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Concurrent vs Sequential Rituximab in HCL

Panelists: Farhad Ravandi-Kashani, MD, The University of Texas MD Anderson Cancer Center; Robert J. Kreitman, MD, National Institutes of Health
Published: Tuesday, Jul 16, 2019



Transcript:

Farhad Ravandi-Kashani, MD: I know that you have been conducting a randomized study of concomitant versus sequential rituximab that perhaps you would like to expand on.

Robert J. Kreitman, MD: Yeah. We’re actually going to be presenting this at the ASCO [American Society of Clinical Oncology] Annual Meeting 2019, and the abstract is in the public domain. We randomized 68 patients between getting the rituximab on the same day as the 5 daily doses of cladribine, which you used in your study. We randomized that to either getting it the same day or at least 6 months later if and when the blood flow became positive or the blood looked otherwise abnormal—that means a CBC [complete blood count] that was consistent with residual hairy cell leukemia. In other words, we used an abnormal blood sample as a trigger for delayed rituximab. If the patient never developed that, then the patient would not get delayed rituximab.

But what we found is that the rate of minimal residual disease [MRD]—and this is most sensitively determined by flow cytometry of the bone marrow aspiration—is 95% or 97% negative if you use the rituximab up front on day 1, and it’s only 24% negative if you use the rituximab delayed by at least 6 months. However, once you use delayed rituximab, many of these patients become MRD-free. But there are a significant number of patients who don’t.

We also find that the durability of the responses… If we give concurrent rituximab and cladribine, and we’ve now followed these patients for the last 9 years—so the median follow-up is about 90-plus months—we find that in the 34 patients who got the concurrent rituximab and cladribine, we’ve only had 2 patients who are not only in complete remission but also MRD-free, meaning that their minimal residual disease is undetectable even by bone marrow aspiration flow. We repeat this at least every 2 years. What we’re also finding is that some of the patients do well with cladribine alone, and they do well with delayed rituximab. They tend to relapse more frequently and earlier, so there’s a significance there. But overall, they do pretty well, and the median MRD-free survival has not been reached yet with delayed rituximab. I think that also is a viable option for patients who don’t want to get their rituximab at the same time.

I think that this approach—which, by the way, is also recognized by the NCCN [National Comprehensive Cancer Network] Guidelines and by the hairy cell leukemia guidelines that were published in Blood journal in 2017 by Michael R. Grever, et al—is an option. It’s an option to use rituximab with purine analog up front and also in later lines. I think this can be done a variety of different ways. It could be done up front. It could be done delayed. One reason why the up-front approach might work better is that there’s evidence that synergy between rituximab and purine analog requires that the rituximab make the cells more sensitive to the purine analog—to the cladribine. This is also the case with bendamustine, another trial we’re doing with rituximab in hairy cell.

If the rituximab is delayed, there’s no more purine analog around because the purine analog has a shorter half-life. This is 1 reason why the concurrent approach might have a better long-term outcome. But in general, the outcome is very good and certainly better than the purine analog alone. But I would repeat that some patients, a minority, don’t seem to require any rituximab. If you follow them carefully, they’ll be MRD-free by the purine analog alone, but this is a low percentage, less than a quarter of the patients in our study.

Transcript Edited for Clarity

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Transcript:

Farhad Ravandi-Kashani, MD: I know that you have been conducting a randomized study of concomitant versus sequential rituximab that perhaps you would like to expand on.

Robert J. Kreitman, MD: Yeah. We’re actually going to be presenting this at the ASCO [American Society of Clinical Oncology] Annual Meeting 2019, and the abstract is in the public domain. We randomized 68 patients between getting the rituximab on the same day as the 5 daily doses of cladribine, which you used in your study. We randomized that to either getting it the same day or at least 6 months later if and when the blood flow became positive or the blood looked otherwise abnormal—that means a CBC [complete blood count] that was consistent with residual hairy cell leukemia. In other words, we used an abnormal blood sample as a trigger for delayed rituximab. If the patient never developed that, then the patient would not get delayed rituximab.

But what we found is that the rate of minimal residual disease [MRD]—and this is most sensitively determined by flow cytometry of the bone marrow aspiration—is 95% or 97% negative if you use the rituximab up front on day 1, and it’s only 24% negative if you use the rituximab delayed by at least 6 months. However, once you use delayed rituximab, many of these patients become MRD-free. But there are a significant number of patients who don’t.

We also find that the durability of the responses… If we give concurrent rituximab and cladribine, and we’ve now followed these patients for the last 9 years—so the median follow-up is about 90-plus months—we find that in the 34 patients who got the concurrent rituximab and cladribine, we’ve only had 2 patients who are not only in complete remission but also MRD-free, meaning that their minimal residual disease is undetectable even by bone marrow aspiration flow. We repeat this at least every 2 years. What we’re also finding is that some of the patients do well with cladribine alone, and they do well with delayed rituximab. They tend to relapse more frequently and earlier, so there’s a significance there. But overall, they do pretty well, and the median MRD-free survival has not been reached yet with delayed rituximab. I think that also is a viable option for patients who don’t want to get their rituximab at the same time.

I think that this approach—which, by the way, is also recognized by the NCCN [National Comprehensive Cancer Network] Guidelines and by the hairy cell leukemia guidelines that were published in Blood journal in 2017 by Michael R. Grever, et al—is an option. It’s an option to use rituximab with purine analog up front and also in later lines. I think this can be done a variety of different ways. It could be done up front. It could be done delayed. One reason why the up-front approach might work better is that there’s evidence that synergy between rituximab and purine analog requires that the rituximab make the cells more sensitive to the purine analog—to the cladribine. This is also the case with bendamustine, another trial we’re doing with rituximab in hairy cell.

If the rituximab is delayed, there’s no more purine analog around because the purine analog has a shorter half-life. This is 1 reason why the concurrent approach might have a better long-term outcome. But in general, the outcome is very good and certainly better than the purine analog alone. But I would repeat that some patients, a minority, don’t seem to require any rituximab. If you follow them carefully, they’ll be MRD-free by the purine analog alone, but this is a low percentage, less than a quarter of the patients in our study.

Transcript Edited for Clarity
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