January 2018 Edition Vol.12, Issue 1

Major Trials Create New Standards of Care in Hematologic Malignancies

By Ted Bosworth

The practice standards for several hematologic malignancies have or will soon change according to major trials presented at the 2017 annual meeting of the American Society of Hematology (ASH). The assertion of a practice change was made on the basis of a biologic to treat cutaneous T-cell lymphoma (CTCL); a single drug substitution in a classic regimen to control Hodgkin’s lymphoma; and a monoclonal antibody to treat transplant-ineligible multiple myeloma. A new strategy for relapsing/remitting chronic lymphocytic leukemia (CLL) and an oral anticoagulant for cancer-related venous thromboembolism prophylaxis (VTE) were also identified as practice changing.

MAVORIC Trial: New Drug for CTCL

Likely to receive regulatory approval, based on results of a phase 3 trial called MAVORIC, the monoclonal antibody, mogamulizumab, doubled the progression-free survival (PFS) in adults with confirmed mycosis fungoides or Sezary syndrome who had failed at least one prior line of therapy. Mogamulizumab is directed against the chemokine receptor 4 (CCR4), which is over expressed on malignant T cells. Given the heavy symptom burden of CTCL, patient-assessed improvement in quality of life on mogamulizumab was also considered a major clinical benefit from this therapy.

“We are very excited about these very positive results, which have been submitted to the FDA,” reported Youn H. Kim, MD, professor of dermatology and director of a multidisciplinary cutaneous lymphoma clinic at Stanford University Medical Center, Stanford, California.

In the study, 372 patients at 59 participating centers in 11 countries were randomized to intravenous mogamulizumab or oral vorinostat in an open-label design. Mogamulizumab was delivered weekly for the first month in a dose of 1.0 mg/kg. Subsequently, doses were delivered every two weeks. The dose of vorinostat was 400 mg delivered intravenous weekly. Treatment was maintained until progression or unacceptable toxicity.

The primary endpoint of median PFS was 7.7 months among those randomized to mogamulizumab versus 3.1 months for those randomized to vorinostat (Figure 1). The hazard ratio (HR) for PFS was reduced by almost 50% (HR 0.53; P<0.0001). For mogamulizumab versus vorinostat, the objective response rates (ORR) were several times greater in patients with mycosis fungoides (28.0% vs 7.1%) or Sezary syndrome (37.0% vs 2.3%). This included higher ORR in those in either group with stage IV disease (36.5% vs 3.1%, respectively).

Overall, mogamulizumab, which was primarily associated with mild to moderate infusion site reactions and skin eruptions, was better tolerated than vorinostat, which was more likely to produce diarrhea (61.8% vs 23.4%), nausea (42.5% vs 15.2%) and thrombocytopenia (30.6% vs 11.4%). In addition, when symptoms of CTCL were evaluated by patients with the validated Skindex-29 and FACT-G instruments, the advantage of mogamulizumab was observed early, and it persisted throughout the trial.

“CTCL is an extremely debilitating type of lymphoma. It produces highly visible and symptomatic skin lesions that are upsetting to patients,” said Laurie Sehn, MD, a professor of oncology at the University of British Columbia, Vancouver, where she frequently treats lymphoma. Participating in an ASH press conference on these data, Dr. Sehn emphasized that traditional forms of chemotherapy offer very limited efficacy in most patients with CTCL.


ECHELON Trial Redefines Management of Hodgkin’s Lymphoma

When brentuximab vedotin was substituted for bleomycin in the classic ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimen for Hodgkin’s lymphoma, both efficacy and tolerability improved, according to results of a phase 3 trial. On the basis of these data, the regimen with brentuximab (A+AVD) is poised to end the reign of ABVD in this disease after more than 40 years.

“A-AVD offers superior efficacy with a lower risk of a non-complete response and less likelihood for need at the end of two years for subsequent anti-cancer therapy,” reported Joseph M. Connors, MD, Director, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, Canada. Delivering the data from this trial, called ECHELON, in the plenary session of the ASH meeting, Dr. Connors suggested a numerical but not yet significant hazard ratio (HR) for an overall survival (OS) advantage favoring A+AVD (HR 0.72; P=0.19) has potential to reach significance with longer followup.

In this study, 1334 previously untreated Hodgkin’s lymphoma patients with stage III or IV disease were randomized. The primary endpoint was a modified PFS. By modified, patients were considered to have progressed if they were given any subsequent therapy whether or not there was objective evidence of disease progression. Dr. Connors explained that this PFS definition is important because second-line Hodgkin’s treatment is often initiated in advance of progression when disease does not regress.

After a median of 24.9 months of followup, the rates of modified PFS were 82.1% and 77.2% for the A-AVD and ABVD arms, respectively (HR 0.77; P=0.03). All secondary efficacy endpoints also favored A+AVD over ABVD. Also important from the clinical perspective, peripheral neuropathy fell from 67% of patients in the ABVD arm to 43% in the A+AVD arm. The ECHELON data were published simultaneously with the ASH presentation (Connors et al. N Engl J Med, 2017; December 11 epub ahead of print).

“Grade 3 or higher peripheral neuropathy occurred in 11% of patients in the ABVD group versus 2% in the A+AVD group,” said Dr. Connors, calling this “a bit of good news for patients.” He also noted that pulmonary toxicity was lower (2% vs 7%). However, Dr. Connors did acknowledge that the total rate of grade 3 or higher adverse events was higher in the A+AVD arm (83% vs 66%) owing primarily to higher rates of grade 3 or higher neutropenia (54% vs 39%).

ABVD has been a difficult combination to beat, according to George P. Canellos, MD, Senior Physician, Dana Farber Cancer Institute, Boston. Although the intensified BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen has been associated with a greater PFS than ABVD, this advantage comes with greater toxicity, and a survival advantage “has never been shown” over ABVD with this or any of the other combinations tested over the past 40 years.


ALCYONE: New Option for Untreated Multiple Myeloma

In transplant-ineligible patients with newly diagnosed multiple myeloma, the addition of daratumumab to the bortezomib, melphalan, and prednisone (VMP) regimen reduced the risk of progression or death by about 50% relative to VMP without daratumumab, according to results of the phase 3 trial called ALCYONE. When daratumumab was added to the VMP regimen, the rate at which patients became negative for minimal residual disease (MRD) was also nearly four times greater than without the drug added to VMP (23% vs 6%; P<0.001).

“These data strongly support D-VMP as a standard of care in this setting,” reported the principal investigator Maria-Victoria Mateos, MD, PhD, consultant physician, Hematology Department, University Hospital, Salamanca, Spain. She acknowledged that the addition of the anti-CD38 monoclonal antibody daratumumab was associated with an increased risk of upper respiratory tract infection (26.3% vs 13.8%), but reported that daratumumab was otherwise well tolerated. The rate of grade 3 or higher peripheral neuropathy was actually lower on D-VMP than VMP (1.4% vs 4.0%).

In the ALCYONE trial, which was published on line simultaneously with the ASH presentation (Mateos et al. N Engl J Med 2017;December 12, epub ahead of print), 706 patients with newly diagnosed multiple myeloma ineligible for stem cell transplant were randomized to the D-VMP or VMP. At a median of 16.5 months of follow-up, the estimated 18-month PFS was 71.6% for D-VMP versus 50.2% for VMP (HR 0.50; P<0.001). The overall response rate (ORR) was high in both the D-VMP and VMP groups (91% vs 74%), but the complete response rate on D-VMP was almost twice as great (42.6% vs. 24.4%; P<0.001).


MURANO Study Identifies Standard in R/R CLL

When either is combined with rituximab, the oral bcl-2 inhibitor venetoclax was found more effective than bendamustine in a multinational trial for the treatment of relapsing or refractory chronic lymphocytic leukemia (CLL). Against bendamustine plus rituximab (BR), venetoclax plus rituximab (VR) reduced the risk of progression or death by more than 80%. Grade 3 or higher neutropenia was more common with VR relative to BR (58% vs 39%), but grade 3 or higher febrile neutropenia was lower (4% vs 10%).

“Venetoclax plus rituximab was associated with clear superiority that was observed across all biological subsets,” reported John F. Seymour, MBBS, PhD, Director of Cancer Medicine, Peter McCallum Cancer Center, Victoria, Australia. He suggested that the data “may establish this combination as one of the standard options in relapsing remitting CLL.”

In this trial, called MURANO, 389 patients were randomized. Forty-three percent had two or more prior lines of therapy, and nearly 80% had been previously treated with an anti-CD20 monoclonal antibody. Approximately 25% had CLL with mutated TP53 and nearly 30% had a del(17p). In the VR arm, there was a 5-week ramp up in the venetoclax dose to a maximum of 400 mg orally in order to reduce the risk of cytokine release syndrome (CRS).

After a 23.8-month median duration of followup, the median PFS was 17 months in the BR group but has not yet been reached in the VR arm (HR 0.17; P<0.0001). The ORR (93.3% vs 67.7%) and CR (26.8% vs 8.2%) were both higher in the VR group. After nine months of treatment, 60% of VR patients had become MRD negative versus only 10% of those randomized to BR. At 18 months, the rate of MRD had declined to <5% in the BR group but remained largely unchanged in the VR group. The estimated 2-year OS also favored VR (91.9% vs 86.6%; P=0.0186), although Dr. Seymour cautioned that this has not yet met the level of significance prespecified to declare an OS advantage.


Cancer-Related VTE: Oral Anticoagulant Non-Inferior to LMWH

In a global trial involving more than 100 treatment centers, the oral factor Xa anticoagulant edoxaban was found non-inferior to the low molecular weight heparin (LMWH) dalteparin for treatment of venous thromboembolism (VTE) in cancer patients. The primary outcome of the trial, called Hokusai, was a composite of recurrent VTE and major bleeding events to capture both efficacy and safety.

The non-inferiority of the oral agent is likely to make it the preferred option, according to Gary Raskob, PhD, Dean, College of Public Health, University of Oklahoma, Oklahoma City. Although LMWH has been identified as the current standard for cancer-associated VTE treatment, the need for subcutaneous injection has complicated its use in the outpatient setting even though the risk of recurrent VTE can persist for months, according to Dr. Raskob.

In this trial, 1050 adult cancer patients with a symptomatic or incidentally detected deep-vein thrombosis or pulmonary embolism were randomized. An independent committee of experts blinded to the treatment adjudicated thrombotic and bleeding events over 12 months of followup regardless of the duration of anticoagulant therapy after randomization. A primary event occurred in 12.8% of the edoxaban group and 13.5% in the LMWH group. These rates were comparable (HR 0.97; P=0.87) and highly significant for a demonstration of non-inferiority for edoxaban (P=0.0006).

Broken down by type of event, thromboembolism was less common in the edoxaban group (7.9% vs 11.3%) but major bleeding events were higher (6.9% vs 4.0%). Almost the entire difference in major bleeding events was confined to the increase rate of upper GI bleeding in the edoxaban group. Intracranial bleeds (2 vs 4) and fatal bleeds (0 vs. 2) were less common on edoxaban.

Based on the convenience of an oral therapy, the results of this trial are expected to change practice. If oral therapy increases the proportion of patients who remain on effective anticoagulation after VTE, it could also result in greater protection from a recurrence, Dr. Raskob speculated. The full results were published simultaneously with the ASH presentation (Raskob et al. N Engl J Med 2017; December 12 epub ahead of print).

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