Improving treatment for patients with chronic lymphocytic leukemia

Abstract

The last two decades have been time of tremendous progress in treatment for patients with chronic lymphocytic lymphoma (CLL). Chemoimmunotherapy (CIT) combining anti-CD20 monoclonal antibodies with purine nucleoside analogs has been a substantial advance for patients with CLL and results in increased response rates, progression-free survival, and overall survival. Despite these improved outcomes, only ∼45% of patients achieve a complete remission with CIT and nearly all patients eventually relapse and their remains a need to improve efficacy. Although new combinations of traditional agents may lead to incremental progress, more substantive improvements are likely to result through therapeutic targeting of novel pathways critical to CLL B-cell survival including targeting: (1) leukemia cell apoptotic resistance; (2) survival signals mediated through the B-cell receptor; and (3) nurturing interactions with the microenvironment. In this mini-review, we summarize Mayo Clinic’s recent efforts to improve CIT for patients with CLL.

Keywords:

• Chronic lymphocytic lymphoma (CLL)
• Small lymphocytic lymphoma (SLL)
• Treatment

Introduction

Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies, accounting for ∼11% of all hematologic neoplasms. CLL affects ∼100 000 individuals in the United States with roughly 15 000 newly diagnosed cases per year. With the exception of allogeneic bone marrow transplant, CLL is currently incurable malignancy. Although 70–80% of patients are now diagnosed with early stage disease, a majority will progress to develop symptomatic disease and require treatment during follow-up. A majority will ultimately die from CLL or CLL-related complications. The median age at the time of CLL diagnosis is ∼70, and since most patients are observed for several years prior to needing treatment, the median age at the time of treatment is initiated typically in the early to mid-70s. These demographics have important implications with respect to the goals, intensity, and level of toxicity that is acceptable in CLL treatments.

The last two decades have been time of tremendous progress in treatment for patients with CLL. Randomized, controlled trials begun in the early 1990s demonstrated superior response rates, progression-free survival, and quality of life for patients treated with fludarabine-based therapy rather than chlorambucil or other alkylating-agent regimens. Long-term follow-up from these studies suggested that this approach may also result in prolonged overall survival.

Three subsequent randomized trials compared the efficacy of single-agent fludarabine to the combination of fludarabine and cyclophosphamide. All three trials found superior overall response rates (ORRs), complete remission (CRs) rates, and progression-free survival (PFS) with the fludarabine/cyclophosphamide (FC) combination. CR rates with the FC combination therapy are typically between 20 and 30%.

The most substantial treatment advance in the last decade for patients with CLL has been the addition of anti-CD20 monoclonal antibody therapy to such purine nucleoside analog-based chemotherapy regimens [e.g. chemoimmunotherapy (CIT)]. The randomized phase II trial conducted by the CALGB demonstrated that combining rituximab with fludarabine increased CR rates to 30 and 40%. Comparison of fludarabine/rituximab-treated patients to a historic CALGB trial of fludarabine monotherapy suggested an overall survival advantage to this approach.1 Concurrent with the CALGB trial, a large phase II trial conducted by MD Anderson Cancer Center, found that the addition of rituximab to FC combination (FCR) therapy led to an ORR >90%, high CR rates, and very durable responses.2

To follow up on these results, the German CLL Study Group conducted a randomized phase III trial comparing FC to FCR (∼408 patients in each arm).3 The median patient age on this trial was 61 years with fewer than 10% of patients aged 70 years or older. FCR treatment was associated with a superior CR rate (44% versus 22%; P<0·0001) as well as superior PFS (median 51·8 months versus 32·8 months; P<0·0001) and overall survival.3

Despite the improved outcomes with FCR-based CIT, only 40–45% of patients achieve a CR and nearly all patients (including those achieving CR) eventually relapse. Although they are not considered curative, aggressive fludarabine-based CIT regimens can result in substantial toxicity, including profound immunosuppression and prolonged cytopenias (which can restrict salvage therapy options at the time of recurrence) and are associated with a 5–10% risk of therapy-related myelodysplasia. These toxicities are highly problematic given the advanced age of most CLL patients and the fact that many patients have coexistent health problems that limit their ability to tolerate CIT. An illustrative example is the MD Anderson experience, where individuals ⩾70 years did not tolerate CIT with FCR; 75% had grade 3/4 myelosuppression, 11% had grade 3/4 infectious complications, and fewer than half of patients aged ⩾70 years were able to complete the intended six cycles of induction.4 The inability to tolerate a full course of induction markedly reduced the efficacy of FCR in elderly patients. The end result is that while FCR-based chemotherapy has been a major advance in CLL treatment, it is an advance that does not benefit the majority of patients with CLL who cannot tolerate this treatment approach. Although some have continued to rely on chlorambucil-based therapy for elderly patients, there remains great interest in developing approaches that allow the benefits of CIT to be applied to elderly patients.

In an effort to develop a better tolerated CIT strategy, Mayo Clinic and the Ohio State University began testing pentostatin-based CIT regimen in 2002.5 We initially tested the combination of pentostatin (2 mg/m²), cyclophosphamide (600 mg/m²), and rituximab (375 mg/m²) in 64 previously untreated patients with CLL in a phase II trial. The median age of patients in this trial was 63 years, and approximately one-third of patients were 70 years or older. The ORR and CR rate were 91 and ∼40% (similar to the efficacy of FCR-based treatment). Importantly, unlike FCR, the PCR regimen was well tolerated in elderly patients, including individuals over the age of 70 years.5 No significant differences in ORR, CR rate, or PFS were observed by patient age, and there were no significant differences in the number of cycles administered, need for dose reductions, or grade 3/4 hematologic, infectious, and other toxicities among patients over age of 70 years as compared to patients under age of 70 years.5 These data led to the addition of PCR therapy as a first-line treatment option for CLL patients in the NCCN guidelines.

The fludarabine/rituximab combination developed by CALGB appears to be another CIT regimen that can be tolerated by many elderly patients. In a population-based experience of 98 patients treated with fludarabine and rituximab, the group from British Columbia reported a 2-year and 4-year treatment-free survival of 69 and 54%, respectively (median 4 years).6 Age of >70 years had no effect on overall survival or treatment-free survival in this analysis, and only 13% of patients had early discontinuation of treatment due to toxicity.6 Dose-reduced FCR platforms (FCR-LITE) have also been developed as a strategy to try and bring the benefits of CIT to elderly CLL patients; however, the efficacy and tolerability of these strategies in elderly patients are not yet well established.

Biomarkers and minimal residual disease (MRD)

The identification of leukemia cell biologic and genetic characteristics associated with clinical outcome has improved to predict patient outcome at diagnosis. FISH, IGHV mutation status, ZAP-70 status, CD38 status, and CD49d status have all been shown to be robust prognostic parameters. Several of these parameters have also been found to be useful for predicting response (or resistance) to specific treatment approaches. The presence of del(17p13) and/or abnormal TP53 function predicts for reduced likelihood of response, short PFS, and short overall survival to purine nucleoside analog-based and alkylating agent-based strategies including the FCR approach. Depending on functional status and comorbidities, patients with del(17p13) are candidates for reduced-intensity conditioning allogeneic stem cell transplants, or alternative treatment approaches using alemtuzumab or corticosteroid-based regimens, ideally as part of a clinical trial. Indirect evidence suggests that patients with a del(11q23) on FISH are at lower likelihood of responding to fludarabine monotherapy or the fludarabine/rituximab combination but suggests that the inclusion of cyclophosphamide in the CIT regimen may overcome this resistance. Based on these data, purine analog chemotherapy regimens that include cyclophosphamide (e.g. FCR and PCR) are the preferred treatment for individuals with this genetic defect. The other molecular biomarkers do not seem to be reliable predictors of response to CIT; however, individuals with IGHV unmutated immunoglobulin genes have consistently been shown to have shorter PFS after CIT (even though they initially respond well).

Although MRD-negative remissions were exceedingly rare with historic treatment approaches, they occur in approximately 10–20% CIT-treated patients. Studies indicate that those who achieve an MRD-negative remission have longer response duration and overall survival. While it is not possible from the current data to determine whether these improved outcomes are due to the depth of remission or the biologic characteristics of the disease that influence whether an MRD-negative remission can be achieved, these observations have created interest in efforts to improve the efficacy of CLL treatment through intensification, consolidation, or maintenance approaches intended to increase the proportion of patients achieving an MRD-negative disease state.

Efforts to Improve CIT through Targeted Strategies

As illustrated above, although the progress in CLL treatment over the last two decades has been exciting, there remains a need to improve the efficacy of therapy and durability of response in younger CLL patients and to improve the efficacy and tolerability of therapy for older CLL patients. While permeations exploring new combinations of existing/traditional chemotherapeutic agents may lead to incremental progress, more substantive improvements are likely to result through therapeutic targeting of novel biologic pathways critical to the survival and/or chemotherapy resistance of CLL B cells. The profound increase in understanding of CLL B-cell biology in recent years provides numerous potential therapeutic targets. The greatest interest to date has centered on targeting: (1) leukemia cell apoptotic resistance; (2) survival signals mediated through the B-cell receptor; and (3) interrupting nurturing interactions between the CLL B cell and its microenvironment.

CLL B cells are characterized by their ability to resist apoptosis for months in vivo but undergo spontaneous apoptosis over several days during in vitro culture. This observation suggests that in vivo cross-talk and interactions between the CLL B cell and its environment may promote leukemia cell survival.7,8 Interactions between the leukemic cell and its environment are complex and involve cell–cell interactions, cell–extracellular matrix interactions, and soluble interactions mediated by cytokines and chemokines.8 These interactions are bidirectional and include interactions between CLL cells and stromal cells, follicular dendritic cells, nurse-like cells (derived from monocytes), and T cells.7 A number of immune cytokines including CCL3, CCL4, CCL2, and vascular endothelial growth factor (VEGF) as well as chemokine CXCR4 and CXCL12 have been implicated.8 Survival signals facilitated through the B-cell receptor also involve a number of potential downstream molecules including Bruton’s tyrosine kinase, PI3 kinase, AKT, SYK, and mTOR, all of which have been pharmacologically targeted.7

The first Mayo Clinic effort to improve the efficacy of CIT involved the addition of lenalidomide consolidation after PCR induction to determine whether this approach could eradicate residual disease and improve PFS. Lenalidomide is an immunomodulatory drug that is thought to mediate its clinical effects through multiple mechanisms including modulation of immune cytokines, immune cell interactions, and possible effects on nurturing signals in the microenvironment. Multiple groups have shown that this agent has single-agent clinical activity in patients with CLL. In the Mayo trial, patients completing PCR induction received 6 months of lenalidomide consolidation followed by a repeat response evaluation and MRD assessment. At the time of restaging, patients who were MRD-negative entered observation while those with residual disease continued on lenalidomide and underwent repeat MRD assessment every 3 months. Lenalidomide was discontinued when an MRD-negative state was achieved. Forty-four eligible patients were enrolled on this trial (median age 65 years; range 44–78 years). On preliminary analysis presented at the ASH 2011 Annual Meeting, six patients improved the quality of their response with consolidation, and, compared to historic controls treated with PCR alone, consolidation appeared to prolong time to retreatment.9

In another effort to improve the efficacy of PCR induction, we initiated a randomized phase II trial of PCR with or without the anti-VEGF therapy bevacizumab. In vitro studies suggest that both paracrine and autocrine signaling through the VEGF receptor leads to up-regulation of antiapoptotic proteins known to mediate apoptotic resistance (including MCL1) and to promote leukemia cell survival. Bevacizumab is an anti-VEGF monoclonal antibody that has been shown to improve response rates and clinical outcomes when combined with chemotherapy for a number of solid tumors, and this agent is currently FDA-approved for colon cancer, non-small cell lung cancer, glioblastoma multiforme, and metastatic renal cell carcinoma. Fifty-seven patients with previously untreated CLL requiring therapy have been accrued to the Mayo Clinic led trial to date. This trial is expected to complete accrual in early 2012 and be valuable for differences in response in late 2012.

The third Mayo Clinic effort to improve the efficacy of CIT involves the substitution of the humanized anti-CD20 monoclonal antibody ofatumumab for rituximab in the pentostatin cyclophosphamide platform (PCO). Ofatumumab is an approved treatment for patients with relapsed CLL that is refractory to fludarabine and alemtuzumab, and the single-agent activity of ofatumumab in patients with refractory CLL suggests that it may have greater efficacy than rituximab. Forty-eight patients were accrued to the PCO trial at Mayo Clinic and Duke University between March 2010 and summer 2011. In preliminary analysis of the first 33 patients accrued to this protocol presented at the ASH 2011 Annual Meeting, the ORR to PCO was 94% (31 out of 33) with 15 (45%) complete remissions, and 5 (15%) complete clinical remissions (restaging bone marrow for final response assessment pending).10 Since the eligibility of these patients treated with ofatumumab-based CIT was similar to our historical trials of rituximab-based CIT (n = 108) using an identical pentostatin and cyclophosphamide chemotherapy backbone, we explored differences in the efficacy and tolerability of these two approaches. Age, gender, and prognostic profiles of the treated patients in these cohorts were similar. Ofatumumab-based CIT appeared to be better tolerated than rituximab-based CIT (⩾grade 3 hematologic toxicity ofatumumab-based CIT = 24% versus rituximab-based CIT = 51%; P = 0·009) and also appeared to have similar or slightly superior efficacy to our previous experience with rituximab-based CIT (CR/complete clinical remission 61% versus 41% in the first 33 patients treated).10

After several groups demonstrated single-agent activity using targeted approaches to interrupt the B-cell receptor signaling pathway with SYK inhibitors, PI3 kinase inhibitors, and Bruton’s tyrosine kinase inhibitors, we have pursued strategies to interrupt this pathway at other checkpoints (e.g. mTOR and AKT). After demonstrating single-agent activity and leukemia cell mobilization with the mTOR inhibitor RAD001 in patients with relapsed/refractory CLL, we are now conducting a salvage therapy trial of this agent in combination with alemtuzumab for patients with CLL. We are also currently conducting a trial of bendamustine and rituximab in combination with an oral AKT inhibitor in the relapsed setting. It is hoped that these efforts along with other efforts to interrupt the B-cell receptor pathway that are ongoing in multiple centers around the world will further improve the efficacy and tolerability of CIT for patients with CLL.

Disclosure

Dr Shanafelt receives research support from Genentech, GlaxoSmithKline, Celgene, Cephalon, Hospira and Polyphenon E International.