Transplanting Bad-acting CLL

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a retrospective review of hematopoietic stem cell transplantation for pre-treated patients with chronic lymphocytic leukemia, who have 17p deletion, three-year overall and progression-free survival were 44% and 37%, respectively. This matches favorably when compared to patients with the same chromosomal abnormality treated with chemotherapy alone. Although an uncommon CLL variant, patients with 17p deletion should be considered candidates for hematopoietic stem cell transplant.

Source: Schetelig J, et al. Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia wit 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis. J Clin Oncol. 2008;26: 5094-5100.

There have been several reports demonstrating that hematopoietic stem-cell transplantation (HSCT) can provide improved remission duration and overall survival in patients with advanced chronic lymphocytic leukemia (CLL).1-3 It would seem logical that patients with adverse prognostic indicators, such as ZAP70 or unmutated VH gene would be most likely to benefit from HSCT, but earlier reports suggest that the presence of these factors does not influence overall transplant outcome.4,5 However, for those with 17p deletion (17p-), HSCT may offer the greatest chance for prolonged survival. The p53 tumor suppressor gene resides on the 17th chromosome, and its absence has been associated with a defect in triggering apoptosis in response to DNA damage, such as that produced by chemotherapy. Thus, CLL patients with 17p- are non-responsive to standard chemotherapy, such as with purine analogues,6 although gratifying but temporary responses frequently result from treatment with the monoclonal antibody alemtuzumab.7,8

To test whether HSCT would improve outcomes after HSCT in patients with CLL and 17p- deletion, Schetelig et al performed a retrospective analysis. For this, baseline data from patients with available cytogenetic data were downloaded from the European Group for Blood and Marrow Transplantation registry. Additional information on the course of CLL and follow-up was collected by questionnaire.

A total of 44 patients with 17p- CLL received allogeneic HCST between March 1995 and July 2006 from a matched sibling (n = 24) or an alternative donor (n = 20). 17p- CLL had been diagnosed by fluorescent in situ hybridization in 82% of patients and by conventional banding in 18% of patients; the median age was 54 years. Before HCST, a median of three lines of chemotherapy had been administered. At HCST, 53% of patients were in remission. Reduced-intensity conditioning was applied in 89% of patients. Acute grade 2 to 4 graft-versus-host disease (GVHD) occurred in 43% of patients, and extensive chronic GVHD occurred in 53% of patients. At last follow-up, 19 patients were alive, with a median observation time of 39 months (range, 18 to 101 months). Three-year overall survival and progression-free survival rates were 44% and 37%, respectively. The cumulative incidence of progressive disease at four years was 34%. No late relapse occurred in nine patients, with a follow-up longer than four years.

Commentary

By fluorescence in situ hybridization, chromosomal abnormalities can be detected in up 80% of CLL cases and most frequently these involve deletions of the 13th or 11th chromosome or trisomy 12. 17p deletion occurs from 3%-7%9 and is a harbinger of a particularly poor prognosis, with a poor response to chemotherapy, a median survival of less than two years, and virtually no progression-free survival beyond three years. Thus, this report, albeit retrospective and relatively small, offers some hope for an effective treatment approach to this selected group of CLL patients. Such patients should be considered candidates for HSCT early in their course, perhaps after initial treatment with alemtuzumab. Additional research is clearly needed to define appropriate HSCT strategies, including approaches to myeloablation and GVH prevention, while not eliminating a graft vs leukemia effect, a feature that was also of apparent importance in this series. Furthermore, there is clearly a need for new agents that are not dependent on p53 inasmuch as HSCT remains a risky procedure for the bulk of CLL patients over the age of 70 years.

References

1. Delgado J, et al. Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood. 2006; 107:1724-1730.

2. Pavletic SZ, et al. Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol. 2005;23: 5788-5794.

3. Sorror ML, et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23:3819-3829.

4. Caballero D, et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-). Clin Cancer Res. 2005;11:7757-7763.

5. Khouri IF, et al. Graft-versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J Haematol. 2007;137:355-363.

6. Zenz T, et al. Molecular diagnostics in chronic lymphocytic leukemia — pathogenetic and clinical implications. Leuk Lymphoma. 2008;49:864-873.

7. Hillmen P, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-5623.

8. Lozanski G, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103:3278-3281.

9. Stilgenbauer S, et al. Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia. 2002;16:993-1007.