New Meets Old: A Case Study and Review of Novel Therapeutics for the Treatment of CLL in Older Patients

NCCN: Continuing Education

Case Report

Patient RS is an otherwise healthy 75-year-old man initially evaluated in February 2004 for an elevated absolute lymphocyte count (ALC) of 15,300 x 10⁹/L. Peripheral blood flow cytometry confirmed a diagnosis of ZAP-70-negative chronic lymphocytic leukemia (CLL). Fluorescence in situ hybridization (FISH) was not performed. He was asymptomatic, without palpable adenopathy or organomegaly, and was monitored expectantly during the next 5 years, remaining free of symptoms or hematologic abnormalities.

By August 2009 he developed mild fatigue, cervical lymphadenopathy, splenomegaly palpable 5 cm below the left costal margin (LCM), and an ALC of 36,000 x 10⁹/L. He was followed until May 2013, at which point his spleen was palpable down to 10 cm below the LCM, with an ALC increase to 80,000 x 10⁹/L from 58,000 x 10⁹/L in November 2012. Given the progression in fatigue and symptomatic splenomegaly, a decision was made to initiate treatment. A baseline PET/CT showed minimally FDG-avid adenopathy and massive splenomegaly (17.4 x 17.1 x 29 cm) corresponding to examination findings. In addition, molecular studies on peripheral blood showed 38% of 200 interphases evaluated by FISH to have lost the short arm of chromosome 17 (del 17p).

Treatment of Older Patients With CLL

The treatment of older or medically frail patients with CLL is in many ways emblematic of a larger struggle confronting hematologists: achieving maximal efficacy while minimizing collateral toxicity. Indications for initiating therapy in older patients include worsening cytopenias secondary to progressive marrow involvement; massive (>6 cm below LCM) splenomegaly; bulky adenopathy (>10 cm in longest diameter); progressive lymphocytosis with an increase in doubling time of less than 6 months or a 50% increase in a 2-month period; autoimmune anemia and/or thrombocytopenia poorly responsive to steroids; and constitutional symptoms.¹ However, a variety of factors can complicate the decision-making process. With a median age of 72 years at diagnosis,² multiple medical comorbidities, poor performance status, and end-organ dysfunction can affect the choice and timing of therapies in this population.

Current NCCN recommendations for the treatment of CLL differ for older patients and are stratified by degree of frailty and presence of comorbid conditions (to view the most recent version of these guidelines, visit NCCN.org).³ Validated clinical tools, such as the NCI Comorbidity Index,⁴ the Charlson Comorbidity Index,⁵ and the Cumulative Illness Rating Scale (CIRS),^6,7 measure chronic illness burden and severity of chronic diseases. The CIRS in particular has been used to evaluate suitability for the treatment of older patients with CLL. Patients can be categorized as either medically fit with no or mild comorbidity and normal life expectancy, and therefore potentially appropriate for intensive therapy irrespective of chronologic age (so called “go-go” patients); medically less fit with multiple or severe comorbidities and an unknown life expectancy (“slow-go” patients); or medically frail with fatal comorbidities and a short life expectancy, and therefore unlikely to benefit from CLL treatment (“no-go” patients).⁸ However, somewhat paradoxically, the patient with CLL and a high burden of comorbid disease is the patient likely to receive dose-attenuated therapy, and is therefore at greatest risk of incurring CLL-related morbidity and mortality in an effort to mitigate treatment-related morbidity.⁹

This underscores the importance of characterizing patient “fitness” through a comprehensive assessment of comorbid disease burden, overall functional status, and treatment-specific determinations of risk versus benefit. For example, the NCCN Guidelines for Non-Hodgkin’s Lymphomas³ list fludarabine in combination with rituximab (FR) or cyclophosphamide and rituximab (FCR) as frontline treatment for patients with del 17p; however, these regimens provide only modest progression-free survival (PFS) and no overall survival benefit in older patients.^10-12 Moreover, fludarabine-based regimens may result in higher rates of treatment discontinuation in older patients because of excess hematologic toxicities and infectious complications. In one study, nearly 70% (22 of 32) of patients older than 65 years were unable to complete an entire fludarabine-based treatment program compared with 25% (12 of 50) of patients younger than 65 years.¹³ Accordingly, FCR is not recommended as first-line therapy for patients in this age group. Alemtuzumab is an option for patients with del 17p based on a study of 36 patients with fludarabine-refractory CLL treated with this agent. Of 15 patients with p53 mutations, deletions, or both, 6 (40%) experienced response compared with 4 of 21 (19%) of patients without these risk features.¹⁴ Despite the relative efficacy of alemtuzumab, however, concern remains over deepening immunosuppression and resultant life-threatening infection. Conversely, rituximab plus high-dose methylprednisolone for patients with del 17p disease may be comparatively less toxic but has not been evaluated in larger frontline studies, and thus its utility remains unclear.¹⁵ Striking a balance between efficacy and toxicity in this patient population is therefore challenging; however, the development of novel therapeutics and targeted agents has recently altered the landscape.

Emerging Therapies

The expanding armamentarium of treatment options for CLL offers the possibility of effective, minimally toxic therapy, even for high-risk disease. Next-generation monoclonal antibodies (mAb) such as obinutuzumab, a type II humanized anti-CD20 IgG1 mAb with a glycoengineered Fc region, represent the next step in mAb therapy.

In combination with chlorambucil, obinutuzumab was recently compared with rituximab and chlorambucil in a phase III trial evaluating its role in treatment-naïve older patients (median age, 73 years) with a relatively high burden of comorbid disease.¹⁶ The median CIRS score of 8 (range, 0-56) across treatment groups reflected the fact that study patients experienced significant comorbid conditions resulting in impaired cardiac, renal, and musculoskeletal function, for example.¹⁷ Treatment with obinutuzumab/chlorambucil compared with rituximab/chlorambucil resulted in prolongation of PFS and higher rates of complete response (CR; 20.7% vs 7.0%).¹⁶ Notably, the number of patients with del 17p was insufficient to determine efficacy in this subgroup. The increase in efficacy did not come with an increased rate of infectious complications, and the most frequent grade 3 or higher adverse events were neutropenia (≈33%) and infusion-related reactions (≈20%). The study¹⁶ showed that obinutuzumab/chlorambucil induced deeper and longer remissions than rituximab/chlorambucil, and the FDA subsequently approved the combination of obinutuzumab/chlorambucil for patients with previously untreated CLL on November 1, 2013.¹⁸

Inhibitors of Bruton tyrosine kinase represent another very promising class of agents for use in treating CLL and other hematologic malignancies. Ibrutinib monotherapy was studied in 85 patients with relapsed/refractory CLL receiving 420 mg of ibrutinib daily. Thirty patients (35%) were aged 70 years or older. The overall response rate (ORR) for the group was 71%, with an estimated PFS rate at 26 months of 75%.¹⁹ The most common nonhematologic adverse events were diarrhea (50%), fatigue (32%), and nausea (18%). Grade 3 and 4 hematologic adverse events included neutropenia (15%), thrombocytopenia (6%), and anemia (6%). An adverse event leading to discontinuation of therapy occurred in 7 study patients (8%). Notably, despite having received a median of 4 prior lines of therapy, ibrutinib did not cause an increase in grade 3 or higher infections during the extended therapy period.

A 14-month update of a phase II trial of ibrutinib plus rituximab reported higher response rates for the combination compared with historical response rates with rituximab alone, with 34 of 40 patients achieving a partial remission, and 3 patients achieving a CR.²⁰ Importantly, the combination seemed to improve the quality of life of patients (median age, 65 years; range 35-82), because the proportion reporting a high quality of life increased from 46% before treatment to 89% after 6 months of therapy. The most common adverse events were similar to those observed in the previously mentioned study, and 2 patients discontinued treatment because of possible ibrutinib-related toxicity (1 subdural hematoma, 1 grade 3 mucositis).

Lastly, a phase II study evaluating ibrutinib’s effect on del 17p CLL suggested that ibrutinib is effective irrespective of del 17p status.²¹ At 20 months, none of the 24 patients with del 17p-negative disease had experienced disease progression and 85% of the 29 patients with del 17p disease remained on treatment; median age for the entire cohort was 66 years (range, 33-85 years). Of patients with a del 17p, 53% experienced response, with 15% of patients experiencing grade 3 or higher infections or cytopenias.

Other promising agents include inhibitors of the bcl-2 family of antiapoptotic proteins and the delta isoform of phosphatidylinositol-3 kinase (PI3K). ABT-199 is a selective small molecule bcl-2 inhibitor undergoing evaluation in a phase I, dose-escalation study. ABT-199 monotherapy showed activity in patients with relapsed/refractory CLL, with a response rate of 84% (N=56). Patients with high-risk CLL showed similar efficacy, with a response rate of 82% in del 17p and 78% in fludarabine-refractory disease. The drug was relatively well tolerated, with most patients (34 of 56; ≈60%) remaining on study for a median overall time of 10 months. The most common adverse events (all grades, ≥25% of patients) were diarrhea (46%), neutropenia (43%), fatigue (34%), and upper respiratory tract infection (29%). Grade 3 or 4 events occurring in 4 or more patients included neutropenia (41%), tumor lysis syndrome (11%), thrombocytopenia (10%), and hyperglycemia (10%).²²

Lastly, the oral small molecule inhibitor of PI3K delta, idelalisib, was evaluated in a phase III trial in combination with rituximab versus rituximab alone in 220 patients. Median PFS was 5.5 months in the placebo group and was not reached in the idelalisib group, and patients receiving idelalisib had improved ORR (81% vs 13%; P<.001) and overall survival at 12 months (92% vs 80%; P=.02).²³ Notably, these findings applied to all subgroups, including patients with del 17p, underscoring its potential role in the treatment of this high-risk entity. Adverse events leading to study-drug discontinuation were reported in 9 patients (8%) in the idelalisib group and 11 patients (10%) in the placebo group. The most common events (any grade) included pyrexia (29% of patients), fatigue (24%), nausea (24%), and elevations in aspartate aminotransferase or alanine aminotransferase (35%).

Case Discussion

This patient was started on lenalidomide, 5 mg/d, in addition to a monthly rituximab infusion, which resulted in an ALC decrease from 80,000 x 10⁹/L to 25,000 x 10⁹/L by July 2013. However, his course was complicated by grade 2 liver function test abnormalities, a grade 2 morbilliform rash, and grade 1 thrombocytopenia. Despite decreasing the frequency of lenalidomide to 5 mg every other day, persistent liver function test abnormalities, new-onset peripheral neuropathy, and muscle cramping prompted discontinuation of the drug by September 2013. He received 6 monthly rituximab infusions through December 2013 and was noted to have a nearly 50% reduction in spleen size by examination, greater than 30% reduction in size of peripheral adenopathy, and plateauing of ALC to 2180 x 10⁹/L. At last follow-up he reported significant improvements in fatigue, early satiety, and size of peripheral lymphadenopathy.

As recently as June 2013, lenalidomide was included in the NCCN Guidelines for Non-Hodgkin’s Lymphomas²⁴ as an option for patients with previously untreated CLL (to view the most recent version, visit NCCN.org). However, a phase III study evaluating its use in the frontline setting was halted in July 2013 because of concerns over increased risk of death in the lenalidomide arm.²⁵ On one hand, this serves as a reminder that clinicians should with-hold judgment of novel therapeutics until a reasonable body of trial data has accumulated so that risk and benefit can be better ascertained. On the other hand, this dynamism underscores the pace with which the field is evolving, and therefore clinicians must reconcile the “current” standards of care (Table 1) with emerging and potentially practice-changing options. How would patient RS, a 75-year-old man with del 17p CLL, be treated today?

Table 1

First-Line Treatment Options for Older Patients with Chronic Lymphocytic Leukemia

View Table