Advances in molecular diagnostics and ex vivo drug sensitivity screening have greatly improved the use of targeted therapies for the treatment of chronic lymphocytic leukemia (CLL), such as B cell receptor signaling inhibitors, which include the Bruton tyrosine kinase (BTK) inhibitors like ibrutinib and acalabrutinib and the phosphoinositide 3-kinase (PI3K) inhibitors duvelisib and idelalisib, as well as the BCL2 inhibitor venetoclax. For most patients that are matched appropriately with these treatments, they show greatly improved progression-free survival and overall survival.
For a subset of patients, these first-line treatments fail due to the development of resistance or severe drug toxicity, and allogeneic hematopoietic stem cell transplantation (allo-HCT) remains one of the only treatment options that can result in durable responses. Allo-HCT involves the transplantation of blood stem cells from donor blood or bone marrow to replace diseased blood cells with healthy donor cells. Allo-HCT requires that recipients undergo high dose chemotherapy or radiation prior to transplantation to destroy malignant cells. In addition to the intensive immunosuppressive conditioning needed prior to transplantation, allo-HCT can cause graft-versus-host disease and organ toxicity, thus making it a potentially high-risk procedure with uncertain outcomes.
Nonetheless, allo-HCT may be the only option remaining for refractory or relapsed patients, and a recent study examined outcomes in patients receiving allo-HCT following one or more failed first line treatments. This retrospective multicenter cohort study followed 65 CLL patients who underwent allo-HCT following one or more prior first-line therapy. Cytogenetic and molecular characteristics were included, as was the type of first-line treatment, which included ibrutinib, venetoclax, PI3K inhibitors, and/or chemotherapy. 24-month progression-free survival (PFS) and overall survival (OS) were 63% and 81% respectively, relapse incidence was 27%, and nonrelapse mortality was 13%. There was also a relatively low incidence of acute or chronic graft-versus-host disease. The overall findings suggest that the number and type of prior treatments does not negatively impact PFS and OS following allo-HCT, and patients with high-risk mutations are also well suited for allo-HCT treatment. Improvements in pre-allo-HCT immunosuppression conditioning treatments have also improved survival outcomes in CLL patients.
Allo-HCT will continue to be a valuable treatment option for some CLL patients, but improvements in specific immunotherapies, including advances in targeted inhibitors and chimeric antigen receptor (CAR) T cells will likely provide more effective first-line treatment options. Improvements in cytogenetic and molecular diagnostics as well ex vivo drug sensitivity screening will also optimize treatment selection for better outcomes in CLL patients.
 Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.
 Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.
 Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322.
 Roeker, Lindsey E., et al. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents. Blood Advances. 2020;4.16: 3977-3989.