Non-Ablative Allogeneic Transplant Demonstrates Promising Long-Term Outcome in Relapsed Patients With CLL

The past decade has brought forward a multitude of new therapies for chronic lymphocytic leukemia (CLL). A combination of these treatments as part of chemo-immunotherapy has improved the response rates, remission durations, and possibly overall survival of patients with this disease. Despite these advances, no currently available therapy is a cure for CLL. Also, many patients with CLL eventually become refractory to traditional treatment modalities, including chemo-immunotherapy, and, ultimately, die as a direct consequence or complication of the disease. Identification of strategies that offer curative intent for CLL would represent a major advance for this disease.

The recent publication by Sorror and colleagues provides more conclusive evidence that non-ablative allogeneic stem cell transplant may represent one such therapy in CLL. Application of ablative allogeneic transplant in the past has been associated with significant treatment-related mortality and has only been applicable to the fewer than 5 percent of patients younger than 50 who develop refractory CLL. Adaptation of non-ablative approaches has broadened the age group of CLL patients eligible for this approach, making it more applicable to the large population of individuals with this disease. Multiple early reports have been published documenting feasibility and surprisingly low early treatment-related mortality as compared to previously published ablative allogeneic stem cell transplant in CLL. More importantly, graft-versus-leukemia was clearly documented with meaningful responses observed, even in patients with measurable CLL at time of transplant. While problems with chronic graft-versus-host disease (GVHD) clearly arise using the non-ablative allogeneic approach, significant excitement across the field exists for this treatment in patients with refractory CLL. The report by Sorror and Maloney provided what all CLL investigators have been looking for — extended follow-up showing that a large minority of patients undergoing this procedure remain disease-free and fully functional at five years. While the authors identified chronic GVHD as problematic early on, this eventually burned out in the majority of patients allowing them to be free of immunosuppressive medication. Given the five-year 50 percent overall survival and 39 percent progression-free survival with a low risk of late relapse in this heavily treated CLL population, we must now consider non-ablative transplant as an option for patients with relapsed CLL. On a practical level, these findings should decrease the commonly identified insurance denial or delay in approval by select insurers that ultimately prevent many individuals from pursuing this potentially curative therapy. Documentation of long-term follow-up of this large cohort of CLL patients receiving non-ablative transplants with very favorable results provides convincing data to support this modality as a standard, as opposed to a research-based therapy for select patients with relapsed CLL. 

Can we improve further on what has been achieved in non-ablative transplant for CLL? Several important questions remain to be answered from the report by Sorror and Maloney and other non-ablative transplant series in CLL. These include:

1) What proportion of high-risk (i.e., del[17p13.1] or complex karyotype) patients are salvaged with non-ablative approaches, and should this treatment be applied earlier in the disease process?

2) Can moderate-intensity regimens or addition of other immune-modulating agents post-transplant afford the same morbidity observed by Sorror and colleagues but diminish the risk of relapse in patients with bulky lymph nodes?

3) Are unrelated donors actually better for transplantation in the CLL population?

To fully pursue these questions and further improve this modality will require well-controlled clinical trials building upon the successes already documented with non-ablative transplants in CLL. Many trials are being initiated to address these questions that hopefully would afford even better outcomes for patients with this disease.