TPLL-1 Protocol of the German CLL Study Group (GCLLSG) - A Prospective Phase II Trial of Fludarabine Phosphate, Mitoxantrone and Cyclophosphamide (FMC) Followed by Alemtuzumab Consolidation in T-PLL.

Introduction: T-cell prolymphocytic leukemia (T-PLL) is an aggressive disease with a poor median overall survival of <12 months. To improve results in T-PLL, the GCLLSG initiated the T-PLL-1 protocol evaluating the efficacy of induction therapy with fludarabine, mitoxantrone and cyclophosphamide (FCM) followed by antibody therapy with alemtuzumab. Patients (pts) and

Methods: Between November 2001 and December 2006 a total of 26 pts were entered in this trial. At the time of analysis eighteen pts. are available with confirmed diagnosis of T-PLL. Twelve patients were untreated and six pretreated. All patients were planned to receive 4 cycles of fludarabine phosphate 25 mg/m² on Days 1–3, mitoxantrone 8 mg/m² on Day 1, and cyclophosphamide 200 mg/m² (FMC) on Days 1–3, which was repeated on Day 29. After 4 courses of chemotherapy, all responding patients were scheduled to receive alemtuzumab 30 mg IV 3 times per week as consolidation therapy for up to 12 weeks. Patients with stable or progressive disease at interim staging, after second cycle of FMC, were treated immediately with alemtuzumab. The median age was 71 years (range 46–75yrs). Median time from diagnosis to study entry was 2 months (range 0.2–6 months). All patients showed a typical marked hyperleukocytosis with a median of 141.600/μl (range 19.9–436.700/μl).

Results: A total of 63 cycles of FMC therapy were documented and a total of 129 weeks of Alemtuzumab at 30 mg with a median of duration of 8 weeks therapy per pt (range 2–12 weeks) were administered, which corresponds to a medium Alemtuzumab dose of 720 mg (range 6 mg -1.033 mg). The overall response (OR= complete response (CR) + partial response (PR)) rates following FMC and alemtuzumab therapies were 66% and 86%, respectively. The best response to FMC therapy included 4 pts who achieved a CR, while 8 pts achieved a PR, 5 pts had SD, and 1pt had PD. Alemtuzumab was subsequently administered as consolidation therapy to 15 pts. Of responding pts. with CR 3 of 4 and with PR 7 of 8 received alemtuzumab as consolidation therapy. The pt with PD received alemtuzumab therapy as well, but the disease continued to progress. In addition, 2 pts with SD after FMC subsequently achieved a CR following alemtuzumab therapy and three pts with SD after FMC achieved a PR. One pt with PR after FMC had a progressive disease during Alemtuzumab therapy. The median overall survival (OS) of patients with T-PLL after FMC and alemtuzumab therapy was 19.2 months and progression free survival (PFS) was 10.6 months. Only one fatal adverse event presenting as myocardial infarction during alemtuzumab run-in phase was observed. FISH analysis was performed in 12 of 20 pts showing typical involvement of the chromosome 14 (t (14; 14), t (14q11)). Furthermore, in 12 pts expression of TCL-1 was tested by PCR. However, no correlation to OS or PFS was detected according to the level of expression.

Conclusion: The combination of a fludarabine phosphate-containing regimen with subsequent alemtuzumab therapy shows clinical benefit in pts with T-PLL. To increase outcome study evaluating FMC combined with alemtuzumab followed by an alemtuzumab maintenance therapy is currently under investigation.