January 2020 Edition Vol.11, Issue 1

Significant Advances, Some Practice-Changing, Emerge at 2019 ASH

By Ted Bosworth

Positive findings—some considered practice-changing—in the areas of first remission acute myeloid leukemia (AML), relapsed or refractory multiple myeloma (R/R MM), and both early and advanced mantle cell lymphoma (MCL) were presented at the 2019 American Society of Hematology (ASH) Annual Meeting. In addition, new information on managing the complications of cancer treatment, including tumor lysis syndrome were presented.

QUAZAR Phase 3 Trial: Oral Formulation of Azacitidine Extends Survival in AML

When employed as a maintenance therapy following first remission AML, an oral formulation of azacitidine provided an overall survival (OS) benefit, according to results from the QUAZAR study, an international, placebo-controlled phase 3 trial. The safety profile of this novel agent, called CC-486, was characterized as manageable.

“We believe CC-486 might represent a new therapeutic standard for AML,” reported Andrew H. Wei, MBBS, PhD, who leads leukemia research at Alfred Hospital in Melbourne, Australia. He said that no prior controlled trial has associated a maintenance therapy with improvement in OS.

QUAZAR enrolled 472 patients with de novo or secondary AML with intermediate or poor risk cytogenetics who had achieved a complete remission (CR) or CR with incomplete count recovery (CRi) after first-line therapy. About 80% of the 472 patients randomized to receive 300 mg CC-486 or placebo following induction therapy had also received consolidation therapy.

The assigned maintenance treatments were administered on days 1 to 15 of each 28-day cycle, although treatment was moved to a 21-day schedule in patients who developed blasts at a level of 5% to 15% during treatment. Treatment was continued until patients received a hematopoietic stem cell transplant, developed a blast count exceeding 15%, or had unacceptable toxicity. OS was the primary endpoint.

At an average followup of 41.2 months, the median OS was 24.7 months among those randomized to CC-486 versus 14.8 months for those receiving placebo. By hazard ratio (HR), this translated into a 31% relative survival advantage (HR 0.69; P=0.0009). There was also a five-month (10.2 vs. 4.8 months relative relapse-free survival for the active therapy (HR0.65; P=0.0001). When stratified by a variety of characteristics, including baseline genetic risk, CR or CRi status at enrollment, or number of consolidation cycles, the relative benefit for CC-485 for both OS and RFS remained consistent.

Side effects were more common on CC-485 than placebo, but most were of mild grade. Health-related quality of life, which was monitored, did not differ in the two arms. Neutropenia (41% vs. 24%) was the most common grade 3 or higher adverse event on CC-486 relative to placebo. Of lower grade events, those occurring more commonly in the active treatment group included nausea (64% vs. 23%), vomiting (59% vs. 10%), and diarrhea (49% vs. 21%).

A spokesman for ASH, Robert A. Brodsky, MD, Director of the Division of Hematology, Johns Hopkins University, Baltimore, agreed these data are practice changing. “Although it is usually easy to get the AML patient into remission with first-line therapy, these remissions are generally short,” Dr. Brodsky said. He considers an OS benefit from a reasonably well-tolerated maintenance regimen a substantial advance.

Benefit of Daratumumab-Carfilzomib Combination Confirmed in Refractory Multiple Myeloma

A combination of the proteasome inhibitor carfilzomib and the anti-CD38 monoclonal antibody daratumumab, which are each approved separately for R/R MM, improve disease control when used together, according to results from CANDOR, a multinational phase 3 trial.

After a median followup of 17 months, the combination of daratumumab, carfilzomib, and dexamethasone provided a 37% advantage (HR 0.63; P=0.0014) for progression-free survival (PFS), which was the primary endpoint of this trial. After a median of 17 months of followup, there is no difference yet in OS.

The triple therapy with daratumumab (KdD) “should be considered a novel efficacious therapeutic option in R/R multiple myeloma,” said Saad Z. Usmani, MD, MBBS, a hematologist associated with Levine Cancer Institute, Atrium Health, Charlotte, North Carolina.

R/R MM patients were eligible for this trial if they had achieved a partial response (PR) or better to at least one line of prior therapy. The 446 participants were randomized in a 2:1 ratio to daratumumab or placebo. All patients received carfilzomib on a 28-day cycle regimen and dexamethasone, which was administered weekly.

In addition to protection against progression, KdD was associated with a deeper response, including higher rates of complete responses (CR) or better (28.5% vs.10.4%) and minimal residual disease (MRD)-negative responses 12.5% vs. 1.3% (P<0.0001).

Although the median treatment duration was substantially longer in the KdD arm (70.1 vs. 40.3 weeks), treatment discontinuation for adverse events was slightly lower in the KdD arm (22.4% vs. 24.8% for Kd). The rate of serious adverse events was higher in the KdD arm (56.2% vs. 45.8%), but the rates of grade 3 or higher cardiac failure (2.9% vs. 8.5%) and discontinuations for a cardiac failure event (3.9% vs. 4.6%) were lower. This latter unexpected finding is being further evaluated.

Despite the absence of an OS benefit, these data are immediately relevant to management of R/R MM, according to Dr. Brodsky. He noted that the substantial PFS benefit with the addition of daratumumab was achieved with a relatively low cost in additional adverse events.

R/R MCL Controlled with Experimental CAR T-Cell Therapy

In patients with R/R MCL, durable responses are achieved with an anti-CD19 CAR T-cell therapy, according to results from ZUMA-2, a phase 2 trial. In patients who had received up to five lines of therapy including a Bruton tyrosine kinase (BTK) inhibitor, 86% were alive and 71% remained in PFS at the end of 12 months.

“The majority of patients achieved a CR and disease control has been durable,” reported Michael Wang, MD, a professor in the Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston. He juxtaposed the OS in this study at 12 months with previously published estimates that place median survival in similar patients at less than six months.

Data from this on-going study were presented on 28 patients. It is the first multicenter phase 2 study of CAR T-cell therapy in R/R MCL. All patients, of whom 80% had stage IV disease, received the experimental agent KTE-X19.

Of the 86% who achieved an objective response (ORR), 57% achieved a CR. The duration of response at 12 months was 83%. The median OS and PFS after a median of 13.2 months of followup have not been reached.

The side effects were consistent with other recent studies with CAR T-cell therapy. Grade 3 or higher adverse events included cytokine release syndrome in 18% and neurologic events in 46% of patients. All but two of these events, both neurologic, were reversible. There was one treatment-related death attributed to pneumonia associated to the conditioning regimen.

Progress with Newer BTK Inhibitors: MCL and CLL

Second-generation BTK inhibitors appear likely to displace the first generation ibrutinib in hematologic malignancies where BTK inhibitors have proven effective, according to data presented in mantle cell lymphoma and chronic lymphocytic leukemia (CLL). One of these drugs, zanubrutinib, received accelerated FDA approval just weeks before the 2019 ASH meeting.

“Zanubrutinib is a next generation BTK inhibitor designed to maximize BTK occupancy and minimize activity off-target kinases,” reported Gavin Cull, MBBS, a clinical hematologist at the University of Western Australia, Perth, who updated a global phase 1/2 trial that enrolled patients with a broad array of B-cell malignancies.

The regulatory approval granted to zanubrutinib was for treatment of MCL after at least one prior line of therapy. It was based on data from the phase 1/2 trial and from a subsequent study known as BGB-3111-206, which evaluated 160 mg of zanubrutinib twice daily. In that study of previously treated MCL patients, zanubrutinib achieved an ORR of 86% and a CR rate of 59%.

Among patients with CLL in the phase 1/2 trial updated at the 2019 ASH meeting, the ORR was 97% even though 95 (82%) of the 117 patients had received at least one prior line of therapy. Due to the increased specificity of action on the BTK target, next generation BTK inhibitors have the potential to be more effective while imposing fewer off-target effects. Zanubrutinib is now being directly compared with ibrutinib in an on-going phase 3 trial in CLL.

“This will be the first phase 3 head-to-head comparison of BTK inhibitors in CLL,” according to the principal investigator Peter Hillmen, MD, PhD, a consultant hematologist at St. James University Hospital, University of Leeds, UK.

Another new generation BTK inhibitor, acalabrutinib received FDA approval for first-line or previously treated CLL just prior to the 2019 ASH meeting. In the phase 3 ELEVATE TN trial that led to approval in the first-line setting, acalabrutinib plus obinutuzumab improved PFS relative to chlorambucil/obinutuzumab, a standard when the trial was initiated several years ago.

In ELEVATE TN 535 patients with previously untreated CLL were randomized to acalabrutinib plus obinutuzumab, chlorambucil plus obinutuzumab, or to acalabrutinib alone. After a median followup of 28 months, both of the arms containing acalabrutinib provided a highly significant PFS advantage over the chemotherapy-containing arm, reaching 90% (HR 0.10; P<0.0001) when acalabrutinib was combined with obinutuzumab and 80% (HR 0.20; P<0.0001) when it was used alone.

The benefit of each relative to the chemotherapy-containing arm “was consistent across subgroups and irrespective of high-risk characteristics,” according to Jeff P. Sharman, MD, Director of Research, Willamette Valley Cancer Institute, Eugene, Oregon.

Acalabrutinib was also generally well tolerated. Discontinuations were less frequent on monotherapy (8.9%) or in combination with obinutuzumab (11.9%) than on chlorambucil plus obinutuzumab (14.1%). Bleeding rates were substantially higher on acalabrutinib but less than 2% reached grade 3 severity.

New Strategies for Minimizing Tumor Lysis Syndrome and Treatment-Related Infection

Of studies providing insight for managing the complications of cancer treatments, two are notable for practical clinical value. In one, the greater efficacy of rasburicase over allopurinol for tumor lysis syndrome (TLS) was credited with a reduction in complications, such as rehospitalizations. In the other, relative risk estimates for daratumumab-related infections in patients with multiple myeloma were cited for encouraging surveillance and early intervention.

The evaluation of rasburicase for TLS was drawn from a database. Of the 265 patients treated with this drug, 189 received treatment in the outpatient setting. None required readmission for TLS, according to Ali McBride, PharmD, MS, Department of Pharmacy, University of Arizona Cancer Center, Tucson.

Of those receiving rasburicase three or more days after the start of chemotherapy, 54% had first received allopurinol, “indicating failure of allopurinol alone,” Dr. McBride reported. As a result, it is likely that initiation of rasburicase aborted a potentially meaningful TLS complication including, for outpatients, rehospitalization.

This is significant because “the published data for charges incurred for inpatient treatment of TLS is shown to be $151,917,” Dr. McBride noted. He believes these data show that allopurinol “is frequently inadequate” for TLS and that utilization of rasburicase in the outpatient setting is “a means to lower the total cost of care.”

In another study relevant to cancer treatment-related complications, the goal was to quantify the risk of infection imposed by daratumumab when employed in the treatment of multiple myeloma. When derived from the published phase 3 data, the results showed a 27% increase in the relative risk (RR) of high-grade infections (RR 1.27; P=0.0001).

These results suggest that multiple myeloma patients taking daratumumab should be monitored for infection so that “timely intervention with proper supportive care” can be provided, according to Thura Win Htut, MBBS, Hematology Department, Aberdeen Royal Infirmary Hospital, Aberdeen, UK.

The risk of infection does not negate the value of daratumumab, which is associated with improved OS in multiple myeloma, but Dr. Htut suggested that awareness of this risk and early control of infection could circumvent the risk of a potentially life-threatening complication. According to the data, the risk of high-grade pneumonia was particularly elevated (RR 2.07) in those with newly diagnosed multiple myeloma.

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