Hope for high-risk chronic lymphocytic leukemia relapsing after allogeneic stem-cell transplantation.

Abstract

Chronic lymphocytic leukemia (CLL) is due to the unremitting accumulation of neoplastic CD5 B cells in blood, bone marrow, and lymphoid tissues. The prognosis of patients with this form of leukemia is extremely variable, from a normal life span in cases with smoldering disease not requiring intervention, to a short survival in those with aggressive disease unresponsive to treatment. Management of these latter patients constitutes a major challenge. As with many other blood cancers resistant to conventional treatment, at the end of the last century, hematopoietic stem-cell transplantations were investigated as a means of controlling CLL refractory to treatment. The first reports were published in 1991 and consisted of a small retrospective series of patients. The results were encouraging for disease control but disappointing regarding treatment-related mortality, which was of around 50%. Despite this, many studies on allogeneic transplantations in CLL ensued, results somewhat improved, and ultimately transplantations became an accepted, albeit not satisfactory, tool in the treatment of CLL with poor prognosis. Importantly, in the last decade results of allogeneic hematopoietic stem-cell transplantations have dramatically improved. This has been mainly possible thanks to a better selection of candidates for transplantation, a refined selection of donors, improvements in supportive care, and the use of reduced intensity conditioning (RIC; nonmyeloablative) regimens that allow engraftment while sparing nonhematopoietic cells from myeloablativerelated toxicity. CLL is the paradigm of the diseases in which RIC allotransplantations are effective. This is due to the low proliferative capacity of the disease and its sensitivity to the graft-versusleukemia (GVL) effect. As shown by minimal residual disease studies, a complete and, importantly, durable clearance of leukemic cells develops over time in a substantial proportion of patients, suggesting the cure of the disease. Altogether these achievements have led to a substantial reduction of the early death rate (ie, death within the first 100 days after transplantation) to less than 5%, and made allotransplantation accessible to older patients who represent the majority of the CLL population. However, long-term nonrelapse mortality after allotransplantation for CLL still remains in the 15% to 25% range, mainly because of graft-versus-host disease; this mandates a careful selection of patients who might benefit from this procedure. Notably, allogeneic transplantations are effective across genetically defined high-risk subsets, such as CLL with del(17p)/ TP53 mutations and unmutated IGHV genes. For all these reasons, allogeneic transplantation is considered a standard option for carefully selected patients with high-risk CLL, particularly if not responding to standard treatments. However, in most studies the relapse rate is 30% to 45% at 5 years post transplantation, implying that disease recurrence has become the most important cause of failure after allotransplantation. In case of disease relapse after transplantation, patients’ outcome is a major concern. A rather generalized opinion has been that prognosis of these patients is dismal. This idea, however, derives from older studies in which heavily pretreated patients were allografted as a last, desperate attempt to control the disease. This, coupled with myeloablative conditioning regimens, led to a meager tolerance to further and, at that time, no effective salvage treatments. Today, however, patients progressing after transplantation can be rescued by a variety of treatment approaches. In the article accompanying this editorial, Rozovski et al report for the first time a systematic analysis of patients with CLL progressing after allotransplantation. In their retrospective study of 72 patients (52 with CLL, 20 with disease-transformation or Richter’s syndrome), most patients (92%) had active disease at the time of transplantation, 22 (31%) had never achieved response, and 50 (69%) had a response but experienced relapse after a median of 7 months (range, 2-85 months), all this delineating aggressive disease. Other poor prognostic factors at diagnosis were del(17p) (29%) and unmutated IGHV status (84%). Most patients had received RIC regimens. The median time from transplantation to relapse was 7 months (range, 7-87 months). Patients received a variety of treatments, reflecting that there is no a standard of care for CLL progressing after transplantation; in most cases, however, rescue treatment included anti-CD20 monoclonal antibodies. Of note, five patients were treated with the kinase inhibitor ibrutinib. Altogether, 2and 5-year progression-free-survival (PFS) times after JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 14 MAY 1