A Phase I Dose Escalation Study of Lenalidomide Following Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

Lenalidomide is an immunomodulatory drug that is FDA approved for treatment of 5q- myelodysplastic syndrome (MDS) and myeloma. It has also been tested as a salvage therapy of refractory/relapsed AML with encouraging activity, especially in patients (pts) who relapsed post allogeneic transplant (alloSCT). In this setting, it has been postulated that lenalidomide may re-activate donor immune system and enhance a graft-versus-leukemia effect. This hypothesis is also supported by evidence of increase graft-versus-disease (GVHD) observed in pts treated with lenalidomide post-alloSCT. Therefore, in order to prospectively study the safety, feasibility, and early impact on risk of disease relapse we performed a phase 1 dose escalation study of lenalidomide administered orally daily following reduced intensity conditioning (RIC) alloSCT in pts with leukemia and lymphoma eligible for transplant. Methods: Pts were enrolled on a two-step process, with initial enrollment prior to transplant followed by a re-registration evaluation post-transplant at day +60 (+/- 7 days) to ensure eligibility. At this screening, pts were required to demonstrate engraftment with ANC >1000/uL, platelet count ³50,000/uL, and T-cell chimerism ³40% by day +30. Pts were required to have a creatinine clearance ³50 mL/min, AST ²3 x ULN, and ECOG PS of 0-2. Grades 1 or 2 acute GVHD (aGVHD) were allowed if controlled on ² 20 mg of prednisone daily; pts with a history of grades 3 or 4 aGVHD were excluded. Lenalidomide was given orally daily for 28 days/cycle. Dosing escalation was performed using a standard 3 x 3 design, with dose level (DL) 1 = 5 mg , DL 2 = 10 mg, and DL 3 = 15 mg. Results: From 6/2011 to 10/2012, 17 pts with AML (n=13), CLL (n=1), and DLBCL (n=3) were enrolled (Table 1) and underwent RIC alloSCT. The majority of patients had a Disease Risk Index (Armand et al. Blood, 2014) of high or very high. Of enrolled pts, only 3 received lenalidomide. Of the pts who did not proceed to treatment at re-registration, 4 were ineligible due to relapse, 3 were ineligible due to elevated creatinine, 3 were ineligible due to GVHD, 2 declined, and 2 were not treated due to study closure. All pts who received lenalidomide were treated at DL 1. The first pt treated (00-06) received cycle 1 without toxicity. On cycle 2 day 9 he developed a skin rash consistent with acute GVHD and discontinued therapy. The second pt treated (00-11) developed skin rash and diarrhea on cycle 1 day 3 and was diagnosed with steroid refractory aGVHD of the GI tract. He expired from complications of treatment. The third pt treated (00-12) developed a skin rash and diarrhea on cycle 1 day 6. Lenalidomide was discontinued. Based on these outcomes, the study was closed due to concerns regarding the risk of severe aGVHD caused by lenalidomide. However, patients 00-06 and 00-12 remain alive and in CR days 958 and 751 post transplant, respectively. In the entire cohort, the median PFS was 103 days (range = 15-992) with median OS 103 days (range = 30-1085). Conclusion: Early administration of low-dose lenalidomide following alloSCT is not feasible due to potential increased risk of severe aGVHD and likelihood of elevated creatinine at this time point. However, 2 of 3 pts who received lenalidomide and responded to treatment for aGVHD remain in CR from their high-risk AML. Thus, an amended approach with lower/fewer dose of lenalidomide/cycle or alternatively, use in transplants that do not utilize calcineurin phosphatase inhibitors (such as T-cell depletion based approaches) warrants additional consideration. | PT | Age | Sex | Diagnosis | Disease Risk Index | Comorbidity Index | Lena Treatment | Progression free survival (days) | Overall survival (days) | Cause of death | | ---------- | ----------- | ----------- | ----------------- | -------------------------- | ------------------------- | ---------------------- | ---------------------------------------- | ------------------------------- | ------------------------ | | 01 | 64 | F | AML | High | 3 | Ineligible1 | 592 | 979 | Relapse | | 02 | 64 | M | AML | Very high | 1 | Ineligible1 | 140 | 229 | Relapse | | 03 | 26 | F | AML | High | 6 | Ineligible2 | 35 | 121 | Relapse | | 04 | 39 | M | DLBCL | Intermediate | | Declined | 789 | 1085 | | | 05 | 64 | M | DLBCL | Intermediate | 1 | Declined | 108 | 121 | Relapse | | 06 | 36 | M | AML | High | 3 | Yes | 958 | 958 | | | 07 | 60 | M | AML | High | 3 | Ineligible3 | 992 | 992 | | | 08 | 61 | M | CLL | Low | | Ineligible3 | 101 | 101 | Acute GVHD | | 09 | 71 | M | AML | High | 1 | Ineligible1 | 957 | 957 | | | 10 | 57 | M | AML | High | 5 | Ineligible2 | 30 | 30 | Regimen Related Toxicity | | 11 | 32 | M | AML | Very High | 2 | Yes | 103 | 103 | Acute GVHD | | 12 | 50 | F | AML | Very High | 4 | Yes | 751 | 751 | | | 13 | 61 | F | AML | Very High | 4 | Ineligible2 | 42 | 242 | Relapse | | 14 | 60 | M | AML | Very High | | Ineligible2 | 15 | 160 | Relapse | | 15 | 63 | F | AML | High | 3 | Ineligible3 | 61 | 61 | Acute GVHD | | 16 | 66 | M | AML | High | 3 | Study closure | 706 | 706 | | | 17 | 68 | M | DLBCL | High | 5 | Study closure | 72 | 72 | Pneumonia | Abstract 3954. Table 1 1 = elevated creatinine 2 = relapse 3 = GVHD Disclosures Off Label Use: Lenalidomide administration following allogeneic transplantation.. Blum: Celgene: Consultancy.