CHOP Therapy for Indolent Lymphoma Eclipsed by Bendamustine
By Ed Susman
Atlanta, Georgia–Researchers suggest that the combination treatment for indolent non-Hodgkin’s Lymphoma, known as CHOP, is rapidly being replaced by the drug bendamustine.
CHOP – cyclophosphamide, doxorubicin, vincristine and prednisone – accounted for just 16 percent of treatment for patients with indolent lymphoma while bendamustine is part of the first-line therapy in 71 percent of patients, said Wolfgang Knauf, MD, professor of hematology at Onkologische Gemeinschaftspraxix, Frankfurt/Main, Germany.
Most often, CHOP and bendamustine are combined with rituximab, resulting in the R-CHOP or R-bendamustine acronyms. But soon, doctors may only be talking about the latter.
“R-CHOP is dead,” Dr. Knauf said at his poster presentation during the 54th annual meeting of the American Society of Hematology. “The registry data we are showing is a description of what is going on in Germany.”
The registry is recruiting 1000 patients with indolent lymphomas; 1000 with chronic myelogenous leukemia; 500 with myeloma and 1000 patients with aggressive lymphomas. He said that the researchers in Germany expected to (be able to) present the outcome of the data next year, but he cited recent clinical trials that showed an advantage for patients treated with bendamustine-based regimens when compared with CHOP-based treatment schedules.
Knauf said that rituximab is used in 94 percent of treatment of the 645 patients in the registry who are diagnosed. It is combined with bendamustine in 66 percent of the cases. Bendamustine-rituximab was employed 428 times. Another two percent of doctors used bendamustine as a monotherapy.
As a second-line therapy, bendamustine again is used more often than CHOP, Knauf illustrated. Of those 121 cases, rituximab was administered to 102 patients; bendamustine was used in 82 patients – in combination with rituximab in 72 patients. Rituximab-CHOP was used as a second line treatment in nine patients.
“Our message, as of now, is that rituximab-CHOP can no longer be considered as a standard-of-care,” Knauf said.
While the role of CHOP therapy is diminished, its obituary might be premature, said Andre Goy, MD, chief of the lymphoma division at Hackensack University Medical Center in New Jersey.
“There is no question that the progression free survival is dramatically different with bendamustine,” Dr. Goy said. “We have to be careful the way we look at these data. There was no difference in complete response rate and in overall survival. Progression free survival in follicular lymphoma does not necessarily translate into overall survival. And there are some hints that bendamustine may be a bit more toxic than its perception.”
The real world of Gleevec
In the real world, treatment of patients on imatinib (Gleevec) works as well in patients with chronic myelogenous leukemia (CML) as in clinical trials – but doctors at the community hospital level may not be testing their patients enough, researchers reported.
In one study, about 75 percent of patients (who were treated in clinical trials) and about 75 percent of patients (who declined to be in a trial) – but were both on imatinib – achieved event-free survival at 10 years (P=0.860), said Musa Yilmaz, MD, clinical fellow in leukemia at the University of Texas MD Anderson Cancer Center, Houston.
“These results suggest that patients with CML treated outside a clinical trial may have the same excellent outcome as those treated on a clinical trial – provided they are managed and followed with the same rigor,” Dr. Yilmaz said.
However, in a second study, researchers found that after six months, 37 patients on imatinib at community hospitals had achieved either a major molecular response or a complete molecular response – yet just 21 of these patients (57 percent) had undergone testing within six months from achieving those responses, said James Gilmore, PharmD, vice president of Georgia Cancer Specialists, Atlanta, a group of 40 practitioners. That is despite guideline recommendations of such a monitoring test every six months.
“Our retrospective review of patients with Philadelphia chromosome-positive chronic phase CML receiving imatinib in a community outpatient setting found there is under-monitoring of treatment response,” said co-author Mansoor Saleh, MD, director of clinical research at Georgia Cancer Specialists. “This may result in under-detection of patients with treatment resistance or suboptimal response which limits the ability to modify or switch tyrosine kinase inhibitor treatment accordingly and ultimately compromises patient outcomes.”
The researchers noted that among 36 patients in their study, who were compliant with monitoring guidelines, there was no indication of disease progression or death. Among the 98 patients who were not in monitoring compliance, 10 had progression of the disease. Three had progressive disease and seven died.
In the MD Anderson study, Dr. Yilmaz and colleagues identified 71 patients who were treated with imatinib as per clinical trial protocol and 65 patients who were treated off protocol. “I compared patients who were treated with 100 mg of imatinib in a clinical trial versus that out of a clinical trial,” he told MedPage Today at his poster presentation. “We thought that the treatment of people treated on protocol and off protocol should be the same, right? That’s what we wanted to determine.
“There is controversy over whether patients off protocol who are not followed as strictly as those in a clinical trial would have the same results. We are reporting that we observe no differences in outcomes.”
In commenting on the studies, Stuart Goldberg, MD, chief of the leukemia division at John Theurer Cancer Center at Hackensack University Medical Center, New Jersey, said, “Imatinib, dasatinib (SpryCel), nilotinib (Tasigna) – all these medicines work well in chronic myelogenous leukemia. “The key to success in treating CML is not the drugs,” he said. “They work. The key to success is the skill of the doctor to perform the necessary tests.”
He suggested that in community hospitals, CML is uncommon and doctors may not be familiar with the critical value of testing. “When the patient is not properly monitored, the first time you realize something is wrong is when he or she loses their hematologic response and move into blast crisis and the patient may die. If you monitor the patient properly, you can spot signs of changes in response and you can intervene. By monitoring, you can catch problems before they become clinically significant. If it becomes clinically significant, it’s too late.”
New drug shows promise
An all-oral regimen for treatment of patients newly diagnosed with multiple myeloma appears active and tolerable. Weekly oral doses of MLN9708 resulted in 58 percent of 64 evaluable patients in the Phase 1/2 trial achieving either a complete response in eliminating detectable M-protein (23 percent) or a very good partial response (35 percent), said Shaji Kumar, MD, associate professor of hematology and medicine at the Mayo School of Medicine, Rochester, Minn.
“The all-oral combination of weekly MLN9708 (ixazomib citrate), lenalidomide, and dexamethasone appears to be generally well tolerated,” Dr. Kumar said in his oral presentation at the meeting that has drawn more than 20,000 blood disorder specialists and allied healthcare professionals.
He said the study was the first attempt to initially treat multiple myeloma with a front-line oral therapy. The researchers enrolled adults with performance status of 0-2 and adequate liver, kidney and hematologic function. They also had to have measurable M-protein in their blood and urine. Patients were not eligible if they had Grade 2 or greater peripheral neuropathy, prior or current deep vein thrombosis or pulmonary emboli or prior systemic multiple myeloma therapy.
Median age was 50 years and about 55 percent of the patients were men. The dose limiting toxicity was established at 2.97 mg/m2 noted as an urticarial rash. The researchers went forward with a recommended Phase 2 dose of 2.23 mg/m2. One person died on the study drug of underlying pneumonia caused by respiratory syncytial virus after cycle 4. It’s considered possibly related to treatment; alternatively related to underlying disease state. Peripheral neuropathy was reported in 21 patients. Grade 3 peripheral neuropathy was reported by two patients.
The median time to response was about one cycle,” Dr. Kumar said. “The duration of response has not yet been reached.” The median time on the regimen was about six months. He suggested that more patients would move into the complete response of very good partial response with time. He said similar responses were seen in patients with favorable and unfavorable cytogenetics.
“At data cut-off, with a median drug exposure of six months, 92 percent of patients overall had achieved partial response or better,” Dr. Kumar said.
For comments, write me at edwardsusman@cs.com
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