CHOP Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Hemolytic Anemia (AIHA) or Richter’s Transformation (RT): First Interim Analysis of a Phase II Trial of the German CLL Study Group (GCLLSG).

Introduction: Fludarabine-based treatment regimen are the most effective treatment option for first or second line treatment of CLL. Pts refractory to F as well as pts with RT, which occurs in 3% to 12% of CLL pts, have a severely impaired prognosis. Moreover, AIHA in general and AIHA after F treatment respectively are well known problems in CLL pts. The combination CHOP plus rituximab has been shown to induce major response rates in B-cell lymphoma. We evaluated the tolerability and efficacy of the CHOP-R regimen in CLL pts refractory to F or with AIHA as well as in pts with RT within a multicentre phase II trial of the GCLLSG.

Patients: Between June 2003 and July 2005 34 pts (mean age 66 [range 40 - 78] years) with advanced stage Binet C and Binet B were enrolled in this trial. Pts received CHOP therapy consisting of cyclophosphamide (750 mg/m² IV), adriamycin (50 mg/m² IV) and vincristine (1.4 mg/m² IV) on day 1 plus prednisolone 100mg/m² for five days orally. From the second treatment course 375 mg/m² rituximab was given on day 0, if the leukocyte count was less than 50.000/μl. The regimen was repeated every 21 days for up to 6 courses in CLL pts and up to 8 cycles in RT pts. Anti-infective prophylaxis with acyclovir and cotrim was recommended for all pts.

Results: Two pts had to be excluded because of violation of the inclusion criteria. 19 pts with F refractory CLL, 7 CLL pts with AIHA and 4 pts with RT were included. Disease status was unknown in 4 pts. By August 1st 2005 data from 25 pts (17 F refractory, 5 pts with AIHA and 3 with RT) and 102 treatment courses were available. 72% of the pts were Binet stage C. The mean number of previously administered treatment courses was 2.1. 48% of the pts have received 3 pretreatments.CHOP-R treatment was well tolerated. Main toxicities were myelosuppression (59% of all documented courses) with anemias in 32%, thrombocytopenias in 29% and leukocytopenias in 26%. Nausea and vomiting were assessed in 26% and infections in 22% of all courses. 4 episodes of severe, CTC grade 3 and 4, infections were observed. 26% of the pts developed alopecia. Side effects, mostly milde fever and chills, occurred in 19% of 78 administered rituximab infusions. 10% of the side effects occurred during the first rituximab administration. No tumor lysis syndrome was reported so far. 17 pts were evaluable for response. The overall response rate (ORR) was 70% for all pts. No complete remission was documented. The ORR was 69% in 13 F refractory pts. Two pts with AIHA documented for response had a partial remission. The hemoglobin level improved in both pts after 6 courses CHOP-R. The Coombs test became negative in one pt. 6 pts died so far (4 pts with F refractory CLL,1 pt each with AIHA and RT), two of them due to infectious complications, 4 pt because of progressive disease.

Conclusion: CHOP-R can be safely administered in pts with F refractory CLL or CLL with AIHA as well as in pts with RT. Main side effects were myelosupression, nausea and infections. These preliminary data show, that CHOP-R is a very effective regimen in poor risk pts with CLL.