Case 4: iFCG in Untreated CLL

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William Wierda, MD, PhD:This is a young, fit patient who received standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. She achieved a complete remission. From our data, at MD Anderson Cancer Center, and from other data, including from the German CLL Study Group, we know that the overall complete remission rate is about 50% to 70%—we’ve reported 70%. Matt, your group has also worked with FCR and has shown a similarly high complete remission rate. These days, we’re monitoring minimal residual disease and minimal residual disease status more closely. Nitin, with standard FCR, in a patient who has these prognostic features (particularly a mutated V gene and trisomy 12), what do we expect to see in terms of MRD-negative rate and complete remission rate?

Nitin Jain, MD:With the mutated V gene, with frontline FCR, it’s been reported that after 3 cycles of FCR, if you were to check for bone marrow MRD-negativity, typically it’s about 25%. However, when the patient gets 6 cycles of FCR, which is the standard duration, approximately 50% of these patients are MRD-negative in the bone marrow. Another 50% of patients will be MRD-positive at the time when they complete the FCR regimen. As you mentioned, the complete response rate was close to 70% in these patients.

William Wierda, MD, PhD:What’s the relevance of achieving a complete remission for a mutated case with FCR, based on the long-term follow-up data that have been reported?

Nitin Jain, MD:Our center has reported that in the patients who are mutated for V gene, who received frontline FCR, the median progression-free survival, or the progression-free survival at 10-plus years, actually, was upward of the 50% to 55% range. These are patients who got 6 cycles of FCR, and they had the mutated V gene. So, that’s a very favorable outcome. Similar data with a shorter follow-up have been reported out by the German CLL Study Group, as well as by David Rossi, of the Italian Group cohort. That’s a group of patients in whom we think that chemoimmunotherapy in the frontline setting has a role for—in patients who have a mutated V gene who do not have deletion 17p.

William Wierda, MD, PhD:I don’t think that the same plateau has been demonstrated on the BR curve, by the German CLL Study Group, in the randomized BR versus FCR trial. We’ve done a prognostic factor prospective evaluation of prognostic features including MRD status with FCR. Certainly, those patients who have a mutated V gene, who are MRD-negative at response assessment in the bone marrow, have a better progression-free survival than anybody else. Patients who are mutated, who are still MRD-positive, tend to relapse and have a shorter progression-free survival. In terms of our programs, in what direction are we going with new chemoimmunotherapy regimens? What are we trying to achieve for those patients?

Nitin Jain, MD:A couple of years ago, we thought of how we could modify the current FCR regimen, which has been our standard of care for the past decade or more. We realized a few things. The patients with a mutated V gene are the patients who have the best long-term outcomes. So, for the new version of the clinical trial, we elected to recruit only patients who had a mutated V gene, without deletion 17p—because that’s not where chemotherapy has any role. Then the CLL11 study had shown that if you compared obinutuzumab plus chlorambucil with rituximab plus chlorambucil, there was a better progression-free survival and overall survival for the obinutuzumab arm. So, based on those data, we felt that obinutuzumab may be a better antibody, compared with rituximab. And then we also elected to use ibrutinib with a time-defined duration. Based on trials, this regimen was shown to be effective, leading to a higher MRD-negativity rate when combined with chemotherapy.

Right now, we have this ongoing clinical trial at MD Anderson Cancer Center. We call this the iFCG regimen. We reported the data at the ASH meeting, this past year. We treated a group of patients with the regimen, and a high number completed the 3 courses. The other important aspect of this regimen is that we’re using only 3 cycles of chemotherapy. So, it’s not 6 cycles of chemotherapy. It’s only 3 cycles of chemotherapy. After that, depending on the MRD status, patients continue to get ibrutinib plus obinutuzumab for up to 1 year. And at 1 year, if the patient is MRD-negative, they will stop all therapy (including ibrutinib) and will be monitored for recurrence.

At the time of this report, we found that at 3 months, when we offered 3 cycles of iFCG, when we did a bone marrow, 86% of the patients were MRD-negative. This seems favorable compared with historical FCR data with the same time point for the same patient population. The MRD-negative rate was 26%, which our group reported several years ago. So, based on that, it looks favorable. At the time of the ASH presentation, we had 12 patients who had reached the 1-year time point. All 12 patients were MRD-negative in the bone marrow and had stopped ibrutinib, and none of these patients had a recurrence. So, that seems to be an effective regimen to induce deep MRD-negative remissions for patients.

One of the toxicities we saw with this regimen was increased neutropenia. We were not using prophylactic G-CSF in these patients, but now we are. We are realizing that there is increased neutropenia for these patients. Otherwise, the regimen is relatively well tolerated. So, that’s an approach that we have taken for treating patients with mutated V gene without deletion 17p, who are young and fit, who are able to tolerate chemotherapy. Right now, as part of a clinical trial, our approach is to treat with this regimen called iFCG.

Adam Bagg, MD:Would you mind if I chimed in with some questions regarding MRD? I have 2 questions, actually. How are you measuring MRD? Are you using flow or molecular technology? The second question is, is it important to do MRD testing in the marrow rather than peripheral blood, compared with, for example, CML, where they are essentially equivalent?

Nitin Jain, MD:Those are excellent questions. The MRD that we are doing at our institution is by flow cytometry, with a sensitivity of 0.01%. That’s what is recommended from the IWCLL guidelines. It can be done on both the bone marrow and the peripheral blood. I think the studies have shown that the bone marrow is more sensitive than peripheral blood when you are using the same technology at both places. We typically have done bone marrow flow cytometry, and those are the data that I reported to you. However, groups such as the German CLL Study Group have done a lot of work with peripheral blood flow cytometry as well. Maybe others can also comment on that question?

William Wierda, MD, PhD:I would add the addition of the CD20 antibody. If you’re testing for MRD in the setting of giving the CD20 antibody, you can skew your results—you’ll get a high rate of MRD-negativity in the blood, where there still is disease in the bone marrow. If patients are receiving a CD20 antibody, we typically will evaluate in the bone marrow unless it’s several months after they’ve completed their CD20 antibody therapy. Then things tend to become more consistent between blood and bone marrow. In general, I think the thought is that bone marrow is a more sensitive place to look. The problem with bone marrow in CLL is that nobody wants to have a bone marrow. And so, in terms of standards of care, I think that the field will move more toward evaluating for minimal residual disease in the blood. We’re interested in more sensitive methodologies, where there may be more of a consistency between blood and bone marrow if we have a higher sensitivity of a test.

Transcript edited for clarity.