Induction Treatment with Alemtuzumab Combined with Polychemotherapy Containing Fludarabine, Cyclophosphamide and Mitoxantrone (FCM) Followed By Alemtuzumab Maintenance in Patients with T-Cell Prolymphocytic Leukaemia (T-PLL): First Analysis of a Prospective Multicenter Phase-II-Trial (T-PLL2) Conducted By the German CLL Study Group (GCLLSG)
Authors: Pflug Natali , Hopfinger Georg , Cramer Paula , Schrader Alexandra , Weit Nicole , Meister Rita , Thiel Miriam , Annolleck Tanja , Westermann Anne , Seiler Till M , Zenz Thorsten , Duerig Jan , Bahlo Jasmin , Kreuzer Karl-Anton , Stilgenbauer Stephan , Fink Anna-Maria , Eichhorst Barbara , Hallek Michael , Herling Marco 
Published: October 2019

Abstract
Introduction: T-cell prolymphocytic leukemia (T-PLL) is a very rare & aggressive disease. Therapeutic advances during recent years have been very limited. Even after initial response, the vast majority of T-PLL patients (pts) relapse quickly and the median overall survival remains below 2 years (ys). This also holds true for induction therapies with the anti-CD52 antibody Alemtuzumab (A). Furthermore, life-threatening viral infections are a severe problem in pts treated with this antibody. In a precursor trial (Hopfinger et al, Cancer 2013), we evaluated a consolidation therapy with A after polychemotherapy induction.
In the T-PLL2 trial, we evaluated feasibility, safety and efficacy of the addition of A s.c. to an induction treatment with Fludarabine, Mitoxantrone & Cyclophosphamide (A-FMC), followed by an A s.c. maintenance therapy.
Patients and Methods: 16 pts (12 untreated and 4 with pretreatments) with T-PLL were enrolled between 06/2010-09/2013. Pts received an induction treatment with A 10mg s.c. on day (d) 1-3 combined with 20mg/m2 Fludarabine i.v. d 1-3, 6mg/m2 Mitoxantrone i.v. d1 & 200mg/m2 Cyclophosphamide d1-3. After 2 cycles the A dose was increased to 30 mg s.c., if a stable disease (SD) or a partial remission (PR) was achieved. A-FMC treatment was administered every 28 days for up to 4 cycles, followed by a maintenance treatment with 30mg A s.c. starting 1 month (mo) after final staging. During the first 6 mo, A s.c. was administered monthly and in addition once in mo 10 and 13. For younger and fit pts, the option of allogeneic transplantation (tx) was explicitly recommended after induction therapy. Peripheral blood (PB) samples were taken at diagnosis & at the time of relapse/progression. Valganciclovir was recommended for prophylaxis.
Results: 16 pts with a median age of 68 ys (range 32-78) and a median score on the cumulative illness rating scale of 3 (range 0-6) were enrolled. The diagnosis of T-PLL was established based on clinico-pathologic characteristics, with the lead finding of a monoclonal mature T-cell population in PB. All leukaemias (100%) were CD52 positive, 15/16 cases (93.75%) expressed TCL1 & the most frequent abnormalities by FISH/classical karyotyping were aberrations involving 14q32.1 in 14/14 cases (100%), gains of chromosome 8q in 10/14 cases (71%), & deletion 11q23 in 8/14 cases (57%).
A median number of 4 courses (range 2-4) were administered for induction treatment. Six pts (37.5%) proceeded with maintenance treatment with a median of 4 (range 1-6) A applications.
In total, 94 non-infectious CTC grade 3-4 adverse events (AE) & 28 episodes of CTC grade 1-4 infections were documented. Non-infectious grade 3/4 AEs were most frequently due to myelosuppression: neutropenia/leukopenia occurred in 14/16 pts (87.5%), anaemia in 7/16 pts (43.75%) & thrombocytopenia in 10/16 pts (62.5%). Two cases of cytomegalovirus (CMV) & 1 case of varicella zoster infection were documented. Most AEs could be successfully managed, however 2 (12.6%), possibly treatment related deaths occurred, both from fatal bleeding in thrombocytopenia. In all pts response data after induction treatment was available. The overall response rate was 68.75% (11/16pts) with complete remissions (CR) in 4 pts (25%), CR with insufficient bone marrow recovery in 1 pt (6.25%) & a PR in 6 pts (37.5%). Progressive disease (PD) was documented in 4 pts (25%), a SD in 1 pt (6.25%). The trial was terminated in May 2014. Until today, 11 deaths (68.75%) were reported & 1 pt (6.25%) was lost to follow-up. Prophylaxis with Valgancyclovir was administered in 12/16 pts (75%), 2 pts (12.5%) received prophylactic Valaciclovir & 2 pts (12.5%) received no viral prophylaxis at all.
Seven pts (43.75%) received an allogeneic tx after the study treatment: 3 pts after the induction phase, 1 pt after 5 maintenance applications & 3 pts after bridging/salvage therapy. Tx outcomes were documented with 5 CRs & 2 PDs.
Conclusion: A s.c. combined with FMC & A maintenance therapy is a relatively safe and feasible regimen in pts with T-PLL. However, safety seems to come at the cost of response quality. Therefore, the authors currently recommend using A i.v. as part of the initial therapy for T-PLL pts. Prophylaxis with Valganciclovir was effective in preventing CMV infection, one of the major threats to pts treated with A. Most importantly, the study emphasizes the need for new therapies and intensified clinical research for pts with T-PLL.

Disclosures
Off Label Use: Therapeutic off-label use of Alemtuzumab, Fludarabine, Cyclophophamide and Mitoxantron in T-PLL. Hopfinger:Genzyme: Research Funding. Weit:Beckman Coulter GmbH, Krefeld, Germany: Employment. Stilgenbauer:Genzyme : Consultancy, Honoraria, Research Funding. Eichhorst:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant Other; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Hallek:Genzyme, Bayer: Research Funding.