Abstract

BACKGROUND:

Azacitidine and decitabine are indicated for the first line treatment of intermediate and high risk MDS. About 40% to 47% of patients respond to 1st line hypomethylating agents. The median duration of response is 13 months. There are no effective therapies for patients who fail to respond to or progress on hypomethylating agents.

A phase II trial of high dose lenalidomide (50mg/day) induction therapy followed by low dose (10mg/day) maintenance therapy in elderly patients with AML had demonstrated a high CR/CRi of 30%. CR was restricted to patients with presenting WBC counts <10000/µL, peripheral blast counts <1000/ µL and < 30%, many of whom could have been classified as having MDS rather than AML by FAB criteria. With the rationale that MDS and AML represent a continuum of disease, and the promising results in AML we aimed to assess the clinical activity of high dose lenalidomide by conducting a clinical trial of high dose Lenalidomide induction followed by low dose maintenance in patients with hypomethylating agent refractory MDS.

METHODS: We conducted an open label, single arm, multi-center phase II trial of high dose lenalidomide induction (50mg/day for two 28 day cycles) followed by low dose lenalidomide maintenance therapy (10mg/day for 12 cycles) for patients with MDS (as defined by FAB criteria) refractory to hypomethylating agents. Patients who had failed to show CR, PR or HI (hematological improvement) after at least 6 cycles of azacytidine or decitabine or who had progressed on treatment were considered eligible. Patients were enrolled in a Simon's optimal two-stage design with an intended sample size of 43. The primary endpoint was proportion of confirmed responses (CR, PR or HI), as defined by international working group criteria, during the 14 cycles of treatment.

RESULTS:

24 patients were enrolled in the first stage of the study. 16 patients completed at least one cycle of therapy and were considered evaluable for efficacy.

Efficacy: Characteristics and outcomes of patients are detailed in Table 1. There were no complete or partial remissions. Marrow complete remission (MCR) was seen in 8/16 patients (50%). One of the 8 patients with a MCR had 5q- karyotype; 3/8 had trisomy 8 and one patient had a complex karyotype with monosomy 7. Median duration of MCR was 70 days (range 28-336 days). MCR lasted beyond the high dose induction period in 2 patients, one of whom had a 5q interstitial deletion (112 days) and one patient with trisomy 8 (336 days). Hematologic improvement (HI) was seen in 2/16 patients (12.5%) (Refer to table below).

Toxicity: ≥grade 3 toxicities included pneumonia (12/24, 50%), sepsis (4/24, 17%), febrile neutropenia (8/24, 33%), rash (2/24, 8%), thromboembolic event (1/24), MI (1/24), new cancer -mammary analogue salivary carcinoma- (1/24).

TABLE 1
Pt No: Age IPSS Prior cycles of 5-aza/ decitabine Cycles of Lenalidomide Reason off trial Best Response 
69 1.5 Pancytopenia MCR 
78 Death-Unrelated SD 
73 Consent withdrawn SD 
87 14 12 Progression MCR, HI-p&n 
72 13 Thrombocytopenia MCR 
69 13 PE SD 
75 New Cancer MCR 
74 Progression SD 
10 75 Progression SD 
11 72 13 Thrombocytopenia MCR 
12 75 Progression PD 
13 78 Gr3 Fatigue MCR 
14 70 19 Progression MCR, HI-p 
15 72 23 Progression PD 
16 73 Gr 3 fatigue MCR 
Pt No: Age IPSS Prior cycles of 5-aza/ decitabine Cycles of Lenalidomide Reason off trial Best Response 
69 1.5 Pancytopenia MCR 
78 Death-Unrelated SD 
73 Consent withdrawn SD 
87 14 12 Progression MCR, HI-p&n 
72 13 Thrombocytopenia MCR 
69 13 PE SD 
75 New Cancer MCR 
74 Progression SD 
10 75 Progression SD 
11 72 13 Thrombocytopenia MCR 
12 75 Progression PD 
13 78 Gr3 Fatigue MCR 
14 70 19 Progression MCR, HI-p 
15 72 23 Progression PD 
16 73 Gr 3 fatigue MCR 

CONCLUSIONS:

High dose lenalidomide followed by standard dose maintenance in hypomethylating agent refractory MDS resulted in a marrow complete remission rate of 50% and hematological improvement rate of 12.5%. Future protocols should explore whether an extended schedule of intermittent dosing of high dose lenalidomide would allow for improved efficacy with acceptable toxicity.

Disclosures

Off Label Use: Lenalidomide is used in this study in patients with MDS both with and without deletion 5q.Use in patients without deletion 5q is off label use.. Tibes:Tetralogic Pharmaceuticals: Research Funding. Stockerl-Goldstein:Celgene: Speakers Bureau. Jacoby:Norvo Nordisk: Consultancy. Cashen:Celgene: Speakers Bureau. Vij:Onyx: Honoraria, Research Funding; Sanofi: Honoraria; Jannsen: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Celgene: Honoraria, Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.