Guidance for Managing the Most Difficult Cases of Chronic Lymphocytic Leukemia

 

Currently, patients with chronic lymphocytic leukemia (CLL) survive longer and suffer fewer toxicities compared to the era of chemoimmunotherapy, largely due to the introduction of targeted therapies, which include anti-CD20 antibodies as well as Bruton’s tyrosine kinase (BTK), B-cell lymphoma 2 (BCL2), and phosphoinositide 3-kinase (PI3K) inhibitors.

However, there are two subgroups of patients who continue to have a poor prognosis and only rarely achieve long-term remission under available therapies. The first consists of patients with CLL who develop resistance to both BTK and BCL2 inhibitors when their malignant cells develop mutations that render the cells resistant. The second subgroup consists of patients with CLL who develop Richter transformation (RT) into aggressive lymphoma, which is usually fatal, either before or during targeted therapy.

This article surveys the state of the art of how to manage the most difficult cases of chronic CLL with a focus on these two patient subgroups. The topics addressed include the roles of available targeted therapies, chemoimmunotherapy, hematopoietic stem cell transplantation (HSCT), and emerging novel therapies, including reversible BTK inhibitors and chimeric antigen receptor (CAR) T-cell therapy.

Options After Resistance to BTK and BCL2

The development of venetoclax as a therapy for CLL has lagged behind the development of the BTK inhibitor ibrutinib, and there are relatively few studies on the use of venetoclax after BTK inhibition. However, these studies indicate that venetoclax has activity in patients previously treated with ibrutinib, with an overall response rate (ORR) of 65% in one prospective study and 74% to 85% in two retrospective studies. Venetoclax has activity both in patients whose reason for discontinuation of ibrutinib was toxicity and in those whose reason for discontinuation of ibrutinib was disease progression.

The use of PI3K inhibitors after BTK inhibitors has not been well studied, but one prospective study of 37 patients treated with the PI3K inhibitor idelalisib after previous treatment with ibrutinib achieved an ORR of 46%, with no complete remissions, and a median progression-free survival (PFS) of nine months, which appeared to be inferior to the efficacy of venetoclax after ibrutinib.

Allogeneic HSCT remains an option for a minority of patients with CLL. Although not suitable for elderly patients, allogeneic HSCT may be considered for patients who become refractory to at least one targeted agent or who have high-risk disease, such as TP53 aberrancy or complex karyotype.

One of the most promising emerging strategies for managing patients after both BTK and BCL2 inhibition is use of a reversible non-covalent BTK inhibitor. The currently available BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib all bind to BTK in a covalent, irreversible fashion. However, pirtobrutinib, formerly known as LOXO-305, binds to BTK in a reversible non-covalent manner and is highly selective for BTK. Phase I/II data for pirtobrutinib ​indicate that it is efficacious and has a favorable toxicity profile in patients previously treated with covalent BTK inhibitors, many of whom had also received prior venetoclax.

Several additional reversible BTK inhibitors are in development for patients with relapsed CLL, including nemtabrutinib, vecabrutinib, and luxeptinib. Novel BCL2 inhibitors are also undergoing study.

Another emerging strategy that offers promise in heavily pretreated patients with CLL is CAR T-cell therapy. The development of CAR T-cell therapy in CLL has lagged in its development in other B-cell malignancies, and CAR T-cell therapy has demonstrated limited efficacy in CLL to date. This may be related to intrinsic T-cell deficiencies in patients with CLL. However, emerging preclinical evidence suggests that inhibition of BTK and PI3K may enhance the function of CAR T cells. The ongoing phase I/II TRANSCEND CLL 004 trial is testing the hypothesis that the addition of BTK inhibition to CAR-T therapy may improve efficacy in patients with CLL.

Therapies for RT

In 1928, Maurice Richter described the first known case of a patient with “chronic lymphatic leukemia” who developed rapid onset of lymphadenopathy and splenomegaly, leading quickly to death. Since then, transformation of CLL to aggressive lymphoma has become known as RT, with the reported incidence ranging from 3% to 20%.

Historically, chemoimmunotherapy regimens have been used to treat RT. However, the conventional chemoimmunotherapy strategy does not usually provide lasting benefit for patients with RT unless it is followed by HSCT, and most patients with RT succumb to the disease quickly.

In the modern era, targeted agents and checkpoint inhibitors have also been explored against RT but with similarly limited success.

Perhaps the most promising area for RT is cellular therapy. In a series of nine patients with RT treated with the CD19-directed CAR T-cell product axicabtagene ciloleucel, seven of whom were also concurrently treated with ibrutinib, 89% of patients responded, although follow-up at the time of publication remained less than one year for all patients.

Patients with RT have also been treated with HSCT, particularly those who can achieve remission with chemoimmunotherapy. Results from existing studies suggest that about 30% to 50% of patients with RT who can get to transplant, whether autologous or allogeneic HSCT, may achieve several years of PFS. Retrospective series have a selection bias in that they have selected only patients well enough to reach transplant.

Summary

The introduction of targeted therapies, beginning with CD20 antibodies and more recently BTK, BCL2, and PI3K inhibitors, has created an era of unprecedented progress in CLL. Despite this progress, there remains a subgroup of patients with CLL resistant to both BTK and BCL2 inhibition, as well as a subgroup that undergoes RT to aggressive lymphoma. These two subgroups are more difficult to treat and portend a poor prognosis. Available thlude reversible BTK inhibitors and cellular therapies, particularly CAR T-cell therapy.