ALBERT

Description: Purine analogs, particularly fludarabine (Fludara®), have a major impact on the management of chronic lymphocytic leukemia (CLL), having achieved overall response rates (ORR) of 60%–80% as a single agent in previously untreated patients. Despite these high response rates as compared with other agents, patients continue to have detectable minimal residual disease (MRD) and will eventually relapse. It has become clear that even with the most highly active combination regimens, chemotherapy alone cannot cure CLL. Monoclonal antibodies such as alemtuzumab (Campath®) that have been developed against antigens expressed on the surface of B-CLL cells act synergistically with fludarabine in vitro and also appear to have synergistic properties in vivo. We, therefore, evaluated the safety and efficacy of a new, 4-weekly combination regimen consisting of fludarabine and the anti-CD52 monoclonal antibody alemtuzumab (FluCam) for patients with CLL in a phase II study. Objectives of this study were to evaluate the feasibility, ORR, duration of response (DR), and the presence of MRD following treatment with FluCam. Patients received FluCam therapy after a short period of alemtuzumab dose escalation, with doses rising from 3 mg to 10 mg to 30 mg on consecutive days. The FluCam regimen consisted of fludarabine 30 mg/m2/day IV over 15–30 min (Days 1–3) immediately followed by alemtuzumab 30 mg IV over 2 h (Days 1–3). This combination was repeated on Day 29 for up to 6 cycles. MRD was measured by 4-color flow cytometry. Currently, 34 patients are eligible for evaluation out of a total of 37 patients included in this study. The median age of the patients was 61.0 years (range, 38–80), 26/34 (76%) were male, 26/34 (76%) had Binet stage C disease, and the median number of prior treatment regimens was 2 (range, 1–8). The ORR was 85%, with 10 (29%) patients achieving a complete response (CR) and 19 (56%) patients a partial response (PR). One (3%) patient had stable disease (SD), while 4 (12%) others had progression of their disease (PD). MRD negativity was achieved in the peripheral blood for 15/34 (44%) patients. CMV reactivation occurred in 2 patients: 1 patient had CMV confirmed by PCR and died due to E. coli sepsis, and 1 patient had subclinical CMV reactivation that was successfully treated with IV ganciclovir. Two patients with refractory disease developed fungal pneumonia. Notably, 7 patients had active autoimmune hemolytic anemia (AIHA) and/or autoimmune thrombocytopenia (AITP) when entering the trial and were successfully treated with FluCam. Moreover, 9 other patients with transfusion-dependent thrombocytopenia and/or anemia due to bone marrow infiltration prior to therapy were successfully treated with FluCam. In conclusion, results from the interim analysis of this new, 4-weekly dosing regimen of FluCam suggest that combination therapy with fludarabine and alemtuzumab is feasible, safe, and effective in treating patients with relapsed and refractory CLL, even in those patients with inherent poor prognostic factors, those who had received multiple prior therapies, or those who were refractory to fludarabine or alemtuzumab monotherapy. Based on these promising results, a prospective, randomized, phase III trial has been initiated comparing FluCam to fludarabine alone in patients with relapsed CLL.

Description: Combination chemoimmunotherapy regimens have shown substantial efficacy in the treatment of lymphoproliferative disorders, particularly in comparison to the efficacy of single-agent therapies. Fludarabine has become an established treatment regimen in CLL, and although overall response rates (ORR) in previously untreated patients range between 60% to 80%, patients who are refractory to fludarabine have poor outcomes. Alemtuzumab, the anti-CD52 monoclonal antibody, is the most effective single-agent therapy in CLL, and is capable of inducing minimal residual disease (MRD)-negative responses even among patients with fludarabine-refractory disease. Our previous clinical experience with the combination of alemtuzumab and fludarabine (FluCam) resulted in 83% ORR in 36 patients with relapsed/refractory CLL, with 30% achieving a complete response (CR; Elter et al J Clin Oncol2005;23:7024–7031). In addition, among 12 patients with fludarabine-refractory disease, 8 achieved responses (4 CRs), and median time-to-progression (TTP) for all patients was 13 months. In order to optimize the dose and schedule of the FluCam combination, we performed pharmacokinetic (PK) analysis of the previously reported 6-cycle regimen. PK data were collected for a 14-patient cohort that participated in the phase 2 FluCam trial. Median patient age was 60 years (range, 49–73), 9 patients had Binet C disease (5 were Binet B), and patients received a mean 2.5 prior therapies. Alemtuzumab 30 mg (after initial dose escalation) and fludarabine 30 mg/m2 were administered on days 1–3 of a 28-day cycle for up to 6 cycles. PK parameters were measured from samples collected before each subsequent cycle, and at days 1, 4, 7, 14, 21, 28, and 42, for a total of 158 patient samples, of which 120 were tested. Plasma concentration of alemtuzumab increased steadily from day 1 to day 4 of therapy to a median Cmax 1.55 mg/mL, but decreased to a median 0.145 mg/mL by 7 days after initiation of treatment. By day 21 of therapy, alemtuzumab plasma concentration decreased to undetectable levels. Because efficacy of alemtuzumab has been shown to correlate with serum levels of this antibody, significant improvement in progression free survival (PFS) may require a elevated plasma levels of alemtuzumab for the duration of the treatment cycle. Therefore, the significant responses seen in this trial can be attributed to documented synergistic activity between alemtuzumab and fludarabine, which has been demonstrated both in vitro and in vivo. Despite low CD4 counts through the duration of therapy, favorable safety results seen in the trial could be attributed to opportunity for hematologic recovery between treatment cycles. Detailed PK analysis is currently being completed and will be presented at the conference. Conclusions: Treatment with the FluCam immunotherapy combination yielded positive results among patients with fludarabine resistant/refractory CLL, a difficult-to-treat population. As shown previously, response rates correlate with higher alemtuzumab plasma concentrations. Therefore, longer PFS durations may require longer, more sustained alemtuzumab plasma levels, which may be achieved with either consolidation or maintenance.

Description: Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin’s lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 × 109/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 × 109/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 × 109/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 × 109/L peripheral tumor cells (P= .0017). Due to massive side effects in the first patient treated with 375 mg/m2 in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m2 dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 × 375 mg/m2 rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.