Outcome Of Chronic Lymphocytic Leukemia (CLL) Patients That Failed Allogeneic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-SCT) has become a therapeutic option for patients (pts) with high risk CLL. The major cause of allo-SCT failure is relapse or disease progression. No standard treatment is available for pts who failed allo-SCT and post-SCT immune manipulation, and the prognosis of these pts is largely unknown.

We performed a retrospective intention-to-treat analysis of pts with CLL who failed allo-SCT and post-SCT immune manipulation between 1998 and 2012 and were referred to the Leukemia Department at MD Anderson Cancer Center for further treatment.

Seventy-three pts with CLL (n=40, 55%) or Richter's transformation (RT, n=33, 45%) who failed or progressed after allo-SCT were referred for further management at a median of 7 months (range 0-85 months) after allo-SCT. Most pts (n=63, 86%) had received non-myeloablative conditioning and 32 (44%) received post allo-SCT donor lymphocyte infusion (DLI). Six patients (8%) had early (4 pts) or late (2 pts) graft failure. Fifty four (74%) pts were male and the median age at time of failure/progression was 59 yrs (range 32–73 yrs).

Of the 73 pts, 68 (93%) received salvage therapy, 1 pt died before treatment was initiated, and 4 pts were considering treatment options at time of last follow-up. A median of 2 treatment regimens (range 0 - 8) were administered between time of post-SCT progression and last follow-up. The most common salvage treatment regimens were chemo-immunotherapy with rituximab (R): R-HyperCVAD (n=24, 33%), OFAR (n=13, 18%), FCR, FBR, PCR, BR (n=24, 33%), immune-modulators thalidomide or lenalidomide (n=21, 29%), alemtuzumab with or without chemotherapy (n=12, 16%), and Bruton's Tyrosine Kinase (BTK) inhibitor (n=5, 7%).

At time of last follow up, 26 pts (36%) were alive. The median overall survival (OS) from time of progression after allo-SCT was 33 months (95% CI, 27– 39) and 60% of the pts were alive 2 years from time of progression. Median OS after allo-SCT failure/progression was 53 months (95% CI, 9–97) for CLL pts and 28 months (95% CI, 12–44) for pts with RT (Log Rank: P<0.0001) (Figure 1). Only 4 pts achieved CR following first salvage treatment. The OS of these pts was 152, 41, 26+, 38+ months (the latter 2 are still alive). Pts with partial response (PR), no-response (NR) or progression after first salvage treatment had similar OS.

Figure 1

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Cumulative survival of pts with CLL and Richter's syndrome from time of disease progression after allogeneic stem cell transplantation.

Figure 1

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Cumulative survival of pts with CLL and Richter's syndrome from time of disease progression after allogeneic stem cell transplantation.

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To identify the best treatment modality we analyzed the OS from progression and from time of initiation of treatment to last follow-up of all regimens used. We found that patients treated with either FCR, alemtuzumab or combination chemotherapy did not have significant difference in OS. Remarkably, 4 of 5 pts treated with BTK inhibitor were alive at time of last follow-up.

Univariable analyses showed shorter OS for pts with a higher ECOG performance status (PS; P=0.036), low hemoglobin (Hb) (P=0.0001), low albumin (P=0.0001), complex cytogenetic abnormalities at last follow up (P=0.026) and RT (P=0.0001). The multivariable Cox model analyses including age, sex, previous DLI, unfavorable cytogenetic abnormalities before or after allo-SCT, albumin, absolute lymphocyte count and platelet count, identified only Hb (P=0.009, 95% CI; 0.58 - 0.93), ECOG 3 (P=0.036, 95% CI; 1.12 - 30.04) and RT (P=0.002, 95% CI: 1.51 - 6.50) as independently associated with shorter OS.

The median OS of pts with high-risk CLL or RT from time of allo-SCT failure/progression was 33 months. The longest OS was observed in pts who attained CR after first salvage treatment (4/73, 6%). At the time of analysis, the 50% OS of pts treated with BTK inhibitors was not reached, however, no treatment modality appeared to be superior. Future studies of treatment options for pts that progress after allo-SCT are warranted.

Off Label Use: Ibrutinib for CLL therapy.