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 AML High Ineligible1 592 979 Relapse 
02 64 AML Very high Ineligible1 140 229 Relapse 
03 26 AML High Ineligible2 35 121 Relapse 
04 39 DLBCL Intermediate Declined 789 1085  
05 64 DLBCL Intermediate Declined 108 121 Relapse 
06 36 AML High Yes 958 958  
07 60 AML High Ineligible3 992 992  
08 61 CLL Low Ineligible3 101 101 Acute GVHD 
09 71 AML High Ineligible1 957 957  
10 57 AML High Ineligible2 30 30 Regimen Related Toxicity 
11 32 AML Very High Yes 103 103 Acute GVHD 
12 50 AML Very High Yes 751 751  
13 61 AML Very High Ineligible2 42 242 Relapse 
14 60 AML Very High Ineligible2 15 160 Relapse 
15 63 AML High Ineligible3 61 61 Acute GVHD 
16 66 AML High Study closure 706 706  
17 68 DLBCL High Study closure 72 72 Pneumonia 
PT
 
Age
 
Sex
 
Diagnosis
 
Disease Risk Index
 
Comorbidity Index
 
Lena Treatment
 
Progression free survival (days)
 
Overall survival (days)
 
Cause of death
 
01 64 AML High Ineligible1 592 979 Relapse 
02 64 AML Very high Ineligible1 140 229 Relapse 
03 26 AML High Ineligible2 35 121 Relapse 
04 39 DLBCL Intermediate Declined 789 1085  
05 64 DLBCL Intermediate Declined 108 121 Relapse 
06 36 AML High Yes 958 958  
07 60 AML High Ineligible3 992 992  
08 61 CLL Low Ineligible3 101 101 Acute GVHD 
09 71 AML High Ineligible1 957 957  
10 57 AML High Ineligible2 30 30 Regimen Related Toxicity 
11 32 AML Very High Yes 103 103 Acute GVHD 
12 50 AML Very High Yes 751 751  
13 61 AML Very High Ineligible2 42 242 Relapse 
14 60 AML Very High Ineligible2 15 160 Relapse 
15 63 AML High Ineligible3 61 61 Acute GVHD 
16 66 AML High Study closure 706 706  
17 68 DLBCL High Study closure 72 72 Pneumonia 

1 = elevated creatinine

2 = relapse

3 = GVHD

Disclosures

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

Author notes

*

Asterisk with author names denotes non-ASH members.