According to results of a phase 2 study of patients with treatment-naive chronic lymphocytic leukemia (CLL), an assessment of the presence or absence minimal residual disease (MRD) in the bone marrow following a limited period of chemotherapy-free induction therapy may help to limit patient exposure to more intensive subsequent treatment. The findings from this study were published in Lancet Haematology.1

In this 2-part, single-arm, open-label, multicenter trial ( Identifier: NCT02666898), medically fit, adult patients with treatment-naive CLL not characterized by a 17p deletion or a mutation in TP53 received 9 months of chemotherapy-free induction therapy with the combination of ibrutinib, a Bruton tyrosine kinase inhibitor, and  obinutuzumab, an anti-CD20 monoclonal antibody. Following induction therapy, those patients with a complete response (CR) and bone marrow MRD status of less than .01% were treated with 6 months of ibrutinib; whereas those achieving a partial response (PR), or a CR and bone marrow MRD greater than or equal to .01%, received 6 months of ibrutinib plus combination therapy with fludarabine/cyclophosphamide, and obinutuzumab.  

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The primary end point of the study was the proportion of patients in the intention to treat (ITT) population achieving a CR characterized by bone marrow MRD of less than .01% on day 1 of month 16 following treatment initiation.

Of the 135 patients with treatment-naive CLL enrolled in the study, the median age was 62 years, and 44% of patients had disease characterized by the IGHV mutation.

In the subgroup of 130 patients evaluable for response, 8% of patients achieved a CR with less than .01% MRD in the bone marrow. While this subgroup received an additional 6 months of treatment with ibrutinib monotherapy, the remaining 92% of patients were treated with immunochemotherapy plus ibrutinib during this period.

Following a 15-month overall treatment period, 62% of the ITT population achieved a CR and bone marrow MRD of less than .01%. IGHV mutation status did not appear to influence the CR rate (ie, 46% and 40% of patients had mutated and unmutated disease, respectively).

During the induction phase (part 1) of the study, the most common grade 3/4 adverse events were thrombocytopenia (ie, 17% [grade 3]; 15% [grade 4]) and neutropenia (ie, 13% [grade 3]; 11% [grade 4]). Similar overall findings were observed in the 125 patients included in part 2 of the study, although rates of grade 3/4 thrombocytopenia were somewhat lower (ie, 8% [grade 3]; 7% [grade 4]), and more grade 3/4 gastrointestinal adverse effects were reported. In addition, ibrutinib administered with or without chemotherapy in this phase was discontinued in 16% and 0% of patients, respectively. No treatment-related deaths were reported.

Although the author of an invited accompanying commentary described these findings as “encouraging,” they were skeptical regarding the impact of this study on current treatment recommendations for several reasons:2

  • Because results of phase 3 trials suggest that first-line targeted therapy approaches are superior to chemoimmunotherapy in patients with CLL characterized by unmutated IGHV
  • There is the potential for increased toxicity with the combination of fludarabine, cyclophosphamide, obinutuzumab, and ibrutinib compared with other low-intensity regimens
  • Preclinical evidence suggests that off-target effects of ibrutinib may inhibit obinutuzumab activity, and that ibrutinib activity is not increased in a synergistic way when combined with antibodies targeting CD20

Both the study authors and the author of the accompanying editorial concluded that use of bone marrow MRD status following a limited-course induction therapy is a promising approach for selecting some patients with CLL whom are likely to benefit from more intensive subsequent therapy. Nevertheless, there was also consensus that, prior to its implementation in clinical practice, this type of strategy should be evaluated in randomized trials.


  1. Michallet ASDilhuydy MSSubtil F, et al. Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease-drivenstrategy in patients with chronic lymphocytic leukaemia (ICLL07 FILO): a single-arm, multicentre, phase 2 trial [published online July 16, 2019]. Lancet Haematol. doi: 10.1016/S2352-3026(19)30113-9
  2. Fink AM. Is chemoimmunotherapy maintenance of value in patients with chronic lymphocytic leukaemia and minimal residual disease? [published July 16, 2019]. Lancet Haematol.  doi: 10.1016/S2352-3026(19)30107-3