Chronic lymphocytic leukemia in 2020: a surfeit of riches?

Current management of chronic lymphocytic leukemia (CLL)

Drugs approved by the US Food and Drug Administration (FDA) for therapy of chronic lymphocytic leukemia (CLL) since the 1940s are displayed in Fig. 1. The chemotherapy era was dominated initially by chlorambucil with or without prednisone, cyclophosphamide followed by purine nucleo-side analogs such as fludarabine and pentostatin in the early 1990s. The introduction of rituximab in 1997 started the era of chemo-immunotherapy (CIT) in which combination therapy with fludarabine, cyclophosphamide, and rituximab (FCR) resulted in complete remission (CR) in about 40% of previously untreated persons with CLL—with long progression-free survival (PFS) in those with mutated immunoglobulin heavy chain (IGHV) genes. However, FCR had poor efficacy in persons with high-risk disease such as del(17p) or del(11q) detected by fluorescence in situ hybridization (FISH), TP53 mutation or complex cytogenetics [1]. Starting in 2009, six new drugs have been approved by the FDA for both initial therapy and for advanced disease. Although these drugs are active in persons with adverse prognostic co-variates, there are several issues with these new approvals including: (1) no cures; (2) new adverse events resulting in management challenges; and (3) high economic burden because of the need for prolonged therapy.

Fig. 1. Timeline of US Food and Drug Administration approvals for chronic lymphocytic leukemia.

FCR fludarabine, cyclophosphamide, and rituximab, PCR pentostatin, cyclophosphamide, and rituximab.

How did we get to these recent and dramatic advances in CLL therapy? The tidal wave resulted from substantial advances in understanding the biology of CLL, especially the reliance of CLL cells on the lymph node and bone marrow microenvironment to survive [2–5]. Small molecule inhibitors of the B-cell receptor signaling pathway such as ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor and idelalisib, a phosphoinositide 3-kinase inhibitor, were approved based on data from randomized studies comparing these drugs to previously approved therapies such as single-agent ofatumumab, chlorambucil, and rituximab [6–8]. However, two major North American Inter Group (NAIG) studies recently reported better PFS with ibrutinib with or without rituximab compared with CIT in previously untreated persons with CLL (FCR in adults <70 years [E1912] [9], and bendamustine and rituximab in those >65 years of age [A041202]) [10]. The E1912 trial also reported better overall survival (OS) of young persons with CLL receiving ibrutinib and rituximab compared with FCR. People typically considered having poor risk disease such as those with unmutated IGHV genes, del(17p), and complex cytogenetics also benefit from ibrutinib. Despite these excellent outcomes, ibrutinib therapy is associated with several issues: (1) non-hematologic adverse events such as hypertension, atrial fibrillation, bleeding, and others requiring stopping therapy in up to 40% of people [11]; and(2) emergence of mutations in BTK and/or PLCG2 resistant to ibrutinib and eventuating in disease progression [12]. Unfortunately, many other BTK inhibitors studied in advanced clinical trials for CLL, such as zanubrutinib and tirabrutinib, or drugs recently approved such as acalabrutinib, are inactive against these mutations.

In most cancers, drugs which are effective and safe in advanced disease work as well or better when given as initial therapy. This is not necessarily so in CLL. For example, use of idelalisib as initial therapy is associated increased risks of opportunistic infections, autoimmune complications, and deaths resulting in the stopping of several clinical trials [13]. These events are an important reminder to rigorously test new drugs in carefully conducted clinical trials before broader clinical use. Advances in our understanding of how CLL B-cells survive led to the finding of an important role for BCL2 in the pathogenesis of CLL. Consequently, it was not surprising venetoclax, a BH3 mimetic, combined with obinutuzumab improved PFS compared with chlorambucil and obinutuzumab [14]. However, this combination does not overcome the poor prognosis associated with TP53 disruption (genetic defects detected by either del(17p) by FISH or TP53 mutation by Sanger or next generation sequencing).

Next frontier in CLL research

Although achieving measureable residual disease (MRD) negativity was rare with BTK inhibitors alone, combining them with venetoclax or using venetoclax in combination with obinutuzumab in previously untreated people results in the MRD test in up to 80% after 1.5 to 2 years of therapy [15]. Importantly, these deep remissions allow people to stop therapy and be monitored for leukemia recurrence similar to the strategy in the CIT era after the usual 6 months fixed duration therapy.

However, despite this substantial progress we raise three issues to consider. First, are these MRD-test negative remissions as durable as remissions seen following FCR therapy in favorable risk persons (such as mutated IGHV genes, low-risk FISH profile such as del(13q) without TP53 mutation), a situation where about 60% of people are leukemia free after more than a decade of follow-up [16]? Second, if MRD-test negativity is a desirable endpoint, what definition of a negative test should be used? Sensitivity of current multi-parameter flow cytometry-based approaches is 10E-4. However, NGS assays such as ClonoSeq^® increase sensitivity to 10E−6⁶. Whether deeper responses defined by MRD detection levels will correlate with duration of therapy-free remission are unknown [17]. Lastly, what is the equipoise between achieving the goal of MRD-test negativity versus accumulating adverse events caused by intensive prolonged therapy, selecting drug resistant clones and cost [18].

These go to the question should we attempt to cure CLL at any price or identify a treatment point short of complete disease eradication after which people can live a high-quality life with persisting leukemia? Although the jury is still out, we favor a less intensive approach for two reasons: (1) CLL is a chronic disease of predominately older persons, often with substantial co-morbidities in whom fixed duration therapy is a desirable endpoint; and (2) time-limited therapy may decrease the risk of clonal evolution and permit re-treatment with the same drugs. Ongoing dialogue and cooperation between CLL focused clinical trial groups such as the NAIG, German CLL Study Group (GCLLSG), and others to develop a coordinated strategic approach to future clinical trials would be optimal pathways to answer these questions.

New areas of investigation

The limited space precludes our discussing all critical issues in CLL therapy, we highlight the following: (1) early intervention for asymptomatic high-risk disease; (2) monoclonal B-cell lymphocytosis (MBL); (3) relapsed/refractory (advanced) CLL, including Richter transformation; (4) developing expertise using immune therapy, especially chimeric antigen receptor T-cell (CAR-T)-based approaches.

Amongst the 21,000 new cases of CLL in 2020, about 70% will have early stage asymptomatic disease [19] not meeting 2018 International Workshop on CLL (iwCLL) criteria for starting therapy [20]. During this watch and wait phase, these people remain at high risk of developing serious infections [21–24], second cancers, especially non-melanoma skin cancers [25], and the associated anxiety of living with an untreated cancer [26]. The CLL-International Prognostic Index (CLL-IPI) is derived from the following five variables: (1) age; (2), Rai stage; (3), del17p and/or TP53 mutation; (4) IGHV mutation; and (5) serum β2-microglobulin; and it can segregate people who are recommended not to be treated (because they do not meet the 2018 iwCLL criteria for starting therapy) into four cohorts with low, intermediate, high, and very high risks of disease progression with corresponding 5-year risks of therapy of 22%, 43%, 68%, and 100% [27]. There are few trials testing if early intervention in high-risk early stage asymptomatic CLL decreases the risk of disease progression and improves survival. Initial results from the GCLLSG CLL12 study indicate people with asymptomatic high-risk CLL treated with ibrutinib compared with placebo have longer event-free survival (EFS) but not an OS benefit [28]. A phase 3 NAIG Study, EVOLVE, expected to open to enrollment this year will randomize previously untreated persons with CLL with high and very high risks of disease progression according to the CLL-IPI to early intervention with venetoclax and obinutuzumab versus delayed therapy with venetoclax and obinutuzumab when they meet 2018 iwCLL criteria.

We are beginning to understand the implication of a diagnosis of MBL, the precursor condition to CLL. MBL is defined as a blood clonal B-cell clonal concentration <5 × 10E + 9/L without lymphadenopathy, organomegaly, or cytopenias [29, 30]. Similar to monoclonal gammopathy of undetermined significance, the incidence of MBL is much higher in the general population than the incidence of CLL indicating not all everyone with MBL progresses to CLL. It is important to recognize that progression to CLL (defined as a clonal blood B-cell count of >5 × 10⁹/L with or without lymphadenopathy or organomegaly) is distinct from progression to CLL requiring therapy, when patients meet the 2018 iwCLL criteria for starting therapy; the latter being a more clinically relevant endpoint. The risk of MBL progression to CLL requiring therapy is estimated at ~1–2% per year. Identifying people more likely to progress and require CLL therapy is an area of active investigation. In addition to the risk of progression to CLL, people with MBL are also at a higher risk of developing serious infections and other cancers [31, 32].

There are increasing numbers of persons with advanced CLL previously treated with BTK inhibitors and/or venetoclax. What is the next best therapy? Clearly there is no standard-of-care. Clinical trials of next generation BTK inhibitors active against BTK mutations [33] are in progress and early results are promising [34, 35]. Identification of BCL2 mutations resistant to venetoclax will result in development of new molecules that bind to BCL2 protein and of drugs targeting other molecules in the apoptosis pathway such as MCL-1. There remain few, if any, effective therapy options for people with Richter transformation, defined as the development of an aggressive B-cell lymphoma in persons with prior CLL [36]. Despite initial enthusiasm for checkpoint inhibitors such as pembrolizumab and nivolumab combined with B-cell receptor antagonists [37, 38], median survival of persons with Richter transformation is usually <1 year. A concerted and coordinated approach to better understand the biology of Richter transformation is needed to develop more effective therapies.

We should not neglect the use of immune therapy in CLL, especially CAR-T approaches [39]. Although the 1st person treated with anti-CD19 CAR T cells 8 years ago remains in remission [40], subsequent studies using anti-CD19 CAR-T in CLL are less encouraging, with CR rates of 20–25% and 18-month PFS estimates of 25% [41, 42]. Several approaches currently being pursued offer hope that these results will improve including: (1) targeting other antigens on the surface of CLL cells such as CD23 and Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1); (2) adding ibrutinib in combination with CAR T cells to reverse T-cell exhaustion in CLL; (3) using allogeneic CAR T cells; and (4) using CAR-natural killer cells [43].

Conclusion

In this perspective we provide a realistic look at where we are in the therapy of persons with CLL, where riches are incremental rather than complementary and highlight new issues arising from this surfeit of therapy options. We are optimistic that a robust collaborative integrated international effort to develop clinical trials build on these major advances will provide answers to some or all questions we raise.