New Directions in Chronic Lymphocytic Leukemia Care: A Review of 2019 Treatment Guideline Updates


blood cellsDIn December 2018, pivotal trial data were presented at the American Society of Hematology Annual Meeting that demonstrated promising results for the first-line treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). In particular, new courses of CLL care in several patient populations emerged from the findings of 3 trials: the Alliance North American Intergroup Study A041202 (ALLIANCE),1 the E1912 trial of the ECOG-ACRIN Cancer Research Group (ECOG E1912),2 and iLLUMINATE.3

The impact of these studies is reinforced by the updates to the 2019 National Comprehensive Cancer Network (NCCN) guidelines for the treatment of CLL. The updated guidelines reflect the increased consideration now given to frailty, significant comorbidities, age, del(17p)/TP53 mutation status, and immunoglobulin heavy-chain variable (IGHV) mutation status in patients with CLL (Table).4 This article reviews the guideline updates.

GUIDELINE UPDATES
First-Line Options Combined for Frail Patients With Significant Comorbidity, Patients Older Than 65 Years, and Younger Patients With Significant Comorbidities Without del(17p)/TP53 Mutation
One of the most significant changes in the 2019 NCCN treatment guidelines is that first-line therapeutic options were combined for patients with CLL older than 65 years, frail patients with significant comorbidity, and younger patients with significant comorbidities without del(17p)/TP53 mutation.4 As a result of the ALLIANCE trial, the safety and efficacy of ibrutinib monotherapy has been established as a preferred regimen for first-line therapy in patients 65 years and older with untreated CLL without del(17p)/TP53 mutation.1,4 Patients in the ALLIANCE trial were treated with bendamustine plus rituximab, ibrutinib plus rituximab, or ibrutinib alone.1 Results demonstrated that the combination of ibrutinib plus rituximab was more effective than the combination of bendamustine plus rituximab.1 Moreover, patients treated with ibrutinib alone or combined with rituximab exhibited longer progression-free survival (PFS) compared with 6 rounds of chemoimmunotherapy with bendamustine plus rituximab, suggesting a role for continuous ibrutinib treatment.

It is important to note that no clearly demonstrated improvements in clinical outcomes have been reported in a randomized clinical trial for patients treated with ibrutinib plus an anti-CD20 monoclonal antibody compared with ibrutinib monotherapy.4 Furthermore, adding rituximab to ibrutinib did not lead to improved clinical outcomes compared with ibrutinib monotherapy in the ALLIANCE trial. In fact, patients treated with the combination of ibrutinib plus rituximab or ibrutinib monotherapy had very similar 2-year PFS rates of 88% and 87%, respectively.1 These results suggest that the prolonged PFS observed in patients treated with the combination of ibrutinib plus rituximab was due to the continued ibrutinib therapy rather than the addition of an anti-CD20 monoclonal antibody.4

Another change to the guidelines in this population was the addition of the combination of ibrutinib plus obinutuzumab as a category 2B, other recommended regimen.4 The iLLUMINATE trial demonstrated a benefit in PFS for ibrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab, leading to the FDA approval of the combination of ibrutinib plus obinutuzumab.3

Additionally, the combination of chlorambucil plus obinutuzumab was updated from a category 1 to category 2A recommendation, while the combinations of chlorambucil plus obinutuzumab, chlorambucil plus ofatumumab, and chlorambucil plus rituximab were revised to “chlorambucil plus anti-CD20 monoclonal antibody” and switched from preferred regimens to other recommended regimens.4 Results from the phase III iLLUMINATE study contributed to these changes.4 The trial included patients with previously untreated CLL or SLL younger than 65 years or older than 65 years with coexisting conditions.3 It was designed to evaluate the first-line combination of ibrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab. PFS was considerably longer in patients treated with ibrutinib plus obinutuzumab than in those treated with chlorambucil plus obinutuzumab (not reached vs 19.0 months, respectively), which suggests that the addition of a monoclonal antibody to ibrutinib leads to improved efficacy of ibrutinib.3

Given the elevation of other therapeutic options to first-line treatment options, the recommendation of bendamustine (70 mg/m2 in the first cycle with escalation to 90 mg/m2 if tolerated) plus an anti-CD20 monoclonal antibody was changed from a preferred regimen to other recommended regimen.

First-line Therapy for Patients Younger Than 65 Years Without Significant Comorbidties and Without del(17p)/TP53 Mutation
Revisions were also made for suggested first-line treatment regimens in patients younger than 65 years with CLL without del(17p)/TP53 mutation without significant comorbidities.4 First, ibrutinib treatment shifted from a category 2A to a category 1 recommendation, based on results from the phase III ECOG E1912 trial.4 The study included patients 70 years and younger and was designed to compare the combination of ibrutinib plus rituximab with the gold-standard chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR).2 Findings revealed that both PFS and overall survival (OS) were significantly improved in patients treated with ibrutinib plus rituximab. The hazard ratio for PFS favored the ibrutinib plus rituximab group compared with the FCR cohort (HR, 0.352; 95% CI, 0.223-0.558; P <.0001). The HR for OS was also superior in the ibrutinib-plus-rituximab arm (HR, 0.168; 95% CI, 0.053-0.538; P = .0003).2 These results indicate that ibrutinib-based therapy should be included as a first-line treatment option for this patient population.

Another change made to this population was the combination of ibrutinib plus rituximab as a category 2B, other recommended regimen, while FCR was changed from a preferred regimen to other recommended regimen and moved from a category 1 to a category 2A recommendation.4 Additionally, bendamustine plus anti-CD20 monoclonal antibody was changed from a preferred regimen to other recommended regimen.4 These recommendations were also based on results from the ECOG E1912 trial. In addition to the improved efficacy data, increased incidences of grade 3 and 4 adverse events (AEs) were reported in patients treated with the FCR regimen compared with the ibrutinib-plus-rituximab regimen (72% vs 58%, respectively).2 Importantly, FCR is still considered an appropriate first-line therapy for these patients, particularly in patients with mutated IGHV.

Relapsed/Refractory Therapy for Patients With Relapsed/Refractory CLL/SLL Without del(17p)/TP53 Mutation
Revisions were made for therapy in patients with relapsed/refractory CLL/SLL without del(17p)/TP53 mutation.4 For instance, bendamustine dose escalation was removed for frail patients with significant comorbidity, patients older than 65 years, and younger patients with significant comorbidities.4 For frail patients with significant comorbidity or older than 65 years, and for younger patients with significant comorbidities, and those younger than 65 years without significant comorbidities, the combination of idelalisib plus rituximab was updated from a category 1 to a category 2A recommendation.4 This decision was based on the toxicity profile of the combination of idelalisib plus rituximab, which includes colitis, diarrhea, and increased infection risk, despite improved median PFS in patients treated with idelalisib plus rituximab in randomized phase III studies.4,5 In a multicenter study, patients with previous therapy-induced myelosuppression, decreased renal function, or major comorbidities were randomized to receive rituximab plus idelalisib or placebo to evaluate the effects on PFS.5 Median PFS was significantly longer in patients who received the combination of rituximab plus idelalisib compared with those receiving placebo (not reached vs 5.5 months).5 At the recommendation of the data and safety monitoring board, the study was stopped at the first prespecified analysis because of overwhelming evidence of efficacy.5 At least 1 serious AE, such as pneumonia, pyrexia, and febrile neutropenia, was reported in 40% of patients receiving the combination of rituximab plus idelalisib and in 35% of patients receiving rituximab plus placebo.5

Because of infection-related toxicity and deaths reported following idelalisib treatment in previously untreated patients with CLL, idelalisib should not be administered as first-line therapy.4 The combination of idelalisib plus rituximab is considered suitable for patients with relapsed/refractory CLL/SLL for whom rituximab monotherapy would be appropriate based on the presence of other comorbidities, including grade 3 or higher neutropenia or thrombocytopenia resulting from effects of prior cytotoxic therapy, or reduced renal function, as determined by creatinine clearance of less than 60 mL/min.4

Unmutated IGHV
Unmutated IGHV, compared with mutated IGHV, has been associated with poor prognosis, significantly decreased survival of patients regardless of disease stage, and shorter treatment-free survival.6,7 Unmutated IGHV status is associated with a short remission period from chemoimmunotherapy.8 For this patient population, and those with high-risk cytogenetics (eg, del[17p] or TP53 mutations), doctors can now consider ibrutinib as a new standard of care for both older and younger patients.8 In the ECOG E1912 trial, patients with unmutated IGHV exhibited prolonged PFS following treatment with the combination of ibrutinib plus rituximab compared with FCR.2 However, this benefit was not seen in patients with mutated IGHV.2 Controversy still exists regarding treatment of the subpopulation of CLL patients with mutated IGHV; these patients can respond well to ibrutinib, but the regimen has to consist of ongoing, continuous therapy to exert beneficial effects.8

CONCLUSIONS AND FUTURE DIRECTIONS
Current recommendations for first-line therapy include ibrutinib as the preferred option for all patients, including high-risk subgroups with del(11q) or del(17p)/TP53 mutation and unmutated IGHV, based on successful long-term disease control. Chemoimmunotherapy with FCR is appropriate for the first-line treatment of patients aged ≥65 years with mutated IGHV based on a defined treatment course. Moreover, most patients with mutated IGHV who are treated with FCR in the first line are expected to experience at least 10 years of PFS or even disease cure. Idelalisib should not be used as a first-line therapeutic option; however, idelalisib with or without rituximab; ibrutinib; acalabrutinib; duvelisib; and venetoclax with or without rituximab are acceptable and effective treatment options for patients with relapsed/refractory CLL/SLL [small lymphocytic lymphoma].

The impact of the ALLIANCE, ECOG E1912, and iLLUMINATE trials has been significant, as reflected by the depth and number of changes to the 2019 NCCN CLL guidelines, as outlined above. Major findings from ALLIANCE and ECOG E1912 support the use of first-line ibrutinib, either alone or combined with an anti-CD20 monoclonal antibody. Additionally, ibrutinib is now considered a new standard of care for older and younger patients with nonmutated  IGHV status. The use of FCR and the combination of chlorambucil plus an anti-CD20 monoclonal antibody were both changed from preferred regimen to other recommended regimen based on findings from the ECOG E1912 and iLLUMINATE studies.
As a follow-up to the ALLIANCE trial, future studies will investigate whether indefinite therapy with ibrutinib is necessary. Studies investigating additional therapies have the potential to redefine first-line therapy in patients with CLL; consequently, NCCN guidelines would be revised to provide better treatment options and outcomes for these patients. 
 

References

  1. 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.
  2. 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.
  3. 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 [Correction appears in Lancet Oncol. 2019;20:43-46]. Lancet Oncol. 2019;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5.
  4. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, version 4.2019. National Comprehensive Cancer Network website. Published March 15, 2019. Accessed May 3, 2019.
  5. 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. doi: 10.1056/NEJMoa1315226.
  6. Hamblin TJ, Davis Z, Gardiner A, Oscier, DG, Stevenson FK.Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848-1854.
  7. Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood. 2002;100(4):1177-1184.
  8. 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?log=f. Published January 8, 2019. Accessed May 6, 2019.
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