Hematopoietic Cell Transplantation and Other Cellular Therapies for Chronic Lymphocytic Leukemia

Background

Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the West, with a median age at diagnosis of 71 years and a male preponderance. Roughly a third of patients are under 65 years of age, ~10% are under 55 years of age, and <2% are under 45 years of age at diagnosis. The disease is characterized by an accumulation of monoclonal, CD5+ B-cells in the bone marrow, peripheral blood, and secondary lymphoid organs. CLL is a very heterogeneous disease with a highly variable clinical course, ranging from indolent disease not needing therapy (in approximately 30% of patients) to aggressive presentations with progressive B-symptoms, lymphocytosis, cytopenias, lymphadenopathy, hepatosplenomegaly, recurrent infections, or autoimmune manifestations. Staging criteria for CLL like the Rai (stages 0–IV) and Binet (stages A–C) were developed in the era of chemotherapy and estimated median life expectancy ranging from 13-, 8- and 2-years for early-, intermediate- and advanced-stage disease, respectively. These have since been replaced by the CLL-International Prognostic Index (IPI) that incorporates fluorescence in situ hybridization and molecular markers and is a better predictor for overall outcomes and time to treatment.

There have been significant advances in our understanding of the molecular biology of CLL in the past three decades, and this has translated into the development initially of chemoimmunotherapy (CIT) replacing chemotherapy and, more recently, novel targeted drugs that have changed the therapeutic landscape for the disease. These U.S. Food and Drug Administration (FDA)-approved novel agents include drugs that target kinases downstream of the B-cell receptor like the Bruton tyrosine kinase inhibitors (BTKi), ibrutinib and acalabrutinib, phosphoinositide-3 kinase inhibitors (PI-3ki), idelalisib and duvelisib, and the BCL2 antagonist, venetoclax. Several large randomized clinical trials have demonstrated a survival benefit for these targeted drugs over CIT in both treatment-naïve and relapsed/refractory CLL.

Despite these major strides, CLL remains an incurable disease with CIT and targeted agents, and allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potential curative treatment option, and still has a role in patients with high-risk disease characteristics. Newer cellular immunotherapies, including chimeric antigen receptor T-cell therapy (CAR-T-cell), are showing promise across the spectrum of B-cell malignancies and are being actively investigated in CLL. In this chapter, we provide a comprehensive review of the evolving role of HCT and other cellular therapies for CLL in the modern era.

Prognostic Markers in Chronic Lymphocytic Leukemia

In the CIT era, the following disease features have shown to predict inferior outcomes in CLL and include cytogenetic abnormalities like del(17p), del(11q), complex karyotype (≥ 3 chromosomal abnormalities), TP53 mutations, unmutated immunoglobulin heavy chain variable genes (U- IGHV ), overexpression of CD38, CD49, ZAP-70, serum beta-2 microglobulin, and gene mutations like NOTCH1 and SF3B1 . These features usually portend a shorter time to initial treatment and shorter remissions after chemotherapy-based treatment, than low-risk CLL features like del(13q), trisomy 12 or mutated IGHV ( M- IGHV) . The CLL-IPI categorizes risk to low, intermediate, high, or very high based on risk factors [del(17p), Tp53 mutation, serum beta-2 microglobulin (<3.5 or ≥3.5 mg/L), age and clinical stage]. The median time to initial therapy from diagnosis ranges from 7 years in low- and intermediate-risk disease (75% patients) compared to 2 years in high/very-high risk disease. However, in recent trials of targeted agents like ibrutinib and venetoclax, the presence of some of these traditional unfavorable features like del(11q) and U-IGHV have lost their prognostic significance with only Tp53 mutation or del(17p) still predictive of inferior outcomes.

Risk Stratification of Chronic Lymphocytic Leukemia in the Setting of Hematopoietic Cell Transplant

In 2007, a consensus paper from the European Research Initiative on CLL (ERIC) and the European Society for Blood and Marrow Transplantation (EBMT) defined “high-risk” CLL for which HCT should be considered as disease refractory to purine analogs, relapsing disease within 2 years after combination therapy with purine analogs, and/or disease with del(17p)/Tp53 mutations. In the modern era of novel agents, the outcomes of patients with Tp53 abnormalities and early relapse post-CIT have improved and the 4-year survival probability has increased from <40% to >80% with ibrutinib. Hence, two new high-risk CLL categories were defined in 2018 ( Table 17.1 ).

• a.

  CLL high-risk-I, CIT-resistant: This group includes patients with Tp53 abnormalities who have failed CIT but are responding to a first-targeted therapy (BTKi or BCL2i). Cellular therapies like HCT should be considered in selected patients with low procedure-related risk.

• b.

  CLL high-risk-II, CIT- and novel-therapy resistant: This group includes patients who, independent of Tp53 status, have failed both CIT and a first-targeted agent (BTKi or BCL2i), even if responding to an alternate novel agent. Cellular therapies are to be strongly considered for eligible patients in this group.

Thus, currently, younger patients (<70 years) with CLL should be evaluated for allo-HCT if their disease has del(17p)/TP53 mutations/complex karyotype and they have failed either a BTKi or venetoclax. Patients whose disease has progressed on both a BTKi and BCL2i should be evaluated for cellular therapies regardless of karyotype/Tp53 status with eventual plans for allo-HCT.

Impact of Novel Agents on Chronic Lymphocytic Leukemia Management