A Phase I Study of Lenalidomide in Patients with Chronic Myelomonocytic Leukaemia (CMML) – AGMT_CMML 1
Authors: Burgstaller Sonja , Greil Richard , Stauder Reinhard , Machherndl-Spandl Sigrid , Pfeilstöcker Michael , Kuehr Thomas , Lang Alois , Mayrbaeurl Beate , Petzer Andreas L. , Valent Peter , Thaler Josef 
Published: October 2019

Abstract
Introduction
Chronic myelomonocytic leukaemia (CMML) is a clonal disorder of a haematopoietic stem cell characterized by the presence of an absolute monocytosis in peripheral blood. CMML is a rare disease with an incidence of 0.5 to 3 per 100 000 per year with median survival of 12 to 20 months. Coexistence of myelodysplastic and myeloproliferative features led 2001 to a classification of CMML outside myelodysplastic syndromes (MDS) within a group of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) by the WHO. In the former FAB classification CMML was part of MDS. For these reasons data regarding the treatment of CMML is largely derived from MDS trials. The studies published so far suggest activity of lenalidomide in a proportion of patients, but the number of CMML patients included was very low. Therefore we conducted a phase 1 dose-escalation trial with lenalidomide in patients with WHO defined CMML.
Methods
Patients with a diagnosis of CMML according to WHO diagnostic criteria with an age of at least 18 years were eligible for study entry. Pretreatment was permitted but had to be stopped 4 weeks prior to initiation of study treatment. Exclusion criteria were impairment of renal (creatinine clearance < 30 ml/min) or hepatic function (AST, ALT > 2.5 ULN) and/or any other serious medical condition. Patients with platelets < 50 G/L were not included. Primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide. Secondary objectives were safety and tolerability. Treatment with lenalidomide was started at a dose of 5mg daily in a cohort of 3 patients. Study treatment was administered day 1 to 28 of a 28-day cycle. In the absence of a dose limiting toxicity (DLT) in all 3 patients respectively not more than 1 out of 6 patients the dose was increased stepwise by 5mg up to a defined maximum dose of 20 mg daily. DLT was defined as one of the following parameters after cycle 1: grade 3/4 non hematologic-toxicity, febrile neutropenia, grade 4 neutropenia ≥ 7 days or grade 4 thrombocytopenia.
Results
20 (17 male, 3 female) patients with CMML were enrolled in this phase 1 trial. Eighteen patients were evaluable for MTD evaluation (2 patients stopped study treatment due to rash before end of cycle 1). Median age was 72 years (range 59 – 81), the majority of patients was older than 70 years (n=14) and 2 patients were older than 80 years. Three out of these 20 patients had prior treatment (≤ 2) whereas the rest received lenalidomide as first line therapy. Prior regimens consisted of hydroxyurea and cytarabine. Median time from diagnosis to study entry (cycle 1, day 1) was 45 days (range 7 – 2309). Six patients were treated in the 5 mg cohort with no DLT. In the 10 mg cohort 2 out of 6 patients experienced DLTs (thrombocytopenia grade 4 (n=1), non- hematologic toxicity grade 3/4 – renal impairment (n=1)). Two out of 6 patients in the 15mg cohort had DLTs (thrombocytopenia grade 4 (n=2), non-hematologic toxicity grade 3/4 – tremor, vertigo (n=1)). Therefore lenalidomide 5mg daily was eventually confirmed as MTD. Other treatment related adverse events were anaemia (n=2), fatigue (n=2), pyrexia (n=3) and erythema (n=2). The median number of treatment cycles achieved was 3 (range 1-25) and 4 patients are still on study treatment. Reasons for discontinuation of study treatment were adverse events in 11 patients and eventual disease progression in 5 patients. At the time of this analysis 15 patients were evaluable for response assessment according to modified IWG criteria. The best response achieved was partial remission in 2 patients and stable disease in 10 patients. Lack of response with primarily progressive disease was seen in 3 patients.
Conclusion
Lenalidomide can safely be administered in patients with CMML. MTD of lenalidomide was determined as 5mg daily. Thrombocytopenia was the main toxicity observed in this cohort of patients. Efficacy needs to be confirmed in further trials.

Disclosures
Burgstaller: Celgene: Honoraria. Greil:Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding. Stauder:Celgene: Consultancy, Honoraria, Research Funding; Ratiopharm: Honoraria, Research Funding; Novartis: Research Funding. Pfeilstöcker:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen-Cilag: Honoraria. Kuehr:Celgene: Honoraria. Petzer:Celgene: Honoraria, unrestricted grant Other. Valent:Celgene: Honoraria.