Introduction
Therapeutic options for chronic lymphocytic leukemia (CLL) have been remarkably expanded in the last few decades. Extension of available options within particular drug classes, such as addition of fludarabine to purine analogs, the development of multiple targeted therapies, from agents such as rituximab and obinutuzumab that target B cells, and the rapid progress of specific inhibitors of the B-cell receptor-dependent signaling cascade have dramatically increased the rates of overall responses and progression-free survival (PFS).1,2 However, sustained remissions are limited and cure remains elusive. Moreover, conventional chemotherapeutic use is associated with significant toxicity, which is particularly pronounced in patients more than 65 years of age, who constitute the majority of patients with CLL. Choosing treatment strategies for patients with relapsed CLL, therefore, presents a significant challenge. In this review, we focus on recent exploration of chemotherapeutic and targeted therapy options directed against relapsed CLL, summarize factors that may predict resistance to therapy and highlight future directions.
Chemoimmunotherapy for Initial Treatment
Rituximab in combination with fludarabine and cyclophosphamide (FCR) or bendamustine (BR) are among the most commonly used chemoimmunotherapy regimens for the initial treatment of patients with CLL. In younger patients with good performance status and limited comorbid conditions, the FCR300 phase II trial proposed FCR as an effective combination therapy and reported an overall response rate (ORR) of 95%, with 72% complete responses (CR) and a median PFS of 6 years.3 The German CLL Study Group (CLL8) trial compared FCR with fludarabine and cyclophosphamide (FC) and further established its efficacy.4 In a similar patient population, the CLL10 trial compared FCR to BR and demonstrated improved CR and PFS, although with a higher incidence of cytopenia and infectious complications.5 However, tolerability and toxicity issues were substantial and survival outcomes were not significantly improved in patients more than 65 years of age, in patients with compromised renal function and multiple comorbid conditions, and in patients with high-risk del(17p) disease. This has led to the development and recent approval of multiple targeted therapies that are very effective and well-tolerated for these patients, and include obinutuzumab,6 ofatumumab,7 and ibrutinib.8 While these agents are being used more frequently, data regarding the optimal management of patients relapsing after these therapies are currently lacking.
Chemoimmunotherapy for Relapsed Disease
The REACH trial, a multicenter, randomized, phase III trial, compared 6 cycles of FCR with 6 cycles of FC) for treatment of patients with previously treated, relapsed CLL.9 The trial enrolled 552 patients who received previous treatment with single-agent regimens containing either chlorambucil with or without a steroid, other nucleoside analogs, or an alkylator-containing combination but not an alkylator/nucleoside-analog combination. After a median follow-up of 25 months, patients who received FCR showed a significantly improved PFS by 10 months (P <.001; median 30.6 months for FCR vs 20.6 months for FC). Furthermore, ORR increased from 58% to 69% (P =.034) and CR rate increased from 13% to 24% (P <.001) in patients treated with FCR compared to those who received FC.
Combination of chemotherapy and targeted therapy was further explored in the large LUCID trial, which studied the addition of lumiliximab (L), a chimeric monoclonal antibody that targets CD23, to FCR for treatment of patients with relapsed CLL who were previously treated with 1 or 2 single-agent or combination regimens.10 The study enrolled 615 patients who were randomized to lumiliximab in combination with FCR versus FCR alone. Even though CR, ORR, and PFS were similar between both groups, this study recognized the utility of FCR in the relapsed setting where patients had received prior combination chemoimmunotherapy and demonstrated an ORR of 72% with a CR of 15% and a PFS of 24 months.
Bendamustine in combination with rituximab was evaluated in a phase II trial of 78 patients with relapsed or refractory CLL and reported an ORR of 59%, with 9% CR and a median event-free survival of 15 months.11 However, ORR was 45% in patients with fludarabine-refractory disease and 60% in patients with fludarabine-sensitive disease. About 50% of patients encountered severe (grade 3/4) hematologic toxicities and 13% experienced severe infections. Patients with del(17p) had only a 7% response to therapy.
Although up to 95% of patients with CLL respond to frontline FCR or BR therapy, 30% to 60% of patients fail to achieve CR and therapy results in significant toxicity.4,7,12 Moreover, no current standard exists to treat patients with relapsed disease after frontline chemoimmunotherapy.13 Efforts have been made to identify optimal regimens for treatment of such patients and various salvage therapeutic options have been evaluated in patients relapsing after frontline FCR, including retreatment with FCR, using lenalidomide-based or other intensive chemotherapy-based regimens.14 Factors such as duration of initial remission were found to have a direct impact on predicted response to salvage therapy, and patients with initial remission of at least 3 years’ duration showed an average post-salvage survival of 63 months versus 13 months in patients who required salvage therapy earlier than 3 years after initial course of FCR. Also affecting the response to salvage therapy were factors such as older patient age, unfavorable cytogenetics (including del[17p]), and factors dependent on the stage of disease at relapse, such as platelet count and β2-microglobulin.14 The negative predictive value of del(17p) status is not surprising, because mechanism of disease response to fludarabine-based regimens has been previously demonstrated to rely on intact p53 function.15 Moreover, the CLL8 trial demonstrated that FCR does not improve OS of patients with del(17p) disease (37% of patients survived at 3-year follow-up after receiving chemotherapy and 38% after chemoimmunotherapy; P =.25).4
Choice of salvage therapy affects response, and survival was reported to be superior in patients treated with FCR-based or lenalidomide-based regimens, compared to alemtuzumab-based or rituximab-based regimens and intensive chemotherapy (median survival of 82 months vs 29 months; P <.001).14 Another recent retrospective study examined patient outcomes with salvage treatment after progression on FCR and showed that bendamustine-rituximab (BR) regimen was most effective when compared to retreatment with FCR, to an alemtuzumab-containing regimen, or to the combination R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).16 The study showed that BR produced an ORR of 86%, compared to values in the 50% to 60% range after treatment with the alternative regimens. However, patients had similar and dismal PFS of 18 months with BR or FCR and 6 months with alemtuzumab-containing regimens or R-CHOP. Predictably, patients with del(17p) disease showed lower rate of response to salvage therapy, and survival outcomes were worse in patients with disease relapse within 3 years of frontline FCR therapy.
Taken together, these studies indicate that outcomes of patients with relapsed CLL after firstline chemoimmunotherapy are poor, especially in patients who relapse less than 3 years after initial therapy, in those with del(17p), and in those with comorbid conditions. Finding effective and well-tolerated regimens for such patients that could prolong PFS and OS is vitally important and their outcomes appear to have been significantly improved with the advent of B-cell receptor (BCR) pathway inhibitors.
Specific BCR Signaling Pathway Inhibitors in Relapsed CLL
Specific inhibitors of B-cell receptor signaling, such as the BTK inhibitor ibrutinib and the phosphoinositide 3-kinase inhibitor idelalisib (in combination with rituximab), have been approved for treatment of relapsed CLL. Ibrutinib is able to inhibit BCR-signaling dependent cell division in vitro,5,17 and has induced substantially higher ORR and PFS in several phase II and phase III studies18,19 in patients with relapsed and refractory CLL.19 In a phase 1b/II study of 85 patients with previously treated CLL, 65% of whom had advanced-stage disease, 33% had de1(17p), 69% had unmutated immunoglobulin variable heavy-chain variable (IGHV) status, and 30% were >70 years of age, and had received a median of 4 previous therapies. Ibrutinib demonstrated an ORR of 91% (71% partial response [PR] and 20% PR + lymphocytosis) irrespective of the presence of high-risk features. Of note, 73% of elderly patients responded to ibrutinib, 83% of patients who were enrolled in the trial survived at 26 months, and 75% of patients were disease-free at follow-up. Ibrutinib was also shown to effectively induce an ORR in 71% and a CR in 13% of 31 elderly patients with previously untreated CLL, 6% of whom had del(17p).20 A phase III trial compared the outcomes of ibrutinib with ofatumumab and evaluated ORR, PFS, and OS among a cohort of patients with relapsed CLL.21 The cohort of interest included patients who were previously treated with a median of 3 prior therapies, most of whom received targeted CD20-directed therapy, and who shared the following characteristics: median age of 67 years, del(17p) in 32%, and del(11q) in 32%. At 6 months, the ibrutinib group had a PFS of 88%. The median PFS was 8 months in the ofatumumab group. Similarly, OS was significantly improved with the use of ibrutinib. These responses and improved outcomes were observed across all cohorts of patients, including patients with high-risk disease features.21 A recent 30-month updated follow-up of the original phase I/II trial of ibrutinib demonstrated a PFS of 69% and OS of 79%. However, response frequency and durability were inferior in patients with high-risk disease features: del(17p) patients had a 30-month PFS rate of 48% and an OS rate of 65%.22
Idelalisib, another inhibitor that selectively targets the BCR-signaling cascade by inhibiting PI3-kinase delta, has also been tested in patients with relapsed and resistant CLL and has shown promising efficacy.23 A phase III trial evaluated this regimen for treatment of elderly (median age 71 years) patients with comorbid conditions and high-risk relapsed disease after a median of 3 prior therapies, in comparison with placebo combined with rituximab. The trial randomized 220 patients to each arm. High-risk features included relapsed progressive disease requiring therapy within 24 months, unmutated IGHV in 83%, and del(17p) or TP53 mutations in 42% of patients. Preliminary results after 12-month follow-up showed 81% ORR, compared with 13% in the placebo-rituximab arm (P <.001), with significant improvement in response rates across all risk subgroups. While more adverse events were reported in the idelalisib plus rituximab group compared to the placebo plus rituximab group, mortality was higher in the placebo group, with 6 deaths in the idelalisib plus rituximab cohort and 13 in the placebo plus rituximab cohort.23
More recently, promising data have been reported with newerBTK inhibitors for the treatment of patients with relapsed disease. Prominent among these is acalabrutinib, which demonstrated an ORR of 95% with the remaining 5% of patients experiencing stable disease. Patients with del(17p) had an ORR of 100% and PFS was 100% at 12 months.12
Development of Resistance and Additional Limitations of Targeted Kinase Inhibitors
Review of a large, 308-patient, single-institution trial at the Ohio State University revealed that only about 10% of patients discontinued ibrutinib because of disease progression at a median follow-up of 20-months.24 Several studies have helped to identify high-risk patients who are less likely to respond to such regimens and complex karyotype appears to be an independent predictor of resistance to ibrutinib.24,25 Whole-exome sequencing from samples of patients with CLL at the onset of disease resistance to ibrutinib identified a C481S mutation within the ibrutinib binding site of the BTK protein that rendered the affinity interaction between BTK and ibrutinib potentially reversible.26 The study also found R665W and L845F mutations in PLCγ2 in 2 separate samples of patients with new-onset ibrutinib resistance and identified them as potential gain-of-function mutations that could allow the BCR-dependent signaling cascade to bypass the inhibition imposed by ibrutinib.24,26
Additionally, other limitations of ibrutinib therapy have been identified, including an increased risk of bleeding, especially in patients on concurrent anticoagulation therapy.27 In review of the Ohio State University experience, up to 19% of patients treated with ibrutinib stopped taking the medication because of toxicities.24 Moreover, patients who developed resistance to ibrutinib did poorly, with most requiring alternative therapy within several weeks of stopping ibrutinib and a median survival of 17.6 months. Eighteen patients developed Richter’s transformation with a median survival of only 3.5 months.5 Similarly, idelalisib use is associated with significant pneumonitis, colitis, and transaminitis that result in significant morbidity in a subset of patients.23
Alternative Therapies for Relapsed Disease
Venetoclax
Targeting of Bcl-2, an anti-apoptotic protein overexpressed in CLL B cells, results in significant apoptosis in vitro and clinical activity in vivo. Venetoclax is a potent, oral Bcl-2 selective inhibitor with limited off-target effects on Bcl-xl expressed on platelets. In a large phase I study it demonstrated impressive activity in relapsed or refractory CLL with an ORR of 79% and a 20% CR. Patients with del(17p) disease had an ORR of 71% with a 16% CR.28 Venetoclax use is complicated by serious cytopenia in almost 50% of patients and fulminant tumor lysis syndrome, especially in the presence of high tumor burden and requires specific mitigation efforts such as stepwise dose escalation.
Lenalidomide
Lenalidomide
Lenalidomide is a potent oral immunomodulatory (IMiD) drug in the thalidomide analog class of therapeutics.14-17 These agents, along with newer pleotropic pathway modifiers (PPM) such as CC-122, have the potential to be an option for patients with aggressive, high-risk disease. Lenalidomide has shown promising activity and reasonable tolerability in multiple clinical trials in patients with relapsed disease but its future development is questionable because the pivotal phase III trial in patients with previously untreated disease had to be halted because of increased mortality. However, it remains a reasonable option for patients with relapsed and refractory disease but patients can frequently experience tumor lysis and/or tumor flare.
Chimeric Antigen Receptor – T (CAR-T) Cells
CAR-T cells are ex vivo engineered, lentiviral-modified, autologous T cells containing an altered T-cell receptor targeting a surface antigen (eg, CD19) on CLL B cells. The chimeric T-cell receptor contains costimulatory domains that increase affinity and specificity towards the target antigen. Multiple formulations of CAR-T cells have been advanced and promising early results with sustained remissions have been reported.29,30 Infusion of these CAR-T cells can result in severe cytokine-release syndrome that might require aggressive and intensive supportive care. Moreover, therapy results in persistent hypogammaglobulinemia from sustained normal B-cell eradication, with the resultant need for immunoglobulin supplementation and prophylaxis for infectious complications. Further design modifications may be able to overcome some of these issues.
Conclusions
While highly encouraging and durable responses are observed in patients with recurrent or resistant CLL who are treated with selective kinase inhibitors ibrutinib and idelalisib, there remains a substantial fraction of patients with relapsed CLL and high-risk disease features who fail to achieve sustained PFS with these therapies. This is despite the fact that many patients with conventional high-risk features, such as old age, unmutated IGHV status, presence of del(17p) or mutated TP53, and complex karyotype have been shown to respond to single-agent or combined therapies with kinase inhibitors. Acquisition of mutations within the mediators of BCR-dependent signaling pathway precipitates resistance to ibrutinib. Additional toxicities and individualized limitations of targeted kinase inhibitors may limit their utility in particular cases of CLL relapse. However, the advent of additional BTK inhibitors, such as acalabrutinib,12 and other BCR pathway inhibitors, such as entospletinib,31 along with Bcl-2 inhibitors such as venetoclax,28 portends a bright future for the management of patients with relapsed CLL and potentially offers better-tolerated and more efficacious options for these patients. Specific considerations for the use of these agents are summarized in Table 1. Together, these considerations highlight the vital importance of enrolling patients with relapsed CLL, especially those with high-risk disease features, into clinical trials to ensure the development of additional potentially curative therapeutic avenues.
Affiliations: Polina Shindiapina, MD, PhD, and Farrukh T. Awan, MD, are with the Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
Disclosure: Dr Awan is on the advisory boards for Gilead Sciences Inc and Novartis Oncology Inc
Address correspondence to: Farrukh T Awan, MD, 320 W. 10th Ave., Columbus, OH 43210. Phone: (614) 688-7942; Fax: (614) 293-7256. Email: [email protected]
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