Conference Coverage

Chemo-free induction in MCL keeps getting better


 

AT14-ICML

– It’s not the end of chemotherapy for young patients with newly diagnosed mantle cell lymphoma (MCL), but it’s a start.

For these patients, induction with a combination of ibrutinib and rituximab, followed by shorter cycles of chemoimmunotherapy, was associated in an early study with an objective response rate of 100%, including 90% complete responses (CR), reported Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This is the first time for a chemo-free therapy – ibrutinib/rituximab – to achieve an overall response rate of 100%. This has an unprecedented efficacy in the frontline in young patients with mantle-cell lymphoma,” he said at the 14th International Congress on Malignant Lymphoma.

In patients with relapsed or refractory MCL, the combination of ibrutinib and rituximab has been associated with durable responses in 88% of patients. The success of the combination suggests that fit patients younger than age 65 years with newly diagnosed MCL might benefit from a chemotherapy-free induction regimen with ibrutinib and rituximab, followed by consolidation with a short but intense course of chemoimmunotherapy, Dr. Wang said.

He presented updated results from the phase II Window I study, first results of which were reported at the 2016 meeting of the American Society of Hematology.

“Frontline therapy is the most important therapy for mantle cell lymphoma, because mantle cell lymphoma cells are most vulnerable to frontline attack. If the frontline therapy is good enough, it could kill all the mantle cell lymphoma cells, therefore leaving no chance for secondary resistance, and thereby (resulting in) long-term survival. And it is really my belief that if we ideally optimized the frontline therapy, that would be a shortcut to a cure,” he said.

To test this idea, Dr. Wang and MD Anderson colleagues initiated a phase II trial at their institution with 50 patients age 65 years or under with newly diagnosed, CD20-positive and Cyclin D1-positive MCL.

A total of 50 patients age 65 years or younger (median age 54) with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib 560 mg, plus rituximab 375 mg/m2 administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating every 28 days with rituximab plus high-dose methotrexate–cytarabine.

Patients who had complete responses to induction received four cycles of chemoimmunotherapy, while those who experienced disease progression and those who had partial responses received chemoimmunotherapy for two cycles beyond the point of complete remissions.

At the time of the presentation, all 50 patients were evaluable for the induction phase (part 2), and 47 were evaluable for both induction and consolidation (part 2) .Of the evaluable patients, the overall response rate (ORR) to chemotherapy-free induction therapy alone (Part 1 ) was 100% (50), with CR in 90% of patients and partial responses (PR) in 10%. Of the 47 patients evaluable for part 2 (chemoimmunotherapy), all had CRs, for an ORR of 100%.

Dr. Wang noted that one patient had a dramatic radiographic reduction in spleen size following just two cycles of chemotherapy-free induction, and two other patients had similar reductions after four and six cycles, respectively.

After a median follow-up of 15.9 months, neither the median duration of response, progression-free survival, nor overall survival have been reached. There have been no deaths and only one case of disease progression after one year of therapy.

The patients generally tolerated the regimen very well, Dr. Wang said. There were no cases of lymphocytosis, bleeding, or atrial fibrillation after 332 combined cycles.

Nonhematological adverse events were primarily grade 1 or 2. Grade 3 fatigue was reported in approximately 10% of patients. There were no grade 4 adverse events.

“This study may provide a window of opportunity to reduce the frontline therapies and reduce the long-term toxicities such as secondary malignancies.” Dr. Wang said.

He acknowledged that four cycles of intensive chemotherapy is still toxic and that further efforts to reduce these toxicities are needed. The investigators are currently planning the Window II study, in which a fraction of patients will be treated with no chemotherapy at all, he said.­­­­

The study was supported by Pharmacyclics and Janssen. Dr. Wang disclosed receiving research grants and honoraria and serving as a consultant for the companies.

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