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PTCL: CHOP Inadequate, but Comparison Clinical Trials Needed for Other Options

Carlson, Robert H.

doi: 10.1097/01.COT.0000430610.01159.1d


NEW YORK—“CHOP in PTCL—we can't live with it, but can we live without it?” was how one speaker here at the International Congress on Hematological Malignancies characterized the CHOP regimen (cyclophosphamide-doxorubicin-vincristine-prednisone) as a standard for treating patients with peripheral T-cell lymphoma.

“A lot of our experience tells us we are close to the end with CHOP,” said Steven Horwitz, MD, Assistant Attending in the Lymphoma Service at Memorial Sloan-Kettering Cancer Center. Historically, he said, overall response rates are 60 to 80 percent in this rare disorder. Complete responses are 30 to 60 percent, and even then “there is a quick downslope, and only 20 to 30 percent or less of patients achieve durable remissions. “These are very beatable numbers, so why do so many patients with PTCL still get CHOP?”

Although various agents have been added to a CHOP-backbone regimen, with resulting incremental improvements in outcomes, benefits are not seen in all PTCL subtypes, and near the maximum tolerated dose the toxicity soon outweighs the benefits, he said.

Another speaker, Ranjana Advani, MD, Professor of Medicine, Oncology, at Stanford University School of Medicine, said that adding a new drug would seem to offer a winning strategy—etoposide, for example. But anthracycline-based regimens that add etoposide still deliver a five-year overall survival rate of just over 50 percent.

Summarizing three recent clinical trials of CHEOP (CHOP with etoposide), Advani said that the combined five-year overall survival rate was 55 percent for patients with PTCL-not otherwise specified (NOS), and 64 percent for those with angioimmunoblastic T-cell lymphoma (AITL).



As would be expected, though, in those trials the combined overall survival rate was higher for patients with ALK-positive anaplastic large-cell lymphoma (ALCL) (89%) than for those with ALK-negative ALCL (74%). A more likely addition to a CHOP-like regimen, though, she continued, might be brentuximab, the anti-CD30 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin E (MMAE). Other combinations in trials with novel agents to watch are pralatrexate-CEOP, and romidepsin-CHOP, she said.

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Is an Anthracycline Necessary?

Horwitz described a different approach to replacing CHOP: He cited a small Phase II study that took what he said was a quite different but very logical tack with a regimen of cisplatin, etoposide, gemcitabine, and prednisone (Cancer 2013;15:119:371-379). Even so, disappointingly, the two-year overall survival rate was only 30 percent, and median overall survival was 17 months. “I don't think this strategy will be going forward,” he said.

Horwitz also discussed adding an antibody to CHOP, the CD52 antibody alemtuzumab, which he said some thought might be a “recapitulated R-CHOP” in B-cell lymphoma: One trial of alemtuzumab at 30 mg plus the CHOP-24 regimen for eight cycles (Blood 2007;110:2316-2323) produced a failure-free survival rate of 48 percent and an overall survival rate of 53 percent at two years, but the toxicities included a 17 percent rate of Grade 4 infections. A more recent study, of CHOP-14 with alemtuzumab also saw a two-year overall survival rate of 55 percent, but at two years, the event-free survival rate was only 27 percent and treatment-related mortality was 20 percent (Ann Onc 2011;22:1595-1600).

“That reaches the levels of risk we see with transplant,” Horwitz said. The message from these and other trials of alemtuzumab plus CHOP is that while response rates increase, it comes at the costs of increased toxicity. “And we've learned that while normal T-cells express CD52 probably 100 percent of the time, that expression is not translated into all T-cell lymphomas.

“For example, large cell lymphoma almost never expresses CD52 and those patients probably can't benefit from [alemtuzumab] therapy but they could experience some toxicity; and in malignant T-cells there is probably some downregulation of CD52.”



He noted that now ongoing in Europe are several large, ongoing randomized trials that, it is hoped, will add some insight into the value of alemtuzumab in PTCL.

Adding bortezomib to CHOP is not a significant improvement over alemtuzumab, Horwitz said, citing a trial last year in patients with stages 3/4 PTCL with bor-tezomib-CHOP in first-line therapy (Eur J Ca 2012:48:3223-3231). The overall response rate was 76 percent and the complete response rate was 65 percent, but at three years, those rates dropped to 47 and 35 percent, respectively.

Horwitz concluded that “CHOP is inadequate for most PTCL patients, but finding something better is not easy, and the standard of care should be a clinical trial whenever possible.”

Advani concluded by saying that the standard of care should be a clinical trial wherever possible: “CHOP will never be put to rest unless it is compared with something else in a Phase 3 trial.”

© 2013 Lippincott Williams & Wilkins, Inc.
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