonged grade 3 CRS (> 72 hours) and grade 3 ICANS, both constituting DLT and necessitating expansion of the cohort without additional DLTs seen. Across all dose-levels, CRS was seen in 13 (68%) patients and was > grade 3 in 4 (21%) with onset typically within the first 24 hours post-infusion. Complete remission (CR) was only seen at DL4 and achieved in 2 subjects, both achieving an MRD negative CR alongside myeloid aplasia. One SCT naïve subject developed candidemia during aplasia but was able to proceed to an allogenic SCT, achieved engraftment, and was in remission at Day +100 post SCT. The second patient (post-two prior SCTs) declined third SCT, had spontaneous count recovery and remained in remission until day +119 (MRD+ relapse). Transient CD33CART expansion was detected in 9 (47.4%) subjects overall and in all 6 (100%) subjects at DL4. Conclusions: CD33CART manufacturing is feasible in children and AYAs with r/r AML with acceptable toxicity experienced in treated subjects. CD33CART expansion was best in subjects treated at DL4 (1 x 10 7/kg) with MRD negative CRs and transient myeloid aplasia occurring in 2 of 5 (40%) subjects evaluable for response (Table). Based on early clinical efficacy at DL4, enrollment continues in the phase 2 portion.

Uproleselan Added to Cladribine Plus Low Dose Cytarabine (LDAC) in Patients with Treated Secondary Acute Myeloid Leukemia (TS-AML)

AML arising from HMA-treated myeloid disorders, also known as “treated-secondary AML” (ts-AML) is associated with an adverse prognosis (Complete Remission [CR] rates 15-30% and median Overall Survival [OS] 6-10 months). E-selectin, a marker of cell survival and resistance to chemotherapy, is highly expressed in the leukemic microenvironment. Exposure of leukemic blasts to HMAs has been shown to increase its expression. Uproleselan is an e-selectin antagonist that has demonstrated antileukemic activity in AML. We sought to study the combination of low-intensity chemotherapy with Cladribine + LDAC (CLAD/LDAC) with uproleselan to overcome local and microenvironmental resistance. This Phase Ib/II clinical trial (NCT04848974) evaluate the safety, tolerability, and efficacy of Uproleselan added to Cladribine and LDAC. A 3+3 dose-escalation approach was implemented to evaluate 2 different dose levels for Cladribine (CLAD)+ LDAC; each 4-week cycle consists of Uproleselan (at fixed dose of 800mg intravenously [IV]). Induction and reinduction if required, included IV uproleselan twice a day from day 1-12; consolidation was given same days but once a day if patients(pts) achieved response (complete response[CR] with incomplete hematological recovery [CRi] or morphologic leukemia-free state [MLFS]). CLAD was IV for 5 days (3.75mg/m2 and 5mg/m2; level -1 and 1 respectively) and subcutaneous LDAC twice daily 10 days (15mg, and 20mg; level -1 and 1 respectively) during induction; consolidation was similar except it was with 3-days of CLAD, for up to 6 cycles, pts aged ≥18 years with a diagnosis of ts-AML with adequate organ function, who have not received therapy for their AML were enrolled. ts-AML is defined as AML arising from previously treated myeloid neoplasm. Presence of the e-selectin was assessed as exploratory analysis. 20 pts have been treated, 18 pts evaluable: 14 (70%) male, median age was 72 yrs (range, 58-86); at the start of therapy, the median bone marrow blasts were 26.5% (20-82%), median WBC was 2.1x10 9/L (0.6-26.4), and median platelets were 26x10 9/L (4-667). Pts had received a median of 1 (1-6) treatments prior to AML transformation. Prior diagnoses were: Chronic Myelomonocytic Leukemia (CMML), MDS, and MDS/MPN in 3 (25%), 14 (70%), and 1 (5%) respectively; all had received HMA, 11 (55%) additionally had received Ven, and 5 (25%) had stem cell transplantation (SCT) prior to enrolling. All pts had unfavorable cytogenetics by ELN 2022. The most frequent mutations were: TET2, TP53, RUNX1 and SRSF2 in 9 (45%), 7 (35%), 6 (30%) and 6 (30%) pts respectively. 18 pts were evaluable for e-selectin; median plasmatic concentration was 26.2ng/mL (15.3-131 ng/mL). Most common AEs were grade(gr) ≥3 neutropenic fever (13 pts, 65%; including 2 gr 5 events), gr 3 bleeding (10%) and gr 2 thrombosis (5%). There were no dose-limiting toxicities observed on dose levels -1 or 1. The chosen dose level was 1 as described above. 2/3 pts who received dose level -1 died during the study follow-up due to sepsis in the first 4-week after induction. Median time to 0.5x10 9/L neutrophil and 50x10 9/L platelets recovery was 30 (17-52) and 38 (20-69) days, respectively. The response rates were 2 (11%) CRi, 1 (6%) CRp, and 4 (22%) MLFS. There was a reduction in BM blasts in 13 pts (72%) (Figure 1). The ORR was 50%(5/10) ( p=0.60) and 20% (1/5) ( p=0.06) among pts who had prior Ven exposure or prior SCT, respectively. The median cycles received was 1.5 (1-4), median cycles at which the best response was achieved was 1 (1-2). 12 pts were taken off protocol due to progression, 3 for death, 3 for allogeneic SCT and 1 continued in remission. The pt who achieved negative MRD-negative by flow cytometry underwent SCT and is still alive. The median follow-up is 8.1 months. Median OS and EFS were 5.3 and 1.4 months respectively; 4-month RFS (CRi, CRp and MLFS) was 30% (Fig 2). In the univariate analysis by Cox regression for plasmatic E-selectin concentration the HR for OS was 1.016 (95% CI 1.002-1.031). Ts-AML, progressing from previously treated antecedent myeloid disorders, is associated with low rates of remission and poor OS. Uproleselan combined with Cladribine + LDAC was well-tolerated with minimal therapy-related AEs - allowing a safe approach to marrow blast reduction and disease control in preparation for a potential allogeneic SCT. We are currently determining the relationship of plasmatic e-selectin concentration and response to treatment.

Efficacy and Safety of Elranatamab in Black Patients with Relapsed/Refractory Multiple Myeloma (RRMM): A Subgroup Analysis of the Magnetismm Studies

INTRODUCTION Multiple myeloma disproportionately impacts ethnic and racial minority groups, affecting both incidence and outcome. There is limited evidence-based data for clinical decision making for minority populations, including Black patients (Habr and Corsaro, Hematol Oncol 2022). Elranatamab is a B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the phase 2 registrational trial MagnetisMM-3, elranatamab demonstrated clinical efficacy in BCMA-naïve and BCMA-exposed patient populations. Here, we report the efficacy and safety of elranatamab in a pooled analysis of Black or African American patients with RRMM across 3 studies in the MagnetisMM program, including MagnetisMM-1 (MM-1; NCT03269136), MagnetisMM-3 (MM-3; NCT04649359), and MagnetisMM-9 (MM-9; NCT05014412). METHODS Eligible patients included in this pooled analysis had previously received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody, and were either naïve or exposed to prior BCMA-directed therapy (antibody-drug conjugate [ADC] and/or CAR T-cells). All patients received subcutaneous elranatamab at the effective doses of 215-1000 µg/kg or fixed dose equivalent of 76 mg (MM-1) or 76 mg once-weekly (MM-3 and MM-9). Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Evaluation of overall response rate (ORR) was assessed per IMWG criteria. Adverse events (AEs) and laboratory abnormalities were graded by National Cancer Institute Common Terminology Criteria for AEs v4.03 (MM-1) or v5.0 (MM-3 and MM-9). American Society for Transplantation and Cellular Therapy criteria (Lee DW, et al. Biol Blood Marrow Transplant 2019) were used for grading cytokine release syndrome (CRS) and immune effect cell-associated neurotoxicity syndrome (ICANS). RESULTS Of 24 Black or African American patients in the pooled analysis who received elranatamab, the median age was 61.5 years (36-76), 75.0% had R-ISS Stage I or II disease, 79.2% had prior stem cell transplant, and 91.7% patients had an Eastern Cooperative Oncology performance status of 0 or 1. Patients had a median of 6 prior lines of therapy (range, 2-14), with 91.7% and 45.8% having triple-class and penta-drug refractory disease, respectively. Seven patients (29.2%) received prior BCMA-directed therapy as either an antibody-drug conjugate (ADC; n=5), CAR-T (n=4), or both (n=2). After a median follow-up of 13.3 months, the median duration of treatment was 9.0 months; 6 (25%) patients were still on treatment. The most common reasons for treatment discontinuation were progressive disease (41.7%), AEs (12.5%), and death (12.5%). The ORR was 58.3%, with 41.7% of patients achieving complete responses (CR) or better (Table). The median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were 18.4, 14.4, and 21.2 months, respectively. Common treatment-emergent AEs (TEAEs) included CRS, anemia, and neutropenia (Table). Infections were reported in 15 patients (any grade, 62.5%; grade 3/4, 20.8%). Two cases of ICANS (both grade 2) were reported. One patient died due to disease progression (metastases to meninges), and four patients died due to a TEAE other than disease progression: 1 patient each due to COVID-19, septic shock, sudden death, and pulmonary embolism. CONCLUSIONS Elranatamab demonstrated clinical activity and a manageable safety profile in Black or African American patients with RRMM, supporting the use of elranatamab in this subgroup of patients. Efficacy and safety results are comparable to those observed for the overall population of patients treated with elranatamab in the phase 2 MagnestisMM-3 trial. No new safety signals were observed.

An Updated Comparison of Clinical Outcomes from 4-Year Follow-up of Zuma-5 (Axicabtagene Ciloleucel) and the International Scholar-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma

Introduction: Axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy), led to durable responses in relapsed/refractory (R/R) follicular lymphoma (FL) in the pivotal ZUMA-5 trial. When 3-year efficacy data from ZUMA-5 were compared to the SCHOLAR-5 external control cohort (ASH 2022, Ghione et al.), axi-cel showed a substantial improvement in clinical endpoints including overall response rate, complete response, progression-free survival (PFS), time-to-next treatment (TTNT), and overall survival (OS). Here we provide an updated analysis of this comparison using an additional 12-months of follow-up data for ZUMA-5. Methods: SCHOLAR-5 is an international, external control cohort of R/R FL patients who initiated a ≥3rd line of therapy (LoT) after July 2014. Patients were recruited from seven institutions in five countries. In addition, patients initiating therapy after receiving idelalisib in the pivotal DELTA trial were included. ZUMA-5 eligibility criteria were applied to SCHOLAR-5 patients, and propensity score and standardized mortality ratio weighting were used to balance prognostic factors between both cohorts. A standardized mean difference (SMD) of <0.1 was considered as balanced. Kaplan-Meier (KM) curves and weighted Cox proportional hazards models were used to evaluate OS, PFS, and TTNT. Best response did not change with longer follow-up, so is not included in the updated analysis. Results: Following propensity score weighting, 143 patients from SCHOLAR-5 were reduced to 129 patients and were compared to the 127 patients from the intention-to-treat population of ZUMA-5. Median follow-up times for each cohort were 26.2 and 47.6 months, respectively. Progression of disease within 24 months of initiation of first-line chemoimmunotherapy (POD24), number of prior LoT, R/R to prior LoT, prior stem cell transplant, size of largest nodal mass, response to prior LoT, and time since last therapy were successfully balanced (SMD<0.1). The median PFS was 57.3 months in ZUMA-5 compared to 13.0 months in SCHOLAR-5 (Figure 1a, hazard ratio [HR]: 0.27, 95% confidence interval [CI]: 0.18-0.40), and median TTNT was 62.2 months compared to 26.6 months (HR: 0.62, 95%CI 0.40-0.95), respectively. Median OS was not reached in ZUMA-5 or SCHOLAR-5 (Figure 1b, HR: 0.58, 95% CI: 0.35-0.96). At 48 months, PFS was 53.0% (95% CI: 43.1-61.9) in ZUMA-5 but was not evaluable in SCHOLAR-5, as all patients had progressed or been censored. Forty-eight-month TTNT was 56.6% (95% CI: 47.4-64.8) in ZUMA-5 compared to 41.9% (95% CI: 28.7-55.0) in SCHOLAR-5. Forty-eight-month OS was 72.4% (95% CI: 63.6-79.4) in ZUMA-5 compared to 61.4% (95% CI: 49.1-73.7) in SCHOLAR-5. Conclusion: These results demonstrate that axi-cel continues to show superior efficacy for R/R FL compared to other available therapies. The response to axi-cel is durable, and offers a clinically meaningful and significant benefit in PFS, TTNT, and OS. These longer follow-up results are particularly important in this indolent disease, where survival outcomes take time to reach maturity. Axi-cel continues to address an unmet medical need for this population of R/R FL patients.

Risk Factors for CD19-Targeting CAR T Manufacturing Failure and Patient Outcomes: A Report from the UK National CAR T Panel

CAR T manufacturing failure (MF) rates reported in literature range between 1-13%. In some cases the manufacturing process fails to yield a product and in others results in one which does not meet pre-specified criteria for release and labelled an out of specification (OOS) product. We conducted a multicentre retrospective review of factors contributing to MF and its impact on patient outcomes. Patients with relapsed or refractory large B cell lymphoma (LBCL), mantle cell lymphoma (MCL) or B acute lymphoblastic leukemia (B-ALL) approved for CAR T therapy with axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel) or tisagenlecleucel (tisa-cel) by the UK national CAR T panel between January 2019 and January 2023 were eligible. Patients with MF were identified from databases of the 11 participating CAR T centres and from the national OOS CAR T panel. In total 1138 patients were approved for CAR T therapy (903 LBCL, 97 MCL and 138 B-ALL). We identified 58 patients who had at least 1 CAR T MF; 38 LBCL (LBCL-MF), 14 MCL and 6 B-ALL with inferred MF frequency of 4.20%, 14.43% and 4.34% respectively. Intended CAR T product was axi-cel in 28 and tisa-cel in 10 LBCL, brexu-cel for all MCL and tisa-cel for all B-ALL patients. Most frequent reasons for MF were poor growth in culture (n=12), low cell viability (n=12) and low T cell purity (n=6). Of the 58 patients with MF, OOS product was available and infused in 19 patients (OOS cohort: 14 LBCL, 2 MCL and 3 B-ALL). Repeat apheresis led to infusion of a product in-specification in 17 patients (MF-delayed-infusion cohort: 10 LBCL, 6 MCL and 1 B-ALL). Another 22 patients did not proceed to CAR T infusion (MF-no-infusion cohort: 14 LBCL, 6 MCL and 2 B-ALL), some despite attempts at remanufacture (n=9) or available OOS product (n=5). We included 25 randomly selected matched (for disease subtype and product) controls (all LBCL: 19 axi-cel and 6 tisa-cel) without MF, 18 of whom received infusion. Univariable analysis of potential baseline clinical factors contributing to risk of MF did not reveal any significant impact of the number of lines of prior therapy, history of prior stem cell transplant or a need for holding therapy prior to apheresis. Bendamustine therapy was significantly associated with risk of MF for all lymphoma patients and the LBCL subset; prior exposure in 4% controls vs 32.7% of all lymphoma MF (p=0.004) and 26.3% of LBCL-MF (p=0.039). This was largely due to therapy within 6 months; 0% of controls vs 19.2% of all lymphoma MF (p=0.026) and 23.7% of LBCL-MF (p=0.009). Factors at apheresis including white cell count, neutrophil count, platelet count, absolute lymphocyte count, CD3 count, CRP, LDH and volume of blood processed had no impact on the risk of MF. With a median follow up of 11.6 months, the 12-month overall survival (OS) from date of approval for CAR T therapy was 45.0% (31.4 - 57.7) for all MF patients (n=58), 49% (24.7 - 69.5) for the OOS cohort (n=19), 64.2% (33.6 - 83.5) for the MF-delayed-infusion cohort (n=17) and 27.3% (11.1 - 46.4) for the MF-no-infusion cohort (n=22). Corresponding 12-month OS was 43.0% (26.7 - 58.3) for all LBCL-MF (n=38), 49.0% (21.6 - 71.7) for LBCL-OOS (n=14), 53.3% (17.3 - 79.8) for the LBCL-delayed-infusion cohort (n=10) and 28.6% (8.8 - 52.4) for the no-infusion cohort (n=14). The 12-month OS for LBCL controls (n=25) was 51.2% (30.3-68.7) for all and 65.5% (38.6 - 82.8) for infused patients (n=18). There was no significant difference between OS for LBCL-MF and LBCL controls (HR 1.38, p=0.31). Though OS was numerically lower for LBCL-OOS compared to infused LBCL controls, it was not statistically different (HR 1.82, p=0.21). For infused patients, the 3 months complete response (CR) rates were similar for the LBCL-OOS (38.5%), LBCL controls (40%) and MF-delayed infusion (53.3%) cohorts. The 3 months overall response rate (OR) was non-significantly lower in the LBCL-OOS (38.5%) compared to LBCL controls (60%) and MF-delayed infusion (53.3%) cohorts. There was no difference between any grade or grade ≥3 CRS or ICANS between the LBCL-OOS, LBCL-control and MF-delayed-infusion cohorts. In summary, outcomes for patients infused with an in-specification or OOS CAR T product following MF are comparable to those of controls. Prior bendamustine therapy within 6 months of apheresis is the only risk factor associated with risk of MF in lymphoma patients. Further analysis will be presented at the meeting.

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes—an international multicentre retrospective study

Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to non-cancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population. We studied patients with underlying malignancies admitted with sepsis to one of 25 paediatric intensive care units (PICUs) participating in two large, multi-centre, observational cohorts from the European SCOTER study (n=383 patients; study period between January 1, 2018 and January 1, 2020) and the U.S. Novel Data-Driven Sepsis Phenotypes in Children study (n=1898 patients; study period between January 1, 2012 and January 1, 2018). We independently used latent class analysis (LCA) in both cohorts to identify phenotypes using demographic, clinical, and laboratory data from the first 24h of PICU admission. We then tested the association of the phenotypes with clinical outcomes in both cohorts. LCA identified two distinct phenotypes that were comparable across both cohorts. Phenotype 1 was characterised by lower serum bicarbonate and albumin, markedly increased lactate and hepatic, renal, and coagulation abnormalities when compared to phenotype 2. Patients with phenotype 1 had a higher 90-day mortality (European cohort 29.2% versus 13.4%, U.S. cohort 27.3% versus 11.4%, p<0.001) and received more vasopressor and renal replacement therapy than patients with phenotype 2. After adjusting for severity of organ dysfunction, haematological cancer, prior stem cell transplantation and age, phenotype 1 was associated with an adjusted OR of death at 90-day of 1.9 (1.04-3.34) in the European cohort and 1.6 (1.2-2.2) in the U.S. cohort. We identified two clinically-relevant sepsis phenotypes in paediatric cancer patients that are reproducible across two international, multicentre cohorts with prognostic implications. These results may guide further research regarding therapeutic approaches for these specific phenotypes. Part of this study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.