ALBERT

Description: Combination therapy with purine analogs, alkylators, and monoclonal antibodies has transformed the treatment paradigm in patients with CLL by dramatically enhancing both the quality and frequency of responses that can be achieved in these patients. However, combinations utilizing fludarabine as the purine analog have augmented myelosuppression and immunosuppression requiring careful attention to dosing and schedule in order to minimize these complications. Even with these precautions many patients are unable to complete the entire treatment program at full dose and for the planned number of cycles. Comparative experience with pentostatin indicates that it is less myelosuppressive than either fludarabine or cladribine. We previously reported our experience with pentostatin and cyclophosphamide. Subsequently, we have added rituximab to this active combination (PCR regimen) and treated a second cohort of 46 patients with previously treated CLL (32 patients) and other low grade lymphoid neoplasms (14 patients). The PCR regimen consists of pentostatin 4mg/m2, cyclophosphamide 600mg/m2, and rituximab 375mg/m2 all given on a single day with anti-emetics, hydration, and careful monitoring of renal function. The treatment was administered every 3 weeks for a total of 6 treatments. Rituximab was not given during the first cycle to reduce the frequency and severity of infusion reactions. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median age of the patients treated was 62 (range 44–80) and the median number of prior regimens was 2 (range 1–7). The overall frequency of response was 75% with 25% achieving a complete response, 3% a nodular response, and 47% a partial response. We have compared these results to the recently reported MD Anderson FCR regimen. In terms of pre-treatment characteristics the patient groups in both studies appear comparable with the exception of a higher proportion of high-risk patients treated with PCR (78%) compared to FCR (50%) (P=0.003). The response frequencies are virtually identical in both studies with responses seen 75% of PCR treated patients and 73% of FCR treated patients and CR achieved in 25% in both studies. In terms of toxicity, however, PCR compares favorably to FCR in the following categories: Grade 3/4 neutropenia PCR 53% vs FCR 81% (P=0.0007), thrombocytopenia PCR 16% vs FCR 34% (P=0.04), anemia PCR 9% vs FCR 24% (P=0.06), and grade 3/4 infections (including fever of unknown origin) PCR 28% vs FCR 47% (P=0.05). PCR also appeared to be better tolerated than FCR as indicated by the fraction of patients completing all planned cycles of chemotherapy at full dose 72% vs 38% (P=0.0004). An important caveat in these comparisons is that myeloid growth factor was routinely administered to patients on the PCR study but was not routinely administered to patients treated with FCR. In conclusion, PCR appears to be equivalent in activity to FCR but may be better tolerated and less toxic. These results indicate that a prospective randomized comparison is warranted.

Description: Targeted modalities are playing a an increasing role in modern oncology. We have previously demonstrated that the unconjugated humanized anti-CD33 monoclonal antibody, HuM195 has activity in the setting of relapsed AML. Given these results, we designed a clinical trial investigating whether antibody therapy can be combined with other therapeutic approaches including dose intensive chemotherapy and drug/growth factor immunomodulation as the initial therapy for adults with AML and whether such patients can safely proceed to stem cell transplantation. Patients in this study were treated with MEC (mitoxantrone 8 mg/m2, etoposide 80 mg/m2, and cytarabine 1 gm/m2 daily for 6 days). HuM195 was administered for 4 days at a dose of 12 mg/m2 on days 6–9 and days 19–22. GM-CSF (250 ug/m2/day) was begun on day 8 and continued until neutrophil recovery. Patients who achieved CR and had a suitable related donor proceeded directly to allogeneic stem cell transplantation (SCT). Others received two additional cycles of high-dose cytarabine followed by autologous SCT augmented by combination cyclosporin and GM-CSF in an effort to induce an autologous graft versus leukemia (GvL) effect. Thirty patients have been treated to date (15 patients with de novo AML; 15 patients with secondary AML). The median age was 51 years (range 24–71). Nineteen of the 28 evaluable patients (68%) achieved CR with 14 of the 15 (93%) de novo AML patients achieving a CR. Three deaths from uncontrolled infection occurred during induction. In patients achieving CR, the median time to recover an ANC 〉 500/mm3 was 23 days (range 20–36) and a platelet count 〉 20,000/mm3 was 17 days (range 12–42). Four patients proceeded directly to allogeneic stem cell transplantation without any consolidation therapy and three remain free of disease with a median follow-up of 24 months. One patient is too early for evaluation. Five patients went on to autologous stem cell transplant (AuSCT) and two remain in remission after 13 and 24 months. Three patients relapsed after AuSCT. Two expired from refractory leukemia, and one was salvaged with allogeneic SCT. Among the AuSCT patients, the median time to recovery of the ANC 〉 500/mm3 and platelet count 〉 20k/mm3 was 7 days (range 1–9) and 7.5 days (range 5–22), respectively, comparable to patients who received standard induction regimens. There was no clinical evidence of graft verses host disease in the AuSCT patients. No evidence of veno-occlusive disease was observed after either autologous or allogeneic transplantation. Preliminary results suggest combined modality therapy is feasible and well-tolerated as initial therapy for AML. Patients are able to receive dose intensive consolidation therapy including transplantation safely after the use of an intensive induction with combined modality therapy incorporating HuM195. All patients who underwent an allograft after induction remain in remission with two year follow up. Further follow-up is needed to determine the effect on long term outcomes.