Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib

Blood. 2021 Dec 30;138(26):2810-2827. doi: 10.1182/blood.2020010146.

Xin Victoria Wang ¹ ², Curtis A Hanson ³, Renee C Tschumper ³, Connie E Lesnick ³, Esteban Braggio ⁴, Elisabeth M Paietta ⁵, Susan O'Brien ⁶, Jacqueline C Barrientos ⁷, Jose Francisco Leis ⁸, Cong Christine Zhang ⁹, Steven E Coutre ¹⁰, Paul M Barr ¹¹, Amanda F Cashen ¹², Anthony R Mato ¹³, Avina K Singh ¹⁴, Michael P Mullane ¹⁵, Harry Erba ¹⁶, Richard Stone ¹⁷, Mark R Litzow ³, Martin S Tallman ¹⁸, Tait D Shanafelt ¹⁰, Neil E Kay ³

Affiliations

1 Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.
2 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA.
3 Division of Hematology and Department of Internal Medicine, Mayo Clinic, Rochester, MN.
4 Department of Hematology/Oncology, Mayo Clinic in Arizona, Scottsdale, AZ.
5 Department of Oncology, Montefiore Medical Center, Brooklyn, NY.
6 Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Irvine, CA.
7 Northwell Health Center for Advanced Medicine, New Hyde Park, NY.
8 Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic in Arizona, Phoenix, AZ.
9 Department of Hematology/Oncology, Kaiser Permanente National Cancer Institute Community Oncology Research Program (NCORP)/The Permanente Medical Group, Fresno, CA.
10 Department of Medicine, Stanford University, Stanford, CA.
11 Department of Medicine, Rochester University, Rochester, NY.
12 Department of Medicine, Washington University School of Medicine, St Louis, MO.
13 CLL Program, Memorial Sloan-Kettering Cancer Center, New York, NY.
14 Fairview Ridges Hospital, Burnsville, MN.
15 Aurora Cancer Care-Milwaukee West, Milwaukee, WI.
16 Department of Medicine, Duke University Medical Center, Durham, NC.
17 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and.
18 Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY.

PMID: 34407545 DOI: 10.1182/blood.2020010146

Abstract

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10-1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10-1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy.

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