ASCO 2017: Chronic Lymphocytic Leukemia Highlights

August 2017, Vol 10, Special Issue: Payers’ Perspectives in Oncology: ASCO 2017 Highlights - Leukemia

In This Article

Results of a Phase 2 Multicenter Study of Obinutuzumab plus Bendamustine in Patients with Previously Untreated CLL

Bendamustine plus rituximab is a frequent first-line treatment for chronic lymphocytic leukemia (CLL), but there is substantial opportunity to improve patient outcomes. For instance, obinutuzumab in combination with chlorambucil significantly improved progression-free survival (PFS) and the complete response (CR) rate compared with rituximab and chlorambucil.

Obinutuzumab is a glycoengineered, type II anti-CD20 monoclonal antibody. As such, this phase 2 study evaluates the efficacy and safety of bendamustine plus obinutuzumab as first-line treatment for patients with CLL.

A total of 102 patients with previously untreated CLL were enrolled and received six 28-day cycles of bendamustine plus obinutuzumab by intravenous infusion. The median patient age was 61 years, 68.6% were male, and 44.1% had Rai stage III or IV CLL. The primary end point was CR assessed using International Workshop on Chronic Lymphocytic Leukemia criteria. The secondary end points included overall response rate (ORR), PFS, overall survival, and minimal residual disease (MRD). The median follow-up at the time of analysis was 11 months.

The CR rate was 49.0%, and the ORR was 89.2% after 6 cycles. MRD negativity in blood, as measured by 4-color flow cytometry, was achieved in 42.7% of patients at the end of induction-response assessment and in 75.5% of patients at any time after induction.

The most frequent all-grade adverse events were infusion-related reactions (72.5%), nausea (52.0%), and pyrexia (36.3%). The most frequent grade 3/4 adverse event was neutropenia (26.5%). The incidence of tumor lysis syndrome (all grade 3) was 4.9%.

Three patients died; none of the deaths were related to the study treatment or CLL.

Bendamustine plus obinutuzumab is effective for the first-line treatment of patients with CLL, inducing a high CR rate after 6 cycles of therapy. No unexpected safety signals were observed.

Source: Sharman JP, Yimer HA, Boxer M, et al. Results of a phase II multicenter study of obinutuzu­mab plus bendamustine in pts with previously untreated chronic lymphocytic leukemia (CLL). J Clin Oncol. 2017;35(15 suppl). Abstract 7523.

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Phase 1a/1b Study of a Novel BTK Inhibitor and Combination Drugs with Everolimus and Pomalidomide in Patients with CLL or Other B-Cell Lymphomas

Synthetic lethality selectively kills malignant cells through the chemical inhibition of 2 aberrant genes. Investigators demonstrated the potential of synthetic lethality with best-in-class combinations of targeted agents, immune modulation, and low-dose combinations. They hypothesized that combining Bruton’s tyrosine kinase (BTK) and mTOR inhibition with an immunomodulatory agent would target multiple key signaling pathways, improve selective killing of malignant cells, and address acquired drug resistance.

Specifically, investigators are examining DTRM-555, which is a combination of the novel BTK inhibitor DTRM-12, with everolimus and pomalidomide. DTRM-555 has shown superior efficacy over single agents at lower combined doses (1/18 of DTRM-12, 1/6 of everolimus, and 1/6 of pomalidomide) in xenograft tumor models. Investigators are conducting a 2-part first-in-human, multicenter phase 1 trial exploring DTRM-555 in patients with chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (NHL). Phase 1a consists of escalating the novel BTK inhibitor DTRM-12 monotherapy doses, and phase 1b will explore in one arm the doublet of DTRM-12 with everolimus, and in another arm the doublet plus DTRM-555. Treatment is administered for 21 consecutive days of a 28-day cycle until disease progression or unacceptable toxicity.

Eligibility criteria for patients with CLL or B-cell NHL were ≥18 years of age and an Eastern Cooperative Oncology Group performance status of ≤1 with no available therapies. Safety is the primary study end point. The secondary end points include antitumor activity and pharmacokinetic studies. Since the start of this study on September 27, 2016, 5 patients have been enrolled in phase 1a, without dose-limiting toxicity. Patients enrolled in phase 1a are receiving a 200-mg dose. Investigators anticipate enrolling up to 18 patients in phase 1a and up to 36 patients in phase 1b.

Source: Gill J, He W, Schuster SJ, et al. A phase Ia/Ib study of a novel BTK inhibitor, DTRMWXHS-12 (DTRM-12), and combination products, with everolimus and pomalidomide, in pts with CLL or other B-cell lymphomas. J Clin Oncol. 2017;35(15 suppl). Abstract TPS7570.

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Immunophenotypic and Quantitative Impacts of Ibrutinib and Chlorambucil on Circulating Immune Cells in CLL

Ibrutinib, a once-daily inhibitor of Bruton’s tyrosine kinase, is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). After the phase 3 RESONATE-2 trial, ibrutinib received approval as frontline therapy in treatment-naïve patients with CLL. In this study, ibrutinib reduced the risk for progression or death by 84% compared with chlorambucil. In an effort to better understand the mechanism by which these agents act on the immune system, quantitative changes in circulating cells were studied throughout the first year of treatment.

Immunophenotypic analyses were performed on a total of 80 patients to assess lymphoid and myeloid cells of treatment-naïve patients with CLL who received 420 mg of ibrutinib once daily (N = 50) or chlorambucil 0.5 to 0.8 mg/kg twice monthly (N = 30). The researchers found substantial differences in the immunophenotypic and quantitative impacts of the 2 therapies during the first year of treatment. Ibrutinib mainly reduced B-cells (90%), myeloid-derived suppressor cells (61%), and certain T-cells—specifically, long-term activated T-cells, PD-1–positive T-cells, regulatory T-cells, and effector T-cells (27%-52%)—while showing limited effect on naïve T-cells, stem-cell memory T-cells, central memory T-cells, and natural killer (NK) cells. Classical monocytes were increased (+187%), while nonclassical monocytes did not increase. Conversely, chlorambucil progressively reduced circulating B-cells, T-cells, NK cells, NK T-cells, myeloid-derived suppressor cells, and monocytes by 69% to 99%. All development stages of CD4+ and CD8+ T-cells, except stem-cell memory T-cells, decreased by 51% to 90%. Long-term activated T-cells, however, were not affected throughout a full year of treatment with chlorambucil.

The data indicate that ibrutinib targets cells involved in tumor growth, while preserving cells that are impor­tant for mounting antitumor responses. Chlorambucil was found to act less specifically than ibrutinib on most immune-cell subsets in circulation. These data help to explain the differential clinical activity and side-effect profiles for ibrutinib and chlorambucil.

Source: Solman I, You H, Taylor M, et al. Ibrutinib vs chlorambucil: immunophenotypic and quantitative impacts on circulating immune cells in chronic lymphocytic leukemia (CLL). J Clin Oncol. 2017;35(15 suppl). Abstract 7524.

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Ibrutinib in Previously Treated CLL: Up to 4 Years’ Follow-Up of the RESONATE Study

Ibrutinib, a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor, is FDA approved for all patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Previous phase 3 RESONATE study data established the superiority of ibrutinib to ofatumumab in patients with relapsed/refractory CLL or SLL, as measured by progression-free survival (PFS), overall survival (OS), and response. Researchers reported updated safety and efficacy results from the RESONATE trial, with up to 4 years’ follow-up.

In the study, patients received ibrutinib 420 mg orally until disease progression, or ofatumumab for up to 24 weeks. At median 9-month follow-up, the Data Monitoring Committee declared the superiority of ibrutinib to ofatumumab for PFS and OS, and ibrutinib access was recommended for all patients receiving ofatumumab.

A total of 391 patients were randomized to receive ibrutinib (N = 195) or ofatumumab (N = 196). The median age was 67 years; 57% had Rai stage III/IV disease. After median follow-up of 44 months, PFS was significantly longer for ibrutinib versus ofatumumab (P <.0001); median PFS was not reached for ibrutinib versus 8 months for ofatumumab. Furthermore, 59% of patients receiving ibrutinib achieved 3-year PFS compared with 3% of patients receiving ofatumumab. A favorable trend in PFS was also seen with ibrutinib for the del11q subgroup; however, outcomes did not achieve significance for other genetic abnormalities. Approximately 66% of patients in the ofatumumab arm crossed over to ibrutinib after losing response. OS was longer for ibrutinib than ofatumumab; the median OS was not reached for either arm. Treatment-related toxicities were generally well-tolerated by patients receiving ibrutinib, and adverse event rates were consistent with earlier data. The incidence of most grade 3/4 adverse events decreased from year 1 to years 2 and 3. Discontinuation most frequently resulted from disease progression (27%) and adverse events (12%).

Long-term treatment with ibrutinib in RESONATE was well-tolerated and continues to show sustained PFS and OS, regardless of high-risk cytogenetics. These data add to the body of evidence supporting ibrutinib as a cornerstone therapeutic option in CLL.

Source: Byrd JC, Hillman P, O’Brien SM, et al. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): up to four years follow-up of the RESONATE study. J Clin Oncol. 2017;35(15 suppl). Abstract 7510.

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Ublituximab and Ibrutinib for Previously Treated, Genetically High-Risk CLL: The GENUINE Study

Ibrutinib monotherapy has shown poor outcomes in patients with chronic lymphocytic leukemia (CLL) and 11q deletion or TP53 mutation or deletion. Ublituximab is a novel monoclonal antibody that targets a unique epitope on the B-lymphocyte CD20 antigen. GENUINE is the first randomized phase 3 trial to assess the addition of a novel agent to ibrutinib in high-risk relapsed/refractory CLL.

Eligible patients were ibrutinib-naïve with del17p, del11q, and/or a TP53 mutation. They were randomized to ibrutinib 420 mg once daily alone or with ublituximab 900 mg on days 1, 8, and 15 of cycle 1; day 1 of cycles 2 through 6; and every 3 cycles thereafter. The primary end point was overall response rate (ORR); secondary end points included complete response (CR) rate, minimal residual disease (MRD) negativity, progression-free survival (PFS), and safety.

Of the 117 patients treated, 59 received ublituximab and ibrutinib; 58 received ibrutinib monotherapy. High-risk cytogenetics were well-balanced, the patients received a median of 3 previous therapies, and >70% were male. At the 12-month follow-up, the ORR per independent central review was 78% for the ublituximab and ibrutinib arm versus 45% for ibrutinib alone (P <.001). Patients receiving ublituximab plus ibrutinib had a CR rate of 7% versus 0% for ibrutinib alone, and an MRD negativity rate of 19% versus 2%, respectively (P <.01). A trend in PFS improvement with the combination was not statistically significant at the time of the analysis.

Overall, treatment was well-tolerated. In the ublituximab and ibrutinib arm, infusion reactions were the most prevalent adverse event (54%; grade 3/4, 5%). There was an increased incidence of neutropenia in the ublituximab plus ibrutinib arm (22% vs 12% with ibrutinib alone); the rates of grade 3/4 neutropenia were similar between the 2 arms.

The researchers concluded that adding ublituximab to ibrutinib demonstrated a superior response compared with ibrutinib alone, without additional clinically significant toxicity. This combination represents a promising investigational target for patients with high-risk relapsed/refractory CLL.

Source: Sharman JP, Brander DM, Mato AR, et al. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: results of the GENUINE phase 3 study. J Clin Oncol. 2017;35(15 suppl). Abstract 7504.

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COSMOS: MOR208 plus Idelalisib or Venetoclax in Relapsed/Refractory CLL or SLL Previously Treated with a Bruton’s Tyrosine Kinase Inhibitor

There are limited treatment options for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who discontinue treatment with ibru­tinib because of disease progression, transformation, or intolerance, and a very poor prognosis. In a phase 1 study, the Fc-enhanced, humanized, CD19 antibody MOR208 showed promising activity in patients with relapsed/refractory CLL or small lymphocytic lymphoma (SLL). Furthermore, preclinical models suggest that MOR208 may be complementary to idelalisib (an inhibitor of PI3Kδ) and venetoclax (an inhibitor of BCL-2), which were approved for CLL.

To evaluate the efficacy and safety of MOR208 combined with idelalisib or venetoclax, investigators initiated a 2-cohort, phase 2 study in adults with relapsed/refractory CLL or SLL. Patients were required to receive previous treatment or demonstrate intolerance to a Bruton’s tyrosine kinase inhibitor, have Eastern Cooperative Oncology Group performance status of 0 to 2, and maintain adequate organ function.

Each cohort is expected to include 120 patients. Patients will receive intravenous MOR208 12 mg/kg (weekly for the first 3 months, every second week for the next 3 months, and monthly thereafter) in combination with oral idelalisib 150 mg twice daily or venetoclax administered on a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg. Treatment will continue for a maximum of 24 cycles or until disease progression. The primary end point is overall response rate based on independent review. Secondary and exploratory end points include progression-free survival and overall survival, time to progression, duration of response, safety, MOR208 immunogenicity and pharmacokinetics, quality of life, and minimal residual disease negativity. The study is expected to shed light on potential treatment options in difficult-­to-treat patients with relapsed/­refractory CLL or SLL.

Source: Wendtner CM, Byrd JC, Foà R, et al. COSMOS: MOR208 plus idelalisib or venetoclax in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) previously treated with a Bruton’s tyrosine kinase inhibitor (BTKi)—a two-cohort phase II study. J Clin Oncol. 2017;35(15 suppl). Abstract TPS7567.

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