Acute Lymphoblastic Leukemia: Treatment Strategies and Considerations - Episode 6
An overview of the treatment implications of testing for minimal residual disease in pediatric and AYA patients with ALL.
James K. McCloskey, MD: How do you handle MRD [minimal residual disease] at your institute? When are you checking? How are you checking it?
Ibrahim Aldoss, MD: MRD is very important in ALL [acute lymphoblastic leukemia] assessments. Typically, every time we do a bone marrow biopsy, we check MRD. We still do more MRD by multicolor flow cytometry because this is the way we used to do it, but MRD can be done by clonoSEQ [assay]. We’re trying to do more of the clonoSEQ using initialization sequencing, but what’s been happening, we’ve been having more difficulty obtaining an original bone marrow biopsy for these cases. But MRD is an important prognostic factor in ALL. It surpasses most of the other prognostic factors, like high white blood cell count, phenotype, all these factors. MRD is the most important thing that determines how the patient’s going to do and if we should do a consolidation with allogeneic stem cell transplant or not. Nowadays we have blinatumomab, which is an FDA-approved drug for patients with persistent MRD. There is controversy over what’s the best timing to have the MRD to determine future outcomes and the need of the consolidation with transplant or not. But there are different studies that show that day-28 bone marrow biopsy MRD is prognostic, like the C10403 [consolidation regimen], that shows day-28, day-29 bone marrow biopsy MRD was prognostic. We do it that day. Then we repeat it after consolidation, which is roughly around…initiating therapy. There is less controversy about that MRD, if that MRD is still positive, then we can give blinatumomab. This patient clearly benefits from allogeneic stem cell transplant based on the GIMEMA study and other studies as well.
James K. McCloskey, MD: Yes, we have a similar approach, and it’s a struggle in the community. I certainly sympathize because I can’t imagine having a clinic full of patients with lung cancer and breast cancer, and having a patient with ALL walk in. There’s a lot of confusion around MRD. I agree, clonoSEQ, having a test that’s commercially available, hopefully it’s going to help with this because clearly, it has now become standard in ALL. It’s something we should all be doing. Here in Hackensack, New Jersey, we are fortunate enough that we have a standardized multicolor flow cytometry assessment available to us, which we use here. Like your approach, we will give patients up to the first cycle of consolidation before we switch to immunotherapy if patients are still MRD positive. Like we’ve talked about, MRD positivity following consolidation probably is the most important prognostic indicator we have. It’s important to identify those patients who need a transplant and need some salvage regimen in preparation for that.
Ibrahim Aldoss, MD: There are always debates about the timing of the MRD [testing] to determine whether to go to transplant. What about these patients who are still MRD positive after induction, and they become negative after consolidation? This is the one we struggle with deciding should we transplant or not? They have a late MRD response. What’s your approach, James, for these patients?
James K. McCloskey, MD: I agree. This is probably the point in a MRD decision-making that is the most challenging, and there’s a lot of heterogeneity between centers. Clearly, we know that an early and deep molecular response, or quick MRD response, is important for the patient. The quicker the better. As we mentioned, we have a goal of cycle 1 of consolidation. There are enough data to support that this is a pretty clear point at which we start to lose some of the good prognostic indications of MRD clearance. Then by the third or second cycle of consolidation, there are more robust data saying that if you remain MRD positive after cycle 2, this is the time in which we should entertain other treatment options, and those patients remain at the highest risk. Most centers will let people go out to a maximum of 3 or 2 cycles of consolidation, which we cut that a little shorter here at cycle 2.
Ibrahim Aldoss, MD: We a have similar approach. For the patient who is MRD positive after consolidation, we frequently recommend a transplant, and frequently we do it after we give blinatumomab, given the high activity of blinatumomab in this setting. Now, for the patient who’s still MRD positive after induction then become MRD negative after consolidation, we take it case by case. Because we are in California, we see a lot of Ph [Philadelphia chromosome]-like patients; high-risk patients, based on genetics, we tend to take them to transplant, even if they clear MRD after consolidation. Patients who develop asparaginase-associated pancreatitis after the first, second dose of asparaginase, then most likely they would receive an adequate therapy, even if we’ve continued this curative regimen, when we recommend taking them to transplant. Others with good-risk genetics, they’re tolerating chemotherapy well, we try to cure with chemotherapy alone.
There’s one interesting study, James. It’s the COG [Children’s Oncology Group] AALL1131 study that was presented at ASCO [American Society of Clinical Oncology annual meeting], where they looked at patients younger than 30 with very high-risk ALL. They asked the question, if you’re still MRD positive at the end of induction and become MRD negative at the end of consolidation, will this improve the outcomes compared with if you remain MRD positive? They randomized patients to either continue on the control cohort, which is mercaptopurine, Cytoxan, cytarabine, vs experiment 1, where they give Cytoxan and etoposide, or experiment 2, the same regimen but they add clofarabine. They closed the second experiment with the clofarabine early due to toxicity. And they saw no difference based on the control, where they received standard consolidation, versus the experimental consolidation. The patients who achieve early MRD negativity, irrespective of what happens after, they still have a better prognosis and disease-free survival compared to the ones who are positive. Although they didn’t see a difference if they became negative or positive with the experimental arm, at the end of consolidation, the patients who received the control arm and achieved MRD negativity, they did better. It’s an area of debate what to do with these patients, and definitely, we need more studies, especially with the introduction of novel drugs early in the course of the treatment of these patients. We still have a lot to learn.
James K. McCloskey, MD: I agree completely, and to build on that, just like you said, I think here when we identify those patients who remain MRD positive, we’ve already established a relationship with our transplanters. So as we transition away from chemotherapy and into immunotherapy or blinatumomab, specifically for those MRD-positive patients, we will always offer patients blinatumomab for MRD clearance prior to transplant. That’s our standard, acknowledging that those patients who are MRD negative prior to transplant have better outcomes.
Transcript Edited for Clarity