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COMMANDS: luspatercept versus epoetin alfa in ESA-naive low-risk MDS-associated anemia
Chronic anemia and transfusion dependency are significant clinical challenges in lower-risk myelodysplastic syndromes (LR-MDS). At EHA 2023, Matteo Della Porta, MD, Humanitas Research Hospital, Milan, Italy, presented the interim analysis of the Phase III COMMANDS study (NCT03682536) comparing luspatercept with epoetin alfa in the treatment of anemia in patients with erythropoietin stimulating agent (ESA)-naive, transfusion dependent, LR-MDS.
The study’s primary endpoint was the achievement of red blood cell transfusion independence (RBC-TI) for ≥ 12 weeks with concurrent mean hemoglobin increase ≥ 1.5 g/dL. The study reported that luspatercept was ~2x likely to result in RBC-TI with hemoglobin increase: 86 (58.5%) of 147 patients in the luspatercept group compared with 48 (31.2%) of 154 patients in the epoetin alfa group.
Luspatercept provided durable and longer duration of RBC-TI regardless of ring sideroblast (RS) status, serum erythropoietin (EPO) level and severity of transfusion dependence. The median duration of RBC-TI was 126.6 weeks compared to 77.0 weeks for epoetin alfa. Baseline mutational frequency was not significantly different between the luspatercept and epoetin alfa treatment arms. Individuals with SF3B1, SF3B1a, ASXL1, and TET2 MDS-associated gene mutations experienced better responses with luspatercept, irrespective of their overall mutational burdens.
The safety profile for luspatercept was consistent with previous clinical reports and no new safety events were reported. Most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept were fatigue (14.6%), diarrhea (14.6%), and hypertension (12.9%), and were asthenia (14.2%), diarrhea (11.4%), and anemia (9.7%) with epoetin alfa.
The study demonstrates the superiority of luspatercept, and the findings could result in a paradigm shift in the treatment of anemia for ESA-naive, transfusion-dependent LR-MDS.1
Preclinical outcomes of ADGRE2 + CLEC12A-targeting ADCLEC.syn1 CAR construct for R/R AML
Relapsed and refractory (R/R) acute myeloid leukemia (AML) represents a large clinical unmet need. Whilst CAR-T therapy has changed the treatment paradigm of hematological malignancies like multiple myeloma and non-Hodgkin lymphoma (NHL), they have been largely unsuccessful in AML. In this press brief, Sascha Haubner, MD, Memorial Sloan Kettering Cancer Center, New York City, NY, discussed the preclinical findings for ADCLEC.syn1, a novel combinatorial CAR concept targeting ADGRE2 and CLEC12A, for the treatment of AML.
ADGRE2 and CLEC12A were identified as promising targets by quantitative target profiling, specifically analyzing antigen distribution and density in bone marrow samples of R/R AML patients vs normal donors. High expression of ADGRE2 and CD33 was observed in leukemic stem cells whereas in normal hematopoietic cells, ADGRE2 expression was found to be substantially less abundant than CD33.
ADCLEC.syn1 comprises of an ADGRE2-targeting-28z1XX-CAR and a CLEC12A-targeting chimeric costimulatory receptor (CCR). This CAR+CCR configuration triggers killing of leukemic cells with high CAR target density alone, whereas cells with low ADGRE2 expression are only killed if the CCR target is co-expressed.
The study shows ADCLEC.syn1 induced durable remission in patient-derived xenograft (PDX) models representing phenotypes found in patients with R/R AML. Whilst a control CD33-CAR was also effective in treating mice engrafted with AML cell lines, AML-engrafted mice that had been reconstituted with normal human hematopoietic cells responded only to ADCLEC.syn1. ADCLEC.syn1 was also shown to be effective in CD33-CAR-relapsed PDX models for AML, and CCR costimulation enhanced sensitivity by minimizing antigen-low escape. Efficacy was maintained in humanized setting with normal myeloid cells, without depleting normal hematopoietic stem and progenitor cells (HSPCs).
Overall, the findings of the study show that quantitative CAR target profiling can help guide the creation of new CAR constructs, and demonstrate the preclinical efficacy of ADCLEC.syn1 in vivo, which will be investigated for R/R AML in a first-in-human Phase I clinical trial (NCT05748197).2
Long-term survival of patients with APL treated with ATRA-ATO
The introduction of targeted agents like all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) or ATRA combined with chemotherapy has transformed the treatment of acute promyelocytic leukemia (APL), and this malignancy is now curable in 75-90% of patients.
In this press brief, Maria Teresa Voso, MD, of the Tor Vergata University, Rome, Italy, presented the long-term survival findings from a study using the HARMONY registry comprising a large international cohort of patients with APL enrolled in clinical trials or treated in real-life clinical practice. Data from 937 patients were collected from the AML 17 (ISRCTN55675535) and APL0406 (NCT00482833) trials, as well as from national registries. In this cohort, 40.6% (n=380) received ATRA/ATO whilst 54.3% (n=509) were treated with an ATRA and idarubicin (IDA) regimen.
The study showed that the combination therapy of ATRA-ATO resulted in a 10-year overall survival (OS) rate of 92%, compared to 75% for patients treated with ATRA-IDA. The Sanz risk score was used to classify patients into low, intermediate, and high-risk groups. While a high-risk score significantly impacted the rate of early deaths (<30 days from diagnosis), the survival advantage of ATRA-ATO remained consistent across all risk groups, with similar rates of early deaths compared to the ATRA-IDA group. Age also played a role in survival, as both a high Sanz risk score and elderly age correlated with OS and event-free survival (EFS).
These results confirm the significant survival advantage provided by the ATRA-ATO treatment regimen for APL. The chemotherapy-free combination demonstrates overall improvement in patient outcomes which include OS, EFS, and cumulative incidence of relapse (CIR). This study showcases the substantial progress made in the treatment of APL which was once considered one of the most fatal forms of AML.3
CLL14 6-year follow-up results: venetoclax-obinutuzumab in previously untreated CLL
In this press brief, Othman Al-Sawaf, MD, University Hospital of Cologne, Cologne, Germany, revealed the long-term findings of the CLL14 trial (NCT02242942) for fixed-duration venetoclax in combination with obinutuzumab (Ven-Obi) compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated chronic lymphocytic leukemia (CLL), who completed 12 months of treatment are now off treatment for over five years.
The primary endpoint, progression-free survival (PFS), shows that Ven-Obi is superior to Clb-Obi. Indeed, after a median follow-up of 76.4 months, Ven-Obi demonstrated a median PFS of 76.2 months, while Clb-Obi had a median PFS of 36.4 months (HR 0.40, 95% CI 0.31-0.52, p<0.0001). At six years, the estimated PFS rate for Ven-obi was 53.1% versus 21.7% for Clb-Obi.
Ven-Obi also led to a significantly longer time to next treatment (TTNT) compared to Clb-Obi with a six-year TTNT of 65.2% versus 37.1% (HR 0.44, 95% CI 0.33-0.58, p<0.0001), observed across all risk groups. Although Ven-Obi treatment indicated a possible benefit to overall survival (OS), the difference compared to Clb-Obi was not significant (Ven-Obi: 78.7%, Clb-Obi: 69.2%; HR 0.69, 95% CI 0.48-1.01, p=0.052). Ven-Obi also showed better measurable residual disease (MRD) response, with 7.9% of patients maintaining undetectable MRD five years post-treatment compared to 1.9% for Clb-Obi.
These follow-up results provide compelling evidence of the long-term benefits of fixed-duration Ven-Obi treatment, particularly in high-risk CLL. These benefits include sustained remission, a high rate of undetectable MRD, and prolonged TTNT. After five years, over 50% of patients remain in remission following Ven-Obi treatment, with 60% of patients not requiring second-line treatment, thereby demonstrating the efficacy of this fixed-duration treatment approach.4
CLIMB THAL-111 & CLIMB SCD-121 interim findings for one-time exa-cel treatment in TDT & SCD
In this press brief, Franco Locatelli, MD, IRCCS Bambino Gesu Children’s Hospital, Rome, Italy, presented the interim analysis results of the Phase III CLIMB-THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) trials, which evaluated the efficacy of exagamglogene autotemcel (exa-cel), a non-viral cell therapy utilizing ex-vivo CRISPR/Cas9 gene-editing. The therapy aims to reactivate fetal hemoglobin synthesis by targeting the BCL11A gene in autologous CD34+ hematopoietic stem and progenitor cells for patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD).
Both studies achieved their primary and secondary endpoints. In CLIMB THAL-111, 88.9% (CI 70.8-97.5, p < 0.0001; 24 out of 27) of patients maintained a hemoglobin (Hb) level of ≥9 g/dL without RBC transfusion for ≥12 consecutive months. CLIMB SCD-121 demonstrated that 94.1% (CI 71.3-99.9, p < 0.0001; 16 out of 17) of patients did not experience severe vaso-occlusive crises (VOCs) for at least 12 consecutive months following exa-cel infusion, with none requiring inpatient hospitalization for severe VOCs during this period.
Both studies reported sustained total hemoglobin and fetal hemoglobin levels, edited BCL11A alleles in CD34+ bone marrow and stable peripheral blood nucleated cells counts. The safety profile of exa-cel aligned with busulfan myeloablative conditioning and autologous hematopoietic stem cell transplantation (autoHSCT). Importantly, patients showed significant improvements in quality of life (QoL) measurements, as well as successful neutrophil and platelet engraftment.
These findings highlight the promising potential of exa-cel as an innovative gene editing therapy offering a one-time cure for patients with TDT and SCD.5
MORPHO: gilteritinib as post-transplant maintenance for patients with FLT3-ITD AML
In this press brief, Mark Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, shared the findings of the Phase III BMT-CTN 1506 trial (MORPHO; NCT02997202) evaluating gilteritinib maintenance therapy versus placebo after allogeneic stem cell transplantation (alloSCT) in patients with AML carrying an internal tandem duplication mutation of FLT3 (FLT3-ITD).
Whilst results show gilteritinib maintenance therapy led to a higher two-year relapse-free survival (RFS) (77.2% vs. 69.9% with placebo), the difference was not statistically significant. In addition, OS rates were similar in both groups. However, a potential benefit of gilteritinib was observed in the subgroup of patients (~50%) with detectable MRD, and the trial reported that gilteritinib improved MRD eradication in patients with detectable MRD pre- or post-alloSCT compared to placebo.
The MORPHO trial sheds light on the advantages of gilteritinib as a post-transplant maintenance therapy for FLT3-ITD AML, indicating a correlation between MRD, RFS, and OS. MRD could be used as a guide to determine which patients should be treated with gilteritinib post-alloSCT. While the impact of gilteritinib was less prominent for patients who were MRD-negative, it is suggested it should be a standard of care treatment in patients who are MRD-positive, both pre- and post-alloSCT.6
REVIVE: rusfertide for uncontrolled erythrocytosis in polycythemia vera
Patients with polycythemia vera (PV) often face the challenge of elevated hematocrit levels (>45%), which increases their risk of thrombotic and cardiovascular events. Current therapies, including therapeutic phlebotomy (TP) and cytoreductive agents, often fail to effectively reduce hematocrit levels to <45%.
In this press brief, Ronald Hoffman, MD, Icahn School of Medicine at Mount Sinai, New York City, NY, presented the withdrawal results of the randomized Phase II REVIVE study (NCT04057040) investigating the effectiveness of rusfertide, a novel hepcidin mimetic, in patients with PV with a high phlebotomy burden.
The 12-week randomized withdrawal phase of the study met its primary endpoints: proportion of responders, absence of PT eligibility, and hematocrit control. Notably, the study revealed a statistically significant response rate (RR) of 69.2% (18 out of 26) in the rusfertide group compared to 18.5% (5 out of 27) in the placebo group. Rusfertide treatment led to sustained hematocrit control, with 92.3% (24 out of 26) of patients in the rusfertide arm avoiding TP throughout the 12-week randomization part of the study. Patients also experienced improvements in PV symptoms, such as fatigue, problems with concentration, pruritus, and inactivity. Importantly, rusfertide demonstrated satisfactory tolerability, with most adverse events being mild to moderate injection site reactions.
The findings of the REVIVE trial highlight the potential of rusfertide, a first-in-class hepcidin mimetic, to achieve sustained and durable control of hematocrit levels and to improve PV-related symptoms. An ongoing investigation in the Phase III VERIFY trial (NCT05210790) aims to further evaluate the effectiveness of rusfertide.7
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References
- Della Porta MG, Platzbecker U, Santini V, et al. S102 Luspatercept versus epoetin alfa for treatment (tx) of anemia in ESA-naive lower-risk myelodysplastic syndromes (LR-MDS) patients (pts) requiring RBC transfusions: data from the Phase 3 COMMANDS study. Hemasphere. June 2023; 7:(S3):8-10.
- Haubner S, Mansilla-Soto J, Nataraj S, et al. S104 Differential target profiles and efficacy of ADCLEC.syn1 and CD33-CARs in humanized AML models. Hemasphere. June 2023; 7:(S3):14-15.
- Guamera L, Lehmann S, Döhner K, et al. S136 Analysis of factors associated with long-term survival in a large acute promyelocytic leukemia (APL) patient cohort: a HARMONY Alliance study. Hemasphere. June 2023; 7:(S3):82-83.
- Al-Sawaf O, Robrecht S, Zhang C, et al. S145 Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized CLL14 study. Hemasphere. June 2023; 7:(S3):103-105.
- Locatelli F, Lang P, Corbacioglou S, et al. S270 Transfusion independence after exagamglogene autotemcel in patients with transfusion-dependent beta-thalassemia. Hemasphere. June 2023; 7:(S3):376-378.
- Levis MJ, Hamadani M, Logan B, et al. LB2711 BMT-CTN 1506 (MORPHO): a randomized trial of the FLT3 inhibitor gilteritinib as posttransplant maintenance for FLT3-ITD AML. Hemasphere. June 2023; 7:(S3).
- Kremyanskaya M, Kuykendall A, Pemmaraju N, et al. LB2710 Targeted therapy of uncontrolled erythrocytosis in polycythemia vera with the hepcidin mimetic, rusfertide: – blinded randomized withdrawal results of the REVIVE study. Hemasphere. June 2023; 7:(S3).
Edited by Elitsa Kamberska
