Along the same lines, the Pharmacyclics-sponsored iLLUMINATE study, presented by Carol Moreno, MD, PhD, of the Hospital de la Santa Creu Sant Pau in Spain, demonstrated superior PFS for the combination of ibrutinib and obinutuzumab compared with chlorambucil plus obinutuzumab in treatment-naive individuals aged 65 years or older with CLL or younger than 65 years with comorbidities or 17p deletion/TP53 mutation.6 Furthermore, a cross-trial comparison reported by Alessandra Tedeschi, MD, of the ASST Grande Ospedale Metropolitano Niguarda in Italy, showed no difference in overall response rates  between single-agent ibrutinib (from the RESONATE-2 trial) and ibrutinib plus obinutuzumab (from the iLLUMINATE trial).7 Although the rate of CR was significantly higher for ibrutinib plus obinutuzumab compared with ibrutinib monotherapy, CR was not necessary to gain long-term PFS benefit with single-agent ibrutinib, as has been well established.

Tait Shanafelt, MD, of Stanford University in California, presented the results of another United States cooperative group study, the ECOG-ACRIN E1912 trial.8 This phase 3 randomized controlled trial demonstrated both superior PFS and overall survival for IR compared with fludarabine, cyclophosphamide, and rituximab (FCR) as first-line therapy in 510 younger (age ≤70 years), fit patients with CLL who did not have 17p deletion. The University of Texas MD Anderson group has previously shown excellent long-term outcomes with frontline FCR in patients with mutated IGHV; consistent with these observations, a PFS benefit for IR over FCR was not observed within this subgroup in the E1912 trial.

Building upon the experience of patients with favorable genomic features with FCR, our group at the University of Texas MD Anderson Cancer Center has designed an MRD-directed, finite duration, frontline regimen for fit patients with mutated IGHV and no 17p deletion/TP53 aberration: ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG), which replaces rituximab with obinutuzumab, shortens the duration of chemotherapy in an effort to reduce the incidence of therapy-related myeloid neoplasms, and adds ibrutinib.9 All patients received ibrutinib for a year and chemotherapy (FC) for only the first 3 cycles. Obinutuzumab was administered for 6 or 12 cycles depending on response. At the end of 12 cycles, patients continued ibrutinib monotherapy only if still positive for MRD4 in the bone marrow by multicolor flow cytometry. After 3 cycles of iFCG, the rate of MRD4-negativity in the bone marrow was 87% — much higher than expected with FCR alone — and responses deepened over time. Bone marrow MRD4 negativity has been reported to be a stronger predictor of long-term treatment outcome compared with conventional CR.

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With the new and powerful tools available in our armamentarium against CLL, there is substantial enthusiasm for fixed duration treatment regimens that can achieve deep, sustained responses and possibly lead to long treatment-free remissions, if not a cure. Thus far, it remains unclear if the addition of obinutuzumab to ibrutinib plus venetoclax provides an incremental benefit in this regard. Longer follow-up of the trials mentioned here and other large, multicenter studies are necessary and will hopefully provide answers to this important question.

In the meantime, it appears that ibrutinib-based therapy will increasingly be adopted in the upfront setting, likely as a single agent in older patients. In younger, fit patients with mutated IGHV and non-adverse cytogenetics, FCR and FCR-like chemoimmunotherapy should probably still remain the standard of care, despite the overall findings from the E1912 trial, while patients with unfavorable genomic features should receive ibrutinib, with or without a CD20 monoclonal antibody. Although the pivotal MURANO trial,10 presented by John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Australia, did not test the venetoclax plus rituximab regimen in patients previously exposed to kinase inhibitors, considerable real world data exist to support the use of venetoclax in patients failing ibrutinib and/or idelalisib. Additionally, the discovery of Gly101Val mutations in BCL2 that lead to acquired resistance to venetoclax is an important translational finding that could spur the development of a new generation of BCL-2 antagonists,11 as has been the case with BTK inhibitors, although protein-protein interactions are much more difficult to target than activated kinases.

This article was part of Hematology Advisor’s coverage of the American Society of Hematology (ASH) 2018 meeting. To read more, please visit the conference page.

References

1.     Jain N, Keating MJ, Thompson PA, et al. Combined ibrutinib and venetoclax in patients with treatment-naïve high-risk chronic lymphocytic leukemia (CLL). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 186.

2.     Hillmen P, Rawstron A, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory CLL: results of the Bloodwise TAP Clarity study. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 182.

3.     Rawstron A, Munir T, Brock K, et al. Ibrutinib and obinutuzumab in CLL: improved MRD response rates with substantially enhanced MRD depletion for patients with >1 year prior ibrutinib exposure. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 181.

4.     Rogers KA, Huang Y, Ruppert AS, et al. Phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 693.

5.     Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup study A041202. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 6.

6.     Moreno C, Greil R, Demirkan F, et al. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 691.

7.     Tedeschi A, Greil R, Demirkan F, et al. Single-agent ibrutinib versus chlorambucil-obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results of a cross-trial comparison [published online November 21, 2018]. Blood. doi: 10.1182/blood-2018-99-111369

8.     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). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract LBA4.

9.     Jain N, Thompson PA, Burger JA, et al. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for firstline treatment of patients with CLL with mutated IGHV and without TP53 aberrations. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 185.

10.  Seymour JF, Kipps TJ, Eichhorst B, et al. MURANO trial establishes feasibility of time-limited venetoclax-rituximab (VenR) combination therapy in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 184.

11.  Blombery P, Anderson MA, Gong J, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract LBA7.