March 14, 2011 (Hollywood, Florida) — A new guideline for transplant lymphoproliferative disorder (PTLD) and revised recommendations for the


March 14, 2011 (Hollywood, Florida) — A new guideline for transplant lymphoproliferative disorder (PTLD) and revised recommendations for the treatment of follicular lymphoma are among the updates to the National Comprehensive Cancer Network (NCCN) guidelines for non-Hodgkin's lymphoma (NHL).

In addition, the use of positron emission tomography (PET) in the assessment of follicular lymphoma was highlighted as a "special topic" during a presentation on NHL by AndrewD. Zelenetz, MD, PhD, here at the NCCN 16th Annual Conference.

Dr. Andrew Zelenetz

Dr. Zelenetz, who is chair of the NCCN panel for NHL and from the Memorial Sloan-Kettering Cancer Center in New York City, walked the audience through the basics of PTLD. He explained that the disorder, which is a type of lymphoma, occurs after either a solid organ or hematopoietic stem cell transplantation and is a life-threatening complication.

In the case of solid organ transplants, the disorder is most often of recipient origin; in stem cell transplants, it is most often of donor origin, he said.

Most PTLD (80%) is Bcell subtype, but Tcell lymphomas and Hodgkin's lymphoma can also occur.

There is an array of risk factors for PTLD, including recipient Epstein-Barr virus seronegativity, which confers a 24-fold increased risk for the disorder, relative to the average posttransplant risk.

The new guideline for PTLD, which is integrated into the larger NHL guideline, details the steps to diagnose and work up the disorder and categorizes those steps as either "essential" or "useful under certain circumstances."

In terms of establishing a diagnosis, histopathology and "adequate" immunophenotype are essential, said Dr. Zelenetz, who noted that the histology can be either polymorphic (mostly a mixture of small- and medium-sized cells) or monomorphic (large-sized cells). Viral-load testing for Epstein-Barr virus is also essential.

"The work-up looks a lot like that of the other evaluations for non-Hodgkin's lymphoma," said Dr. Zelenetz. Evaluating a patient's performance status, recording his or her transplant immunosuppressive regimen, and checking albumin levels are among the essential work-up details.

Treatment depends on the PTLD subtype and has varying rates of response. The treatment options include reducing posttransplant immunosuppression, from which "roughly 25% [of patients] will have a sustained response," said Dr. Zelenetz. Reducing immunosuppression is the most common treatment and is the primary therapy for patients with "early lesions," polymorphic systemic PTLD, and monomorphic PTLD, according to the guideline.

Other treatment options include antiviral therapy, rituximab, chemotherapy, and stem cell transplantation, which is reserved for a "select few," said Dr. Zelenetz.

Follicular Lymphoma: Improving Care for a Paradox

There are 2 outstanding treatment-related changes to the follicular lymphoma section of the NHL guideline.

First, the combination of rituximab and bendamustine (Treanda, Cephalon) is now a category1 recommendation for suggested first-line therapy, which means the recommendation is based on high-level evidence, such as data from randomized controlled trials, and that there is uniform NCCN consensus; the designation is an upgrade from its former2A status (lower-level evidence).

Second, the options of rituximab maintenance and radioimmunotherapy after first remission are also now category1 (upgraded from 2B, which is lower-level evidence that lacks NCCN consensus of opinion).

Before detailing these changes, Dr. Zelenetz noted that "follicular lymphoma is a disease of paradoxes." He explained that it is "incurable but has a long natural history," and that it is "highly responsive to therapy but that relapse is inevitable." Also, the "potentially curative" therapy of allogenic stem cell transplantation has a high rate of treatment-related mortality — that is, it "kills about 20% of patients," said Dr. Zelenetz.

Follicular lymphoma, in particular, requires individualized treatment planning, said Dr. Zelenetz. "Follicular lymphoma treatment depends on the stage and extent of disease," he said. To illustrate his point, he told the story of a new follicular lymphoma patient who spent time talking to 3 other patients in his waiting room in New York City one day. After learning of the varied treatment approaches among the other patients, the woman declared, upon finally seeing Dr. Zelenetz, "I don't think you know what you are doing."

The use of bendamustine in follicular lymphoma has been established by a clinical trial from Germany. The trial showed that bendamustine plus rituximab significantly improved progression-free survival, compared with standard therapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab (CHOP-R) in patients with advanced follicular lymphoma, as well as in those with mantle cell lymphomas and other miscellaneous lymphomas. In patients receiving bendamustine plus rituximab, progression-free survival was 54.9 months; in patients receiving CHOP-R, it was 34.8 months (P= .00012). "This surprised many of us," said Dr. Zelenetz. The therapy also significantly improved complete response rates; however, there was no difference in overall survival between the 2 treatment groups.

Bendamustine plus rituximab was also better tolerated than CHOP-R in the trial, with no alopecia and less hematologic toxicity. On the downside, the long-term toxicity of bendamustine is unknown, said Dr. Zelenetz.

"Any grade1 or 2 follicular lymphoma patient who needs therapy should consider bendamustine plus rituximab," said Ephraim Paul Hochberg, MD, from the Massachusetts General Hospital Cancer Center in Boston. Dr. Hochberg, who attended the NCCN meeting, told Medscape Medical News that the drug combination is a "big deal" in follicular lymphoma for the same reasons mentioned by Dr. Zelenetz — the combination of improved progression-free survival, no hair loss, and a relative lack of neutropenia.

Another change to the follicular lymphoma treatment section of the NHL guideline involves therapy options after first remission. Recent studies have shown that progression-free survival is improved with postremission therapy (either radioimmunotherapy after chemotherapy or rituximab maintenance). These 2 approaches are now category1 recommendations, up from category2B. Unfortunately, overall survival is not affected, Dr. Zelenetz.

PET is Helpful Tool

In the section of the NHL guideline on the work-up of grades1 to 2 follicular lymphoma, there is mention of the fact that PET scanning might be useful in select patients.

Recent trials have suggested that fludeoxyglucose-PET imaging can distinguish between indolent and aggressive lymphoma, explained Dr. Zelenetz, pointing out that the likelihood of aggressive disease increases with higher standardized uptake values.

This is helpful when there is a concern that a patient might experience a "transformation" from indolent to aggressive disease, he said.

"The PET scan results can help guide the site for the optimal biopsy if there is concern about transformation of indolent lymphoma; however, it cannot replace a biopsy," said Dr. Zelenetz in a press statement from the NCCN. In other words, the scan does not provide a pathologic diagnosis, but it can "show you which lymph node is best to biopsy," he said, adding that this is different from the "most convenient lymph node."

In addition, PET-computed tomography scans can also be useful in evaluating a patient's response to treatment for follicular lymphoma. A recent study indicated that "patients with PET positivity at the end of treatment for follicular lymphoma are going to do really badly," said Dr. Zelenetz.

"The predictive power of posttreatment PET is stronger than, and independent of, other prognostic factors," he said.

Dr. Zelenetz reports receiving grant/research support from Amgen, Genentech, and GlaxoSmithKline; and being a consultant to Celgene, Cell Therapeutics, Cephalon, Genentech, GlaxoSmithKline, and Sanofi-Aventis.

National Comprehensive Cancer Network (NCCN) 16th Annual Conference. Presented March11, 2001.





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