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Updates on the Management of Chronic Lymphocytic Leukemia

Jonathan Angus, PharmD
PGY-2 Oncology Pharmacy Resident
WVU Medicine
Morgantown, WV


Chronic lymphocytic leukemia (CLL), a disease state that has seen impressive treatment changes over the past 5 years, continues to drive oncologic therapeutic innovation. Advances in the biologic and genetic understanding of CLL, the increasing ability to accurately risk-stratify patients, and the development of targeted therapies have increased the median progression-free survival (PFS) and, as a result, the median overall survival (OS) for these patients. With the introduction of targeted therapies, 5-year relative survival has most recently been reported at 82.6% (2006–2012), up from 67.5% in 1975.1 Before the introduction of newer agents to the market, relapsed or refractory (R/R) CLL was typically treated with chemoimmunotherapy consisting of rituximab or ofatumumab plus various cytotoxic agents such as bendamustine, fludarabine, or chlorambucil. Some of the most exciting developments in the realm of targeted CLL therapy include (1) expanded applications for ibrutinib, (2) significant responses to the substitution of venetoclax for patients intolerant to kinase inhibitors, (3) lenalidomide maintenance therapy, and (4) introduction of the novel phosphoinositide 3-kinase-delta (PI3K-δ) inhibitor idelalisib.

Updates on Ibrutinib
Ibrutinib, the first-in-class oral Bruton’s tyrosine kinase (BTK) inhibitor, gained approval from the U.S. Food and Drug Admin- istration (FDA) in November 2013 for mantle cell lymphoma. An FDA indication for CLL for patients who had received at least one previous therapy followed shortly in February 2014. The overall response rate (ORR) of patients treated with single-agent ibrutinib was 71%.2 Since that time, its CLL indications have expanded significantly, and in March 2016, it was approved for first-line treatment. A number of positive clinical trials have contributed to these expanded applications.

The phase 3 HELIOS study assessed response to bendamustine and rituximab (BR) plus either ibrutinib or placebo in R/R CLL or small lymphocytic lymphoma (SLL) patients who had received one or more prior systemic cytotoxic regimens. Patients with del(17p) were excluded secondary to known poor prognosis with the BR regimen. In the study, 578 patients were evenly randomized to receive BR given in cycles of 4 weeks (bendamustine: 70 mg/m2 on days 2–3 of cycle 1 and on days 1–2 of cycles 2–6; rituximab: 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2–6) with either ibrutinib (420 mg daily) or placebo until the disease progressed or an unacceptable level of toxicity was reached. The addition of ibrutinib resulted in a statistically significant increase in median PFS (PFS not reached [NR] vs. 13.3 months; p < .0001). Median OS was not reached in either group and is difficult to assess because of the indolent disease course and the allowance of crossover in the study. The most common grade 3–4 adverse events (AEs) were neutropenia (54% vs. 51%) and thrombocytopenia (15% in each group). Overall, similar side effect profiles were seen in the experimental and control groups.3

The phase 3 RESONATE trial compared ibrutinib to ofatumumab in R/R CLL or SLL patients who had received  one or more previous therapies and who were considered to be inappropriate candidates for purine analogue treatment (i.e., who experienced a short PFS following chemoimmunotherapy, had a coexisting illness, were age 70 years or older, or had chromosome 17p13.1 deletion). These patients were randomized to receive ibrutinib 420 mg/day until the disease progressed or an unacceptable level of toxicity was reached (n = 195) or ofatumumab 300 mg intravenous followed by 2,000 mg for 11 doses over 24 weeks according to package labeling (n = 196). The primary goal of this study was to provide updated efficacy and AE data relative to genetic features and prior treatment exposure over a median duration of 16 months. PFS was NR in the ibrutinib group and 8.1 months in the ofatumumab group (p < .0001). Most AEs were grade 1 and included diarrhea, fatigue, nausea, pyrexia, cough, neutropenia, anemia, upper respiratory infection, peripheral edema, sinusitis, arthralgia, muscle spasms, constipation, headache, pneumonia, thrombocytopenia, and vomiting. Seven percent of patients in the ibrutinib arm experienced atrial fibrillation, and 8% experienced bleeding.4 Approximately 32% of patients included in the RESONATE trial had CLL with del(17p). Recent data on a subset analyses of the RESONATE trial reported worse outcomes in the presence of del(11q) in ofatumumab patients but the ibrutinib cohort did not seem to be affected.5

CLL is primarily a disease of the elderly, with a median age of diagnosis of 72 years. The phase 3 RESONATE-2 trial compared ibrutinib to chlorambucil in untreated CLL or SLL patients age 65 years or older. Of note, patients with chromosome 17p13.1 deletion were ineligible for inclusion in this trial because ibrutinib was already a primary first-line therapy according to consensus guidelines at the time the trial was initiated. A statistically significant increase in PFS and OS was seen in the ibrutinib group versus the chlorambucil patients (PFS NR vs. 18.9 months; p < .001 and estimated 2-year OS of 98% vs. 85%; p = .001). AEs were largely the same in the two groups, and ibrutinib was determined to be tolerable in this patient population. Ibrutinib exhibited superior efficacy compared with chlorambucil in high-risk subgroups, including genetic abnormalities and immunoglobulin heavy chain variable region (IGHV)–unmutated patients; however, data demonstrating improved outcomes with the addition of CD-20 antibody therapy to chlorambucil were not available at the time of trial initiation.6 Comparisons of up-front use of ibrutinib with more common first-line CLL regimens (BR, fludarabine- cyclophosphamide-rituximab [FCR], and obinutuzumab- chlorambucil) are in progress.7

In a large single-center study, Maddocks and colleagues reported the indications for discontinuing ibrutinib seen in their practice. Disease progression, more common later in therapy, or intolerable toxicities, more common early in therapy, or both were the most common reported indications for discontinuation. B-cell lymphoma 6 (BCL6) abnormality and complex karyotype resulted in statistically significant increases in discontinuation because of progression, with hazard ratios (HRs) of 2.70 (p = .01) and 4.47 (p = .007), respectively. Characteristics associated with an increased rate of ibrutinib discontinuation because of toxicity included 10- year increase in age and number of prior treatments (HR 1.87; 95% confidence interval [CI] 1.33–2.64; p < .001; and HR 1.09; 95% CI 1.00–1.19; p = .054, respectively). It is important to note that the data indicate that patients who discontinue ibrutinib because of disease progression have poor outcomes, and additional therapies and targets are needed following ibrutinib failure.8

Acalabrutinib and BGB-3111 are second-generation BTK inhibitors with mechanisms of action similar to those of ibrutinib. These agents are more selective for BTK in vitro than ibrutinib, which may decrease interference with other kinases and result in fewer AEs. Because both acalabrutinib and BGB-3111 bind to the same site as ibrutinib, they are unlikely to overcome mutations conferring primary resistance to ibrutinib.9,10

Idelalisib
Idelalisib is an oral PI3K-δ inhibitor that works by inducing apoptosis and inhibiting proliferation of malignant B-cells via inhibi- tion of chemotaxis, reduction in cell adhe- sion, and decreased cell viability.11 In a phase 3 trial, rituximab was studied with and without idelalisib in relapsed CLL patients who were not candidates for cytotoxic therapy and had histories of one or more prior anti-CD20 therapies or two or more prior cytotoxic therapies. Patients were then randomized to receive either idelal- isib 150 mg twice daily plus rituximab (n = 110) or placebo twice daily plus rituximab (n = 110). Patients in the idelalisib group who experienced progression had their dose increased to 300 mg twice daily, and patients in the placebo group were started on idelalisib 150 mg twice daily. Idelalisib plus rituximab resulted in a statistically significant increase in PFS and OS compared with the placebo plus rituximab group (PFS NR vs. 5.5; p < .0001 and OS 92% vs. 80% at 12 months; p = .02). The most significant AEs in the treatment group were neutropenia, thrombocytopenia, diarrhea, transaminase elevations, and pneumonitis.12 In a phase 3 study comparing idelalisib plus BR with BR alone in the R/R setting, it was shown that the three-drug combination resulted in a statisti- cally significant increase in PFS over BR alone (PFS 23.1 vs. 11.1; p < .0001).13 Although there is interest in using idelalisib in the first- line setting, the increased risk of death, primarily due to infectious complications, in phase 3 trials assessing the use of idelalisib in the up-front setting resulted in suspension of the trial. An FDA alert to healthcare professionals has also been issued.11

Venetoclax
CLL is a disease characterized by high B-cell lymphoma 2 (BCL2) protein expression. Venetoclax is an oral, highly selective inhibitor of BCL2, a protein that promotes survival of B-lymphocytes in CLL, and results in caspase-mediated apoptosis through release of cytochrome C.14 It recently received accelerated approval by the FDA for patients with relapsed CLL harboring del(17p) on the basis of a phase 1 dose-escalation trial conducted by Roberts and colleagues.15 In a phase 2 single-arm study, patients with del(17p) R/R CLL were given venetoclax in a dose-escalating manner up to a final dose of 400 mg daily until disease progression or discontinuation for another reason. At a median follow-up of 12.1 months, overall response was assessed in the 107 patients enrolled in the study and found to be 79.4%. Median PFS and OS were not reached at time of median follow-up. Grade 3–4 AEs reported were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%). Patients who were switched from a failing regimen to venetoclax experienced high response rates and attainment of minimum residual disease (MRD). Because of its activity in reducing CLL cells, venetoclax initiation was associated with an increased risk of tumor lysis syndrome (TLS) and required risk mitigation strategies such as assignment of TLS risk category (low, medium, high), admission to hospital for TLS prophylaxis prior to first doses, and appropriate TLS lab monitoring. Overall,  this therapy appears to be active for patients with high-risk R/R CLL with a favorable tolerability profile.16 An ongoing phase 3 trial is evaluating venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated CLL (NCT02242942).

Lenalidomide Maintenance
According to the interim results of the phase 3 CLLM1 trial by the German CLL Study Group, lenalidomide maintenance after front- line therapy substantially prolonged PFS in patients with high- risk CLL. In this study, patients were stratified into the high-risk category if they had MRD levels of 10-2 or greater or MRD levels of greater than 10-4 to less than 10-2 with unmutated IGHV, del(17)p, or TP53 mutation and were randomized to receive either lenalidomide or placebo until disease progression. At a median follow-up of 17.7 months, the median PFS in the placebo group was 14.6 and NR in the lenalidomide group (p < .0006). Lenalidomide was associated with more significant rates of neutropenia (30.4% vs. 3.4%), gastrointestinal disorders (55.4% vs. 27.6%), central nervous system disorders (30.4% vs. 13.8%), respiratory disorders (35.7% vs. 13.8%), and skin disorders (60.7% vs. 27.6%). Infections and thrombotic disorders showed no difference in event rates between the two arms. These data show that lenalidomide maintenance in high-risk CLL patients after chemoimmunotherapy is a reasonable option that improves PFS over placebo and increases the induction rate of MRD negativity.17

CLL Treatments on the Horizon
An intergroup phase 3 trial of ibrutinib plus rituximab versus FCR has finished enrolling young, fit CLL patients in an attempt to determine the role of targeted therapies in this patient population (NCT02048813). Results of this phase 3 trial, if positive, will result in a paradigm shift in the standard of care. Similarly, the phase 3 Alliance A041202 study (NCT01886872) compared ibrutinib alone versus ibrutinib in combination with rituximab versus BR in patients 65 years of age and older. Results of these trials are eagerly awaited because it is hoped that they will help determine the ideal regimen in the up-front setting of younger and older CLL in the era of novel agents.18

The more selective BTK inhibitor, acalabrutinib, is being studied in a phase 3 study for previously untreated patients with CLL and a high Cumulative Illness Rating Scale (CIRS) score as single-agent acalabrutinib versus acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab (NCT02475681).Venetoclax in combination with various agents (including venetoclax plus rituximab, venetoclax plus obinutuzumab, and venetoclax plus BR) for use in R/R CLL is being studied in multiple phase 1 trials. A phase 1b study of dose-escalation of venetoclax plus obinutuzumab/ibru- tinib for up to 14 cycles in the absence of unacceptable toxicity or progression of disease is under way and will be followed by a phase 2 study. The German CLL Study Group is conducting a phase 2 open-label study of ibrutinib plus venetoclax/obinutuzumab. In the United Kingdom CLARITY trial, investigators are conducting a phase 2 study of ibrutinib plus venetoclax. Duvelisib, a PI3K γ/δ inhibitor, is being studied for relapsed CLL in phase 3 trials (NCT02004522). Some limited data support the use of chimeric antigen receptor (CAR) T-cells targeting CD19, and further data are necessary to determine their role in CLL management.19

Conclusions
With the addition of new targeted agents such as ibrutinib, idelal- isib, and venetoclax to the CLL treatment landscape, traditional chemoimmunotherapy is increasingly becoming displaced as the standard of care for treatment-naive patients. Targeted agents hold the promise of reduced toxicity and decreased risk of secondary malignancies, especially in elderly patients who do not tolerate standard treatments as well. In addition to their reduced toxicity, these agents have proven efficacy in patients with high-risk disease such as del(17p) and TP53 mutations. Increasing knowledge of CLL biology and drug-resistance mechanisms will aid our understanding of how best to use our growing arsenal of treatment options. Ongoing trials will also seek to answer questions related to the optimal combinations and sequence of therapies for the manage- ment of CLL and SLL.

References

1. National Cancer Institute. Cancer Stat Facts: Chronic Lymphocytic Leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html. Accessed January 24, 2017.

2. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.

3. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200-11.

4. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-23.

5. Brown J, Hillmen P, O’Brien S, et al. Updated efficacy including genetic and clinical subgroup analysis and overall safety in the phase 3

6. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-37.

7. U.S. National Institutes of Health. Ibrutinib Combination First Line CLL. Clinical Trials Website. https://clinicaltrials.gov. Accessed January 27,  2017.

8. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1(1):80-7.

9. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-32.

10. Wu J, Liu C, Tsui ST, Liu D. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016;9(1):80.

11. Product Information: ZYDELIG(R) oral tablets, idelalisib oral tablets. Gilead Sciences, Inc. (per FDA), Foster City, CA, 2014.

12. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997- 1007.

13. Zelenetz A, Robak T, Coiffier B, et al. Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia: results of a phase 3 randomized double- blind placebo-controlled study. Blood (ASH Annual Meeting Abstracts). 2015;126(23):LBA-5.

14. Anderson MA, Deng J, Seymour JF, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood. 2016;127(25):3215-224.

15. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311- 22.

16. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768-78.

17. Fink A, Bahlo J, Sandra R, et al. Lenalidomide maintenance after front line therapy substantially prolongs progression free survival in high risk CLL: interim results of a phase 3 study (CLL M1 study of the German CLL Study Group). Blood (ASH Annual Meeting Abstracts). 2016;128(22):229.

18. Robak T, Stilgenbauer S, Tedeschi A. Front-line treatment of CLL in the era of novel agents. Cancer Treat Rev. 2016;53:70-8.

19. Mato A, Porter DL. A drive through cellular therapy for CLL in 2015: allogeneic cell transplantation and CARs. Blood. 2015;126(4):478-85.

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