Remission Status at Transplantation and Treatment History Determine the Survival Chances of Patients after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia Who Had Received Pre-Treatment with Idelalisib: A Report from the EBMT Chronic Malignancies Working Party

BACKGROUND: Numbers of patients with high-risk Chronic Lymphocytic Leukemia (CLL) who have failed Ibrutinib, Idelalisib or Venetoclax when they are referred for allogeneic hematopoietic stem cell transplantation (alloHCT) are increasing. No data is available on patients with CLL who were referred for alloHCT and were on Idelalisib prior to the start of the conditioning regimen. Therefore, we retrospectively analyzed registry data on patients with CLL who had been exposed to idelalisib prior to alloHCT.

METHODS: Patients were eligible if they had been registered with the EBMT data office for alloHCT for CLL after exposure to idelalisib at any time before transplantation. Minimal essential transplant data were collected on standard forms.

RESULTS: As of June 23, 2017, 45 patients with CLL (67% male) had received alloHCT after exposure to idelalisib and were registered with EBMT. Median age at alloHCT was 58 (36-68) years. Almost all patients (98%) had a Karnofsky Performance Status of 80% or higher. 42% of patients had CLL with deletion 17p and/or TP53-mutation. The median number of treatment lines prior to alloHCT was 4 (1-7), including treatment with ibrutinib in 11 patients (24%) and venetoclax in 2 patients (4%). Idelalisib plus Rituximab was the last regimen administered prior to alloHCT in 38 patients (84%). Complete or partial remissions were reported for 80% of patients at the time of alloHCT. Reduced intensity and myeloablative conditioning was administered in 71% and 29% of patients. Anti-Thymocyte globulin was given to 64% of patients and alemtuzumab to 27% of patients. Donors were HLA-identical siblings for 36% of patients, mismatched related donors for 13% of patients and unrelated donors for the remaining patients. One patient received cord blood and three patients received bone marrow, while the predominant graft sources were peripheral blood stem cells. No primary graft failure and one secondary graft failure were reported. Acute GVHD grade 2-4 was observed in 44% of evaluable patients, and chronic GVHD in 25% of patients at risk.

Thirty-three patients were alive at last follow-up with a median observation time of 8 (0-24) months after alloHCT and 12 patients had died. Three patients died following relapse or progression whereas 9 patients died from complications after alloHCT with infections being the cause of death which was reported most often. For the whole cohort of patients, the probability of 12-month progression-free and overall survival (OS), relapse incidence and non-relapse mortality was 57% (95%-CI, 38% to 75%) and 60% (95%-CI, 41% to 79%), 14% (95%-CI, 2% to 26%), and 29% (95%-CI, 12% to 47%) respectively. Overall survival of patients who had received Idelalisib as last treatment prior to alloHCT was not statistically different to patients who had received Idelalisib in their pre-treatment history but had received other bridging therapy immediately prior to alloHCT. Patients who were not in remission at the time of alloHCT had a trend towards worse OS (OS at 6-months 63% versus 85%, log-rank test p=0.07). Notably, patients who had received greater or equal versus less than 4 lines of pre-treatment had a lower survival probability (74% versus 84%, log-rank test, p=0.009). Also, patients who had been treated with both pathway inhibitors, ibrutinib and idelalisib, had worse survival chances compared to patients pre-treated with idelalisib only (OS at 6-months 51% versus 89%, log-rank test, p=0.03).

CONCLUSIONS: The relatively high incidence of non-relapse mortality in the first year after alloHCT in this contemporary cohort of patients is a warning signal. However, the pattern of results (better survival in patients who achieved a remission prior to alloHCT and with less extensive pre-treatment) indicates that idelalisib itself is a valuable bridging option for patients with high-risk CLL scheduled for alloHCT in time. Patients with far advanced disease stages especially after failure on BTK-inhibition are at high risk of early mortality after alloHCT.