Drs Al Malki on Outcomes With PTCy-Based GVHD Prophylaxis 

“The primary end point was overall survival at 1 year. This study met its primary end point and show promising results in that regard.”

Monzr Al Malki, MD, associate professor, Division of Leukemia and Hematopoietic Cell Transplantation, director, Unrelated Donor BMT Program, director, Haploidentical Transplant Program, City of Hope; and Jeffery J. Auletta, MD, chief scientific director, Center for International Blood and Marrow Transplant Research, senior vice president, Health Equity, National Marrow Donor Program, discuss findings from the phase 2 ACCESS trial (NCT04904588) evaluating post-transplant cyclophosphamide (PTCy)–based graft-vs-host disease (GVHD) prophylaxis following HLA-mismatched unrelated donor (MMUD) peripheral blood stem cell transplantation using myeloablative conditioning in patients with hematologic malignancies.

The study assessed 1-year overall survival (OS) as its primary end point, which was met, according to Al Malki. Patients who underwent a MMUD transplant with PTCy prophylaxis experienced a 1-year OS rate of 84%. In previously reported data from the phase 2 15-UUMD trial (NCT02793544), which also explored PTCy prophylaxis in the same patient population, the 1-year OS rate was 72%. The 1-year GVHD-free, relapse-free survival rate was 48% in for patients treated in ACCESS vs 38% for those treated in 15-UUMD. Notably, OS and GVHD outcomes were similar in ACCESS irrespective of whether patients had 1 HLA mismatch or at least 2 mismatches.

Auletta explains that these are intriguing results using the most common source for transplant—peripheral blood stem cells—in the content of patients with UUMD donors. These outcomes lay the groundwork for giving myeloablative conditioning to a larger number of patients, he says. By leveraging myeloablative conditioning in combination with MMUD transplantation, high-dose chemotherapy can also provide a graft-vs-leukemia effect to enhance disease control, Auletta says. By inducing donor-derived immunity and giving myeloablative conditioning, the PTCy-based strategy simultaneously eradicates malignant clones through both chemotherapeutic and immune-mediated mechanisms, he concludes.

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“The study is designed as a phase 1 study, having a treatment arm and a control arm. [Patients] get randomly assigned biologically based on the status of HLA-1 or HLA-2, [and these patients] can receive the treatment; their donors should be HLA-1 or HLA-2 negative.”

Monzr M. Al Malki, MD, hematologist/oncologist, associate professor, Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation; director, Unrelated Donor BMT Program; and director, Haploidentical Transplant Program, City of Hope, discusses the rationale for the ongoing phase 1 ALLOHA trial (NCT05473910) and its approach to using treatment with TSC-100 and TSC-101 to reduce relapse risk in patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndromes (MDS).

Al Malki notes that haplo-HSCT with reduced-intensity conditioning has expanded transplant eligibility, particularly for older and medically unfit patients, Al Malki explains. However, reduced-intensity conditioning regimens are associated with a 40% to 50% relapse rate due to lower-intensity chemotherapy failing to eradicate all malignant cells, he says. The ALLOHA trial seeks to address this challenge through biologically driven randomization to receive the engineered T-cell therapies TSC-100 and TSC-101 based on HLA-1 and HLA-2 status, allowing for targeted intervention in patients at higher risk of relapse.

In this phase 1 study, patients enrolled to the investigational arm are stratified based on HLA-1 and HLA-2 expression, Al Malki states. Patients with HLA-1 or HLA-2 expression are eligible to receive the investigational therapies, and their donors must be negative for both markers. The study is evaluating whether this T-cell therapeutic approach can enhance post-transplant immune responses and reduce relapse rates.

The study’s design reflects the curative potential of allogeneic HSCT and acknowledges the limitations of current reduced-intensity conditioning strategies, Al Malki adds, given that post-transplant relapse remains the leading cause of mortality in this setting. The ALLOHA trial’s biologically driven randomization introduces a precision-medicine approach to post-transplant disease control.

Going forward, Al Malki and colleagues will continue this study further assess the clinical effects of HLA-based stratification on long-term outcomes with T-cell therapy following haplo-HSCT, he concludes.

Monzr M. Al Malki, MD, discusses reducing relapse risk in patients undergoing haploidentical hematopoietic stem cell transplantation.

Dr Al Malki on Reducing Relapse Risk in Patients Undergoing Haplo-HSCT

Dr Al Malki on the Potential Use of TSC-100 and TSC-101 After Transplant in AML, ALL, and MDS 

“We are trying to address a pitfall for some [patients] with hypoidentical donors. We want to reduce the chances of relapse and improve the chances of success [following] transplant. If [data from the Alloha trial] pans out to be positive, this should improve people's survival [post] transplant.”

Monzr M. Al Malki, MD, hematologist/oncologist, associate professor, Divison of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation; director, Unrelated Donor BMT Program; director, Haploidentical Transplant Program, City of Hope, discusses preliminary findings from the phase 1 Alloha trial (NCT05473910), evaluating TSC-100 and TSC-101 as adjuvant TCR-T cell therapies for patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC).

TSC-100 and TSC-101 are donor-derived T-cell receptor engineered T-cells designed to selectively eliminate residual disease cells post-transplant by targeting HA-1 and HA-2 antigens,

Alloha is exploring the potential of these agents to reduce relapse rates and improve relapse-free survival (RFS) in this high-risk population.

Early findings from the study showed that 8% (2/26) of patients in the treatment arm experienced disease relapse compared with 33% (4/12) with transplant alone. Additionally, event-free survival (EFS) strongly favored the treatment arm, (HR = 0.30). The median time to relapse was not evaluable in the TSC-treated arm, compared with 160 days in the control group. Additionally, TSC-100 and TSC-101 TCR-T cells demonstrated durability, with detectable levels persisting beyond 1-year post-infusion and showing a clear dose-persistence relationship.

The therapies were well-tolerated, with no dose-limiting toxicities or unexpected adverse effects (AEs) reported. The safety profiles for TSC-100 and TSC-101 were consistent with that observed with HSCT alone, supporting the feasibility of incorporating these therapies into the post-transplant care regimen for patients undergoing RIC HSCT. The most common adverse effects of special interest included acute graft-vs-host disease (GvHD), which occurred in 50% of patients in both treatment groups compared with 33% in the control group.

Grade 3/4 acute GvHD was reported in 17% of patients in the control arm and 8% in the TSC-101 arm. No grade 3/4 AEs were observed with TSC-100. Cytokine release syndrome (CRS) occurred in 40% and 67% of patients treated with TSC-100 and TSC-101, respectively, with all events limited to grade 1-2 severity. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported across any groups.

Al Malki states that these findings have the potential to address relapse risk in transplant recipients, particularly those with haploidentical donors. Further evaluation of TSC-100 and TSC-101 is ongoing; additional data are expected to validate these early findings, he concludes.

Monzr M. Al Malki, MD, discusses the potential use of TSC-100 and TSC-101 following allogeneic stem cell transplant in patients with AML, ALL or MDS. 

Monzr M. Al Malki, MD, discusses outcomes with mismatched unrelated donor transplantation using post-transplant cyclophosphamide–based GVHD prophylaxis.

Dr Al Malki on Outcomes With PTCy-Based GVHD Prophylaxis in Hematologic Malignancies

Monzr M. Al Malki, MD, associate professor, Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation; director, Unrelated Donor BMT Program, Haploidentical Transplant Program, City of Hope, discusses the impact of post-transplant cyclophosphamide (PTCy)–based graft-vs-host disease (GVHD) prophylaxis on survival outcomes following mismatched unrelated donor (MMUD) peripheral blood stem cell (PBSC) transplantation in patients with advanced hematological malignancies, as assessed in the phase 2 ACCESS study (NCT04904588).

The goal of this prospective, multi-center study was to determine whether survival outcomes in adults who underwent PBSC from MMUD would be comparable with those of patients undergoing bone marrow transplant, Al Malki begins. Adult patients were stratified according to whether they received a myeloablative or reduced-intensity conditioning regimen. In the singular pediatric cohort, both conditioning regimens were used.

Results from a planned interim analysis of the first 70 adult patients enrolled onto the reduced-intensity conditioning PBCS cohort were reported at the 

, he states. At 1 year following transplantation, the overall survival (OS) rate within the reduced-intensity conditioning stratum in ACCESS was 79% (95% CI, 68%-87%). This outcome was comparable with the OS rate of 77% (95% CI, 71%-82%) observed with bone marrow grafts in the phase 3 BMT CTN 1703 study (NCT03959241).

Transplants using mismatched related donors have historically been challenging due to the higher incidence of GVHD, Al Malki notes. However, the rates of GVHD and other complications in the ACCESS study were comparable to those in HLA-matched donor recipients. In the reduced-intensity conditioning cohort, the rate of grade 2-4 acute GVHD was 43% (95% CI, 32%-55%), the rate of grade 3/4 GVHD was 9% (95% CI, 3%-16%), and the rate of moderate/severe chronic GVHD was 9% (95% CI, 3%-17%). In the BMT CTN 1703 PTCy arm, these rates were 56% (95% CI, 49%-62%), 8% (95% CI, 5%-12%) and 7% (not reported), respectively. Overall, these data highlight the efficacy and safety of using reduced-intensity conditioning PBSC transplantation from MMUD, which could significantly expand patient access to stem cell transplants, Al Malki concludes.

Monzr M. Al Malki, MD

Articles

Drs Al Malki and Auletta on PTCy GVHD Prophylaxis in Patients With HLA-UUMD

Dr Al Malki on Reducing Relapse Risk in Patients Undergoing Haplo-HSCT

Dr Al Malki on the Potential Use of TSC-100 and TSC-101 After Transplant in AML, ALL, and MDS

Dr Al Malki on Outcomes With PTCy-Based GVHD Prophylaxis in Hematologic Malignancies