Study Findings on Novel Therapies for Hematologic Malignancies


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Here is an update on five different studies featured at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition. Topics center on possible newer treatment regimens in both Hodgkin and Burkitt lymphomas, relapsed or refractory chronic lymphocytic leukemia, and newly diagnosed multiple myeloma.

Lymphoma

Study: Brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, dacarbazine (A+AVD) as front-line therapy demonstrates superior modified progression-free survival vs ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma: The phase III ECHELON-1 study1,2

Key Findings: The primary endpoint of modified progression-free survival was met (hazard ration [HR] = 0.770 [95% confidence interval (CI) = 0.603–0.982]; P = .035), with 117 events in the A+AVD arm and 146 events in the ABVD arm and was consistent with investigator-reported modified progression-free survival (HR = 0.725 [95% CI = 0.574–0.916]; P = .007). Modified progression-free survival events were attributed to disease progression (90 vs 102), death (18 vs 22), or receipt of additional anticancer therapy for incomplete response (9 vs 22) after A+AVD or ABVD, respectively. The 2-year modified progression-free survival was 82.1% (95% CI = 78.7%–85.0%) with A+AVD vs 77.2% (95% CI = 73.7–80.4) with ABVD and per investigator 81.0% (95% CI = 77.6%–83.9%) with A+AVD vs 74.4% (95% CI = 70.7%–77.7%) with ABVD. There were 28 deaths in the A+AVD arm and 39 deaths in the ABVD arm (interim overall survival HR = 0.721 [95% CI = 0.443–1.173]; P = .186).

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Safety profiles were consistent with known toxicities of the single agents. Neutropenia was reported in 58% of patients receiving A+AVD and 45% receiving ABVD. Grade ≥ 3 infections were more common in the A+AVD arm (18%) than in the ABVD arm (10%). In patients receiving A+AVD, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF; n = 83) reduced febrile neutropenia from 19% to 11% and grade ≥ 3 infections and infestations from 18% to 11%. Peripheral neuropathy occurred in 67% of patients receiving A+AVD and in 43% receiving ABVD; 67% of patients experiencing peripheral neuropathy in the A+AVD arm had resolution or improvement at last follow-up. Pulmonary toxicity was more frequent and more severe with ABVD. Of the on-study deaths, seven of nine in the A+AVD arm were associated with neutropenia; these deaths occurred in patients who had not received G-CSF primary prophylaxis. Of 13 on-study deaths in the ABVD arm, 11 were due to or associated with pulmonary toxicity.

Clinical Implications: These data require longer follow-up. The detailed results of the study were published in The New England Journal of Medicine moments before the plenary session during the 2017 ASH meeting.2

 

Study: Risk-adapted therapy in adults (including patients with HIV infection [n = 29]) with Burkitt lymphoma: Results of NCI 9177, a multicenter prospective phase II study of DA-EPOCH-R (n = 113)3

Key Findings: Patients with normal lactate dehydrogenase levels, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, ≤ stage II, and no tumor lesion > 7 cm were considered at low risk (n = 14), and all others were considered at high risk (n = 99). Low-risk patients received two cycles of DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin plus rituximab [Rituxan]) without intrathecal therapy followed by an interim positron-emission tomography (PET) scan. If interim PET was negative, low-risk patients received one more cycle of chemotherapy. High-risk patients with negative brain magnetic resonance imaging and cerebrospinal fluid cytology/flow cytometry received two cycles of DA-EPOCH-R without intrathecal therapy followed by PET. Unless the interim PET showed disease progression, high-risk patients received an additional two cycles of DA--EPOCH-R including intrathecal methotrexate. High-risk patients with active central nervous system disease at baseline received concurrent intrathecal methotrexate.

After a median potential follow-up of 35.7 months, the progression-free survival for all patients beyond 10.2 months is 85.7% (95% CI = 77.3%–91.1%); freedom from disease progression is 91.8% (95% CI = 84.2%–95.8%), and overall survival is 85.9% (95% CI = 77.3%–91.4%). HIV status did not impact survival, and therapy was equally effective across all age groups. Patients with bone marrow and/or central nervous system involvement were at highest risk of treatment failure. With current follow-up, no disease progression or death occurred in the low-risk group. There were 14 deaths, all in the high-risk group. Seven deaths were due to disease progression: three occurred during therapy, and four occurred following completion of therapy.

Clinical Implications: This multicenter study confirms that DA-EPOCH-R cures most adult patients with Burkitt lymphoma irrespective of HIV status. Patients with protocol-defined low-risk Burkitt lymphoma may be cured with three cycles of systemic therapy, and no intrathecal therapy may be required. The outcome of protocol-defined high-risk patients compares favorably with more intensive regimens. Earlier prophylactic intrathecal methotrexate for high-risk patients with bone marrow involvement is advocated.

Leukemia

Study: Venetoclax (Venclexta) plus rituximab (VR; maximum of 2 years or less in patients with disease progression) is superior to bendamustine plus rituximab (BR; total of six cycles) in patients with relapsed or refractory chronic lymphocytic leukemia (CLl). Results from preplanned interim analysis of the randomized phase III Murano trial4

Key Findings: At a median follow-up of 23.8 months, progression-free survival was superior for VR (n = 194) vs BR (n = 195), with a hazard ratio of 0.17 (95% CI = 0.11–0.25; P < .0001). Key secondary efficacy endpoints showed consistent improvements with VR vs BR, including in overall survival (HR = 0.48, 95% CI = 0.25–0.90). The overall response rates were 93.3% with VR vs 67.7% with BR (Δ = 25.6%, 95% CI = 17.9%–33.3%); complete response/complete remission with incomplete blood cell count recovery was achieved in 26.8% vs 8.2% of patients, respectively.

Consistent with known safety profiles of the two regimens, grade 3/4 neutropenia was higher in patients on the VR regimen, but there was no increase in febrile neutropenia or grade 3/4 infection. Adverse effects leading to death were seen in 5.2% vs 5.9% of patients in the VR and BR arms, respectively.

Clinical Implications: The primary analysis demonstrates profound improvement in progression-free survival with VR compared with BR chemoimmunotherapy in patients with relapsed or refractory CLL.

Multiple Myeloma

Study: Phase III randomized study of daratumumab (Darzalez) plus bortezomib (Velcade), melphalan, and prednisone (D-VMP; n = 350) vs bortezomib, melphalan, and prednisone (VMP; n = 356) in newly diagnosed patients with multiple myeloma who are ineligible for autologous transplant (ALCYONE)5,6

Key Findings: At a median follow-up of 16.5 months, the hazard ratio for progression-free survival (D-VMP vs VMP) was 0.50 (95% CI = 0.38–0.65, P < .0001), representing a 50% reduction in the risk of disease progression or death for patients treated with D-VMP. Median progression-free survival was not reached vs 18.1 months for D-VMP vs VMP, respectively.

The most common (≥ 10%) grade 3 and 4 treatment emergent adverse events (D-VMP/VMP) were neutropenia (39.9%/38.7%), thrombocytopenia (34.4%/37.6%), anemia (15.9%/19.8%), and pneumonia (11.3%/4.0%). Second primary malignancy occurred in 2.3% vs 2.5% of patients treated with D-VMP and VMP, respectively.

Clinical Implications: These results favor the use of D-VMP in autologous transplant–ineligible patients with newly diagnosed multiple myeloma. Currently, daratumumab is not approved by the U.S. Food and Drug Administration for use in this specific clinical setting. Complete results of the study were published in The New England Journal of Medicine after the 2017 ASH meeting.6

Study: Minimal residual disease (MRD) assessment using clonoSEQ kit in patients with newly diagnosed multiple myeloma: Final analysis of the IFM2009 trial7

Key Findings: MRD was evaluated in 269 patients with newly diagnosed multiple myeloma who achieved at least a very good partial response. Patients who did not achieve a very good partial response were considered MRD-positive. First, investigators found sensitivity to be important: patients with an MRD level below 10–6 had a better progression-free survival than did patients not achieving this level. Using this cutoff, at a median follow-up of 55 months, the median progression-free survival for patients achieving MRD negativity was not reached, vs 29 months for patients who did not achieve MRD negativity.

FEATURED TRIALS FROM ASH 2017

Lymphoma

  • ECHELON-1 study
  • NCI 9177 study

Chronic Lymphocytic Leukemia

  • Murano study

Multiple Myeloma

  • ALCYONE trial
  • IFM2009 trial

Second, they analyzed the results according to treatment arm. If more patients in the autologous transplant arm achieved MRD negativity, they did not observe any difference in progression-free survival in patients with MRD negativity, suggesting those who were able to achieve MRD negativity without transplant had a similar outcome as those transplanted.

Third, they looked at the role of high-risk cytogenetics on outcomes. Protocol-defined high-risk patients who achieved MRD negativity had a better outcome than did standard-risk patients who did not achieve MRD negativity, implying the high-risk category is a dynamic concept that should be reevaluated during specific treatment.

Fourth, overall survival was significantly longer in patients who achieved MRD negativity.

Clinical Implications: The study suggests the MRD level of 10–6 should be the optimal cutoff using the clonoSEQ kit method, which distinguishes differences in progression-free and overall survival between the groups treated on the IFM2009 trial. ■

Dr. Abutalib is Assistant Director in the Stem Cell Translant & Cell Therapy Program at Cancer Treatment Centers of America in Chicago.

DISCLOSURE: Dr. Abutalib has been on an advisory board for Juno Pharmaceuticals.

REFERENCES

1. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma: The phase 3 ECHELON-1 study. 2017 ASH Annual Meeting. Abstract 6. Presented December 10, 2017.

2. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. December 10, 2017 (early release online).

3. Roschewski M, Dunleavy K, Abramson JS, et al: Risk-adapted therapy in adults with Burkitt lymphoma: Results of NCI 9177, a multicenter prospective phase II study of DA-EPOCH-R. 2017 ASH Annual Meeting. Abstract 188. Presented December 9, 2017.

4. Seymour JF, Kipps TJ, Eichhorst BF, et al: Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: Results from pre-planned interim analysis of the randomized phase 3 Murano study. 2017 ASH Annual Meeting. Abstract LBA-2. Presented December 12, 2017.

5. Mateos MV, Dimopoulos MA, Cavo M, et al: Phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma patients ineligible for transplant (ALCYONE). 2017 ASH Annual Meeting. LBA-4. Presented December 12, 2017.

6. Mateos MV, Dimopoulos MA, Cavo M, et al: Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. December 12, 2017 (early release online).

7. Avet-Loiseau H, Lauwers-Cances V, Corre J, et al: Minimal residual disease in multiple myeloma: Final analysis of the IFM2009 trial. 2017 ASH Annual Meeting. Abstract 435. Presented December 10, 2017.


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