CHOP-Campath for PTCL

Abstract & Commentary

By Andrew Artz, MD, MS, Division of Hematology/Oncology, University of Chicago, Chicago, IL. Dr. Artz reports no financial relationship to this field of study.

Synopsis: This multicenter trial evaluated the efficacy of combining alemtuzumab (Campath 1-H) to standard CHOP for peripheral T-cell lymphomas. Among 24 evaluable patients, the complete response rate was 17/24 (71%) using 8 cycles of CHOP plus 30 mg of Campath monthly. Infectious complications were not infrequent and included Jacob-Creutzfeld (JC) virus encephalitis, invasive aspergillosis, CMV reactivation, and bacterial sepsis. CHOP plus Campath has promising disease activity in PTCL although may also lead to increased infectious complications.

Source: Gallamini A, et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as a first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood. 2007;110:2316-2323.

The peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas that account for <15% of non-Hodgkin’s lymphoma diagnoses. Peripheral T-cell lymphoma, unspecified (PTCL-U) is the most common type. Other subtypes include anaplastic large cell (ALCL), angioimmunoblastic-like T-cell lymphoma (AILD-T), extranodal NK/T-cell lymphoma-nasal type, subcutaneous panniculitis-like T-cell lymphoma, enteropathy-associated T-cell lymphoma (EATCL), and hepatosplenic gamma/delta T-cell lymphoma.

Peripheral T-cell lymphomas have a poor prognosis with median survival of < 2 years.1 Initial treatment frequently consists of standard combination chemotherapy using cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). The prognosis remains < 50% at 5 years, even for treated patients, except for those harboring low-risk features.2 Thus, novel approaches are warranted to improve outcome for PTCL. The expression of CD52 in PTCL, although variable, raises the possibility of using Campath-1H (alemtuzumab), an anti-CD52 humanized monoclonal antibody.3

From June 2003 to December of 2005, 14 Italian institutions within the GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospectively enrolled 25 patients on this protocol. Treatment consisted of 8 cycles of monthly CHOP chemotherapy and concomitant Campath (CHOP-C). The first four patients received Campath during the first four cycles of CHOP (CHOP-C). Then CHOP without Campath was given in cycles 5-8. Following that, subsequent patients received CHOP-C for all 8 cycles. Campath was administered subcutaneously using standard pre-medication. Escalation during the first course followed a schedule of a starting dose of 3 mg on day -2, 10 mg on day -1, and 30 mg on day 0. For subsequent cycles, 30 mg of Campath was given the day before CHOP. Infection prophylaxis included 400 mg of acyclovir twice a day, sulfamethoxazole/trimethoprim twice a day on alternative days, itraconazole 400 mg/day and ciprofloxacin when the absolute neutrophil count fell below < 500/uL. The Eastern Cooperative Oncology Group NHL response criteria defined responses.

The mean age was 52 years. Central review confirmed PTCL in all but one case, leaving 24 evaluable subjects. The histologic subtypes enrolled included PTCL-U (58%), AILD-T (25%), and alk negative ALCL (12.5%), and EATCL (4%). One third of patients had an international prognostic index (IPI) of 0-1. The remainder had a score of 2-5. In the 15 patients where immunostains were evaluable, 11 showed CD52 positivity and 4 did not (threshold not provided).

The complete and overall response rate was 17/24 (71%) and 18/24 (75%), respectively, as only one patient achieved a PR. Actuarial overall survival was 70% at 1 year and 53% at 2 years whereas progression-free survival was 54% at 1 year and 48% at 2 years. Neutropenia accounted for most of the hematologic toxicity at 34% of chemotherapy cycles. Cytomegalovirus reactivation occurred in 9% of chemotherapy courses. Other infectious complications include one case of J-C virus encephalitis leading to dementia and 2 cases of invasive aspergillosis. One patient developed Pneumocistis carinii pneumonia. One patient was suspected of having atypical mycobacteriosis.

Commentary

Peripheral T-cell lymphomas represent a heterogeneous group of lymphoma subtypes. Results with standard chemotherapy such as CHOP have been disappointing. The improvement in outcomes for B-cell lymphoma, spurred by the use of anti-CD20 antibodies such as rituximab, stands in contrast to the limited progress for T-cell lymphoma. Progress has been severely hampered as an uncommon lymphoma making enrollment on clinical trials difficult.

The majority of PTCL appear to express CD52, making Campath, an anti-CD52 humanized antibody, a reasonable therapeutic consideration. The 71% complete response rate in 24 patients using CHOP plus Campath (CHOP-C) appears to be an incremental gain compared to the historical results of 50% or less using standard CHOP. The authors deserve credit for prospective accrual for this uncommon and highly variable lymphoma. The survival results are sobering: overall survival was approximately 50% at 2 years. The small sample prevents further stratifying by pre-treatment characteristics. Longer time follow-up will be also been needed. Since 1/3rd of patients had low-risk disease by the international prognostic index, it is not possible to conclude that CHOP-C improved outcome. Another recent study of 20 PTCL patients using a 3 week scheduled of CHOP-C showed a similar 65% CR rate.4 The study closed early due to excessive infectious complications.

Not surprisingly, there were a considerable number of opportunistic and bacterial infections despite a relatively low dose of Campath (30 mg once a month) and close infectious monitoring and prophylaxis. While an appealing strategy would be dose escalation of Campath or shortening CHOP-C cycles (eg every 14 or 21 days), infectious complications might be dose limiting. Another strategy may be employing Campath only in cases where lymphoma cells strongly express CD52.

The results should be taken in the context of other therapeutic options. Autologous transplant in first complete remission has not been successful. Allogeneic transplant, particularly using reduced intensity conditioning, continues to be explored. Randomized studies may be required to determine whether CHOP-C offers a benefit compared to standard therapy.

CHOP-C represents one option for upfront treatment of PTCL but requires aggressive monitoring for infectious complications.

References:

1. Ansell SM, et al. J Clin Oncol. 1997;15:2296-2301.

2. Gallamini A, et al. Blood. 2004;103:2474-2479.

3. Rodig SJ, et al. Clin Cancer Res. 2006;12:7174-7179.

4. Kim JG, et al. Cancer Chemother Pharmacol. 2007;60:129-134.