The OBR Blog

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.

This year’s ASH Annual Meeting will be chock-full of interesting, informative, and clinically useful presentations, according to a whirlwind tour of highlights presented at a pre-meeting Webinar by ASH President Charles Abrams, MD, and Stephanie Lee, MD, ASH Secretary.

Starting with the most immediately clinically applicable studies, Dr. Lee singled out two studies of approved agents in narrow disease states: Abstract 182 and 145.

Abstract 182 provides results of the Phase 3 ALCANZA trial comparing brentuximab versus physician’s choice of therapy (methotrexate or bexarotene) in CD30-expressing cutaneous T-cell lymphoma (CTCL), a relatively rare disease. The study included 128 randomized patients followed for 17.5 months. For the primary endpoint, overall response rate (ORR) at 4 months, brentuximab was significantly superior to physician’s choice of therapy: 56% versus 13%, respectively (P<.0001). Median progression-free survival (PFS) was 16.7 months versus 3.5 months, a highly significant difference favoring brentuximab (P<.0001).

“This study showed that brentuximab has a significant advantage over the other two options used to treat CTCL,” Dr. Lee told listeners.

Abstract 145 presents final results of the Phase 3 LyMa trial that compared rituximab maintenance every 2 months for 3 years versus observation in younger patients with mantle cell lymphoma (MCL) in response after undergoing autologous stem cell transplant (ASCT). The study included 240 patients with a median follow-up of 50 months. Four-year event-free survival (EFS) was 78.9% for rituximab maintenance versus 61.4% for observation (P=.0012). Four -year progression-free survival (PFS) and overall survival (OS) were also improved with rituximab maintenance therapy. Four-year PFS was 8.2.% versus 64.6%, respectively (P=.0005), and 4-year OS was 88.7% versus 81.4%, respectively (P=.0413).

“This study provides good evidence that rituximab improves outcomes after ASCT in younger patients with mantle cell lymphoma. Some hematologists are already doing this, and now there is evidence [to support this practice] from a Phase 3 trial,” Dr. Lee noted.

Abstract 6 showed a 34% reduction in risk of progression or death with obinutuzumab versus rituximab as induction and maintenance therapy in about 1200 patients with previously untreated follicular lymphoma with Stage 3 or 4 or bulky Stage 3 disease, according to primary results of the Phase 3 GALLIUM trial.. Patients were randomized 1:1 to obinutuzumab versus rituximab (both anti CD20 agents) at induction. No difference in complete response or partial response was observed after induction therapy. Patients continued on maintenance therapy for 2 years. More Grades 3 and 5 severe adverse events occurred with obinutuzumab.

“These data show that obinutuzumab is more effective in prolonging time to relapse, but the caveat is greater toxicity,” Dr. Lee commented.

CAR-T THERAPY

Dr. Abrams highlighted two studies using genetically engineered chimeric antigen receptor (CAR) T cells. A late-breaker (Abstract LBA 6) showed that Kte-CD19 CAR T cells induced responses in 76% of 101 patients from 22 institutions with refractory diffuse large B-cell lymphoma in the pivotal Phase 2 ZUMA-1 trial. ORR was 76% (47% complete response [CR] rate and 29% partial response rate [PR]). PFS was 56% at 3 months, which Dr. Abrams called “impressive.”

“The T-cells were engineered within 17 days from apheresis, which is a relatively quick turnaround. This treatment is not for the faint of heart, but it does induce complete remissions in some patients. This novel technology can be extended to many centers in the community, even those with no experience using CAR T,” Dr. Abrams noted.

A second study (Abstract 650) found that anti-CD22 CAR T cells had encouraging results in a small study of 9 “tough to treat” patients (children and young adults) with relapsed/refractory acute lymphoblastic leukemia (ALL). All 9 patients had at least 1 prior transplant, and 2 had undergone 2 prior transplants. Patients had chemotherapy and then were given anti-CD22 CAR T. Interim results at 1 month showed that 4 of the 9 patients had CR with no evidence of minimal residual disease.

“This approach with CAR T is a little different, aimed at a different target of T cells with CD 22 expression. This is encouraging, suggesting that the target of CAR T can be expanded. Someday we may be using a panel of targets,” Dr. Abrams commented.

OTHER HEMATOLOGIC MALIGNANCIES

Patients with high-risk chronic lymphocytic leukemia (CLL) were randomized 2:1 to lenalidomide maintenance versus placebo after front-line chemotherapy in the randomized, controlled, German CLLM1 trial (Abstract 229). Interim analysis of the first 89 patients of a planned enrollment of 200 showed such robust results for lenalidomide, that the trial was stopped early. At a median follow-up of 17.7 months, PFS was not yet reached in the lenalidomide-treated group versus 14.6 months for placebo. Patients treated with lenalidomide were 80% more likely to be converted to node-negative disease compared with placebo. No difference in OS was observed between the two groups with short follow-up.

“These interim findings suggest that lenalidomide maintenance is beneficial in high-risk CLL. We need continued follow-up of these patients,” Dr. Lee commented.

Although the investigational drug pacritinib was found effective in myelofibrosis in a Phase 3 trial (Abstract LBA 5), development of the drug was put on hold by the FDA due to potential cardiovascular excess deaths and hemorrhagic events in the PERSIST-1 trial. The Phase 3 PERSIST-2 study evaluated pacritinib versus best available therapy (including the JAK inhibitor ruloxitinib in 44%) in 311 patients with myelofibrosis and platelet counts <100,000 µ/l. Patients were randomized 1:1 to pacritinib versus best available therapy. Pacritinib was superior, with a 35% reduction in spleen volume, and significantly more improvement in time to symptoms at 24 weeks. Although some gastrointestinal and hematologic toxicities were observed with pacritinib, no difference between the two treatment arms was seen in cardiovascular events and bleeding.

PERSIST-2 is the only randomized trial to date in patients with myelofibrosis and thrombocytopenia and prior JAK2 inhibitor exposure. “This study is intriguing. Pacritinib did improve symptoms and spleen volume, but it remains to be seen what the FDA will do,” Dr. Lee said.

Another late-breaking abstract (LBA 1) was based on the randomized, controlled, Phase 3 StaMINA trial, which compared three different approaches to multiple myeloma in transplant-eligible patients using upfront autologous hematologic cell transplant (auto HCT): auto HCT plus RVD (bortezomib, lenalidomide, dexamethasone); tandem auto HCT plus lenalidomide maintenance (TAM); and auto HCT with lenalidomide maintenance (AM). The study enrolled 758 patients. At 38 months, PFS and OS were similar in all three groups. The probability of PFS was 57%, 56%, and 52% for the three approaches, respectively; the probability of OS was 86%, 82%, and 83%, respectively.

This is the largest randomized U.S. transplant trial in myeloma. “Results of StaMINA suggest that the addition of more chemotherapy or more transplant does not improve outcomes. All of these are reasonable approaches,” Dr. Lee noted.

SESSION ON QUALITY

Turning to a different area, Dr. Lee cited a Special Symposium on Quality of Care in the Era of Health Improvement Technology. Three different speakers will tackle the question of whether the new technology is having an impact on patient care.

“I hope this symposium will dig into the current experience for patients and for researchers,” she said.

“There is something for everyone at the upcoming ASH meeting,” she noted.

 

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