A Phase I Dose Escalation Study of Lenalidomide Following Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation
Authors: Andritsos Leslie A. , Blum William , Klisovic Rebecca B. , Vasu Sumithira , Penza Sam , Lee Jodi , Marcucci Guido , Byrd John C. , Devine Steven M. 
Published: October 2019

Abstract
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.
Abstract 3954. Table 1 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 0 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 0 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 0 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
1 = elevated creatinine
2 = relapse
3 = GVHD

Disclosures
Off Label Use: Lenalidomide administration following allogeneic transplantation.. Blum:Celgene: Consultancy.