December 03, 2018 - 03:12 am Posted in ASH Conference Coverage Posted in Leukemia (includes ALL, AML, APL, CLL, CML, MDS, Myeloproliferative Disorders, Myelofibrosis) Posted in Personalized Oncology (includes Cancer Genetics) 0 Comments
Six presentations were given today at the plenary session at the 2018 American Society of Hematology (ASH) Annual Meeting. We take a look at three presentations related to malignant hematology.
The Medalist Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions (1)
Alan F. List, MD, Moffitt Cancer Center, Tampa, Florida, said that the rationale for the MEDALIST trial (NCT02631070) was based on the lack of treatment options for patients with low risk MDS. There has not been a new treatment for this condition in 12 years.
Patients with transfusion-dependent, non-deletion (5q) MDS have a transitory response to erythropoiesis-stimulating agents (ESA), and are at risk for iron overload, secondary organ complications, at greater risk of progression to AML, and have an inferior overall survival (OS) compared with patients who are transfusion-independent.
This randomized, double-blind, placebo-controlled, phase 3 trial compared treatment with luspatercept, an investigational, first-in-class erythroid maturation agent that neutralizes select TGF-beta superfamily ligands to inhibit aberrant Smad2/3 signaling and enhances late-stage erythropoiesis in MDS models. In a phase 2 study, it was associated with transfusion reduction or red blood cell transfusion independent (RBC-TI) in MDS patients with ring sidseroblasts (MDS-RS). These cells have large iron deposits in peri-nuclear mitochondria.
In the phase 3 trial, 153 patients were randomized to luspatercept and 76 received placebo. The luspatercept arm resulted in a significantly higher percentage of patients who became transfusion-independent, had a major transfusion reduction, or increase in hemoglobin compared with the placebo arm. At 8 weeks, 37.9% of patients were RBC-TI in the luspatercept arm (95% CI 30.1-46.1) versus 13.2% in the placebo arm(95% CI 6.5-22.9; P<.0001).
Responses to luspatercept were durable, with about 40% of patients having a sustained RBC-TI at 12 months. Luspatercept was generally well tolerated. Dr. List concluded that this agent is a potential new therapy for patients in the study population.
Multiplex CRISPR/Cas9-Based Genome Editing of Mouse Hematopoietic Stem Cells Recapitulates Acute Erythroid Leukemia and Identifies Therapeutic Targets (5)
Ilaria Iacobucci, PhD, Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, described successful efforts to generate genetically-defined models of acute erythroid leukemia (AEL), a rare form of AML (<5% of adult cases) that is high-risk and poorly understood.
CRISPER/Cas 9 genome editing was used to induce combinations of loss-of-function of mutations in nine recurrently mutated genes in AEL. Pools were generated of six lentivirus vectors with different combinations of single guide RNAs (sgRNA) to induce multiplex genome editing in Cas9-eGFP mouse lineage-negative hematopoietic stem cells, which were transplanted into lethally irradiated congenic mice.
TP53 and Bcor mutations were identified as main players in driving the erythroid phenotype. TP53 mutated AEL cells are chemo-resistant to a wide variety of compounds, and sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors.
Ibrutinib Alone or in Combination with Rituximab Produces Superior Progression Free Survival (PFS) Compared with Bendamustine Plus Rituximab in Untreated Older Patients with Chronic Lymphocytic Leukemia (CLL): Results of Alliance North American Intergroup Study (6)
Jennifer A. Woyach, MD, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, presented results from the Alliance North American Intergroup Study, A041202 (NCT01886872). This randomized phase 3 trial showed that ibrutinib with or without rituximab in older patients with untreated CLL resulted in superior PFS compared with bendamustine plus rituximab. The study was published on-line in the New England Journal of Medicine.
The study was undertaken to determine the most effective therapy for older patients who represent the majority of patients with CLL, but are underrepresented in clinical trials. The efficacy of ibrutinib versus standard chemotherapy has not been investigated, and whether rituximab improves outcomes with ibrutinib has not been established.
Patients with untreated CLL at least age 65 years were stratified by risk factors, then randomly assigned 1:1:1 to either bendamustine 90 mg/m2 on days 1 and 2 of each day cycle, plus rituximab 375 mg/m2 on day 0 of cycle 1 (BR), then 500 mg/m2 on day 1 of cycles 2 to 6 (n=183); or to ibrutinib 420 mg daily until disease progression (I) (n=182); or to the same dose of ibrutinib plus rituximab 375 mg/m2 weekly for 4 weeks starting cycle 2 day 1, then day 1 of cycles 3 to 6 (IR) (n=182).
For the primary endpoint, PFS, there was no significant difference between the I and IR groups (HR 1.00; 95% CI 0.62-1.62; P=.49). The 24-month estimated PFS was 74% (95% CI 66-80) in the BR group; 87% (95% CI 81-92) in the I group; and 88% (95% CI 81-92%) in the IR group. When I or IR were compared with BR, PFS was significantly higher (P<.001).
For patients with del(17p13.1), a high-risk subgroup, the 24-month estimated PFS was zero, that is, all patients had died by this time point, whereas for both I and IR, PFS was not reached (75% and 73%, respectively). I and IR were also superior to BR for patients with other cytogenetic risk factors, and for those both with and without complex karyotypes. For patients with lower risk disease (Zap-70 methylated or IgVH mutated), there was not much difference in PFS between treatments, although there were low numbers of patients in these groups.
There were more complete responses in the BR group (26%) versus I (7%) and IR (12%), but the overall response rates were higher with ibrutinib (81% for BR; 93% for I; and 94% for IR). It is not known if responses will deepen in time. There is no difference in survival at 3 years of follow-up.
Investigators looked at grade 3, 4, and 5 adverse events (AEs) known to occur with the treatments, as these are well characterized. Bendamustine causes significantly more hematologic AE and febrile neutropenia, whereas I and IR are associated with more atrial fibrillation and hypertension.
By Lynne Lederman, PhD