PREVIEW OF ASH 2017 HIGHLIGHTS

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
  • Targeted therapies
  • Thrombosis

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.

Targeted Therapies

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.

Thrombosis

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

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