Intensive Reinduction Chemotherapy Followed by Early Allogeneic Hematopoietic Cell Transplantation for Relapsed/Refractory High-Grade Myeloid Neoplasms.

Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols.

Dose-Adjusted EPOCH Plus Inotuzumab Ozogamicin in Adults With Relapsed or Refractory B-Cell ALL: A Phase 1 Dose-Escalation Trial.

Importance: Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL. Objective: To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL. Design, Setting, and Participants: This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment. Interventions: DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design. Main Outcomes and Measures: The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects. Results: A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively. Conclusions: In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03991884.

Retrospective review of the toxicities and change in dosing patterns for pegaspargase in patients with acute lymphoblastic leukemia/lymphoma and T-cell lymphoma.

INTRODUCTION: Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity. METHODS: A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted. RESULTS: Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities. CONCLUSION: Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.

HA-1-targeted T cell receptor (TCR) T cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.

Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective anti-leukemic effect post-HCT. We conducted a phase I clinical trial employing a novel TCR-T product targeting the minor H antigen HA-1 to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T post-HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8-co-receptor were successfully manufactured from HA-1 disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to nine HCT recipients who had developed disease recurrence post-HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, four patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with one ongoing at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial is registered at clinicaltrials.gov as NCT03326921.

Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL.

ABSTRACT: The phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard-of-care chemotherapy (SC). Here, we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n = 43; SC, n = 48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery were observed with InO vs SC in patients with BCR::ABL1-like ALL (85.7% [6/7] vs 0% [0/5]; P = .0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8]; P = .0047), and in the high-risk BCR::ABL1- (BCR::ABL1-like, low-hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P < .0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1-like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1-like subtype or harboring TP53 alterations is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT01564784.

Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia.

Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3+ T-cells to engage and lyse CD19+ target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.gov, NCT04521231), heavily pretreated adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) received SC blinatumomab at two doses: (1) 250 µg once daily (QD) for week 1 and 500 µg three times weekly (TIW) thereafter (250 µg/500 µg) or (2) 500 µg QD for week 1 and 1000 µg TIW thereafter (500 µg/1000 µg). The primary endpoint was complete remission/complete remission with partial hematologic recovery (CR/CRh) within two cycles. At the data cutoff of September 15, 2023, 29 patients were treated: 14 at the 250 µg/500 µg dose and 13 at 500 µg/1000 µg dose. Data from two ineligible patients were excluded. At the end of two cycles, 12 of 14 patients (85.7%) from the 250 µg/500 µg dose achieved CR/CRh of which nine patients (75.0%) were negative for measurable residual disease (MRD; <10-4 leukemic blasts). At the 500 µg/1000 µg dose, 12 of 13 patients (92.3%) achieved CR/CRh; all 12 patients (100.0%) were MRD-negative. No treatment-related grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) were reported. SC injections were well tolerated and all treatment-related grade 3 CRS and NEs responded to standard-of-care management, interruption, or discontinuation. Treatment with SC blinatumomab resulted in high efficacy, with high MRD-negativity rates and acceptable safety profile in heavily pretreated adults with R/R B-ALL.

Craniospinal irradiation for CNS leukemia: rates of response and durability of CNS control.

PURPOSE: Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited. METHODS: We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated. RESULTS: Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18 Gy to the brain and 12 Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12 Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI. CONCLUSION: CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space.