Trials Explore Treatments for Elderly Patients With CLL

Treatment of chronic lymphocytic leukemia (CLL) is complicated by the fact that most patients are diagnosed at a later age, with a median age at diagnosis of 72 years. In the United States, 75% of patients with CLL are more than 65 years of age.¹Despite this, the elderly population is typically underrepresented in clinical trial populations, which have age ranges of 58 to 62 years.¹The optimal therapy for patients 65 years of age and older with CLL is not known, particularly for less fit patients; accordingly, a number of studies are investigating treatments in this important population.²New developments in this topic were presented at the American Society of Hematology (ASH) 55th Annual Meeting and Exposition (December 2013) in New Orleans.

A presentation by Baumann and coworkers³examined the characteristics, prognosis, and treatment of elderly patients with CLL in a retrospective, single-center study (N = 949; n = 367 defined as ages 70 years or greater). The study found that elderly patients were diagnosed at a more advanced clinical stage (P<.001), and were treated less frequently than were younger patients (39% vs 62%;P<.001); in contrast to younger patients, there was also an equal sex distribution in the elderly. In terms of treatments, compared with younger patients, elderly patients had a higher use of alkylating agents (70%), but a lower use of purine analogues (10%) or chemoimmunotherapy (5%). While no apparent differences in biology of disease were observed between the elderly and younger patients, elderly patients had a lower overall response rate (ORR; 49% vs 69%;P<.001), shorter overall survival (OS; 6.6 vs 13.3 years;P<.001), and a higher incidence of mortality that was unrelated to CLL (at 10 years, 34.9% vs 6.9%;P<.001). The findings of this study, in addition to defining some important characteristics for the elderly population with CLL, also highlight the smaller proportion of elderly who receive treatments, and provide a rationale for exploring new regimens that are both active and well tolerated in this population.³

CLL10 Trial

REAL07 Trial

Pentostatin With Cyclophosphamide and Ofatumumab

Ofatumumab With Chlorambucil

Efficacy With Tolerability

The standard first-line treatment for CLL (ie, fludaribine/cyclophosphamide/ rituximab; [FCR]) is associated with side effects.⁴Although FCR may be a viable therapy for older fit patients with fewer comorbidities, it is not known whether or not novel combination therapies may be better suited for less fit patients.¹The CLL10 trial compared the efficacy and safety of FCR versus bendamustine/ rituximab (BR). At a median observation time of 27.9 months, the ORR was identical in both arms (97.8%), and no difference in OS was observed (at 2 years, 94.2% vs 95.8%, respectively, for FCR and BR;P= .593). Notably, when comparing progression-free survival (PFS) in patients <65 years and >65 years, a difference was observed between treatments in the <65 group (PFS, 36.5 months BR vs not reached [NR] for FCR;P= .016), but no such difference was seen in the elderly (ie, >65 group) patients (not reached [NR] vs 45.6 months, respectively;P= .757). Moreover, in the FCR arm, a higher rate of severe neutropenia was seen (81.7% vs 56.8%;P<.001), and resulted in a significantly higher rate of severe infection in the elderly patients (47.4% FCR vs 26.5% BR;P= .002). Results of the trial did not allow for a recommendation for one regimen over another for patients with good fitness.⁴Lenalidomide is an immunomodulatory agent that had previously been shown to have activity in multiple myeloma and CLL.⁵The phase II REAL07 Trial of the Fondazione Italiana Linfomi (FIL) evaluated the use of lenalidomide with rituximab- CHOP21 in elderly patients with diffuse large B-cell lymphoma (DLBCL).⁶Previous phase I findings had shown the feasibility of this combination therapy in elderly patients, with 15-mg lenalidomide established as the maximum tolerated dosage with RCHOP21. Fit patients aged 60 through 80 years were included (n = 49, enrolled). Notably, there were no grade IV extrahematologic events and no toxicity-related deaths during the treatment; with 94% (277 of 294) of the planned LR-CHOP21 courses administered. Complete remissions (CR) were observed in some 86% of patients (n = 42), with another 6% (n = 3) having partial remissions (PR); there were three nonresponders (6%) and one additional homicide-related death. At 28 months median follow up, the 2-year OS rate was 92% and the 2-year PFS rate was 80%; event-free survival at 2 years was 70%. The ORR for both germinal center (GCB) and non-GCB patients was 88%, with complete responses observed in 81% and 88%, respectively; corresponding 2-year PFS was 71% and 81%, respectively, at a median 28 months follow up. Overall, the results of this trial demonstrated that LR-CHOP21 was effective in the elderly population, and these results serve as the basis for a future phase III study designed to evaluate LR-CHOP21 versus R-CHOP21 for previously untreated non-GCB patients with DLBCL.⁶For younger and physically fit patients with CLL, purine analogs in combination with the anti-CD20 antibody rituximab (chemoimmunotherapy) is the standard of care for initial treatment.⁷But because fludaribine-containing regimens may frequently be inappropriate for elderly patients and for those with comorbid conditions, more tolerable treatment choices are needed.⁷Ofatumumab is a fully-human anti-CD20 monoclonal antibody with single-agent activity in fludaribine- resistant CLL. Unlike FCR, which may be associated with significant hematologic toxicity, pentostatin, a purine analog, has been noted for its lower myelotoxic profile in use with agents such as cyclophosphamide.⁸A presentation by Marco Montillo and coworkers examined the use of pentostatin with cyclophosphamide and ofatumumab (PCO) in older (65 years and over; ECOG 0-2) patients (n = 49) with previously untreated CLL in a phase II Italian multicenter study.⁸Results showed that 94% of patients (n = 30) were able to receive the intended 6 cycles of treatment, with 90% receiving a full dose. Myelosuppression was the main reason for dose reduction or discontinuation of treatment. Neutropenia was the most common adverse event (AE) of grade 3 or higher; a total of 19 patients experienced grade 3 or 4 AEs, and no deaths occurred during treatment. Among the grade 1 or 2 toxicities were fever, hypotension, nausea and vomiting, and skin rash. ORR, the primary endpoint, was 93.7%, with 41% CR. Collectively, the findings of this study demonstrated the activity of the PCO chemoimmunotherapy regimen and showed it to be well tolerated in this older population of patients with CLL. Compared with prior studies evaluating the same chemotherapies with a rituximab backbone, the PCO regimen showed comparable efficacy and more manageable toxicity.⁸Ofatumumab was also evaluated in a phase III study in combination with chlorambucil (CHL), a standard of care for older, less fit patients, versus CHL alone.^5,7Patients requiring therapy for CLL who were of advanced age or who had comorbidities and were thus considered inappropriate for fludaribinebased therapy were randomized (N = 447). A minimum of 3 with best response up to 12 cycles, was the intended treatment duration. A median duration of 6 cycles of treatment were administered and 82% of patients received 6 or more cycles of the ofatumumab/chlorambucil (O+CHL) regimen. Independent Review Committee (IRC)-assessed PFS was significantly prolonged for patients randomized to O+CHL, at 22.4 months versus 13.1 months (P<.001). A significant benefit of the combination was also seen in ORR (82% vs 69%;P<.001), with more CR observed (12%) compared with the CHL arm (1%). Grade 3 and 4 AEs (start of therapy to 60 days after last dose) occurred in 50% and 43% of patients treated with O+CHL and CHL, respectively; neutropenia (26% vs 14%) was most common among these. Grade 3 or higher infections occurred in 15% and 14% of patients in the respective treatment groups. In both arms, deaths during treatment occurred in 2% of patients. Collectively, the results demonstrated clinically meaningful improvements in disease with ofatumumab/ chlorambucil, and manageable toxicities in this challenging-to-treat population of patients who are inappropriate for fludaribine-based therapy.⁷These findings highlight the importance of the elderly as a patient group in CLL requiring treatment that is both effective and well tolerated. While no definitive conclusions could be made about the use of standard FCR versus bendamustine and rituximab, the findings of CLL10 highlighted the higher rates of severe neutropenia with FCR, which could contribute to more severe infections, particularly in the elderly.⁴The FIL trial, on the other hand, has contributed important findings about the combination of lenalidomide with rituximab and CHOP21 in elderly patients with DLBCL, with high rates of complete remissions and with comparable ORRs for both GCB and non-GCB untreated patients; results of a future phase III trial are awaited.⁶Ofatumumab has demonstrated superiority over rituximab in preclinical findings. This anti-CD20 therapy has demonstrated clinically important activity in combination with pentostatin and cyclophosphamide,⁸and in combination with chlorambucil⁷with manageable toxicity in each case. All of these emerging regimens offer promise for this important population of elderly patients.

References

1. Tadmor T, Polliack A. Optimal management of older patients with chronic lymphocytic leukemia: some facts and principles guiding therapeutic choices.Blood Rev. 2012;26(1):15-23.
2. Wu M, Akinleye A, Zhu X. Novel agents for chronic lymphocytic leukemia.J Hematol Oncol. 2013;6:36.
3. Baumann T, Delgado J, Santacruz R, et al. Initial characteristics, treatment, and prognosis of elderly (&ge; 70 years) patients with chronic lymphocytic leukemia (CLL): an analysis of a series of 367 cases. 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 4155.
4. Eichhorst B, Fink A-M, Busch R, et al. Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia (CLL): results of a planned interim analysis of the CLL10 Trial, an international, randomized study of the German CLL Study Group (GCLLSG). 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 526.
5. Smolewski P, Witkowska M, Korycka-Wołowiec A. New insights into biology, prognostic factors, and current therapeutic strategies in chronic lymphocytic leukemia.ISRN Oncol. 2013; 740615.
6. Chiappella A, Franceschetti S, Castellino A. Final results of phase II study of lenalidomide plus rituximab-CHOP21 in elderly untreated diffuse large B-cell lymphoma focusing on the analysis of cell of origin: REAL07 Trial of the Fondazione Italiana Linfomi. 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 850.
7. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study complement 1 (OMB110911). 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 528.
8. Montillo M, Rossi D, Motta M, et al. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab (PCO) in older previously untreated chronic lymphocytic leukemia (CLL) patients. 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 4177.