Overview of the Current Treatment Paradigm in Chronic Lymphocytic Leukemia, Part 2

JHOP - Sept 2016 Vol 6, No 3
Austin J. Combest, PharmD, BCOP, MBA
Senior Director of Clinical Science
Pharmaceutical Product Development (PPD)
Department of Global Product Development
Wilmington, NC
University of North Carolina/PPD Drug Development Fellowship
Chapel Hill, NC
Ryan C. Danford, PharmD
Staff Pharmacist
Burlington, NC
Elizabeth R. Andrews, PharmD
Drug Development Fellow
Pharmaceutical Product Development
Department of Global Product Development
Wilmington, NC
Ashley Simmons, PharmD
Associate Director of Clinical Operations
Parion Sciences
Raleigh-Durham, NC
Paulina McAtee, PharmD
Associate Director
Clinical Pharmacy Services
Pharmaceutical Product Development
Department of Global Product Development
Wilmington, NC
Dirk J. Reitsma, MD
Vice President and Head of Oncology
Pharmaceutical Product Development
Department of Global Product Development
Wilmington, NC
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Background: The clinical development landscape for chronic lymphocytic leukemia (CLL) is evolving rapidly, and continuously challenges current therapeutic guidelines. Several new agents have recently gained approval from the US Food and Drug Administration and European Medicines Agency, including venetoclax, ibrutinib, idelalisib, and obinutuzumab. These new therapies, together with recent updates to the guidelines from the National Comprehensive Cancer Network and European Society for Medical Oncology, reflect findings of improved progression-free and overall survival rates, and represent a new age in the treatment of CLL. Part 1 of this series was published in this journal in June 2016.

Objective: The objective of this article is to provide an overview of recent changes to the CLL landscape, as well as future directions to inform practitioners and clinical researchers.

Discussion: Because of these changes, it is likely that the future will bring further development of niche drugs that target cytogenetic abnormalities—specifically 11q and 17p—as well as more active and tolerable regimens for older patients. Tolerable regimens and convenient routes of administration are needed to enable outpatients to self-administer their treatment long-term, and improve their quality of life.

Conclusion: The increasing number of novel agents for CLL management presents new challenges for appropriate sequencing of these agents, and comparator arm choices for future trials. Collaboration between developers can lead to more efficient and less costly clinical trials. Increased enrollment in clinical trials, especially among older patients, will be critical for the continued development of novel agents in the treatment of CLL.

J Hematol Oncol Pharm.
Part 2 of a 3-part series

Disclosures are at end of text

Chronic lymphocytic leukemia (CLL) is a disease that predominantly occurs in older adults; the median age at diagnosis is 71 years.1 Therefore, the CLL population typically has age-related comorbidities. Although CLL may have a chronic natural history, the disease is incurable with currently available therapies, and disease course is variable, especially early in its evolution. Patients without an immediate requirement for treatment can defer treatment until disease progression occurs, or until justification for treatment arises, such as disease-related symptoms (eg, B-symptoms, which include fever, night sweats, and weight loss), threatened organ function, or symptoms specifically related to bulky disease.

A patient’s age and comorbidities affect their ability to tolerate chemotherapy; therefore, age range (older or younger than age 70 years) and performance status are used in conjunction with prognostic factors to select initial treatment options for each patient. Prognostic factors for poor outcome include higher stage of disease at the time of diagnosis, shorter lymphocyte doubling time, diffuse bone marrow pattern, and certain cytogenetic abnormalities.

The most common cytogenetic abnormalities occur in chromosomes 12 or 14.2 Worse outcomes are associated with deletion 17p (del17p), whereas patients with deletions of chromosome 11q (del11q) may have a favorable response to alkylator-based therapies (Table).3 More favorable outcomes are associated with a sole deletion of 13q.2 Furthermore, ZAP-70, an intracellular tyrosine kinase, and the degree of immunoglobulin heavy-chain variable gene mutation may help predict the aggressiveness of CLL.


Current treatment guidelines initially recommend stratifying patients into 2 groups using fluorescence in situ hybridization cytogenetic testing: those with del17p/mutation, and those without del17p. Patients without del17p are further stratified based on age (ie, ≥70 or ≤69 years), comorbidities, and del11q status.4 Historically, as first-line treatment, frail patients without del11q or del17p might have received chlorambucil (with or without rituximab), rituximab monotherapy, or pulse corticosteroids.

More recently, combination treatment with obinutuzumab and chlorambucil has become a preferred first-line regimen for frail patients with comorbidities, based on data from the CLL11 phase 3 trial, in which obinutuzumab and chlorambucil demonstrated significant and clinically relevant improvements in the rates of progression-free survival (PFS; 26.7 months vs 15.2 months); complete response (21% vs 7%); and minimal residual disease (MRD)-negative status (29.4% vs 2.5%) relative to rituximab and chlorambucil.5 The median overall survival was not reached in the obinutuzumab and chlorambucil arm, versus 58.5 months in the chlorambucil arm (hazard ratio, 0.62; 95% confidence interval, 0.42-0.92), based on updated survival results presented at the 57th American Society of Hematology Annual Meeting and Exposition in 2015.6

Another preferred regimen in this population is ibrutinib as a single agent. In general, older patients—and patients who are younger but have comorbidities—may be treated with a variety of single- or multiple-agent chemotherapies, immunotherapies, or chemoimmunotherapy. The combination of obinutuzumab and chlorambucil, and ibrutinib as a single agent recently emerged as the preferred regimens, according to the 2016 update to the treatment guidelines of the National Comprehensive Cancer Network (NCCN).3 However, in the clinical setting, initial use of obinutuzumab and chlorambucil in older patients has not been common practice.7 The ibrutinib category 1 recommendation was added in version 2 of the 2016 NCCN guidelines, so prescribing uptake is yet to be determined.3

Another potential option for first-line treatment in older patients or younger patients with significant comorbidities is ofatumumab combined with chlorambucil. Although ofatumumab’s current role is limited in CLL, it has been an option in this setting since improvement versus chlorambucil alone in median PFS was demonstrated in the COMPLEMENT1 trial (22.4 months vs 13.1 months for chlorambucil alone).8 Comparing results for the CLL11 and COMPLEMENT1 trials, it appears that obinutuzumab may be slightly more active than ofatumumab (PFS, 26.7 months vs 22.4 months, respectively); however, serious infusion reactions during the first cycle are more common with obinutuzumab.

Younger patients without comorbidities (or del17p) should receive chemoimmunotherapy, usually including a purine-antimetabolite and rituximab, as shown in Figure 1.3 Regimens can include fludarabine, cyclophosphamide, and rituximab (FCR); fludarabine and rituximab (FR); pentostatin, cyclophosphamide, and rituximab (PCR); bendamustine alone or in combination with rituximab (BR); or obinutuzumab plus chlorambucil.

Figure 1

The CLL8 trial demonstrated that adding rituximab to fludarabine and chlorambucil (FC) improved the median PFS period (51.8 months vs 32.8 months) and the overall survival rate (69.4% vs 62.3% at 5.9 years’ follow-up).7,9

In another study, the median overall survival in the FC arm was 86 months, and was not reached in the FCR arm.8 In the frontline setting, the CLL10 trial demonstrated that FCR was superior to BR in young, previously untreated, fit patients with advanced CLL.10 The CR and MRD-negative rates were 40.7% versus 31.5%, and 74.1% and 62.9% in the FCR and BR arms, respectively. The median PFS period was significantly longer in the FCR arm than in the BR arm (53.7 months vs 43.2 months). The 36-month overall survival rate differed only minimally between the arms (90.6% in the FCR arm and 92.2% in the BR arm). Severe neutropenia and infections were more common in the FCR arm, especially in older patients. Because toxicity was higher in older patients, dose reductions led to similar efficacy between both regimens. Although FCR is the current standard therapy for very fit, younger patients, obinutuzumab and chlorambucil, ibrutinib, or BR are more appropriate regimens for older patients with CLL, or patients with significant comorbidities and CLL.3

Patients with del17p respond poorly to current treatment; therefore, ibrutinib in the first-line setting, and the recently approved BCL-2–selective inhibitor venetoclax (ABT-199) in the relapsed and refractory setting, may be warranted. In patients with complex karyotype (≥3 abnormalities), following a response to ibrutinib, allogeneic stem-cell transplantation, or enrollment into a clinical trial should be considered before progression. Patients with del11q respond better to alkylating treatment, and may preferentially receive such therapy. Some of these patients may become eligible for allogeneic stem-cell transplantation (Figure 1).3

In the relapsed or refractory setting, ibrutinib monotherapy or idelalisib plus rituximab are recommended irrespective of age, comorbidities, or cytogenetics; venetoclax is also being recommended (category 2A per version 3.2016 NCCN guidelines) as an option for patients with del17p (Figure 2).3 A cross-trial comparison of these 2 regimens (ie, ibrutinib alone and idelalisib plus rituximab) shows that the PFS and overall survival rates are essentially the same. Both options are acceptable, and recommended treatment will depend on multiple patient parameters, including previous therapy. One major consideration is the recent safety alert regarding idelalisib, as well as the tolerability profile of idelalisib in general.3

Figure 2

All 6 ongoing idelalisib trials were stopped amid an increased rate of adverse events, specifically deaths related to Pneumocystis jiroveci pneumonia and cytomegalovirus infection. The current US Food and Drug Administration and European Medicines Agency recommendation is to continue to use idelalisib in patients who are benefiting, but closely monitor them for signs of infection. In addition, all patients should receive prophylaxis for P jiroveci pneumonia during idelalisib treatment.

As a precaution while the data are being reviewed, idelalisib should not be started as first-line treatment in patients with CLL who have del17p. However, use of idelalisib can be continued in combination with rituximab in patients with relapsed or refractory CLL. The regimen with the best historical PFS period and overall survival rate in previously treated patients with CLL is ibrutinib in combination with BR from the HELIOS phase 3 trial; however, this is not an NCCN-recommended regimen as of the last guideline update (version 2.2016).4,11

In fludarabine-refractory CLL—defined by a relapse within 6 months of the last treatment—single-agent options include ibrutinib or rituximab. Combination options for fludarabine-refractory CLL include ibrutinib and bendamustine, or idelalisib and rituximab. Enrolling in a clinical trial is another good option in this setting. Venetoclax alone or in combination with other therapies should be considered.

In a phase 1/2 venetoclax dose-escalation trial, 57% of patients had fludarabine-refractory CLL.12 The overall response rate in fludarabine-refractory CLL was 79%, which included several patients with MRD-negative status. In the overall population and fludarabine-refractory subgroup, venetoclax induced a high rate of durable remissions.12

Allogeneic hematopoietic stem-cell transplantation (HSCT) for curative intent is another option for eligible patients with fludarabine-refractory CLL. Although controversial in CLL treatment, HSCT following maximum response to a novel targeted therapy—ibrutinib with or without rituximab, and bendamustine, idelalisib, and rituximab, or venetoclax—is an option that should be considered over continuation of targeted therapy. Although complete responses are not particularly common (up to 21.4% with ibrutinib, bendamustine, and rituximab, and 22% with venetoclax), deep remission (ie, significant reduction in disease burden) and MRD-negative disease are possible with these regimens.11,12 Some considerations before choosing HSCT include access to novel therapies (and their cost), previous treatments, cytogenetics and disease risk, donor match, physiologic age and comorbidities, and patient goals.13

These promising new therapies are not without toxicity, and the decision to select a particular regimen should also take into account the adverse event profile of each agent. Because CLL is a disease predominantly of older adults, treatment can be complicated by comorbidities and performance status. Although ibrutinib is generally well-tolerated (common adverse events include fatigue, diarrhea, infection, cytopenia, cough, rash, and arthralgia), the slightly greater risk of atrial fibrillation is a relevant concern for older patients. The bleeding risk associated with ibrutinib is rare, but there is a potential concern in patients on anticoagulation therapy for comorbid conditions such as atrial fibrillation, venous thromboembolism, and valvular heart disease.14

Common adverse events in response to idelalisib include fatigue, diarrhea, colitis, nausea, hypertension, pneumonitis, edema, and elevated liver transaminase values, so close monitoring of hepatic function at baseline and during therapy is required. Close monitoring for pulmonary symptoms such as cough, dyspnea, and bilateral infiltrates is also required. Currently, all patients receiving idelalisib must receive prophylaxis for P jiroveci pneumonia and cytomegalovirus, and be closely monitored for signs of infection.15

The most common adverse events related to obinutuzumab treatment include serious infusion reactions (especially during the first cycle), neutropenia, and thrombocytopenia. Infusion reactions are anticipated during the first cycle and can be managed; however, the severity of such reactions can be a concern for older patients, particularly because obinutuzumab plus chlorambucil is considered the standard of care for untreated older patients or patients with comorbidities. With venetoclax, specific tumor lysis syndrome prophylaxis and monitoring are recommended, based on tumor burden.3

Prophylaxis includes 1.5 to 2 L of oral hydration—with intravenous hydration in patients with medium and high tumor burden—with allopurinol. Rasburicase is reserved as an option if baseline uric acid levels are elevated in patients with high tumor burden. Frequent blood chemistry monitoring following venetoclax administration is also warranted, with inpatient monitoring during the first dose for patients with high tumor burden or poor renal function.

The most frequently prescribed first-line regimens for untreated patients include FCR, BR, chlorambucil (with or without rituximab or obinutuzumab), or rituximab monotherapy (common in the United States). The popularity of prescribing obinutuzumab has been slower than expected since it was demonstrated in 2013 that the combination of obinutuzumab and chlorambucil achieved superior PFS rates and other outcome measures compared with chlorambucil alone, and versus the combination of rituximab and chlorambucil.16

Chlorambucil is an established and frequently used therapy (as monotherapy or in combination with rituximab or obinutuzumab), and is generally used for patients with comorbidities who are not fit to receive fludarabine-based regimens—including FCR—or if aggressive treatment is not indicated. However, use of chlorambucil as monotherapy in the frontline setting is no longer considered standard of care based on results of the CLL11 trial, and should no longer be used as a control regimen in clinical trials.

In the past, prescribing patterns have closely aligned with evidence-based first-line treatment algorithms. However, a recent survey of hematology-oncology physicians showed that prescribers have been slow to adopt newer treatment modalities despite their inclusion as first-line options in treatment guidelines, opting instead for BR as first-line therapy in 43% to 67% of cases.7

Moreover, most new targeted therapies for relapsed or refractory populations were approved in a short time span, between the end of 2013 and July 2014, and were only recently approved and recommended for first-line use. Therefore, these agents are generally not yet widely available and approved as first-line agents.

As the use of ibrutinib, idelalisib, venetoclax, and other targeted therapies is transitioned from patients with relapsed or refractory CLL to those with untreated CLL, and these drugs become approved for first-line treatment in all patients—not only those with del17p or those who are older or frail—it is likely that prescribing practices will change substantially.

In Europe, use of newer agents has been slow because reimbursement decisions by national health authorities are often delayed long after approval. Furthermore, in the South American countries surveyed, access to the new agents beyond compassionate use or expanded-access programs was limited because reimbursement was not provided as of early 2015.

Author Disclosure Statement
Dr Combest, Dr McAtee, and Dr Reitsma are employees of Pharmaceutical Product Development (PPD), Wilmington, NC. Dr Danford is a Research Fellow at PPD, and the University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC. Dr Andrews and Dr Simmons have no relevant disclosures to report.

1. Surveillance, Epidemiology, and End Results (SEER) Program Research Data (1973-2012), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch. http://seer.cancer.gov/data/. Published April 2015. Accessed May 2, 2016.
2. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916.
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas. Version 3.2016. www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Published 2016. Accessed May 2016.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas. Version 2.2016. www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Published 2016. Accessed December 2015.
5. Goede V, Fischer K, Busch R, et al. Head-to-head comparison of obinutuzumab (GA101) plus chlorambucil (Clb) versus rituximab plus Clb in patients with chronic lymphocytic leukemia (CLL) and co-existing medical conditions (comorbidities): final stage 2 results of the CLL11 trial [Abstract]. https://ash.confex.com/ash/2013/webprogram/Paper60276.html. Accessed January 2015.
6. Goede V, Fischer K, Bosch F, et al. Updated survival analysis from the CLL11 study: obinutuzumab versus rituximab in chemoimmunotherapy-treated patients with chronic lymphocytic leukemia [Abstract]. https://ash.confex.com/ash/2015/webprogram/Paper80155.html. Accessed May 2016.
7. Green MR, Williams ME, Willey J, et al. First-line prescribing preferences of U.S. hematology-oncology physicians for patients with CLL: impact of novel agents [Abstract]. https://ash.confex.com/ash/2014/webprogram/Paper76723.html. Accessed January 2015.
8. Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385:1873-1883.
9. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164-1174.
10. Zinzani PL, Caligaris-Cappio F, Seymour JF, et al. Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study) [Abstract]. https://ash.confex.com/ash/2014/webprogram/Paper69485.html. Accessed December 2015.
11. Chanan-Khan AAA, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): first results from a randomized, double-blind, placebo-controlled, phase III study. J Clin Oncol. 2015;33(Suppl):Abstract LBA7005.
12. Seymour JF, Davids MS, Pagel JM, et al. ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): high complete response rate and durable disease control. J Clin Oncol. 2014;32:Abstract 7015.
13. Dreger P, Schetelig J, Andersen N, et al; European Research Initiative on CLL (ERIC) and the European Society for Blood and Marrow Transplantation (EBMT). Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood. 2014;124:3841-3849.
14. Sanford DS, Wierda WG, Burger JA, et al. Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice. Clin Lymphoma Myeloma Leuk. 2015;15:385-391.
15. The Lancet Haematology. Straying from the target. Lancet Haematol. 2016;3:e205.
16. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus clb versus clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): final stage 1 results of the CLL11 (BO21004) phase III trial [Abstract]. http://meetinglibrary.asco.org/content/116249-132. Accessed January 2015.

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