The Shifting Therapeutic Spectrum for Chronic Lymphocytic Leukemia

Over the past several years, the treatment landscape for chronic lymphocytic leukemia (CLL) has changed significantly. For patients with CLL, including those with high-risk disease, the availability of novel targeted therapies and monoclonal antibodies offers an increased potential for improved outcomes.^1,2 Several agents that inhibit CD20 have been developed because of the role of CD20 in the process of differentiation and growth of B cells³; obinutuzumab, ofatumumab, and rituximab have subsequently been approved.¹ Additionally, several agents targeting the B-cell receptor pathway have achieved FDA approval,⁴ including the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, the phosphatidylinositol 3-kinase inhibitors idelalisib and duvelisib, and the B-cell lymphoma 2 inhibitor venetoclax.¹ Initially, several of these agents were approved by the FDA in combination with other approved agents, such as idelalisib plus rituximab, obinutuzumab plus chlorambucil, and ofatumumab plus chlorambucil. The Table includes a list of FDA-approved agents.^5-13

Positive results from clinical trials that explored additional combination regimens have led to expanded indications for agents already approved by the FDA, including ofatumumab plus fludarabine and cyclophosphamide, and ibrutinib plus obinutuzumab. Importantly, indications range among the various approved monotherapies and combination regimens. Despite the availability of several agents in multiple drug classes, therapeutic selection for optimized regimens can be challenging, particularly because new evidence continues to emerge that further elucidates the clinical profile of FDA approved therapies. In particular, 3 studies presented at the 2018 American Society of Hematology (ASH) meeting showed promising results for the role of ibrutinib in the frontline treatment landscape of CLL: the Alliance North American Intergroup Study A041202 (ALLIANCE A041202),¹⁴ the E1912 trial of the ECOG-ACRIN Cancer Research Group (ECOG E1912),¹⁵ and the iLLUMINATE trial.¹⁶ The published results of these trials have already impacted the 2019 National Comprehensive Cancer Network guidelines for the patient populations who were evaluated in these trials.¹⁷ This article reviews these key findings.

ALLIANCE

The phase III ALLIANCE trial (ClinicalTrials.gov identifier: NCT01886872) evaluated the efficacy of ibrutinib treatment alone and in combination with the anti-CD20 monoclonal antibody rituximab against the standard-of-care chemoimmunotherapy in older patients with CLL: bendamustine (an alkylating agent) plus rituximab.^14,17 Sponsored by the National Cancer Institute of the National Institutes of Health,¹⁴ ALLIANCE is the first head-to-head trial to compare ibrutinib against bendamustine/rituximab.¹⁸ Additionally, the benefit of adding rituximab to ibrutinib has not been established in previous trials. ALLIANCE is the second trial to investigate ibrutinib treatment alone or in combination with rituximab in CLL; the first trial was done in previously treated patients with CLL and results showed no difference in progression-free survival (PFS) or overall survival (OS) outcomes between treatment arms.¹⁹

ALLIANCE assessed patients 65 years and older who had previously untreated CLL as defined by the 2008 International Workshop on CLL criteria.¹⁴ Of the patients selected, 183 were given bendamustine plus rituximab, 182 were assigned ibrutinib, and 182 were administered ibrutinib plus rituximab.¹⁴ The median age was 71 years (range, 65-89).¹⁴ More than half of the patients (54%) had high-risk disease according to modified Rai stage.¹⁴ A quarter of patients had high-risk cytogenetics, including del(17p) (6%) and del(11q) (19%). The primary endpoint was PFS.¹⁴

Researchers found that treatment with ibrutinib either alone or in combination with rituximab was more successful, in terms of PFS benefit, compared with

6 rounds of chemoimmunotherapy with bendamustine plus rituximab.¹⁴ No significant difference in median PFS was observed between the ibrutinib and ibrutinib-plus-rituximab groups (HR, 1.00; 95% CI, 0.62-1.62; P = .49).¹⁴ This result suggests that adding rituximab to ibrutinib did not provide any additional benefit versus ibrutinib alone.

It was demonstrated that ibrutinib offers superior PFS compared with standard chemoimmunotherapy in this patient population.²⁰ The 2-year PFS was 74% for bendamustine plus rituximab, 87% for ibrutinib monotherapy, and 88% for ibrutinib plus rituximab.¹⁴

Ibrutinib is a promising treatment option in CLL patients with high-risk cytogenetics (eg, del[17p] or TP53 mutation).²¹ Although the ALLIANCE study did not have sufficient power to detect statistical differences among subgroups,¹⁴ results indicated a PFS benefit with ibrutinib treatment alone or in combination with rituximab in all cytogenetic factor—related subgroups and among patients regardless of their immunoglobulin heavy chain variable region gene (IGHV) mutation status.¹⁴ The strongest PFS benefit was observed in patients with del(17p13).¹⁴ An improved median PFS was seen in patients with mutated versus unmutated IGHV (HR, 0.51; 95% CI, 0.32-0.81).¹⁴ PFS benefit was also shown in patients with a complex karyotype (defined as the presence of at least 3 unrelated abnormalities).¹⁴

There was no significant difference in OS among the 3 treatment groups.¹⁴ In a recent OncLive^® Peer Exchange panel, Susan O’Brien, MD, noted that the crossover design of the study may have contributed to the lack of observable OS difference.²²

Ibrutinib treatment alone or in combination with rituximab demonstrated a favorable safety profile compared with bendamustine plus rituximab. Grade 3, 4, or 5 hematologic adverse events (AEs) were reported at a higher rate with bendamustine plus rituximab versus ibrutinib or ibrutinib plus rituximab (61% vs 41% and 39%, respectively).¹⁴ However, the rates of grade 3, 4, or 5 nonhematologic AEs were higher in the ibrutinib-treated patients (74%) compared with those treated with bendamustine plus rituximab (63%).¹⁴ Significantly higher rates of hypertension (P <.001) and atrial fibrillation (P = .05) were seen with ibrutinib-based treatments¹⁴; investigators recommend closely monitoring this patient population.²³

These findings suggest that ibrutinib should be considered a standard-of-care treatment in older patients with CLL.²³ Although the results show efficacy in patients treated with continuous ibrutinib therapy, they implicitly raise the question of whether indefinite BTK inhibitor treatment is necessary.¹⁴ This issue will be evaluated in upcoming clinical trials carried out by the National Cancer Institute’s National Clinical Trials Network.¹⁴

Eastern Cooperative Oncology Group E1912

E1912 (ClinicalTrials.gov identifier: NCT02048813) is a randomized, open-label, phase III study that compared the combination of ibrutinib plus rituximab with the gold-standard chemoimmunotherapeutic regimen of fludarabine, cyclophosphamide, and rituximab (FCR) in adult patients aged 18 to 70 years with previously untreated CLL.¹⁵ FCR, a primary treatment in patients younger than 65 years,¹⁷ is thought to be the most efficacious chemoimmunotherapeutic regimen.²² The trial was sponsored by the National Cancer Institute of the National Institutes of Health, designed by researchers with the ECOG-ACRIN Cancer Research Group.²⁴

Within the accrual period of January 31, 2014, to June 9, 2016, a total of 529 patients were assigned to either ibrutinib plus rituximab (n = 354) or FCR (n = 175).¹⁵ The authors completed the first interim analysis in September 2018.¹⁵ Patient characteristics were well balanced between the treatment arms, with a median age of 57 years in the ibrutinib-plus-rituximab group and 58 years in the FCR group.²⁵ Those with del(17p) were excluded from the study.

The primary endpoint was PFS and the secondary endpoint was OS,¹⁵ and the median follow-up was 33.4 months.¹⁵ A total of 77 PFS events and 14 deaths were reported.¹⁵ Ibrutinib plus rituximab improved PFS and OS in this patient population.¹⁵ The hazard ratio favored the ibrutinib-plus-rituximab group for both PFS (HR, 0.352; 95% CI, 0.223-0.558; P <.0001) and OS (HR, 0.168; 95% CI, 0.053-0.538; P = .0003; prespecified P = .0005).¹⁵

Ibrutinib plus rituximab was superior to FCR across all subgroups in terms of PFS benefit, which was observed in patients independent of age, sex, performance status, disease stage, or del(11q23) status.¹⁵ IGHV mutation status was tested in 82% of patients; 71.1% of these did not have an IGHV mutation.²⁶ The results of the subgroup analysis showed an increased likelihood of PFS with the ibrutinib-plus-rituximab combination in patients without an IGHV mutation (HR, 0.262; 95% CI, 0.137-0.498; P <.0001).¹⁵ A trend toward PFS improvement with the ibrutinib-plus-rituximab combination was observed in patients with an IGHV mutation (HR, 0.435; 95% CI, 0.140-0.1350; P = .07).¹⁵

Ibrutinib demonstrated a favorable safety profile compared with FCR. ²² Grade 3 and 4 treatment-related AEs were observed in 58% of the ibrutinib-plus-rituximab group and 72% of the FCR group (P = .0042).¹⁵ Grade 3 and 4 neutropenia developed in 23% of the ibrutinib-plus-rituximab group versus 44% of the FCR group (P <.0001); grade 3 and 4 infectious complications developed in 7.1% of the ibrutinib-plus-rituximab group versus 17.1% of the FCR group (P <.0001).¹⁵

The combination of ibrutinib plus rituximab was superior to standard chemoimmunotherapeutic treatments in CLL patients 70 years and younger.¹⁵ It was also well tolerated in young patients.²⁶ Quality of life was measured throughout the study, but the data have not yet been published.²⁴

Compared with FCR, the combination of ibrutinib and rituximab provides superior PFS and OS and a preferential safety profile in patients 70 years and younger with previously untreated CLL.¹⁵ The results of this trial suggest practice changes that incorporate ibrutinib-based therapy as a frontline CLL regimen in young, previously untreated patients.²⁴ The investigators noted that the findings establish ibrutinib-based therapy as the most effective treatment option in this patient population.²⁵

iLLUMINATE

The FDA approval of the combination of ibrutinib plus obinutuzumab (an anti-CD20 monoclonal antibody) for the first-line treatment of CLL was based on the results of the phase III iLLUMINATE study (ClinicalTrials.gov identifier: NCT 02264574).^16,27 In iLLUMINATE, investigators compared ibrutinib plus obinutuzumab against standard chemoimmunotherapy.¹⁶ This study was presented at the 2018 ASH Meeting and published simultaneously in The Lancet Oncology. iLLUMINATE is the first study to prospectively evaluate a nonchemotherapy regimen with ibrutinib against a chemoimmunotherapy regimen in treatment-naïve patients with CLL, including those with high-risk cytogenetics (eg, del[17p] or TP53 mutation).¹⁶

This randomized, open-label, multicenter study was completed at 74 academic and community hospitals in Australia, Canada, Israel, New Zealand, Russia, Turkey, the European Union, and the United States.¹⁶

The study population consisted of previously untreated patients with CLL or small lymphocytic leukemia in 2 cohorts: those older than 65 years, and those 65 years and younger who had considerable comorbidities or high-risk cytogenetics (ie, Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del[17p] or TP53 mutation).²² A total of 229 patients were either administered ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116). The median age was 71 years; 65% of patients in both groups had high-risk disease (del[17p], TP53 mutation, del[11q], or unmutated IGHV).¹⁶

With a median follow-up of 31.3 months,¹⁶ iLLUMINATE met its primary endpoint and improved PFS.²⁸ At 30 months, the PFS rate was 79% in the ibrutinib-plus-obinutuzumab group and 31% in the chlorambucil-plus-obinutuzumab group.¹⁶ Patients treated with ibrutinib plus obinutuzumab had a significantly improved PFS compared with those treated with chlorambucil plus obinutuzumab (median PFS, not reached vs 19 months; P <.0001).¹⁶ Similar trends were observed comparing median PFS of patients with high-risk features in the ibrutinib-plus-obinutuzumab group versus the chlorambucil-plus-obinutuzumab group (unmutated IGHV, not reached vs 14.6 months; del11q: not reached vs 15.2 months; del[17p]: not reached vs 11.3 months).¹⁶ Findings showed a 77% reduction in risk of progression or death compared with chlorambucil plus obinutuzumab (HR, 0.23; 95% CI, 0.15-0.37), which led to the combination’s FDA approval.²⁷ Patients with high-risk disease (del[17p]/TP53 mutation, del[11q], or unmutated IGHV) experienced an 85% reduction in risk of progression or death (HR, 0.15; 95% CI, 0.09-0.27) with ibrutinib plus obinutuzumab.²⁷ The overall response rate was 88% (complete response/complete response with incomplete hematologic recovery [CR/CRi], 19%) in the ibrutinib-plus-obinutuzumab group and 73% (CR/CRi, 8%) in the chlorambucil-plus-obinutuzumab group.¹⁶

Similar percentages of patients in each group developed grade 3 or grade 4 AEs (68% in the ibrutinib-plus-obinutuzumab group vs 70% in the chlorambucil-plus-obinutuzumab group).¹⁶ The most common grade 3 or 4 AEs were pneumonia (4%), atrial fibrillation (3%), febrile neutropenia (3%), and decreased neutrophils (3%) in the ibrutinib-plus-obinutuzumab group, and febrile neutropenia (6%), hypertension (4%), pneumonia (3%), hyperglycemia (3%), and leukopenia (3%) in the chlorambucil-plus-obinutuzumab group.¹⁶ Serious AEs were reported in 58% of patients who were treated with ibrutinib plus obinutuzumab and 35% who received chlorambucil plus obinutuzumab.¹⁶

This study provides evidence that adding a monoclonal antibody to ibrutinib can improve the efficacy of the drug. This combination is an alternative first-line option and a safe chemotherapy-free treatment in previously untreated CLL.¹⁶ Currently, several studies of novel combination therapy with ibrutinib are underway, including 2 phase III trials that are assessing ibrutinib plus obinutuzumab with or without venetoclax (EA9161; ClinicalTrials.gov identifier: NCT03701282 and A041702; ClinicalTrials.gov identifier: NCT03737981).²⁹

Conclusions

The results of ALLIANCE, iLLUMINATE, and ECOG E1912 could have a significant impact on broad treatment approaches to CLL. Ibrutinib monotherapy is, potentially, more beneficial than bendamustine plus rituximab in patients 65 years and older, while the combination of ibrutinib plus rituximab appears to show more benefit than FCR does in patients 70 years and younger. Additionally, the efficacy of ibrutinib plus obinutuzumab has been validated by the FDA approval of the combination regimen. Collectively, these findings suggest that ibrutinib, both in combination with other agents and as a monotherapy, will play an integral role in the evolving treatment spectrum of CLL.

References

1. Sharma S, Rai KR. Chronic lymphocytic leukemia (CLL) treatment: so many choices, such great options. Cancer. 2019;125(9):1432-1440. doi: 10.1002/cncr.31931.
2. Jain N, O’Brien S. Initial treatment of CLL: integrating biology and functional status. Blood. 2015;126(4):463-470. doi: 10.1182/blood-2015-04-585067.
3. Payandeh Z, Bahrami AA, Hoseinpoor R, et al. The applications of anti-CD20 antibodies to treat various B cells disorders. Biomed Pharmacother. 2019;109:2415-2426. doi: 10.1016/j.biopha.2018.11.121.
4. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120(6):1175-1184. doi: 10.1182/blood-2012-02-362624.
5. FDA approves venetoclax for CLL and SLL. FDA website. fda.gov/drugs/resources-information-approved-drugs/fda-approves-venetoclax-cll-and-sll. Published May 15, 2019. Accessed May 16, 2019.
6. FDA approves ibrutinib (IMBRUVICA) in combination with obinutuzumab (GAZYVA) for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) [news release]. New York, NY: Lymphoma Research Foundation; January 28, 2019. lymphoma.org/newsarchive/fda-approves-ibrutinib-imbruvica-in-combination-with-obinutuzumab-gazyva-for-chronic-lymphocytic-leukemiasmall-lymphocytic-lymphoma-cllsll/. Accessed May 16, 2019.
7. Duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). FDA website. fda.gov/drugs/resources-information-approved-drugs/duvelisib-copiktra-verastem-inc-adult-patients-relapsed-or-refractory-chronic-lymphocytic-leukemia. Published September 24, 2018. Accessed May 16, 2019.
8. FDA approves venetoclax for CLL or SLL, with or without 17 p deletion, after one prior therapy. FDA website. fda.gov/drugs/resources-information-approved-drugs/fda-approves-venetoclax-cll-or-sll-or-without-17-p-deletion-after-one-prior-therapy. Published June 8, 2018. Accessed May 16, 2019.
9. FDA approves rituximab plus hyaluronidase combination for treatment of FL, DLBCL and CLL. FDA website. fda.gov/drugs/resources-information-approved-drugs/fda-approves-rituximab-plus-hyaluronidase-combination-treatment-fl-dlbcl-and-cll. Published June 22, 2017. Accessed May 16, 2019.
10. Arzerra [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. accessdata.fda.gov/drugsatfda_docs/label/2016/125326s063lbl.pdf. Accessed May 16, 2019.
11. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality [news release]. Silver Spring, MD: FDA; April 11, 2016. fda.gov/news-events/press-announcements/fda-approves-new-drug-chronic-lymphocytic-leukemia-patients-specific-chromosomal-abnormality. Accessed May 16, 2019.
12. Defitelio (defibrotide sodium). FDA website. fda.gov/drugs/resources-information-approved-drugs/defitelio-defibrotide-sodium. Published March 30, 2016. Accessed May 16, 2019.
13. Chronic lymphocytic leukemia/small lymphocytic lymphoma: FDA updates. Lymphoma Research Foundation website. lymphoma.org/aboutlymphoma/cll/cllfdaupdates. Published May 15, 2019. Accessed May 16, 2019.
14. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528. doi: 10.1056/NEJMoa1812836.
15. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN cancer research group (E1912). Blood. 2018;132(abstr LBA-4). doi: 10.1182/blood-2018-120779.
16. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5.
17. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, version 4.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/cll.pdf. Published [Au: date]. Updated March 15, 2019. Accessed May 10, 2019.
18. For older patients with CLL, ibrutinib-based treatment beats standard chemoimmunotherapy. ASH [American Society of Hematology] Clinical News website. ashclinicalnews.org/on-location/older-patients-cll-ibrutinib-beats-standard-chemoimmunotherapy/. Published January 15, 2019. Accessed May 7, 2019.
19. Helwick C. Expert Point of View: Susan M. O’Brien, MD. The ASCO [American Society of Clinical Oncology] Post website. ascopost.com/issues/december-10-2018/epov-susan-obrien/. Published December 10, 2018. Accessed May 7, 2019.
20. Dangi-Garimella S. Ibrutinib alone better than chemoimmunotherapy as frontline in older patients with CLL. American Journal of Managed Care website. ajmc.com/conferences/ash-2018/ibrutinib-alone-better-than-chemoimmunotherapy-as-frontline-in-older-patients-with-cll. Published December 3, 2018. Accessed April 16, 2019.
21. Davids MS, Daver NG, Pollyea DA. Treatment options for chronic lymphocytic leukemia. OncLive website. onclive.com/insights/therapeutic-agents-aml-cll/treatment-options-for-chronic-lymphocytic-leukemia. Published January 8, 2019. Accessed May 16, 2019.
22. Loguidice CT. Experts dissect 3 practice-changing studies for newly diagnosed CLL. OncLive website. onclive.com/publications/Oncology-live/2019/vol-20-no-7/experts-dissect-3-practicechanging-studies-for-newly-diagnosed-cll?p=2. Published April 1, 2019. Accessed April 11, 2019.
23. Helwick C. Ibrutinib vs standard of care in front-line treatment of older patients with chronic lymphocytic leukemia. The ASCO [American Society of Clinical Oncology] Post. ascopost.com/issues/december-10-2018/ibrutinib-vs-standard-of-care-in-older-patients-with-cll. Published December 10, 2018. Accessed May 7, 2019.
24. Ibrutinib plus rituximab superior to standard treatment for some patients with chronic leukemia [news release]. Bethesda, MD: National Cancer Institute; December 4, 2018. cancer.gov/news-events/press-releases/2018/cll-ibrutinib-trial. Accessed April 11, 2019.
25. Ibrutinib versus FCR: a “paradigm shift” for younger patients with treatment-naïve CLL. ASH [American Society of Hematology] Clinical News website. ashclinicalnews.org/on-location/ibrutinib-paradigm-shift-younger-cll/. Published January 1, 2019. Accessed May 7, 2019.
26. Agathou S. ASH 2018: ibrutinib plus rituximab provide superior outcomes than FCR in naïve CLL patients: results from the ECOG-ACRIN phase III trial E1912. Lymphoma Hub website. lymphomahub.com/medical-information/ash-2018-ibrutinib-plus-rituximab-provide-superior-outcomes-than-fcr-in-naive-cll-patients-results-from-the-ecog-acrin-phase-iii-trial-e1912. Published January 29, 2019. Accessed May 7, 2019.
27. Columbus G. FDA approves ibrutinib plus obinutuzumab in frontline CLL/SLL. OncLive website. onclive.com/web-exclusives/fda-approves-ibrutinib-plus-obinutuzumab-in-frontline-cllsll. Published January 28, 2019. Accessed April 12, 2019.
28. iLLUMINATE trial of ibrutinib plus obinutuzumab for first-line therapy of CLL/SLL meets primary endpoint. The ASCO [American Society of Clinical Oncology] Post website. ascopost.com/News/58942. Published June 13, 2018. Updated September 14, 2018. Accessed April 11, 2019.
29. Inman S. Ibrutinib/rituximab improves OS, PFS versus FCR for untreated CLL. OncLive website. onclive.com/conference-coverage/ash-2018/ibrutinibrituximab-improves-os-pfs-versus-fcr-for-untreated-cll Published December 4, 2018. Accessed May 7, 2019.