August 03, 2015
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Doublet therapy safe, effective in heavily pretreated non-Hodgkin's lymphoma

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Combination therapy with temsirolimus and bortezomib demonstrated safety and efficacy in patients with heavily pretreated B-cell non-Hodgkin’s lymphoma, according to the results of a phase 2 study.

“For many types of non-Hodgkin’s lymphoma, there remains a significant unmet need for additional treatment options, especially in the relapsed and refractory setting,” Timothy S. Fenske, MD, associate professor of medicine at Medical College of Wisconsin, told HemOnc Today. “Individually, each of these drugs has shown activity in different types of lymphoma, and preclinical data suggests that treatment with two classes of drugs may have additive or synergistic effects.”

Timothy S. Fenske, MD

Timothy S. Fenske

Combined therapy with proteasome inhibitors and mammalian target of rapamycin inhibitors exhibit activity in several B-cell malignancies and have demonstrated synergy in vitro and in mouse models, according to study background.

Fenske and colleagues conducted a single arm, phase 2 trial to study the efficacy of temsirolimus (Torisel, Pfizer) plus bortezomib (Velcade; Takeda, Millennium Pharmaceuticals) for patients with relapsed and refractory B-cell non-Hodgkin's lymphoma using a dosing scheme previously evaluated in multiple myeloma. The study included data from 39 patients (median age, 68 years; 72% men) who received a median of four prior lines of therapy (range, 1-11).

Most patients had the diffuse large B-cell lymphoma (DLCBL) subtype (n = 18). Other subtypes in the population included follicular lymphoma (n = 9), mantle cell lymphoma (n = 7), small lymphocytic lymphoma (n = 3) and marginal zone lymphoma (n = 2).

Patients received IV bortezomib (1.6 mg/m2) on days 1, 8, 15 and 22 and IV temsirolimus (25 mg) on days 1, 8, 15, 22 and 29 per 35-day cycle for a maximum of six treatment cycles. Researchers amended the treatment cycle by eliminating the day-29 temsirolimus dose after patient 14, due to a relatively high rate of thrombocytopenia.

Overall response rate (ORR) and PFS served as the primary endpoints. Secondary endpoints included complete response rate, duration of response and OS.

Following treatment, researchers observed an ORR of 31% (95% CI, 17-48). Three patients achieved a complete response (7.7%; 95% CI, 1.6-21) and nine patients achieved a partial response (23%; 95% CI, 11-39).

The overall patient population achieved a median PFS of 4.7 months (95% CI, 2.1-7.8). Longer median PFS periods occurred in patients with follicular lymphoma (16.5 months) and mantle cell lymphoma (7.5), whereas patients with DLBCL exhibited a shorter median PFS period (2 months).

Despite the abbreviated median PFS for patients with DLBCL, two heavily pretreated patients in that cohort achieved a complete response.

No unexpected toxicities occurred. Eighty percent of the population (n = 31) experienced a grade 3 adverse event, including thrombocytopenia (44%), neutropenia (26%), gastrointestinal toxicities (15%), lymphopenia (15%), anemia (13%), rash or pruritus (13%) and infections (11%). Two patients reported a grade 4 toxicity. Five patients discontinued treatment due to adverse events.

“This regimen could serve as a platform to which additional targeted therapies could be added,” Fenske said. “In addition, performing molecular profiling on tumor specimens would be of great interest, to hopefully identify a biomarker that would predict for good response, such as was seen in the two responding DLBCL patients.” – by Cameron Kelsall

For more information:

Timothy S. Fenske, MD, can be reached at Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226; email: tfenske@mcw.edu.

Disclosure: Fenske reports personal fees from Celgene, Pharmacyclics and Seattle Genetics. Other researchers report grants from Cellectar and GlaxoSmithKline and consultant roles with Millennium Pharmaceuticals.