Chemoimmunotherapies have become a very potent tool to achieve long-lasting remissions in chronic lymphocytic leukemia (CLL) and the addition of rituximab to fludarabine and cyclophosphamide (FCR) was the first treatment shown to increase overall survival.1 Because alemtuzumab as a single agent is more potent than rituximab in CLL, the rationale for this study was to combine this anti-CD52 antibody with a FC chemotherapy backbone.2, 3, 4
A previous trial of fludarabine with alemtuzumab (FluCam) showed excellent results (overall response rate (ORR) 83%, complete response rate (CR) 30%) in relapsed or refractory patients, with a time to progression (TTP) of 35.6 months for all heavily pretreated patients.5 These results have been confirmed in a large randomized phase III trial, comparing FluCam to fludarabine monotherapy in 335 patients with relapsed or refractory disease.6 FluCam demonstrated an excellent treatment outcome and found that both progression-free survival (PFS) (23.7 months vs 16.5 months) and overall survival were significantly better with the combination treatment than with fludarabine alone.5, 6
Therefore, the German CLL Study Group performed a prospective, multicenter, open-label, non-randomized phase II trial to investigate the safety and efficacy (ORR) of a triple combination consisting of fludarabine, cyclophosphamide and alemtuzumab (FCCam) in patients with primary high-risk (deletion 17p), relapsed or refractory CLL (EudraCT2005-003017-32).
The secondary objectives of this study were the efficacy in biological defined risk groups, duration of response, and event-free survival (EFS), minimal residual disease (MRD) response rate, CR and toxicity. All patients who received at least one dose of study drug were included in the safety analysis.
Approval for this study was obtained from the Institutional Review Board of the University of Cologne and in accordance with an assurance filed with and approved by the Department of Health and Human Services; all patients gave written informed consent according to the Declaration of Helsinki.
FCCam was given for a total of 3 consecutive days, which was repeated every 28 days for a total of six cycles. In detail, one cycle consisted of 3 days of alemtuzumab 30 mg subcutaneously, fludarabine 25 mg/m2 intravenously (i.v.) over 30 min and cyclophosphamide 200 mg/m2 i.v. over 30 min; premedication, infection prophylaxis and monitoring was performed according to actual standards.7
Diagnosis and restaging was carried out according to the 1996 National Cancer Institute (NCI) criteria.8
Of the 61 CLL patients recruited from March 2005 to November 2008 in centers across Germany, four patients did not receive therapy owing to withdrawn consent or revision of diagnosis. A total of 57 patients received treatment, but 5 patients were not evaluable for response as 4 patients died within the first three cycles and another patient developed a secondary malignant disease.
The median age of treated patients was 63 years (36–78), with 41 male and 16 female patients. Binet stages A, B and C were seen in 13, 14 and 30 patients, respectively. Treatment indication for Binet A patients was mainly B-symptoms, but also lymphadenopathy in 11 patients, autoimmune hemolytic anemia (AIHA) in one case and fast progressing lymphocytosis in two patients with del(17p).
The median number of prior therapies was one (0–4), but five patients harboring a del(17p) received FCCam as first-line treatment. The majority was pretreated with bendamustine- or fludarabine-based regimen (n=48, 84%), 13 of them in combination with rituximab. 19 patients (33%) were refractory to the previous line of therapy.
Cytogenetic abnormalities were found in 86% of patients, with 19% of patients harboring a del(17p). The majority of patients (79%) showed an unmutated immunoglobulin variable heavy chain (IGHV) status.
A total of 57 patients received a median of five cycles and 21 patients received all six intended cycles. Reasons for early termination were hematological side effects (10 patients), early death (7 patients), progressive disease (4 patients), AIHA (1 patient) and infections (6 patients). Two patients proceeded to allogeneic transplantation without completion of all 6 cycles, one patient refused cycle 5 after achieving an early CR.
As expected, leukocytopenia and neutropenia common toxicity criteria (CTC) °3–4 were the most frequent hematological side effects (40.7%). Of two treatment-related AIHA, one resulted in a fatal event, the other was effectively treated with steroids. Thrombocytopenia CTC °3–4 affected 16 patients, 6 of whom received platelet support.
The time frame for serious adverse events (SAE) related to therapy was defined to be 6 months after the last therapy has been given. In this period, 27 patients sustained 57 SAEs, the vast majority (42 SAEs, 74%) were infectious complications, 8 of which were fatal.
Fever of unknown origin was the most common side effect and affected 18 patients, resulting in four fatal cases of sepsis. Eight patients developed pneumonias (one fatal Pneumocystis jirovecii pneumonia (PCP)) and seven patients showed Cytomegalovirus (CMV) infections (two fatal).
A total of 12 patients developed fatal SAEs during therapy or within 6 months after the last cycle has been given, 5 of which were clearly associated with FCCam treatment: One patient died from refractory AIHA after the fifth cycle and one patient with del(17p) developed a necrotizing tonsillitis followed by septic shock after the first cycle. One patient rejected intensive care treatment after developing a pneumonia in addition to a severe chronic obstructive pulmonary disease (COPD). Another two patients died of CMV infections, both of which were not sufficiently monitored for reactivation.
Three fatal cases were most likely not associated with FCCam, as one patient with known coronary heart disease died due to myocardial infarction, another patient developed multiple brain metastasis of a carcinoma of unknown primary and one patient died after a diverticulitis perforated 6 months after completion of chemoimmunotherapy.
The remaining four documented fatal events happened in patients with progressive CLL, two after initiation of relapse therapy.
As shown in Table 1, the ORR based on an intention to treat (ITT) analysis including all 57 patients was 56% according to NCI criteria, with 6 (11%) patients achieving a CR. Altogether 26 (45%) patients showed a partial remission, 11 (21%) patients had stable disease and 9 patients did not respond to therapy (17%). Five patients (9%) had no response assessment, as mentioned earlier. Of note, the results are based on a strict intention to treat analysis including also the patients without response assessment.
Analyzed by subgroups, no significant differences in response were detected according to cytogenetics or IGHV mutational status. Among 11 patients with del(17p), ORR was 80% in 5 untreated patients and 50% in 6 pretreated patients; ORR was 60% for those 45 patients showing an unmutated IGHV.
As expected, response was better for less intensively pretreated patients, resulting in an ORR of 85% for fludarabine monotherapy vs only 42% for FC- or bendamustine plus rituximab (BR)-pretreated patients (20%) and 33% for fludarabine-refractory patients.
After a median observation time of 23 months the median overall survival for all patients was 45 months (95% CI: 22–68 months) with a median EFS of 11 months (95% CI: 8–13 months) and PFS of 17 months (95% CI: 10–25 months). As expected, EFS was dependent on response (P<0.001). Owing to a small number of only 24 patients tested for MRD, only a trend towards a significant difference in EFS based on MRD results could be demonstrated (P=0.062). Calculated by subgroups, EFS was independent of mutational status (P=0.104) or presence of deletion 17p (P=0.226, Figure 1).
The final results of this phase II trial clearly did not meet our expectations in terms of response and safety. With respect to efficacy, FCCam seemed inferior to other relapse regimens such as FCR and FluCam.6, 9 More importantly, FCCam induced a higher rate of toxicity including fatal complications clearly related to the treatment in 5 of 57 patients, resulting in an inacceptable treatment-related mortality rate of nearly 9%. One possible explanation for these inferior results with FCCam might have been the patient selection, as most patients have been pretreated with fludarabine containing regimen including rituximab combinations (88%). For those patients being only pretreated with fludarabine (n=15), the overall response showed to be 85% compared with only 42% in FC-pretreated patients (n=27). 79% of our patients were IGHV unmutated and 19% of patients showed a del(17), indicating a high-risk population.
On the other hand, a BR combination trial of our group with a similar patient selection showed a similar ORR of 59% with complete remissions (CR) in 9% of patients, but a much better safety profile.10 In FCCam, 62% of patients tested for MRD in peripheral blood showed to be MRD-negative, compared with only 7.4% in BR-treated patients, likely reflecting preferential clearing of the blood compartment by alemtuzumab.11 The high-risk features del(17p) or unmutated IGHV did not affect EFS and PFS.
Comparing FluCam with FCCam, it is important to consider that not only the addition of cyclophosphamide might explain the striking differences in the safety profile but also the different routes of administration of alemtuzumab. A subcutaneous administration with 4 weekly intervals is not the approved way of administration, and the correlations of plasma levels of alemtuzumab to response and toxicity are still not well-enough understood.
In conclusion, an ORR of 56% and a treatment-related mortality of 9% do not justify the use of FCCam in unselected, relapsed patients with CLL. Therefore, and in contrast to FluCam, FCCam cannot be recommended as therapy of relapsed or high-risk CLL patient.
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The trial was planned and conducted as an investigator-initiated trial by the GCLLSG. It was supported by research grants from Bayer-Schering AG and Genzyme. The GCLLSG receives financial support by the German Cancer Aid. TE, AE, SS, C-MW and MH received honoraria from Bayer-Schering AG and Genzyme. The other authors declare no conflict of interest.
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Elter, T., James, R., Busch, R. et al. Fludarabine and cyclophosphamide in combination with alemtuzumab in patients with primary high-risk, relapsed or refractory chronic lymphocytic leukemia. Leukemia 26, 2549–2552 (2012) doi:10.1038/leu.2012.129
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