Introduction:
Rituximab (R) is an integral component of therapy for B-
cell lymphoid malignancies;
bortezomib (Btz) has shown provocative
single agent activity in
Follicular Lymphoma (FL), Mantle
Cell Lymphoma (MCL) and Waldenstrom's Macroglobulinaemia (WM), providing the rationale for investigating the combination.Patients+Methods: Forty-five
adult patients (pts.) (30 men, 15 women) with histologically confirmed recurrent CD20+ve FL, MCL or WM, median age 60 years (range 45-79), FL: 17, MCL: 18, WM: 10, stage III / IV 40 (93%),
bone marrow (BM) infiltration 32 (73%), elevated LDH 22 (49%),
performance status ≥1 22 (49%), were enrolled in a randomised trial comparing 2 schedules of Brz+R: Arm A (twice weekly) Btz: 1.3 mg / m2 (on days 1, 4, 8, 11 of a 21-day cycle) and R: 375 mg / m2 (on day 1) for 8 cycles, or Arm B (weekly) Btz: 1.6 mg / m2 (on days 1, 8, 15, 22 of a 35-day cycle) and R: 375 mg / m2 (on days 1, 8, 15, 22 of cycles 1 and 4) for 6 cycles (23 arm A, 22 arm B). The median number of previous treatments was 2 (range 1-7). Seventeen pts. had received a R-containing
regimen, with response lasting >6 months, and 8 high-
dose treatment. Response was evaluated using the IWR criteria (Cheson et al, JCO 17:1244, 1999) and the updated response criteria from the 3rd International Workshop on WM (Treon et al, Blood 107:3442, 2006)Results: Ability to deliver the therapy,
toxicity and
efficacy were equivalent in both arms. The median number of cycles given in arm A was 4 and 5 in arm B. Haematological
toxicity (grade≥3: anaemia 0%,
neutropenia 25%, thrombocytopenia 22%) was significantly influenced by the high percentage of pts. with BM infiltration and concomitant
cytopenia on entry to the trial. The most common non-haematological adverse events were fatigue (76%),
nausea (56%), diarrhoea (56%),
lethargy (46%).
Neurotoxicity occurred in 19 pts. (46%) (10 pts. grade 1, 7 pts. grade 2, 2 pts. grade 3). Btz
dose was reduced in 7 pts.; 5 doses were omitted because of neuro or haematological
toxicity. In 16 pts., treatment was delayed by 1-14 days and in 24 pts. treatment was stopped prematurely. The reasons for stopping treatment were: treatment-related toxicity 11 pts., progressive
disease 9 pts., patient's preference 3 pts.,
myocardial infarction 1 pt. One pt. was excluded having been found ineligible post randomisation. Thirty-nine pts. (21 arm A, 18 arm B) are evaluable for response so far, one having only received 1 cycle of therapy, which had to be discontinued because of excessive toxicity. 15 / 32 were in remission (CR, CRu, PR) at the completion of therapy, 7 / 7 at “mid-therapy” assessment, and 5 have yet to be evaluated. Thus the overall response rate (RR) presently is 22 / 39 (56%) (CR, CRu, PR), FL 44%, MCL 46%, WM 90%.Conclusions:The combination was active in pts. with recurrent NHL especially WM (RR 90%), despite multiple previous treatments, The weekly schedule is preferable being more convenient, as efficacious and no more toxic.Further investigation is warranted, despite not insignificant therapy compromising toxicity.