Experts Provide Tips on Harnessing MRD to Guide ALL Therapy

Mark R. Litzow, MD

Monitoring minimal or measurable residual disease (MRD) has proved a powerful risk-stratification tool in determining treatment for both pediatric and adult patients with acute lymphocytic leukemia (ALL). Defined as the presence of leukemic cells below the limit of detection on conventional morphology, MRD has demonstrated clinical impact as a prognostic factor in the management of ALL. Currently, MRD is used for assessing initial treatment response and subsequent definition of MRD-based risk groups with consequent risk stratification, monitoring disease burden in the setting of stem cell transplantation, and serving as an early marker of impending relapse.¹ Novel therapies including bispecific T-cell engagers, monoclonal antibodies, and chimeric antigen receptor (CAR) T cells have recently advanced the treatment landscape.

During a recent OncLive Peer Exchange^®, a panel of experts in adult and pediatric leukemia provided insight on how they use MRD to guide treatment decisions, including transplantation and choice of therapy in patients who demonstrate MRD positivity after induction and first- and subsequent-line therapies. They also offered an overview of blinatumomab (Blincyto), currently the only treatment approved for patients with ALL who have MRD-positive status in first or second complete hematologic remission, as well as other therapies that can be considered in patients with persistent MRD positivity, including inotuzumab ozogamicin (Besponsa) and CAR T-cell therapies.

Transplantation

Patients who remain persistently MRD positive pose a significant treatment challenge, and it is unclear whether additional approaches should be pursued to achieve MRD-negative status before these patients are taken to transplantation. “I don’t think there’s any straightforward approach, but for me, after 1 or 2 months of a treatment, if their MRD status is not changing, then those are the patients who we’ll just take to transplant,” panelist Jae Park, MD, said. He added that the decision also depends on the patient’s MRD level. “If it’s a low level, less than 0.01% or 0.1%, then you may consider those relatively lower levels of MRD to go to transplant. But with a high level of MRD, I may try a little bit more. It all depends on the condition of the patient, their previous lines of therapy, what additional therapeutic tools we have, and if there’s a reasonable chance I’m going to achieve that MRD negativity.”

On the pediatric side, panelist Rachel E. Rau, MD, said that she will try to do everything possible to get her patients to an MRD-negative status before transplantation because these patients have significantly improved outcomes. “Their chances of being cured are much greater if we can get them to that state,” she explained. She mentioned a study by Pulsipher and colleagues that found that even patients with MRD-positive status on next-generation sequencing (NGS), which is much more sensitive at detecting residual disease than its more commonly used counterpart, flow cytometry (FC), had inferior posttransplant outcomes, including a much higher risk of relapse and lower overall survival.² Compared with FC, which can detect 1 cancer cell in 10,000 normal cells, NGS can detect 1 cancer cell in 1 million normal cells.³ In the study, NGS-MRD predicted relapse and survival more accurately than multichannel FC-MRD (P <.0001), especially in the MRD-negative cohort (relapse, 0% vs 16%; P = .02; 2-year overall survival, 96% vs 77%; P = .003).² Based on these findings showing the importance of MRD-negative status, Rau said, she will use “CAR T, blinatumomab, inotuzumab ozogamicin, or other agents to try to get [patients] into MRD-negative status before sending them to transplant.”

Panelist Ryan D. Cassaday, MD, agreed that persistent MRD positivity is a challenging situation and explained that a careful balance is required. “Transplant is probably the only thing that’s going to be able to give that patient a chance of long-term remission, and we must always be mindful of the fact that these therapies we’re giving to try to achieve that level [of MRD negativity] may not work. It may make patients sicker. It may preclude them from moving ahead with the therapy that we’re ultimately trying to get them to,” he said, indicating there is a need for novel approaches to transplantation in this complex patient population.

Blinatumomab

Blinatumomab is a first-in-class bispecific T-cell engager antibody against CR19/CD3. On March 29, 2018, the FDA granted blinatumomab accelerated approval as a treatment for adult and pediatric B-cell precursor (BCP)—ALL in first or second complete hematologic remission with an MRD of at least 0.1%.⁴ It was previously approved for the treatment of relapsed or refractory (R/R) BCP-ALL in adults and children.⁵

Accelerated approval of blinatumomab in BCP-ALL patients with MRD-positive status was based on data from the open-label, single-arm BLAST trial (NCT01207388). The study included 113 evaluable patients aged 18 years or older who had received at least 3 chemotherapy blocks of standard ALL therapy and were in complete hematologic remission but had an MRD level of at least 0.1% using an assay with a minimum sensitivity of 0.01%.⁶ Patients received blinatumomab 15 μg/m² per day by continuous intravenous infusion for up to 4 cycles and could undergo allogeneic hematopoietic stem cell transplantation (HSCT) anytime after cycle 1. Of the 113 patients, 88 (78%) achieved a complete MRD response. In the subgroup of 110 patients with Philadelphia chromosome (Ph)—negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In the landmark analyses, the RFS was 23.6 months in complete MRD responders and 5.7 months in MRD nonresponders (P = .002), and the OS was 38.9 months versus 12.5 months in these cohorts, respectively (P = .002).⁶

More recently, a 5-year follow-up analysis of the BLAST study showed a median OS of 36.5 months after blinatumomab treatment, with median OS not reached among the patients with a complete MRD response during cycle 1 of treatment.⁷ These data support the long-term efficacy of blinatumomab in adult patients with BCP-ALL and MRD-positive status.

BLAST is notable because it replicated the results of a smaller study, according to moderator Mark R. Litzow, MD. “[In the study] of 20 patients, 16 [80%] converted to MRD negativity,” he said.⁸ After a median follow-up of 33 months, the Kaplan-Meier estimate of hematologic RFS in this cohort was 61%. In a subgroup of 9 patients who received allogeneic HSCT after blinatumomab treatment, the hematologic RFS by Kaplan-Meier estimate was 65%. Of the subgroup of 6 Ph-negative MRD responders with no further therapy after blinatumomab, 4 were in ongoing hematologic and molecular remission at the time of the follow-up study’s publication, also suggesting good long-term efficacy with blinatumomab.⁸

The panelists agreed that blinatumomab is usually the first agent they use in their adult and pediatric patients with BCP-ALL and MRD-positive status following standard chemotherapy because it is approved for this indication and has shown good safety and efficacy in these patients. In the BLAST trial, adverse events (AEs) were consistent with previous studies of blinatumomab. The most common severe AEs included neurologic events and cytokine release syndrome (CRS).⁶ Most neurologic events resolved, and even patients who experienced severe events were usually able to resume blinatumomab after the event resolved.⁶ Because patients in complete hematologic remission with MRD-positive status have a low disease burden, Litzow said CRS tends to be much milder in these patients than what is generally observed with blinatumomab in the R/R setting.

The panelists noted a few exceptions to the use of blinatumomab over other therapies in the MRD population. Rau said other treatments may be preferable in patients who may benefit from CD19-directed CAR T-cell therapy. “There’s some concern that blinatumomab may drive a CD19-negative situation, where it wouldn’t be amenable to CAR T,” she said. Cassaday said he would also be inclined to use a nonblinatumomab tactic in some Ph-positive patients. “For example, [if] I had started chemotherapy and imatinib and their response wasn’t very good but still relatively deep, I might continue the chemotherapy backbone but swap out the tyrosine kinase inhibitor for dasatinib [Sprycel],” he said.

Emerging Data

The panelists proceeded to discuss exciting emerging data for blinatumomab, along with some important trials that have the potential to better define and expand its use. Rau discussed the results of the Children’s Oncology Group phase 3 AALL1331 study, which was presented as a late-breaking abstract at the 2019 American Society of Hematology meeting.⁹

“I think we’re all very excited about the results of this trial, because it was a first relapse trial in which we took patients who were in their first relapse and defined them as high, intermediate, or low risk on the basis of timing of relapse, site of relapse, and then response to a 4-drug reinduction regimen. Patients who were high risk were defined as those who had an early relapse or didn’t achieve MRD less than 0.1%, and those patients were randomized post induction to either 2 blocks of blinatumomab or standard chemotherapy,” Rau said.

The AALL1331 study found blinatumomab to be superior to chemotherapy in both efficacy and safety, she said. Among patients with detectable MRD (≥0.01%) at the completion of block 1 of chemotherapy, the proportion that achieved undetectable MRD (<0.01%) after block 2 chemotherapy versus blinatumomab cycle 1 was 21% versus 79% (P <.0001).⁹ The tolerability of blinatumomab was also striking. “Very few patients on the blinatumomab arm had any substantial toxicity, whereas those on the standard chemotherapy arm, as you would predict, had higher rates of sepsis, febrile neutropenia, and some mortality due to therapy,” she said. As with the BLAST trial in adults, the pediatric patients treated with blinatumomab in the AALL1331 study had relatively low rates of CRS because most had a relatively low disease burden when the agent was introduced. As in adults, neurotoxic events were fairly common but fully resolved.

Based on the AALL1331 study data, Rau suggested that blinatumomab is a good bridge to transplant in high- and intermediate-risk relapsed patients. “[These] patients we still feel warrant transplant in second complete remission,” she said. The results for the low-risk arm of the trial have yet to be released. “For those patients, we replaced some of the intensive chemotherapy with blocks of blinatumomab versus just standard chemotherapy alone,” she said. “That is a population we think we can cure without stem cell transplant, so it will be really interesting to see if we were able to do that to a higher degree in patients treated with blinatumomab instead of just chemotherapy alone.”

Both Litzow and Rau said they are involved in studies assessing blinatumomab in the upfront setting. Litzow said his randomized phase 3 study (NCT02003222), which finished accruing patients in October 2019, is comparing combination chemotherapy with blinatumomab to see how well it works compared with induction chemotherapy alone in patients aged 30 to 70 years with BCP-ALL.¹⁰ Rau said the clinical trial (NCT03914625) she is conducting just opened in 2019 and will include a cohort of patients who are MRD positive by FC and a cohort who are MRD positive by NGS, both of which will be randomly assigned to chemotherapy either alone or with blinatumomab.¹¹ This study also includes patients with Down syndrome, a population normally excluded from such trials.

“Patients with Down syndrome have substantially higher rates of B-cell ALL,” Rau said. “They don’t respond well to our chemotherapy, so their outcomes are poor, and they don’t tolerate the therapies we give them either. They tend to really fall apart with our standard chemotherapy regimens. So, for our high-risk patients with Down syndrome, we’re going to nonrandomly assign them to chemotherapy arms in which we replace some of the intensive and toxic elements of therapy with courses of blinatumomab.”

Inotuzumab Ozogamicin

Inotuzumab ozogamicin combines a humanized CD22 monoclonal antibody with the cytotoxic agent calicheamicin. CD22 is expressed on leukemic blasts in more than 90% of patients with ALL.¹² On August 17, 2017, it was approved by the FDA for the treatment of adults with R/R BCP-ALL.¹³ Unlike blinatumomab, it is not approved for patients with BCP-ALL in first or second complete hematologic remission and MRD-positive status.

“Blinatumomab is usually our first choice to get to MRD negativity for patients with B-cell ALL, [but] if they’re persistently positive, inotuzumab might be a consideration, especially if they received a multiagent chemotherapy and asparaginase-based chemotherapy, as well, [because] then we don’t really have a lot of other chemotherapeutic options,” Park said. He indicated that it would be reasonable to use inotuzumab ozogamicin alone or in combination with immunochemotherapy in this setting.

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The panelists noted that a concern with inotuzumab ozogamicin is the risk of veno-occlusive disease (VOD). In the INO-VATE trial, VOD occurred in 23 of 164 patients (14%) treated with inotuzumab ozogamicin compared with 3 of 143 (2.1%) treated with standard-of-care chemotherapy.¹⁵ Park suggested a strategy for reducing the risk of this complication. “If you use inotuzumab to get to transplant, if you’re able to get to MRD negativity after 1, hopefully, or maybe even 2 cycles, and you’re not getting that much exposure to the inotuzumab, the risk for developing VOD could be minimized by avoiding the blood clotting agent and conditioning chemotherapy,” he said.

CAR T-Cell Therapy

Currently, CAR T-cell therapy is approved only for children, adolescents, and young adults (≤25 years) with R/R BCP-ALL; however, the panelists were hopeful that it will eventually be an option for older adults and suggested it may be ideally suited for the MRD-positive setting. “On the adult side, [CAR T-cell therapy] hasn’t really been tested in early-line settings just yet, although it’s been tested in the minimal disease setting,” Park said. “Some of our early trial data have shown that either way, with a couple different CAR T-cell therapies targeting CD19, the initial response rate is the same regardless of disease burden. You can have 80% bone marrow blast, or you can have 0.5% [very low-level disease], and you will get MRD negativity at the same rate, usually about 80% of the time.” He noted that the longterm outcome is better when patients receive CAR T-cell therapy when they have a lower disease burden.

Park also suggested that CAR T-cell therapy may be ideally suited for the persistent MRD setting. “If the persistently MRD-positive patients have received blinatumomab or some other agents, I think that would be a perfect setting where we should be studying the CAR T-cell therapy. That hasn’t been studied yet. I think it’s going to work very well in that setting, but again, we don’t have the data,” he said.

The panelists suggested that off-the-shelf CAR T-cell therapies may also have benefits in the MRD patients. “[These therapies] may overcome some of the limitations of T-cell quality, potency, or issues with patients, certainly for those patients who have had a lot of the chemotherapy. Because of immediate availability, it does make it possible to incorporate into the earlier-line setting, as opposed to waiting for collection and then somehow coming up with a way to maintain that MRD-negative state before you give the autologous CAR T therapy,” Park said. He noted that clinical trial data are needed to draw definitive conclusions.

Future of MRD Testing and ALL Management

Currently, in the United States, FC is the most-used modality to test for MRD, though more sensitive tools like NGS are already available and even more sensitive tools are on the horizon. “We’ll be able to pick up the smaller levels of a disease. The more challenging thing is what to do with that information. For that small disease, is it worthwhile to intensify or change the therapy that has been previously working or just continue with it? Hopefully, we can address these issues in large trials to really answer them, rather than borrowing the data piecemeal,” Park said.

Another important consideration with current DNA-based MRD testing modalities, according to Cassaday: They do not provide information on patients’ CD19 or CD22 expression. “In the future, if we start using blinatumomab, CAR T-cell therapy, or inotuzumab ozogamicin in the frontline setting, we know that those agents can downregulate expression of the targeted agents. So, if we are detecting at these superlow levels, but we don’t know anything about the immunophenotypic features, we may give them blinatumomab, but there’s no CD19 there to target. I think that’s going to be one thing that, as a field, we’re going to have to be cognizant of and sensitive to as not only the methods get better but [also] as these targeted agents get moved into therapy sooner,” he said.

In their concluding remarks, the panelists envisioned a future where patients with ALL will be spared from enduring countless invasive procedures and burdensome chemotherapy treatments. “I think of acute promyelocytic leukemia and how that was the worst prognostic acute leukemia 30 or 40 years ago, and now it’s the best prognosis and we’re not using chemotherapy. I think I see us moving in that direction in Ph-positive ALL, and I think with the Ph-like setting and some of these agents, we’re going to be in that direction, as well. I think the future is bright,” Litzow said.

References

1. Della Starza I, Chiaretti S, De Propris MS, et al. Minimal residual disease in acute lymphoblastic leukemia: technical and clinical advances. Front Oncol. 2019;9:726. doi:10.3389/fonc.2019.00726
2. Pulsipher MA, Carlson C, Langholz B, et al. IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very lowand very high-risk ALL patients. Blood. 2015;125(22):3501-3508. doi:10.1182/blood-2014-12-615757
3. MRD at a glance. Spark ALL. 2019. Accessed April 19, 2020. bit.ly/3eyf9nT
4. FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. FDA. March 29, 2018. Accessed April 26, 2020. bit.ly/2zz1dK5
5. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome-positive B cell. FDA. July 11, 2017. Updated July 12, 2017. Accessed April 27, 2020. bit.ly/2yQBGeY
6. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. doi:10.1182/blood-2017-08-798322. Published correction appears in Blood. 2019;133[24]:2625. doi:10.1182/ blood.2019001109
7. Gökbuget N, Dombret H, Zugmaier G, et al. Blinatumomab for minimal residual disease (MRD) in adults with Bcell precursor acute lymphoblastic leukemia (BCPALL): median overall survival (OS) not reached at 5 years for complete MRD responders. Abstract presented at: 24th European Hematology Association Annual Congress; June 13-16, 2019; Amsterdam, Netherlands. Abstract S1619. bit.ly/2y5ruPX
8. Topp MS, Gökbuget N, Zugmaier G, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120(26):5185-5187. doi:10.1182/blood-2012-07-441030
9. Brown PA, Ji L, Xu X, et al. A randomized phase 3 trial of blinatumomab vs. chemotherapy as post-reinduction therapy in high and intermediate risk (HR/IR) first relapse of B-acute lymphoblastic leukemia (B-ALL) in children and adolescents/young adults (AYAs) demonstrates superior efficacy and tolerability of blinatumomab: a report from Children’s Oncology Group Study AALL1331. Blood. 2019;134(suppl 2; abstr LBA-1). doi:10.1182/blood-2019-132435
10. Combination chemotherapy with or without blinatumomab in treating patients with newly diagnosed BCR-ABL-negative B lineage acute lymphoblastic leukemia. ClinicalTrials.gov. Updated May 5, 2020. Accessed May 10, 2020. https://clinicaltrials.gov/ ct2/show/NCT02003222
11. A study to investigate blinatumomab in combination with chemotherapy in patients with newly diagnosed B-lymphoblastic leukemia. ClinicalTrials.gov. Updated May 5, 2020. Accessed May 10, 2020. https://clinicaltrials.gov/ct2/show/NCT03914625
12. Uy N, Nadeau M, Stahl M, Zeidan AM. Inotuzumab ozogamicin in the treatment of relapsed/refractory acute B cell lymphoblastic leukemia. J Blood Med. 2018;9:67-74. doi:10.2147/JBM.S136575
13. FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL. FDA. Published August 17, 2017. Accessed April 28, 2020. bit.ly/2ShxcVD
14. Jabbour E, Gökbuget N, Advani A, et al. Impact of minimal residual disease status in patients with relapsed/refractory acute lymphoblastic leukemia treated with inotuzumab ozogamicin in the phase III INO-VATE trial. Leuk Res. 2020;88:106283. doi:10.1016/j. leukres.2019.106283
15. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125(14):2474-2487. doi:10.1002/cncr.32116

Park said there is a growing body of data regarding inotuzumab ozogamicin in the MRD setting. “Most of the data are coming from the morphologic relapse, salvage 1, and salvage 2 settings and in the later lines of relapse,” he said. The panelists did not discuss any of these data during the Peer Exchange; however, one such study, the phase 3 INO-VATE trial (NCT01564784), showed that patients with complete hematologic remission who achieved MRD-negative status had improved survival compared with MRD-positive patients, with the greatest survival benefit observed in those who achieved MRD-negative status during salvage 1 with inotuzumab ozogamicin.¹⁴ Overall, patients who proceeded to HSCT experienced the best outcomes.¹⁴ These findings are consistent with what has been observed with blinatumomab.