Allogeneic Stem Cell Transplantation in Chronic Lymphocytic Leukemia: An Archaic Intervention or a Necessary Evil?

Oncology (Williston Park). 30(6):539–540.

Over the last few years, with the development of novel targeted agents, significant advances have been made in the treatment of patients with chronic lymphocytic leukemia (CLL). Four new agents-obinutuzumab, ibrutinib, idelalisib, and venetoclax-have been approved in the last 3 years alone. These new therapeutic strategies tout impressive response rates and duration, with limited toxicities. In addition, these advances have stimulated reflection on standard therapies, such as allogeneic hematopoietic stem cell transplant (HSCT), and re-evaluation of where the latter modality will fit within the modern management of CLL. Here, Schwarzbich and colleagues review trials of HSCT for CLL patients, the potential adverse effects of HSCT, and alternative treatment options.[1] The question that arises from these data could be formulated as: Is allogeneic HSCT in CLL an archaic intervention or a necessary evil?

The authors review landmark clinical trials using allogeneic HSCT for CLL patients, which highlight the most attractive feature of HSCT in this population: its ability to cure CLL. Up to 50% of CLL patients who are candidates and who undergo allogeneic HSCT may be cured of their disease, which is a notable benefit not currently offered by any other treatment modality.[2] In addition, HSCT can overcome the negative impact of high-risk genetic features, including del(17p).[3] However, the clear downside to treatment with allogeneic HSCT is its toxicity. Despite improvements in transplant-related mortality (within 100 days of transplant), nonrelapse mortality is reported as ~25% in the first 2 years after transplant. The authors note that chronic graft-vs-host disease (cGvHD) affects over 50% of these patients and contributes significantly to nonrelapse mortality. Unfortunately, cGvHD is closely correlated with the graft-vs-leukemia effect, an important factor in the response to transplant.[4] A major consideration of the high number of CLL patients who develop cGvHD is quality of life (QOL). The majority of studies that have evaluated QOL in patients following allogeneic HSCT report a significant negative relationship between QOL and cGvHD.[5] One study reported that only 60% of patients with cGvHD were able to work, which is an important consideration, especially for young patients considering allogeneic HSCT.[6] As with any therapeutic intervention, the risks and benefits need to be clearly delineated for patients considering allogeneic HSCT.

An additional important consideration described by Schwarzbich and colleagues is the careful selection of CLL patients who can be considered for allogeneic HSCT.[1] The authors provide a practical algorithm to aid clinicians in the decision of whom to refer for transplant. Given that the average CLL patient is over 70 years of age and has medical comorbidities, the majority of patients will not even be considered candidates for HSCT. The group most suitable for transplant includes young and/or fit patients with high-risk disease (dysfunctional TP53 and/or relapsed/refractory to purine analog–based therapy) who have a well-matched donor and who accept the potential toxicities of allogeneic HSCT. With the introduction of novel agents, this group has become increasingly smaller. As described by the authors, the B-cell receptor tyrosine kinase inhibitors ibrutinib and idelalisib have greatly improved the outcomes of CLL patients, including those with high-risk disease. Unfortunately, CLL patients who suffer relapse while being treated with ibrutinib have very poor clinical outcomes.[7] However, emerging data reveal favorable outcomes in CLL patients who switch to an alternate kinase inhibitor after discontinuation (ibrutinib → idelalisib or idelalisib → ibrutinib), with overall response rates (ORRs) of over 50% and progression-free survival not yet reached.[8] Additionally, venetoclax (a B-cell lymphoma 2 inhibitor) has demonstrated preliminary evidence of efficacy in patients after discontinuation of ibrutinib or idelalisib and has been approved by the US Food and Drug Administration for use in patients with relapsed CLL and del(17p).[9] Chimeric antigen receptor (CAR) T cells induce over 50% ORRs and some long-standing complete responses without the risk of cGvHD. Still, despite the promise of these novel agents, follow-up times are relatively short compared with follow-up times for allogeneic HSCT, and none of the new agents are without their own set of toxicities. Although most toxicities with these agents are limited, some are life-threatening, including hemorrhage (ibrutinib), autoimmunity and opportunistic infections (idelalisib), tumor lysis syndrome (venetoclax), and cytokine release syndrome (CAR T cells). Moreover, in contrast to allogeneic HSCT, none of the new agents have yet been shown to cure CLL.

In conclusion, the authors have provided a practical and clinically useful review of data on the use of allogeneic HSCT in CLL patients, an algorithm for patient selection, and discussion of novel treatment options. For now, allogeneic HSCT remains a necessary evil in a select subset of CLL patients. However, with longer follow-up of novel therapeutic agents, allogeneic HSCT may someday be viewed as an archaic intervention for patients with CLL.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Schwarzbich MA, McClanahan F, Gribben J. Allogeneic transplantation for chronic lymphocytic leukemia in the age of novel treatment strategies. Oncology (Williston Park). 2016;30:526-33, 540.

2. Dreger P, Dohner H, Ritgen M, et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010;116:2438-47.

3. Dreger P, Schnaiter A, Zenz T, et al. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013;121:3284-8.

4. Brown JR, Kim HT, Armand P, et al. Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia. 2013;27:362-9.

5. Pidala J, Anasetti C, Jim H. Quality of life after allogeneic hematopoietic cell transplantation. Blood. 2009;114:7-19.

6. Worel N, Biener D, Kalhs P, et al. Long-term outcome and quality of life of patients who are alive and in complete remission more than two years after allogeneic and syngeneic stem cell transplantation. Bone Marrow Transplant. 2002;30:619-26.

7. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80-7.

8. Mato A, Nabhan C, Barr PM, et al. Favorable outcomes in CLL pts with alternate kinase inhibitors following ibrutinib or idelalisib discontinuation: results from a large multi-center study. Blood. 2015;126:719.

9. Jones J, Mato AR, Coutre S, et al. Preliminary results of a phase 2, open-label study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after or refractory to ibrutinib or idelalisib therapy. Blood. 2015;126:715.