About 25,000 attendees from all over the world are expected to attend the 59th Annual Meeting of the American Society of Hematology (ASH). Attendees can choose from a cornucopia of 4500 presentations (1000 oral presentations and 3500 poster presentations) to update them on the latest in management of hematologic cancers and other hematologic diseases.
“ASH 2017 is the largest hematology meeting on the planet,” said Joseph R. Mikhael, MD, chair of the ASH committee on communications, Mayo Clinic in Phoenix, AZ. Speaking at a pre-meeting ASH webinar, Dr. Mikhael outlined key themes of the meeting related to hematologic cancers:
CAR-T Cell Therapies
ASH President Kenneth C. Anderson, MD, Dana-Farber Cancer Institute, Boston, MA, singled out three new CAR-T cell studies (Abstracts 578, 577, and 740). Re-engineered CAR-T cells are a fertile area of investigation in both hematologic and solid tumors.
These T cells collected from a patient, re-engineered ex vivo to express an antigen, expanded, and then re-infused into the patient act as “an autologous army against the patient’s leukemia, lymphoma, and myeloma,” he noted.
Two CD19 CAR-T products have been FDA approved: Kymriah™ (Novartis) for pediatric B-cell acute lymphoblastic leukemia (B-ALL) and Yescarta™ (Kite Pharma) for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Abstracts 578 and 577 build on the excitement about CAR-T in treating lymphomas. Abstract 578 is a follow-up of the pivotal long-term ZUMA-1 trial of Yescarta in refractory aggressive non-Hodgkin lymphoma (NHL). In these patients who had exhausted all other treatment options, overall response rate (ORR) was 82% and complete response (CR) rate was 54%.
“At 8 months of follow-up, 44% of patients continued to have ongoing responses. [CRS] and neurologic events occurred,” said Dr. Anderson.
At the meeting, one-year follow-up on responses and toxicity will be presented. ZUMA-1 provides clues about causes of resistance to CD19 CAR-T: loss of CD19 and gain of PD-L1 expression in tumors are identified as potential resistance mechanisms.
Abstract 577 presents the primary analysis of the global multicenter phase 3 JULIET trial in adults with relapsed/refractory DLBCL treated with Kymriah. Among 81 patients with more than 3 months of follow-up, ORR was 53% and CR was 39%. Among 46 patients evaluable at 6 months, CR was 30% and partial response (PR) rate was 7%. Overall, 86% had Grade 3 or 4 adverse events, and CRS occurred in 58%.
“Both studies show that CRS can be severe with CAR-T, but these promising data show that CAR-T can be used in the real world at centers of excellence in a multicenter trial,” said Dr. Anderson.
Abstract 740 describes early experience with a second-generation CAR construct targeting a different antigen, B-cell maturation antigen (BCMA), to redirect T cells to myeloma cells along with a co-stimulatory molecule bb2121 referred to as bb2121 anti-BCMA CAR-T cell therapy.
In a dose-escalation, Phase 1 trial of 21 patients, ORR was 89%. Response rate was dose-dependent; patients treated at a dose of 15 x 107 had 100% CR with manageable toxicity, and these responses were ongoing. At the meeting, data on additional 5 months of follow-up will be presented.
“This study demonstrates that this new treatment has good tolerability, and it can achieve impressive responses in patients with multiple myeloma who have no other treatment options. This novel CAR-T has promising safety and activity and reduced toxicity,” commented Dr. Anderson.
Dr. Anderson also reviewed results of four abstracts showing impressive results with targeted therapy (Abstracts 817, 2, 428, and 6).
Standard treatment of cutaneous T-cell lymphoma is with vorinostat, but results are disappointing. Abstract 817 describes results of the phase III MAVORIC trial of a new strategy using an anti CCR-4 monoclonal antibody, mogamulizumab. In 372 patients with adult T-cell lymphoma that failed on previous treatment, mogamulizumab more than doubled progression free survival (PFS). PFS was 3 months with vorinostat versus 8 months with mogamulizumab. This very promising therapy also improved ORR and quality of life (QOL).
“These results extend a targeted therapy to T-cell lymphoma,” Dr. Anderson told listeners.
Abstract 2 described preliminary results of a first-in-man phase 1 trial of Blu-285, a highly selective inhibitor of KIT D816V, in advanced systemic mastocytosis.
In this new study, the vast majority of patients responded to Blu-285: 28 out of 30. The dose of 300 mg will be moved forward in testing.
“This is reminiscent of the Gleevec story in chronic myeloid leukemia 20 years ago. Gleevec targeted the BCL abnormality, and Blu-285 targets the KITD816V mutation that causes proliferation of malignant mast cells that cause organ dysfunction and toxicity,” said Dr. Anderson.
The combination of ibrutinib plus venetoclax achieved high rates of overall response, CR, and minimal residual disease in 50 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) according to results of the CLARITY trial (Abstract 428). Many of these patients had negative prognostic features, such as 17 p del. All 25 patients treated for 6 months responded, and 15/25 (60%) achieved CR.
At 6 months, 84% had no morphological evidence of CLL in the marrow, 76% had less than 1% of CLL cells in the marrow, and 28% have achieved an MRD-negative remission.
“This study is ongoing, and this combination is something to watch at ASH,” said Dr. Anderson.
In the large Phase 3 ECHELON-1 study (Abstract 6), the combination of brentuximab plus doxorubicin, vinblastine, and dacarbazine (A + AVD) improved outcomes for patients with previously untreated stage III or IV Hodgkin lymphoma (HL) compared with standard doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD). The A + AVD regimen includes the CD30-directed antibody brentuximab instead of bleomycin used in ABVD.
ECHELON randomized 1134 patients to receive either A+AVD versus ABVD. Two-year event-free survival (EFS) was 82% with the brentuximab-containing regimen versus 77% with standard ABVD. Incorporating brentuximab led to a 23% reduction in risk of progression or death or the need for additional anti-cancer therapy compared with standard therapy.
“The idea is to avoid the pulmonary toxicity from bleomycin by incorporating brentuximab in the experimental arm,” Dr. Anderson told listeners.
Pulmonary toxicity was more frequent and severe with standard ABVD than the experimental arm. Eleven of the 13 on-study deaths in the ABVD arm were associated with pulmonary toxicity, while 7 of the 9 on-study deaths in the experimental arm were associated with neutropenia.
“Brentuximab plus AVD is a new frontline option for patients with advanced HL. The experimental arm may be more cost effective as well,” noted Dr. Anderson.
Venous thromboembolism (VTE) is an important and increasingly frequent challenge in cancer patients. At present, all treatments for VTE are given subcutaneously. Although several new oral anticoagulants are available, there has been concern about safety of these in cancer patients and few studies have been conducted to compare available treatment options.
Two abstracts to be presented at the meeting (625 and LBA-6) show that oral anticoagulants are safe and appropriate in patients with cancer.
The SELECT-D pilot trial directly compared the oral Factor Xa inhibitor rivoroxaban versus the low-molecular weight heparin (LMWH) dalteparin in 406 cancer patients with VTE (Abstract 625).
At 6 months, the rate of recurrent VTE was 11% with dalteparin versus 4% with rivoroxaban. The rate of major bleeding was about the same with both agents, and there was no difference in survival. There were more clinically relevant non-major bleeds in the rivoroxaban arm. A larger phase 3 trial is planned to confirm the use of rivoroxaban in cancer patients.
A separate multi-national, randomized, open-label trial evaluated the efficacy and safety of the factor Xa inhibitor edoxaban versus the LMWH dalteparin in 1050 patients with acute or symptomatic VTE (LBA-6).
The study, designed as a non-inferiority trial, met its primary endpoint. The risk of recurrent VTE or major bleeding over the first 12 months was 12.8% for edoxaban versus 13.5% for dalteparin. The incidence of major bleeding events was similar in each group, and there was no difference in survival at 12 months free of recurrent VTE and major bleeding.
“This is big news. This is a better way to administer anticoagulation. The long and short of it is that these studies confirm that the newer oral anticoagulants are at least as good as the older drugs. This is important for cancer doctors and hematologists,” said ASH Secretary Robert Brodsky, MD, Johns Hopkins Medicine, Baltimore, MD.
by John McCleery
Director of Content Development, OBR
By Lynne Lederman, PhD
At this past December’s American Society of Hematology (ASH) annual meeting, the late-breaking abstract (LBA) session was devoted to presentations selected by the Program Committee for featuring substantive, novel, and groundbreaking data that were not available by the general abstract submission deadline and would not otherwise have been presented at the meeting.
The presentation on phase 2 results of the ZUMA-1 trial of the chimeric antigen receptor (CAR) therapy KTE-C19 (axicabtagene ciloleucel) in patients with chemotherapy-refractory diffuse large B-cell lymphoma1 has attracted a lot of attention.2
Here we report on 4 other presentations in the LBA session that are also likely to affect the outcome of patients with cancer in the future.
Adding Consolidation or Second Transplant to Single Transplant and Maintenance Does Not Improve Outcomes in Multiple Myeloma
Edward A. Stadtmauer, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, presented primary results from the randomized, prospective phase 3 trials of the Bone and Marrow Transplant Clinical Trials Network (BMT CTN) 0702 STaMINA trial (NCT01109004).3
This trial investigated whether the addition of a second autologous hematopoietic stem cell transplant (AHCT) or consolidation therapy combining a proteasome inhibitor (PI) with an immunomodulatory agent (IMiD) to upfront treatment of multiple myeloma (MM) with AHCT plus lenalidomide maintenance would provide additional benefit.
The study enrolled transplant-eligible patients with symptomatic MM who were age £70 years within 2 to 12 months of initiating ³2 cycles of systemic therapy, without prior disease progression, who had sufficient autologous stem cells available. Patients (N=758) were randomly assigned to receive:
All patients also received maintenance therapy with lenalidomide, initially at 10 mg/day for 3 cycles, then 5 to 15 mg/day for 3 years as tolerated. In 2014 an amendment to the protocol allowed maintenance therapy to continue for an indefinite duration until disease progression.
The primary objective was to compare 38-month progression-free survival (PFS) of patients in the three arms. The events for PFS included progression, non-protocol anti-myeloma therapy, or death. The 38-month period allowed 2 months to obtain the first transplant plus 3 years of follow-up.
Secondary endpoints in all 3 arms included overall survival (OS); response rates; rate of conversion to complete response (CR) for patients who did not have CR; toxicity, including infections, after each intervention and long-term toxicity; rate of non-compliance with protocol therapy; treatment-related mortality; and quality of life (QoL).
Enrollment was completed ahead of the projected time. Patients were stratified by risk, with high-risk MM defined by high beta-2 microglobulin and high risk cytogenetic abnormalities. Demographics were balanced across the groups. Over 90% of patients had either a proteasome inhibitor (PI) or immunomodulatory drug (IMiD) as initial therapy, and over 50% had both. The median follow-up time for myeloma status was 37.8 months.
The second AHCT was not administered to 32.0% in the tandem AHCT arm; 11.8% of patients in the AHCT/consolidation arm did not receive consolidation. Maintenance therapy was not started in 16.6% and 16.9% of patients in these arms, respectively, whereas only 5.4% of patients in the single AHCT arm did not receive maintenance.
There was no difference in the primary endpoint, PFS, among arms, with a 38-month estimate of PFS of 56.5 months in the tandem transplant arm, 56.7 months in the transplant/consolidation arm, and 52.2 months in the single transplant arm. Likewise, there was no significant difference in OS among the groups (82.0, 85.7, and 83.4 months, respectively), or in PFS or OS for patients with either standard-risk or high-risk MM.
Treatment-related mortality was low: 4 deaths in the tandem group, 3 in the consolidation group, and 1 in the single transplant group. Secondary primary malignancies were reported in all arms (5.1% in the total population; 14, 15, and 10, incidents respectively),
This trial is the largest randomized comparison of post-transplant approaches for MM in the United States. It shows that after initial therapy with PIs and IMiDs, an initial AHCT, and prolonged lenalidomide maintenance therapy, the addition of consolidation therapy with bortezomib, lenalidomide, and dexamethasone after transplant or use of a second transplant do not produce incremental PFS benefits.
These results also show that induction triplet therapy containing a PI and IMiD followed by a single transplant is sufficient, and may spare patients the additional burden of a second transplant or consolidation.
Companion protocols to this trial include BMT CTN 07LT, which continues long-term follow-up and maintenance therapy to patients in the original trials who completed 3 years of maintenance therapy without disease progression. An analysis including PFS, OS, second primary malignancies, event-free survival, and quality of life (QoL) will be conducted when all surviving patients are >5 years post-randomization, which is expected around 2018.
The PRiMER protocol adds a minimal residual disease (MRD) assessment by flow, and correlative analyses of bone marrow and blood samples to be conducted in 2017. MRD assessment by gene sequencing is on-going.
Newly Identified Mutations Increase Risk for Hereditary ALL
Inherited mutations in the gene IKZF1 are associated with increased risk of developing childhood acute lymphocytic anemia (ALL), the most common childhood cancer, and a leading cause of cancer-related death in children. Both common and rare germline variants have been previously reported to be associated with inherited risk of childhood ALL.
Michelle L. Churchman, PhD, St. Jude Children’s Research Hospital, Memphis, Tennessee, reported on identification of a germline mutation in the IKZF1 gene that is associated with multiple cases of childhood ALL in a single famliy.4
The IKZF1 gene encodes the protein Ikaros, a member of the family of zinc finger transcription factors, which plays a role in lymphocyte development. Analysis of members of this family suggested that an inherited mutation in IKZF1 was associated with ALL.
The aims of this project were to determine the prevalence of inherited IKZF1 variants in ALL, and to determine if germline variants affect the function of IKZF1.
Germline DNA from 4,957 patients with sporadic ALL enrolled in frontline trials of St. Jude Children’s Research Hospital and the Children’s Oncology Group was subjected to targeted IKZF1 next-generation sequencing.
Common variants, non-coding, and synonymous variants were excluded; 44 patients were found to have germline IKZF1 mutations, of which 27 were unique variants.
These unique variants were shown to de-repress transcriptional targets, deregulate adhesion molecule expression leading to aberrant cell-stroma adhesion in the bone marrow in vivo, and conferred reduced response to treatment with dexamethasone and dasatinib in vitro and in vivo.
The results identify IKZF1 as a new ALL predisposition gene, and that germline variants play a role in the pathogenesis of ALL and response to therapy. An important question to answer is whether or not germline IKZF1 variants can be used to predict prognosis in ALL.
Ibrutinib Resolves Steroid-Resistant GVHD
Chronic graft-versus-host disease (cGVHD) is the most common cause of morbidity in patients who have received an allogeneic stem cell transplant. There are no approved treatments for cGVHD that is unresponsive to corticosteroids. David Miklos, MD, Stanford University, Stanford, California, presented the results of a multicenter, open-label, phase 2 study of ibrutinib in patients whose cGVHD failed to respond to corticosteroids and were in need of further treatment (PCYC-1129; NCT02195869).5
Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) that also inhibits interleukin-2 (IL-2)-inducible T-cell kinase (ITK), and has been approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), including CLL/SLL with 17p deletion, Waldentrom’s macroglobulinemia, and mantle cell lymphoma that has been treated with at least 1 prior therapy.6
Ibrutinib had been shown to reduce the severity of cGVHD in preclinical models and early clinical studies. Early results from the study supported the designation of ibrutinib as breakthrough therapy for cGVHD after failure of one or more lines of systemic therapy.7
The study enrolled patients with cGVHD that had failed £3 prior lines of therapy who had either >25% body surface area erythematous rash or a National Institutes of Health (NIH) mouth score >4.
Ibrutinib was given orally at 420 mg until progression of cGVHD or unacceptable toxicity. The primary endpoint was response per the 2005 NIH consensus response criteria. Secondary endpoints included rate of sustained response, change in symptoms and corticosteroid requirements, and safety. Additional exploratory endpoints included effects on lymphoid and myeloid signaling pathways and plasma cytokines and chemokines.
The 42 enrolled patients had myeloablative (43%) or non-myeloablative (57%) transplants from related (40%) or non-related (60%) donors. Most had matched peripheral stem cells. Indications included acute and chronic anemias and other hematologic malignancies. All had prior corticosteroid, with a median of 2 prior regimens.
At a median follow-up of 14 months, 29% of patients were still taking ibrutinib; adverse events were the most frequent cause of discontinuation (33%).
Adverse events (AEs) were consistent with those reported for B cell malignancies treated with ibrutinib and those observed in patients with cGVHD treated with corticosteroids, and included fatigue, diarrhea, muscle spasms, nausea, and bruising.
Serious AEs occurred in 52% of patients including pneumonia, septic shock, and fever; 2 deaths due to multilobular pneumonia and bronchopulmonary aspergillosis occurred. Dr. Miklos commented that the lack of cardiac complications might be attributed to the small patient population.
A complete response (CR) (defined as complete resolution of all reversible manifestations of cGVHD) was observed in 9 patients; the overall response rate was 67% (CR plus partial response); 71% of the 28 patients with complete or partial responses had a sustained response for at least 5 months.
Responses were observed across multiple affected organs including skin, mouth, liver, and gastrointestinal tract, and patients with multiple organ involvement generally had responses in 2 or more organs. Overall, 62% (n=26) of patients had corticosteroid doses of <0.15 mg/kg daily, representing a reduction in corticosteroid use, during the study, and 5 discontinued all corticosteroids.
Soluble plasma factors related to inflammation, fibrosis, and cGVHD, such as pro-inflammatory cytokines, chemokines, and tissue growth factors, including tumor-necrosis factor alfa, interleukins, and epidermal growth factor, decreased with ibrutinib therapy.
These results support the investigation of ibrutinib for the front-line treatment of cGVHD in a randomized, double-blind study that is on-going.8
Pacritinib Benefits Patients with Myelofibrosis
John Mascarenhas, MD, Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, New York, New York, presented the results of the PERSIST-2, open-label, phase 3 study, which compared the safety and efficacy of pacritinib (200 mg twice daily or 400 mg once daily) to currently available therapies, including ruxolitinib, in patients with myelofibrosis who had platelet counts of £100,00 per microliter.
Ruxolitinib is a Janus kinase (JAK1/2) inhibitor, approved by the FDA in 2011 to treat intermediate- or high-risk myelofibrosis, which is a life-threatening condition. Ruxolitinib reduces splenomegaly and myelofibrosis symptoms, but causes dose-limiting cytopenias, and is not indicated for those with platelet counts <50,000 per microliter.10 Therefore, individuals with myelofibrosis and severe thrombocytopenia represent a population with unmet needs.
Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, and other enzymes, and reduced spleen volume and controlled symptoms of myelofibrosis compared with best available therapy (BAT excluding JAK2 inhibitors) regardless of platelet count.
Pacritinib was placed on full clinical hold by the FDA on February 8, 2016 due to concerns about interim survival results, bleeding, and cardiovascular events. The trial was shortened due to the clinical hold.11 However, the hold was recently lifted, and a new trial is set to begin that is enrolling as many as 105 participants with primary myelofibrosis who have failed previous ruxolitinib therapy.12
Of patients enrolled in the pacritinib once daily (n=104), pacritinib twice daily (n=107) or BAT (n=100) groups, nearly all discontinued treatment, mostly due to the clinical hold.
Analyses were done at week 24 prior to the hold. Half the patients in the BAT had crossed over to pacritinib treatment. BAT had consisted of ruxolitinib (45%), hydroxyurea (19%), or “watch and wait” (19%).
Pacritinib was associated with statistically significant reduction in spleen volume vs BAT (P=.001 vs pacritinib groups combined, P=.017 vs once daily, P=.001 vs twice daily).
The twice daily dose of pacritinib was associated with significant ≥50% reduction in total symptom score vs BAT, whereas the once daily dose was not. This may be due to higher steady-state plasma levels associated with the twice daily dose.
Platelet count in patients with a baseline platelet count of <50,000 per microliter increased in both pacritinib groups, and to a greater extent in the once daily group.
Patients treated with pacritinib also had lower requirements for red blood cell transfusion that those in the BAT group at weeks 12 and 24. OS for the pacritinib groups and the BAT group censored at the date of clinical hold were not significantly different.
Pacritinib was associated with more AEs than BAT, primarily diarrhea, nausea, vomiting, anemia, and thrombocytopenia, and were generally less frequent with twice daily dosing. Deaths due to AEs and/or progressive disease occurred in all groups at about the same rate.
In the discussion that followed his presentation, Dr. Mascarenhas said pacritinib was well tolerated and offered symptom relief in a patient population that was quite ill. He continued that his opinion as a clinical investigator is that pacritinib is an effective drug, with a benefit-risk ratio in its favor, and he hopes to see the drug move forward, although additional trials will require FDA approval.
Presenting you with timely market feedback from the 58th ASH Annual Meeting held in December 2016, OBR and MDoutlook® are pleased to share results from MDoutlook’s OncoPolls™ conducted immediately after the meeting. This report examines US oncologists’ awareness, views and early involvement with the CAR-T cell therapies being developed for a variety of hematologic malignancies.
For a more detailed analysis report, please click here to download the full report.
Submitted by Dr Robert Stephan, VP, Research and Physician Society, and Dr Jan Heybroek, President MDoutlook.
In an effort to provide you with timely market feedback from the 58th ASH Annual Meeting held in December 2016, OBR and MDoutlook® are pleased to share results from MDoutlook’s OncoPolls™ conducted last month immediately after the meeting. This report explores the choice between Rituxan® and Gazyva® in the front line setting for follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) and the use of Rituxan and Revlimid® in the maintenance setting for mantle cell and CLL, respectively.
Institutional Setting by Attendance of Respondents
Use of anti-CD20 mAbs in the Front Line for Different B-cell Lymphomas
Awareness of Abstracts #6 & #470
General Clinical Importance of Different anti-CD20 mAbs in FL & DLBCL
Expected Impact on anti-CD20 Usage in FL & DLBCL
Use of Maintenance Strategies for Mantle Cell Lymphoma and CLL
Awareness of Abstracts #145, #229 & #230
General Clinical Importance of Maintenance Strategies for Mantle Cell Lymphoma and CLL
Expected Impact on Maintenance Usage in Mantle Cell Lymphoma and CLL
Conclusions: Immediate Impact of 2016 ASH Presentations on Clinical Practice for B-cell Lymphomas
Submitted by Dr Robert Stephan, VP, Research and Physician Society, and Dr Jan Heybroek, President MDoutlook.