POTENTIAL SYNERGY FROM AZACITIDINE AND ANTI-CD47 ANTIBODY COMBINATION
The First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Azacitidine Is Effective in MDS and AML Patients: Ongoing Phase 1b Results
A phase 1b trial of magrolimab (anti-CD47 antibody) and azacitidine combination therapy in patients with either myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) was presented by David A. Sallman, MD (H. Lee Moffitt Cancer Center and Research Institute, Tampa FL). By blocking the macrophage immune checkpoint CD47 in addition to inducing “eat me” signals on cancerous cells, this combination regimen was hypothesized to synergistically boost tumor phagocytosis. The expansion cohort from the ongoing trial was discussed, including previously untreated MDS and AML patients.
Thirty-five patients with MDS and twenty-seven with AML were treated with this combination. The safety profile with the addition of magrolimab was similar to that of azacitidine alone, with one patient discontinuing due to an adverse event. At data cut-off, 22/24 evaluable MDS patients had an objective response, and 14/22 AML patients did as well. Complete response rates were also 50 and 41% for MDS and AML, respectively. Notably, the addition of magrolimab reduced the time to response compared to that of azacitidine alone, and the median duration of response had not yet been reached in either group of patients. Mutational analyses to correlate outcomes and genetic characteristics are ongoing; however, the investigators did determine that 7/9 evaluable patients with mutant TP53 experienced an objective response. This combination treatment therefore may hold promise for treating both MDS and AML, given its relative safety and high level of therapeutic activity.
ADOPTIVE NK CELL THERAPY MAY ENHANCE OUTCOMES AFTER SCT
Improved Outcomes for Patients Receiving High-Doses of IL-21 Ex Vivo Expanded NK Cells after Haploidentical Transplantation (haploSCT): Long-Term Follow-up of a Phase 1/2 Clinical Trial with Comparison to CIBMTR Controls
Stefan O. Ciurea, MD (University of Texas MD Anderson Cancer Center, Houston TX) discussed the long-term follow-up of a phase 1/2 study of adoptive NK cell therapy in high-risk patients with myeloid malignancies who received haploidentical transplantation. Ex vivo expanded NK cells were generated from the same donor as the transplant and stimulated with mbIL21, and patients received up to three doses, at which time outcomes were compared to CIBMTR controls.
Twenty-four patients were evaluable with a median follow-up of over 44 months, all of whom achieved engraftment after a mean of 19 days. The rate of acute graft-versus-host disease in this population was 42% at one year post-transplant; at the same time, the 1-year relapse rate was only 4%. Those patients without donor-specific antibodies had PFS rates of 79% and 73% at one and three years. When the outcomes for this study were compared to historical controls, higher disease-free survival rates and lower relapse rates were observed with the addition of NK cell therapy, specifically, DFS at two years was 66% on-study compared to 44% historically, and relapse rates were 4% vs 38%. Given the promise observed in this study, future investigation of this combination treatment regimen is ongoing.
HIGHER CR RATES ACHIEVED WITH CD123/CD3 BISPECIFIC
Flotetuzumab, an Investigational CD123 x CD3 Bispecific Dart® Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients
Given the difficulty of treating primary refractory acute myeloid leukemia (AML), Geoffrey L. Uy, MD (Washington University School of Medicine, Saint Louis MO) and colleagues investigated a bispecific dual-affinity re-targeting antibody (DART®) in this patient population. By targeting both CD123, found on AML blasts, and CD3 on immune cells, the immune response to refractory disease may be enhanced with this antibody, known as flotetuzumab. Patients received the recommended phase 2 dose and were monitored using standard methods in addition to gene expression profiling.
All of the patients treated with flotetuzumab in this study had relapsed/refractory AML, and the majority of these were primary refractory. The primary refractory patients demonstrated higher CD123 expression on AML blasts, higher inflammatory signatures, and increased expression of known chemotherapy-resistance genes. Among the evaluable primary refractory and early relapse population, the complete remission rate was 32.1%, which was well above the expected traditional salvage therapy remission rate of <10%. Anti-leukemic activity was correlated with higher CD123 expression, IFN-gamma scores, and tumor inflammation signatures. Any-grade cytokine release syndrome occurred in the majority of patients, with the incidence of higher-grade CRS no different between responders and non-responders, even in the presence of higher CD123 expression. This bispecific treatment is therefore a potential treatment for difficult-to-manage AML.
ALLOGENEIC STEM CELL TRANSPLANT MAY BE SAFE AFTER IMMUNE CHECKPOINT THERAPY
Safety and Efficacy of Allogeneic Hematopoietic Stem Cell Transplant after Programmed Cell Death 1 (PD-1) / Programmed Cell Death Ligand 1 (PD-L1) Blockade for Classical Hodgkin Lymphoma: Analysis of a Large International Cohort
As immune checkpoint inhibitors move into frontline treatment settings, options for treatment after relapse need to be considered, such as allogeneic stem cell transplant in classical Hodgkin lymphoma patients as discussed by Reid W. Merryman, MD (Dana-Farber Cancer Institute, Boston MA). Given the immune activation that occurs with anti-PD-(L)1, there is concern that their use prior to stem cell transplant may increase the incidence of adverse events. Therefore, this retrospective study systematically evaluated outcomes of patients who underwent transplantation after PD-(L)1 blockade.
Medical records were evaluated for 197 patients who had received a median of 9.5 (range 1-74) doses of anti-PD-(L)1 agents, with best responses of CR (39%), PR (38%), SD (12%) and PD (11%). Stem cell transplantation was conducted a median of 82 days (range 17-1029) after the last dose of PD-(L)1 blockade, with the majority of patients (59%) in CR at the time of transplant. After a median follow-up of 24.3 months, the overall survival and progression-free survival were 82% and 68%, respectively, and the incidence of relapse and non-relapse mortality were 18% and 14%. Across all patients, the incidence of chronic GVHD of any severity was 38% after two years, while the 6-month incidence of acute GVHD was 38% (grades 2-4). PFS and OS were not associated with either shorter time from PD-(L)1 blockade to transplant nor higher number of doses of PD-(L)1 blockade; however, a shorter time to transplant did correlate with higher likelihood of severe acute GVHD (6-month incidence of 27% if transplanted <45 days, and 10% if transplanted >90 days from last dose of PD-(L)1 blockade). Patients who received prophylactic GVHD prevention using post-transplant cyclophosphamide had lower levels of chronic GVHD and relapse, with a 2 year GVHD-free/relapse-free survival of 58 vs 30%, while enjoying an improvement in PFS of 76 vs 60%. As such, with proper patient management, stem cell transplantation after PD-(L)1 blockade therapy may be a reasonable therapeutic option for classical Hodgkin lymphoma and PD-(L)1 blockade may be considered in the future as a potential bridge to alloHSCT.
IMPROVED QOL REPORTED WITH CAR T THERAPY OVER STEM CELL TRANSPLANT
Patient Experience of Chimeric Antigen Receptor (CAR)-T Cell Therapy Vs. Stem Cell Transplant: Longitudinal Patient Reported Adverse Events, Cognition and Quality of Life
Surbhi Sidana, MD (Mayo Clinic – Stanford and Stanford University, Stanford CA) discussed a study of patient experiences on three common treatments for hematologic malignancies: CAR T therapy and autologous or allogeneic stem cell transplantation. Beyond treatment outcomes, the impact on patients’ quality-of-life (QOL) needs to be considered in order to properly manage symptoms and provide optimal patient education. Therefore, patients were prospectively enrolled to receive one of these three treatments and asked to complete QOL questionnaires throughout the therapy.
At baseline, QOL across all measured indexes was similar for the three groups. As a whole, patients receiving CAR T experienced less worsening of QOL compared to the transplant groups. The worst QOL was reported in all groups at 2 weeks post-intervention and gradually returned to baseline. The QOL reported by CAR T patients was significantly better than the other two groups at week 2, month 1, and month 2, and better than allogeneic transplant at month 3 as well. Between the CAR T and autologous transplant groups, no differences were noted in the most common patient-reported adverse events; however, a statistically higher proportion of adverse events were reported in the allogeneic transplant group over the CAR T patients. CAR T patients did not experience significant changes in side effect bother, while side effects impacted the transplant groups to a greater extent, measured by the FACT-G Side Effect Bother measure. These different patient experiences on various hematologic cancer therapies should be considered during patient consultation and monitoring throughout therapy.
ANTI-CD20/CD3 BISPECIFIC MAY IMPROVE B-NHL MANAGEMENT
Clinical Activity of REGN1979, a Bispecific Human, Anti-CD20 x Anti-CD3 Antibody, in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)
Results of a phase 1 trial of REGN1979, an anti-CD20/anti-CD3 bispecific antibody, in patients with R/R B-cell non-Hodgkin lymphoma (B-NHL) were reported by Rajat Bannerji, MD, PhD (Rutgers Cancer Institute of New Jersey, New Brunswick NJ). Patients for whom prior CD20-directed therapy failed were eligible for enrollment in this safety- and tolerability-finding study.
One hundred and ten patients with diffuse large B-cell lymphoma (55.5%), follicular lymphoma (28.2%), mantle cell lymphoma (8.2%), marginal zone lymphoma (5.5%), or other B-NHL were treated with a median of 9 doses of REGN1979, at levels ranging from 0.03-320 mg. Across the study, no dose-limiting toxicities were observed, with the most common grade 3-4 AEs including anemia, lymphopenia, infections, neutropenia, and hypophosphatemia. Six patients discontinued REGN1979 due to AEs. In DLBCL, higher doses of REGN1979 led to improved patient outcomes, with 42% of patients receiving doses >=80 mg achieving a CR; at the same time, follicular lymphoma patients treated with doses of at least 5 mg displayed enhanced outcomes with a CR rate of 77%. Interestingly, baseline CD20 expression did not correlate with responses; however, there was some evidence that loss of CD20 may lead to progression. A phase 2 study is ongoing with REGN1979 given the encouraging safety and efficacy observed in this study.
ELIMINATING CAFS LEADS TO ENHANCED OUTCOMES IN MULTIPLE MYELOMA
Targeting Cancer Associated Fibroblasts in the Bone Marrow Prevents Resistance to Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma
Reona Sakemura, MD, PhD (Mayo Clinic, Rochester MN) discussed a novel approach to overcome relapse and resistance of multiple myeloma (MM) to BCMA-targeted CAR T therapy: additional targeting of cancer-associated fibroblasts (CAFs). The investigators utilized preclinical models to verify the hypothesis that eradication of CAFs with a targeted CAR T therapy would enhance the efficacy of BCMA CAR T therapy as well.
Initial studies verified that CAFs inhibited the efficacy of BCMA CARs both in vitro and in vivo, primarily through secretion of TGF-beta. Fibroblast associated protein (FAP) and CS1 were identified as markers of MM-CAFs, leading the group to develop two CARs targeting these two proteins. Dual CAR T cells were also developed, binding FAP/BCMA and CS1/BCMA. Upon incubation with BCMA+ MM cells and CAFs, the proliferation of BCMA CAR T cells was reduced; however, the dual-targeting cells remained proliferative and generated effector cytokines. In murine studies, BCMA CAR therapy was able to eradicate BCMA+ MM in the absence of CAFs, but mice succumbed to the disease within two weeks if CAFs were present. Dual-targeting CAR T cells, on the other hand, resulted in durable remissions in those mice with both MM and CAFs, indicating that targeting of CAFs indeed does enhance outcomes and may help to overcome MM resistance to CAR T therapy.
PEMBROLIZUMAB PLUS AZACITIDINE POTENTIAL OPTION FOR AML SUBSETS
Multi-Center Phase 2 Study of Pembroluzimab (Pembro) and Azacitidine (AZA) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Newly Diagnosed (≥65 Years) AML Patients
Since azacitidine up-regulates expression of immune evasion pathways in acute myeloid leukemia (AML), Ivana Gojo, MD (Johns Hopkins University, Baltimore MD) and colleagues explored the combination of azacitidine and pembrolizumab therapies. Two groups of patients were enrolled in this phase 2 study: cohort 1 included R/R AML patients after a minimum of 2 other cycles of therapy, while cohort 2 was made up of newly-diagnosed AML in older patients.
In cohort 1, 78% of the 37 enrolled patients were evaluation-eligible, and four patients achieved CR/CRi, with one other patient reaching a PR and four patients with hematologic improvement. After a median follow-up of 19.3 months, those patients experiencing a CR/CRi/PR had a median overall survival (mOS) of 19.1 months, while the entire cohort had a mOS of 11.2 months. The event-free survival in CR/CRi patients was also higher than those with other responses. Grade 3/4 adverse events occurred in 24% of patients in this group, and one patient died from multi-organ failure.
For patients in cohort 2, higher response rates were noted: 53% of evaluable patients achieved a CR/CRi. This led to an mOS for the entire cohort of 13.4 months, with the mOS of the CR/CRi/PR patients at 20.2 months after over 20 months median follow-up. Grade 3/4 AEs also occurred in 14% of patients in this group. Taken together, the results of this study indicate that azacitidine and pembrolizumab combination therapy is feasible and relatively safe in AML, particularly in the frontline setting for older patients.
MULTIPLE MYELOMA PATIENTS MAY BENEFIT FROM NOVEL BCMA CAR THERAPY
Updated Results from an Ongoing Phase 1 Clinical Study of bb21217 Anti-Bcma CAR T Cell Therapy
Jesus G. Berdeja, MD (Sarah Cannon Center for Blood Cancers, Nashville TN) presented results from an ongoing phase 1 study of bb21217, an anti-BCMA CAR T therapy, in patients with relapsed/refractory multiple myeloma (RRMM). The CAR construct, bb21217, uses the same lentivirus as the previously-reported bb2121 CAR T cell therapy, but is additionally supplemented with the PI3K inhibitor bb007 during culture to enrich for memory-like T cells, which may be more persistent and potent. This first-in-human study aims to determine the safety, pharmacokinetics, and efficacy of bb21217.
To date, 38 patients have received bb21217 at doses from 150-450x106 CAR+ T cells. Median followup of these patients was 6 months, at which point all patients have developed at least one treatment-emergent adverse event. All adverse events, but one grade 5 CRS, responded to appropriate care of their symptoms. Evaluable patients included 20/33 with a clinical response. Of the patients receiving the lowest dose of cells, 6/10 have progressed; however, no patient at the higher dose levels has experienced progression. CAR cells demonstrated persistence in vivo, evidenced through detection in blood samples in 8/10 patients at 6 months and 2/4 at 12 months. With longer follow-up, the encouraging results found in this study may lend support to another CAR therapy for RRMM patients.