Good But Short-Lived Responses to Rituximab in LPHD

ORLANDO—The activity of rituxi-mab (Rituxan) in lymphocyte-predominant Hodgkin’s disease (LPHD) warrants additional investigation, according to a presentation at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 1052).

"Rituximab appears to have some activity in patients with LPHD, but the duration of response is quite short, and two cases transformed to large-cell non-Hodgkin’s lymphoma, so there is some debate about whether it is an appropriate therapy," lead author Bradley C. Ekstrand, MD, PhD, senior oncology fellow, Stanford University Medical Center, told ONI in an interview. "It will require a lot more investigation."

Lymphocyte-predominant Hodgkin’s disease is rare, constituting only 5% of all Hodgkin’s disease cases, and misdiagnosis is common because pathologic features may be similar to those of other types of Hodgkin’s disease. Although LPHD is typically relatively indolent and limited to the lymph nodes, it represents a therapeutic challenge.

"With the standard therapy of radiation therapy and chemotherapy, 96% of patients have a complete response, but they tend to relapse over time, with relapses continuing up to 20 years after remission," Dr. Ekstrand said. "Significant late effects of therapy include secondary cancers."

The rationale for using the anti-CD20 antibody rituximab is that the malignant cells of LPHD are CD20 positive, and therefore rituximab may have activity with fewer adverse late effects than conventional chemotherapy.

In this phase II trial, 22 patients with either untreated or relapsed CD20-positive LPHD and measurable disease on CT scans received four consecutive weekly doses of rituximab at 375 mg/m2. Patients who had previously received rituximab were excluded, and steroid treatment during the study period was prohibited.

Median age at treatment was 45 years (range, 18 to 61 years). Of 10 previously treated patients, six were in their first relapse, three in their second relapse, and one in fourth relapse. Three had relapsed after chemotherapy alone, three after radiotherapy alone, and four after combined modality treatment. Median duration of remission before receiving rituximab was 9 years. Of 12 patients with untreated disease, 6 were stage I or II, and 6 were stage III.

The most frequent sites of disease were the neck and axilla, with iliac and inguinal regions also frequently involved. Retroperitoneal, mediastinum, and spleen involvement was significantly less common. The majority of patients had only 1 to 2 Ann Arbor sites of disease at the time of treatment.

Treatment-related adverse events were minimal, with no reported grade 3-4 toxicities. Patients had restaging studies at 1, 3, and 6 months, and every 6 months thereafter.

Criteria for complete response, as confirmed on CT, were that all pathologically involved lymph nodes had to shrink to 1.5 cm in diameter or less. If lymph nodes were smaller than 1.5 cm when found to have pathologic involvement, they had to shrink to 1 cm or less.

100% Response Rate

All 22 patients have responded, with complete response in 9 (41%), complete response unconfirmed in one (11%), partial response in 11 (50%), and one partial response 1 month after treatment completion (11%) that has yet to be confirmed. Response rates were similar among untreated and previously treated patients.

With a median follow-up of 13 months, 9 patients have relapsed. "Despite an initial high response rate, re-lapses are common and occur quickly," Dr. Ekstrand said. "There were no relapses before 6 months, but relapses were fairly common after that."

The quality of response to rituximab was a significant predictor of relapse, he noted, with only 2 of 10 patients who achieved a complete response relapsing at the time of analysis, compared with 7 of 12 patients with a partial response.

Five of the relapsing patients underwent re-biopsy; all were still CD20-positive. Three of these relapsing patients had recurrent disease, although one of these had microscopic features that were suggestive of, but not diagnostic of, transformation to T-cell-rich B-cell lymphoma. These three patients were retreated with four weekly doses of rituximab. One achieved a complete remission and the other two had stable disease.

There were two cases of transformation. One patient transformed to CD20-positive diffuse large-cell lymphoma. This patient became PET-negative after four weekly doses of rituximab before receiving CHOP chemotherapy. An additional patient transformed to T-cell-rich B-cell lymphoma. Dr. Ekstrand called these two transformations "a cause for concern that warrants further investigation."

The investigators concluded that rituximab can induce prompt tumor reduction in LPHD patients with minimal toxicity. Although responses were generally short-lived, rituximab retreatment after relapse was effective in some patients, suggesting that strategies incorporating rituximab in alternative dosing schedules or combinations merit further investigation.

Although the effect of rituximab on the LPHD cell is still unknown, Dr. Ekstrand said that it could be knocking out background CD20-positive cells. The next planned study is to further define the single-agent utility of rituximab, using alternate dosing, most likely in a maintenance protocol.

"Oncologists in practice should bear in mind that even though rituximab may have some activity in certain situations, it is too early to incorporate it into clinical protocols," Dr. Bradley told ONI. "I wouldn’t recommend that an untreated patient get rituximab first; it may be too early to consider it as an upfront therapy outside clinical trials."