The OBR Blog

By Lynne Lederman, PhD

As the 2018 American Society of Hematology (ASH) Annual Meeting continues, we focus on two studies that have the potential to be practice-changing for the treatment of older patients with AML and younger patients with favorable-prognosis diffuse large B-cell lymphoma (DLBCL), the development of a personalized risk stratification model for patients with myelodysplastic syndromes (MDS), and the finding that pre-hematopoietic cell transplant (HCT) microbiota injury is associated with poorer overall survival (OS).

Initial Report of the Beat AML Umbrella Study for Previously Untreated AML: Evidence of Feasibility and Early Success in Molecularly Driven Phase 1 and 2 Studies (559)

Results from the Beat AML umbrella study demonstrated that it was feasible to implement a rapid treatment assignment within 7 days or less for 95.8% of elderly patients with AML, reported Amy Burd, PhD, Leukemia and Lymphoma Society.

This precision medicine trial tested the hypothesis that outcomes for patients could be improved by matching them to the increasing number of available targeted therapies. The primary objectives were to determine (1) the feasibility of completing molecular, immunophenotypic, and/or biochemical studies in ≤7 calendar days, (2) the feasibility of assigning patients to sub-studies in the master protocol based on the test results, and (3) the clinical efficacy of novel treatment strategies in each of the sub-studies.

The trial enrolled patients age ≥60 years with previously untreated AML. Treatment was assigned based on the best curative option using molecular profiling results. Median age was 72 years, and 37.9% of patients were age ≥75 years.

So far 365 patients have been enrolled, of whom 285 were assigned treatment; 146 patients received the assigned treatment. Most of the patients who were not treated received other therapies, including standard of care, alternative treatment prior to assignment, or enrollment in an alternative trial after assignment; 7 died during the 7-day period, and 23 opted to enter palliative care.

The trial began with 3 sub-studies, which has since increased to 11 sub-studies, providing more options. Promising efficacy has been seen in several treatment arms, and early death and disease progression prior to treatment assignment is uncommon outside of MLL rearranged AML which progresses rapidly and requires early treatment initiation. Two sub-study updates are being presented at the meeting (abstracts 4053 and 287).

Excellent Outcome of Young Patients (18-60 years) with Favourable-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL) Treated with 4 Cycles CHOP Plus 6 Applications of Rituximab: Results of the 592 Patients of the Flyer Trial of the Dshnhl/GLA (781)

Results of the FLYER trial showed that reducing cycles of CHOP-like chemotherapy from the standard 6 cycles of rituximab (R)-CHOP to 4 cycles of CHOP plus 6 doses of R maintained efficacy and reduced toxicity for younger patients with good prognosis DLBCL.

Viola Poeschel, MD, Department of Hematology, Oncology and Rheumatology, Saarland University Medical School, Homburg/Saar, Germany, presented the results. FLYER enrolled previously untreated patients age 18 to 60 years with stage I/II aggressive B-cell lymphoma, with age-adjusted International Prognostic Index of zero and no bulky disease. Patients were randomly assigned to treatment with 6 cycles or R-CHOP or 4 cycles R-CHOP plus 2 additional cycles of R in 21-day cycles.

The primary endpoint was progression-free survival (PFS). The 36 month PFS was 94% (95% CI 91%-97%) for the 6 x R-CHOP-21 group (n=295), and 96% (95% CI 94%-99%) for the 4 x R-CHOP-21 + 2 x R group (n=293) at a median follow-up of 66 months.

Likewise, the 36-month overall survival (OS) was similar between the treatment groups: 98% (95% CI 96%-99%) in the standard therapy group and 99% (95% CI 98%-100%) in the reduced chemotherapy group at a median follow-up of 67 months.

Fewer hematologic adverse events (AE) were reported in the reduced chemotherapy group, as well as an overall reduction of non-hematologic AEs by approximately one third.

A Personalized Prediction Model to Risk Stratify Patients with Myelodysplastic Syndromes (793)

Current treatment guidelines for MDS are based on risk stratification for progression to AML, and although HCT is potentially curative in high-risk disease, associated toxicities make it inappropriate for low-risk disease. Aziz Nazha, MD, Cleveland Clinic, Cleveland, OH, described the development of a prediction model that uses a machine learning approach to provide a personalized, patient-specific estimate of risk.

Dr. Nazha’s group show that when looking at survival of patients with MDS by Revised International Prognostic Scoring System (IPSS-R) for MDS risk category, outcomes are heterogeneous.

The model was developed using clinical and mutational data from patients with MDS in a combined cohort from the Cleveland Clinic and Munich Leukemia Laboratory (training cohort, n=1471) and validated in a separate cohort (validation cohort, n=831) from the Moffitt Cancer Center. Forty gene mutations commonly occurring in myeloid malignancies were sequenced. Patients undergoing HCT were censored at the time of transplant. An algorithm was used to build the model that randomly selected clinical and molecular variables to determine survival. Variables were ranked from the most to the least important for OS.

A clinic-friendly web application tool has been built from the final model, allowing input of important risk factors to calculate predicted OS for individual patients. Dr. Nazha said that this new model has a better predictability index for OS and leukemia-free survival than the IPSS.

Multicenter Microbiota Analysis Indicates that Pre-HCT Microbiota Injury Is Prevalent across Geography and Predicts Poor Overall Survival (811)

The intestinal microbiota composition is associated with important outcomes after allogeneic (allo) HCT including OS, organ toxicity, relapse, graft-versus-host disease (GvHD), and infection. Most studies have looked at the microbiota after transplantation. Jonathan U. Peled, MD, PhD, Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, described this study looking at the intestinal microbiota composition in 1922 stool samples from patients both before and after allo-HCT in three geographic regions.

Dr. Peled said it was striking that no matter where in the world these patients lived, their intestinal microbiota composition and diversity were comparable at baseline. Higher diversity pre-HCT microbiota is associated with better OS than low diversity (HR 0.69; P=.002), as well as with peri-neutrophil engraftment. After transplant, a decrease in diversity and domination of single species are correlated with poorer outcomes.

Approaches that could manipulate microbiota-host interactions to prevent damage include antibiotics, prebiotics, probiotics, and postbiotics.

 

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/mon days 1 and 2 of each day cycle, plus rituximab 375 mg/mon day 0 of cycle 1 (BR), then 500 mg/mon 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/mweekly 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

November 26, 2018 - 01:11 pm comments0 Comments

At the 60th Annual Meeting of ASH, more than 25,000 attendees from all over the world will gather In San Diego, December 4-8 to hear the latest and greatest news in the field of hematology. Reporters got a sneak preview of what to expect at an official ASH pre-meeting webinar on November 20, 2018. Below are highlights from the webinar on hematologic cancers organized around key themes.

CAR-T Cell Therapies: New Research and Updates from Pivotal Trials

Key abstracts to watch for in the CAR-T space include two small feasibility studies and two larger trials showing durability of response to CAR-T cell therapies.

Abstract 299 describes a small phase 1/2 study designed to compare CD19-specific CAR-T cells alone or in combination with ibrutinib in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). Patients treated with fludarabine/cyclophosphamide lymphodepletion followed by CAR-T were compared with a cohort of patients treated the same way with the addition of ibrutinib given at least 2 weeks prior to leukapheresis until at least 3 months after CAR-T infusion.

“In this small study, ibrutinib was well tolerated and preliminary results suggest that ibrutinib can reduce the incidence of cytokine release syndrome and may actually improve outcomes,” said ASH Secretary, Robert A. Brodsky, MD.

A second small study (Abstract 556) looked at the addition of a checkpoint inhibitor to augment response to CD19-directed CAR-T in 14 children with relapsed B-cell acute lymphoblastic leukemia (ALL).

“The idea is that after patients relapse, pembrolizumab will take the brakes off the immune system and re-initiate an immune attack on the cancer. In this study, it appears that pembrolizumab is safe to combine with CAR-T, and this approach may turn out to be efficacious,” Dr. Brodsky commented.

Long-term follow-up of two large trials of CAR-T provides reassurance that CAR-T-achieved remissions can be deep and durable. Abstract 895 describes longer follow-up of the phase 2 ELIANA trial of 79 pediatric and young adults with relapsed/refractory ALL treated with CAR-T infusion. Response rate was 81% and two thirds of responders remain in remission at 18 months.

Abstract 1684 follows patients enrolled in the phase 2 JULIET trial that enrolled 167 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL)—115 patients underwent a single infusion of CAR-T. Many of these patients had received multiple therapies including transplant. At a median follow-up of 18 months, the probability of sustained remission and survival was 43%.

A fifth study (Abstract 967) showed that late recurrences were reduced and survival improved in patients who received bone marrow transplant (BMT) as consolidation after CAR-T cell-induced remission. The study compared outcomes in patients who did and didn’t undergo BMT after CAR-T. Almost all the patients had ALL.

Observing the 17 patients who did not get BMT prior to CAR-T, at remission 14 of them received BMT; and of those, two relapsed. For the other three patients who did not get BMT, two relapsed.

Of the 33 patients who had BMT before CAR-T and were offered a second transplant, 10 received the transplant and five remained in remission. Of the remaining 23 patients who did not undergo a second BMT, 15 remained in remission.

“This small retrospective study suggests that BMT can be used for consolidation of remission after CAR-T. The role of second BMT is less clear,” noted Dr. Brodsky.

Four Key Abstracts for the Treatment of Blood Diseases and Disorders

Abstract 781 shows that treatment can be de-escalated in younger (age 18-60 years), favorable-prognosis patients with DLBCL. Prior to this study, the standard of care was 6 cycles of rituximab-CHOP chemotherapy (R-CHOP).

The FLYER study was a large, international, randomized, phase 3 trial in 592 younger, favorable-prognosis DLBCL patients showed that 4 cycles of R-CHOP can achieve comparable outcomes as standard of care. These findings suggest that 2 cycles of CHOP can be avoided in these younger patients, potentially reducing toxicity.

“This study is almost certainly practice-changing,” said Dr. Brodsky.

Another practice-changing, randomized, phase 3 study (Abstract 6) compared ibrutinib alone and ibrutinib/rituximab (IR) versus bendamustine/rituximab (BR) in 547 older untreated CLL patients.

Ibrutinib is approved for untreated CLL, but this study was based on comparison with chlorambucil, an older drug. Until now, ibrutinib has not been compared with modern chemo-immunotherapy. Progression-free survival (PFS) was 41 months in the BR arm and not yet reached in both ibrutinib-containing arms.

“In this study, both ibrutinib alone and IR improved progression-free survival at 32 months versus BR,” noted Dr. Brodsky. “These results showing superiority to standard chemotherapy in older patients are likely to be practice-changing.”

Patients with low- to intermediate-risk myelodysplastic syndrome (MDS) have new hope, according to results of the Medalist trial—a phase 3 randomized, double-blind, placebo-controlled study.

In this study, 229 patients with low- to intermediate-risk MDS and anemia requiring transfusions who were refractory or intolerant to erythropoiesis-stimulating agents were randomized 2:1 to luspatercept versus placebo. Luspatercept—a first-in-class experimental red blood cell maturation agent—reduced the likelihood of the need for transfusion and was generally well tolerated.

“Luspatercept is moving through the pipeline, and this is potentially a practice-changing study [once the drug is approved],” commented Dr. Brodsky.

Abstract 793 discusses a new personalized prediction model for MDS that incorporates traditional criteria (age, hemoglobin, cell counts, cytogenetics, number of blasts in bone marrow, etc.) as well as genomics. Next generation sequencing (NGS) of 40 gene mutations commonly found  in MDS and other myeloid malignancies was performed. The training cohort for the new model included 1,471 patients and the validation cohort had 831 patients.

The new model outperformed both standard models (IPSS and IPSS-R) in predicting overall survival and transformation to acute myeloid leukemia (AML).

“This could be very exciting and can inform the design of clinical trials,” said Dr. Brodsky.

A multicenter analysis of 1922 stool samples from 991 patients on three different continents undergoing allogeneic BMT for a variety of underlying cancers showed that the pre-transplant microbiome can predict outcome (Abstract 811). A decrease in pre-BMT intestinal flora predicted for poorer survival following BMT.

“These findings will lead to studies exploring whether interventions that change the microbiome can improve outcomes from allogeneic BMT,” said Dr. Brodsky.

The Beat UMBRELLA trial of patients with previously untreated AML utilized rapid NGS to identify personalized treatments early in the course of disease (Abstract 559). “Most of those patients were over age 60 and tended to be poor risk,” said ASH President Alexis A. Thompson, MD.

This ongoing study now has 11 treatment arms using seven novel agents based on AML subtype according to genetic mutations. At ASH, data will be presented on 268 patients with a median age of 72 years.

“The study shows that it’s feasible to use precision medicine approaches in older AML patients using treatment tailored to mutations. This will impact how we design our clinical trials. We need to see if this approach impacts outcomes,” said Dr. Thompson.

By John McCleery, Content Director, OBR

September 12, 2018 - 11:09 pm comments0 Comments

By Christina Bennett, MS

Tennessee Oncology, New York Cancer & Blood Specialists, and West Cancer Center have joined forces to form a new company, OneOncology. Backed by more than $200 million from investor General Atlantic, OneOncology officially launched on Tuesday, September 12, and will bring together more than 225 community oncologists from more than 60 national sites of care. The joint venture comes at a time when community oncologists are facing more challenges than ever to keep practice doors open and stay competitive in the current healthcare environment.

“The pace of innovation in drug therapy, in medical technology, and in practice approaches is very challenging for even the largest centers to keep up with,” said Tracy Bahl, President and Chief Executive Officer at OneOncology. Among the myriad of challenges are keeping up with the pace of regulation and the ability to access capital to advance and expand the continuum of cancer care.

The need to confront those challenges was, in part, a driver of the creation of OneOncology.

“Approximately 30 percent of community oncology practices in the country have gone out of business in the last five years due to the pressures faced,” said Jeffrey Patton, MD, President and CEO of Tennessee Oncology. Dr. Patton is also president of physician services at OneOncology. “We need a solution to help keep the choice and the option for community oncology to be viable in the market place,” he said.

Lee Schwartzberg, MD, a member of the OneOncology board of directors and executive director of West Cancer Center, said that the transition to value-based care requires a new infrastructure that even experienced practices need. “In order to make this change to value-based care, we need to partner, and we believe that OneOncology is a perfect vehicle to enhance this transformation,” he said.

Dr. Patton echoed a similar view, “Even at a practice with the size and scale of Tennessee Oncology, we’re convinced that to compete and survive in the value-based world, we need larger scale, more expertise, and better technologies to survive long-term as we move toward value-based care.”

Peter Ellis, MD, Deputy Director of Clinical Services and Associate Chief Medical Officer at UPMC Hillman Cancer Center, told OBR he is not surprised by the formation of OneOncology. In fact, he likened it to the formation of American Oncology Resources, Inc., (now U.S. Oncology) back in the 1990s.

It makes sense, Dr. Ellis said, given that oncology reimbursement continues to be challenging and Medicare and other payers are being aggressive in their reductions in reimbursement. “In order to stay efficient and be able to continue to provide the best quality care for patients, size and economics matter.” He added, “If [the three practices] didn’t bind together, they’d be vulnerable to the whims of reimbursement.”

Representatives from OneOncology assert that the company size will leverage greater purchasing power and help reduce costs. Access to capital will help practices expand to meet the needs of their communities. The rural cancer care setting is one example of how OneOncology may improve the delivery of care. In rural settings, meaningful services are not necessarily provided in the community, resulting in patients travelling long distances for radiation or chemotherapy, which is not only an inconvenience but also impacts adherence, and in turn, survival rates.

Bahl explained that before, a practice might have had to dip into its own pockets or find some other source of capital, and now with OneOncology, “we can identify and address that need, with the capital that OneOncology has available.”

OneOncology will also offer expertise for providers. “We’ll build a broader team with each one of our [founding] partners,” said Robin Shah, Chief Development and Marketing Officer at OneOncology. Providers will also have access to experts in technology, finance, operations, managed care, and all the other services that surround the ability to operate an oncology practice.

Dr. Patton explained that the advantage of having a network of practices across the country is access to best practices, and by having a common IT platform (provided by Flatiron), providers will be able to share and implement those best practices.

In the long-term, the vision of OneOncology is to “partner progressively” with other leading community oncology practices across the country.

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