ASH Highlights for Tuesday, December 4, 2018

As the ASH Annual Meeting concludes, the late-breaking abstracts are always of great interest. We take a brief look at one non-malignant hematology presentation that has implications for oncology, as well as three malignant hematology presentations on advances in targeted therapies for CLL and multiple myeloma.

Rivaroxaban Thromboprophylaxis in High-Risk Ambulatory Cancer Patients Receiving Systemic Therapy: Results of a Randomized Clinical Trial (CASSINI) (LBA-1)—short summary of this one

Patients with cancer have a higher risk for venous thromboembolism (VTE), which can lead to death, morbidity, hospitalization, and delay in cancer treatment.

Alok A. Khorana, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, reported results of the CASSINI trial (NCT02555878), a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE, defined as Khorana score ≥ 2 for a risk-adapted approach to prophylaxis.

Patients were randomly assigned to rivaroxaban, a direct oral anticoagulant (n=420), or to placebo (n=421) for 6 months. An important aspect of the trial was the use of ultrasonography of the lower extremity at baseline to identify pre-existing clots, which occurred in 4.5% of screened patients who were therefore not enrolled.

There was no significant difference between groups in the primary efficacy outcome of cumulative thromboembolic events; 38.7% of events occurred in patients who had discontinued treatment. For patients who remained on treatment, rivaroxaban significantly reduced events (2.62%) versus placebo (6.41%; P=.007), and significantly reduced a composite of the primary endpoint and all-cause mortality (P=.003).

There were no significant differences in safety outcomes between the groups for bleeding. A risk-benefit analysis showed that the number needed to treat (NNT) was 26 for patients who remained on treatment. The number needed to harm (NNH) was 101 for major bleeding and 135 for clinically relevant non-major bleeding for patients on treatment.

Dr. Khorana concluded that baseline screening for VTE could be considered for patients starting systemic cancer therapy. The findings of this study, along with a similar study that has just concluded, should inform future recommendations for thromboprophylaxis for higher-risk ambulatory patients with cancer.

Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA) (LBA-2)

Thierry Facon, Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France, presented the pre-specified interim analysis of the MAIA study, a phase 3 trial evaluating daratumumab plus lenalidomide and low dose dexamethasone (D-Rd) versus Rd in patients with transplant-ineligible, newly diagnosed multiple myeloma. Daratumumab is a human, CD38-targeted, IgG1κ monoclonal antibody.

Patients were randomly assigned to D-Rd (n=368) or Rd (369); treatment continued until disease progression. Median age was 73 years, and notably, 44% of patients were age ≥75 years. The primary endpoint was progression-free survival (PFS).

At a median follow-up of 28 months there was a 44% reduction in risk of progression or death in the D-Rd group (71% at 30 months vs 56% for placebo; HR 0.56; 95% CI 0.43-0.73; P<.0001). Median PFS in the Rd group was 31.9 months and not reached in the D-Rd group. This benefit was seen across most sub-groups analyzed.

The overall response rate was 93% for D-Rd versus 81% for Rd (P<.0001); complete response rates and at least very good partial response rates were higher for D-Rd than for Rd. The minimal residual disease (MRD)-negative rate was significantly higher for D-Rd (24%) than for Rd (7%; P<.0001). Patients who were MRD negative had longer PFS. There is no difference between groups in overall survival (OS) at this follow-up time.

The safety profile was consistent with that seen for these combinations in other studies. Because of the inclusion of lenalidomide, the incidence of secondary primary malignancies (SPM) was determined; it was 3% for D-Rd and 4% for Rd; hematologic SPM occurred in 0.5% of each arm.

Dr. Facon concluded that the results of this study support D-Rd as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma.

A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912) (LBA-4)

The E1912 (NCT02048813) trial showed that ibrutinib plus rituximab (IR) improves PFS and OS compared with fludarabine, cyclophosphamide, and rituximab (FCR) in younger patients with previously untreated CLL. FCR has been the most active chemo-immunotherapy to date for CLL and has not been compared with ibrutinib as an initial treatment for younger patient with CLL.

Patients age ≤70 years (median age 58 years) with CLL were randomly assigned 2:1 to IR (n=354) or to 6 cycles of FCR (n=175). Patients in the IR group received 1 cycle ibrutinib, 6 cycles IR, then ibrutinib until disease progression.

At a median follow-up of about 3 years, PFS was significantly longer in the IR group (HR 0.35; 95% CI 0.22-0.5; P≤.00001), as was OS (HR 0.17; 95% CI .05-0.54; P≤.0003). Neutropenia, anemia, thrombocytopenia, and neutropenic fever occurred significantly less often with IR than FCR; atrial fibrillation and hypertension occurred significantly more often with IR than FCR. There were no significant difference in infection, bleeding, or diarrhea.

Presenter Tait D. Shanafelt, MD, Stanford University, Stanford, CA, concluded that these results establish IR as the most effective first-line therapy in patients age ≤70 years with CLL.

Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia (LBA-7)

Venetoclax, a selective BCL2 inhibitor induces deep and durable responses in CLL. However, most patients treated with venetoclax will eventually experience disease progression, and the mechanisms of resistance to venetoclax in patients are largely unknown.

This study looked at 67 patients with relapsed CLL; 21 had CLL-type progressions; of these, 15 had samples suitable for genomic analysis. A new mutation that was not present in pre-treatment samples, BCL2 Gly101Val, was detected in four patients using targeted amplicon sequencing. This is the first acquired BCL2 mutation described in patients with CLL treated with venetoclax. BCL2 Gly101Val occurs in the BH3-binding groove and has not been detected in other B-cell malignancies. BCL2 Gly101Val reduces the binding of venetoclax to BCL2 as much as 180-fold.

Piers Blombery, MBBS, University of Melbourne, Melbourne, Australia, said that they have detected BCL2 Gly101Val in patient samples months to years before relapse, and the mutation has subsequently been detected in three additional patients in the original group of 15 studied.

Cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax and the mutation confers a growth advantage over wild-type cells in the presence of the drug.

Dr. Blombery pointed out that alternative resistance mechanisms can co-exist with BCL2 Gly101Val. These study results could provide a rationale for a limited time course for venetoclax.

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