ASH 2023: Coverage of ALL

Pivotal Results Show Revumenib Holds Promise for Patients With KMT2Ar Acute Leukemia

Patients with KMT2Ar acute leukemia, who until now have lacked a therapy targeting their condition, may have hope with news of phase 2 results for revumenib, which blocks the protein interactions that put cells on the path to developing into leukemia.

Ibrahim T. Aldoss, MD | Image: City of Hope

Ibrahim T. Aldoss, MD, a hematologist/oncologist at City of Hope National Medical Center, presented results December 12, 2023, for AUGMENT-101 (NCT04065399), which is evaluating revumenib in a pair of leukemias, during the late-breaking session of the 65th American Society of Hematology Annual Meeting and Exposition (ASH) in San Diego, California.¹

Revumenib, developed by Syndax, is being studied in several related blood disorders, with results presented earlier during ASH.² Preliminary efficacy and safety were previously demonstrated in a phase 1 study, described in Nature, that examined both relapsed/refractory (R/R) KMT2Ar– and nucleophosmin 1–mutated (NPM1m) acute leukemias.³ At the session, Aldoss presented results from an interim analysis for R/R KMT2Ar acute leukemia.

Patients in the trial with R/R KMT2Ar acute leukemia had high overall response rates; despite being heavily pretreated, 40% were able to proceed to transplant and the KMT2Ar cohort was stopped early.
This could be quite a turn of events for these patients: right now, those diagnosed with right now, those diagnosed with histone-lysine N-methyltransferase 2A ()–rearranged acute leukemia are treated with chemotherapy and hematopoietic stem cell transplant (HSCT), but nearly all relapse; complete remission rates are quite low at 5%.⁴

As Aldoss reminded the audience during the late-breaking session, KMT2Ar accounts for 10% of all acute leukemias and is the most common type of acute leukemia in children.³

“It’s a disease with unmet therapeutic needs,” Aldoss said in a press briefing before the late-breaking. “These patients are at high risk of relapse after transplant and after chemotherapy.”

He elaborated in an interview with Evidence-Based Oncology. “There have been different attempts at targeting therapy for KMT2A, but so far, nothing has shown to be effective. So we’re very excited by revumenib, because it is already showing us, in patients who have chemorefractory disease, have relapsed, and are heavily pretreated, that a single agent is able to actually achieve responses in these patients with a manageable safety profile.”

Mechanism of Action. As Aldoss explained, acute leukemia occurs when menin interacts with KMT2A, driving cell behavior during the immature phase, causing the cells’ failure to differentiate and become active. When this happens, the immature cells also take the space of healthy cells. Revumenib targets menin to disrupt the interaction that triggers this process, he said, allowing “the immature ones to become actually mature, healthy, functioning cells.”

The concept of blocking the mechanism that prevents differentiation is not new, but it can cause adverse effects known as differentiation syndrome (DS). Thus, AUGMENT-101 would seek to evaluate not only efficacy but also safety, including whether DS occurs in patients receiving the drug.

Methods. Patients diagnosed at least 30 days prior with R/R KMT2Ar acute leukemia were enrolled in cohort A, which was mixed phenotype acute leukemia (MPAL); cohort B, which was acute myeloid leukemia (AML), or cohort C, which continues to enroll patients with NPMIm and will be reported later. Patients received 163 mg of revumenib (or 95 mg/m2 if they weighed less than 40 kg) every 12 hours with an antibiotic in 28-day cycles. Treatment continued until unacceptable toxicity or lack of at least morphological leukemia-free state after 4 cycles.

Primary end points were safety and tolerability of revumenib and complete response (CR) plus complete response with partial hematological recovery (CRh). Key secondary end points included the composite CR rate (CRc), the CRc with incomplete platelet recovery (CRp), the CRc with incomplete count recovery (CRi), and the overall response rate (ORR).

A planned interim analysis (IA) of pooled adult and pediatric patients took place. The 94 patients evaluated as of July 24, 2023, after receiving at least 1 dose of the study drug were included in the safety analysis. According to the abstract, the IA efficacy analysis included all patients in phase 2 with centrally confirmed KMT2Ar acute leukemia and at least 5% blasts in the bone marrow at baseline who received at least 1 dose of study drug before there were 38 patients with AML who could be evaluated for efficacy. The IA was specified to occur when 57 patients had been followed for 6 months.

Results. The results of the safety analysis were as follows:

• Median age was 37 years (range, 1.3-75 years); 24.5% were younger than 18 years and 13.8% were 65 years or older; and 17.5% were non-White.
• 78 patients (83%) had AML and 16 (17.0%) had ALL/MPAL.
• Patients were heavily pretreated, with a median of 2 prior lines of therapy (range, 1-11), and 43.6% of patients had at least 3 prior lines of therapy, with 57.4% unresponsive to their most recent salvage treatment.
• 50% had prior HSCT.
• Treatment-related adverse events were seen in 81.9% of the safety group, with the most common being nausea (more than 27%), DS (26.6%), and QTc prolongation (23.4%). Grade 3 or higher TRAEs were seen in 54.3% of patients with the most common being DS (16%), febrile neutropenia (13.8%), and QTc prolongation (13.8%).
• 6.4% of patients stopped therapy due to TRAEs, but none stopped due to DS or QTc prolongation.

Results from the interim efficacy analysis were as follows:

• After a median follow-up of 6.1 months, 13 patients (22.8%) achieved CR+CRh, which investigators said surpassed the predefined IA efficacy boundary for the KMT2Ar group (95% CI, 12.7-35.8).
• Median duration of CR+CRh was 6.4 months (95% CI, 3.4-not reached).
• CRc was 43.9% (95% CI, 30.7-57.6)
• ORR was 63.2% (95% CI, 49.3-75.6)
• Minimal residual disease (MRD) status: Most patients with a CR or CRh response who had MRD reported also achieved MRD negativity (15/22, 68.2%).
• 14 of the 36 patients who responded to treatment were able to proceed to HSCT, with half resuming treatment with revumenib after transplant.

Aldoss said revumenib is being studied in combination with other therapies and also in earlier lines of care. “The next step is, how can we better combine this agent with other standard treatments? How can we give it more post transplant to reduce the risk of relapse?”

Giving it to patients in earlier lines of care could prove critical; in response to a question, Aldoss said patients who had received venetoclax had much lower response rates than those who had not received this therapy.

In an emailed statement, officials from Syndax said they remain on track to submit a New Drug Application to FDA for revumenib for the treatment of R/R KMT2Ar acute leukemia by the end of 2023. 

References
1. Aldoss I, Issa GC, Thirman M, et al. Revumenib monotherapy in patients with relapsed/refractory KMT2Ar acute leukemia: topline efficacy and safety results from the pivotal augment-101 phase 2 study. Blood. 2023;142(suppl 21):LBA 5. doi:10.1182/blood-2023-192042
2. Syndax announces positive data for revumenib in patients with acute leukemias from the BEAT AML, SAVE AML, and AUGMENT-102 phase 1 combination trials. News release. Syndax Pharmaceuticals. December 11, 2023. Accessed December 12, 2023. https://bit.ly/3GLii2E
3. Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPMI-mutant leukaemia. Nature. 2023;615(7954):920-924. doi:10.1038/s41586-023-05812-3
4. Issa GC, Zarka J, Sasaki K, et al. Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements. Blood Cancer J. 2021;11(162). doi:10.1038/s41408-021-00557-6

SPOTLIGHT: Ibrahim T. Aldoss, MD, on Targeting a Hard-to-Treat Leukemia

Ibrahim T. Aldoss, MD, is a hematologist-oncologist who is associate professor in the Department of Leukemia and Stem Cell Transplant at City of Hope, in Duarte, California. He spoke with Evidence-Based Oncology (EBO) about the mechanism of revumenib, which was the focus of the late-breaking abstract he presented at the 65th American Society of Hematology Annual Meeting and Exposition in San Diego, California.¹ In AUGMENT-101 (NCT04065399), a phase 2 trial, revumenib produced promising results in relapsed/refractory KMT2A-
rearranged (KMT2Ar) acute leukemia, an aggressive disease with high likelihood of central nervous system involvement and early relapse.^1,2

EBO: From your description of how revumenib works in KMT2Ar acute leukemia, it sounds like it strikes at the heart of what makes the disease leukemia, essentially. Can you elaborate?

Aldoss: So, leukemia is not one disease. You have all these different subtypes driven by different genetics. And this is a unique subtype of leukemia, the KMT2A-rearranged leukemia; in this leukemia, it’s the interaction between the menin and the KMT2A that would actually drive the leukemia to develop and to continue. What happens with this interaction [is that] it blocks the cells from becoming healthier cells in [a process] called differentiation, [prevents them from becoming] fully active, different kinds of blood cells. And when you block this interaction, you actually have these “stuck” cells in an immature phase; they cannot become fully mature cells and become able to function. This is the basis of cancer—you have these immature cells, they’re not functioning, but they’re taking space from healthy cells.

EBO: So until now, you have not had a precise treatment for this type of leukemia. Can you explain what has been lacking in prior treatments that this treatment addresses?

Aldoss: We know that this disease is what we call chemorefractory; if we’re just doing standard chemotherapy, it tends to be resistant. And even if the patients achieve initial response, there is high risk of relapse afterward. And we frequently use bone marrow transplant, at least in adults, whenever we achieve remission in this disease. Even with initial treatment, this is a way to reduce the risk of relapse in the future. But unfortunately, even with the transplant, the risk of relapse is high. There have been different attempts to look into different types of targeted therapy for KMT2A, but so far, nothing has [been] shown to be effective.

So, we’re very excited by revumenib, because it is already showing that [efficacy] as a single agent in patients who have chemorefractory disease, who have relapsed, are heavily pretreated—a single agent was able to actually achieve responses in these patients with manageable safety profile.

EBO: Almost half the patients were able to bridge to transplant. What about this therapy seems to work well for this purpose?

Aldoss: Anytime we have relapsed disease, the goal is always to try to get the patient into remission. And again, although the primary end point of the study was [a composite response rate], which mean full count recovery or partial liquid count recovery, if you look at the bigger picture, you have 63% of patients responded.... And that is usually enough to take a patient to transplant. Now the challenge is [that it is] not always easy to take these patients to transplant, because many of them have already had a failed transplant; the donor situation there may be [in doubt], they may have other comorbidities and they’re not eligible for transplant. So, the fact that 40% of responders were able successfully to clear the disease from the bone marrow with variable degrees of cancer recovery to the point where you can take them to a stem cell transplant and successfully go through the transplant—this is very meaningful and important for our patients.

EBO: You presented results involving a heavily pretreated population. It makes one wonder what the results would look like in an earlier line or treatment-naive population.

Aldoss: Sure, many others they do—and there are actually a lot of initiatives [that have] already started looking at this question. There’s a study, actually, moving revumenib early on, as part of the initial induction for KMT2A, either in combination with standard intensive chemotherapy or less intensive with older and fit patients with [acute myeloid leukemia]. We have some interest in moving into this in [acute lymphoblastic leukemia] as well, because KMT2A can present as AML, as ALL, as an acute leukemia [from] [paroxysmal nocturnal hemoglobinuria]; it can be seen across different disease phenotypes. This is where most of the interest is—are we able to move it early on? We know the toxicity doesn’t overlap with the standard chemotherapy, so this may be an optimal drug to combine it with.

EBO: Looking ahead, if the therapy is approved, is the testing landscape adequate to identify which patients will benefit? Are there gaps in testing where you would worry about finding the right patients?

Aldoss: Unfortunately, in some places they will not wait to initiate therapy until they have KMT2A rearrangement status, against 10% of all acute leukemia. Now, there are different ways of identifying this genetic alteration—it can be done with the standard testing; at many centers, they do something called conventional cytogenetics. And that takes just 2 weeks, [although] sometimes it misses the KMT2A rearrangement. Now, you have to do FISH [fluorescence in situ hybridization], and FISH is able to do it faster; at the same time, it may be more sensitive, but sometimes FISH is not included for KMT2Ar. Another way of detecting is using next-generation sequencing, [but] that may not be available for all centers. I think as we move this drug earlier into the treatment of acute leukemias, identifying these genetic abnormalities becomes important, where we have an efficient way of testing and have the results before initiating therapy, so patients can move to [a revumenib] combination early on, and maybe that will improve the outcomes for these patients. 

References
1. Aldoss I, Issa GC, Thirman M, et al. Revumenib monotherapy in patients with relapsed/refractory KMT2Ar acute leukemia: topline efficacy and safety results from the pivotal Augment-101 phase 2 study. Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Abstract LBA-5. https://ash.confex.com/ash/2023/webprogram/Paper192042.html
2. Górecki M, Kozioł I, Kopystecka A, Budzyńska J, Zawitkowska J, Lejman M. Updates in KMT2A gene rearrangement in pediatric acute lymphoblastic leukemia. Biomedicines. 2023;11(3):821. doi:10.3390/biomedicines11030821

Final Results Reported for COG Study of Recombinant Erwinia chrysanthemi Asparagine

Final results from the Children’s Oncology Group (COG) study of recombinant  Erwinia chrysanthemi asparagine (ASP) confirm its effectiveness and safety as well as the sustained serum ASP activity of the intramuscular (IM) formulation.¹ Interim results from the study, known as AALL1931 (NCT04145531), led approval of the therapy in June 2021.2 The updated data were reported in abstract at the 65th American Society of Hematology Annual Meeting and Exposition, held in San Diego, California.

Recombinant Erwinia chrysanthemi ASP is used as a component of a chemotherapy regimens to treat acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in pediatric and adult patients who develop hypersensitivity to Escherichia coli–derived asparaginase. At the time of approval, the product was especially welcomed because Erwinaze, which had been used by these patients, had become unavailable due to manufacturing issues.² The new product, sold as Rylaze, is made by Jazz Pharmaceuticals.

The COG study was a 2-part, open-label phase 2/3 trial that evaluated efficacy, safety, pharmacokinetics (PK) of Rylaze. Eligible patients who developed hypersensitivity—either a grade 3 or higher allergic reaction or silent inactivation—to E coli–derived pegaspargase received Rylaze as part of a multiagent regimen. According to the abstract, each dose of pegaspargase was replaced with 6 doses of Rylaze given either through IM injection or intravenously (IV) on Monday, Wednesday, and Friday over 2 weeks (course 1).

This study had 3 groups receiving the drug through IM at different dosing levels and 1 group receiving the drug via IV. To determine efficacy, investigators measured the share of patients maintaining therapeutic nadir serum ASP activity (NSAA) ≥ 0.1 IU/mL at the last 72-hour (primary end point) or 48-hour (key secondary end point) mark during course 1. A population PK model was created from serum data and used to simulate alternative dosing regimens.

Final data cutoff was November 2022; 167 patients had received Rylaze via IM and 61 had received it through IV. Results for the patients receiving IM showed that patients receiving the dose of 25/25/50 mg/m2 for Monday, Wednesday, and Friday had 90% reaching the NSAA levels target at 72 hours and 96% reaching it at 48 hours. Modeling showed the following that NSAA levels are achieved in the vast majority of patients when Rylaze is administered as follows:

• via IM at 25 mg/m2 every 48 hours (7 doses) or 25/25/50 mg/m2 on Monday, Wednesday, and Friday (6 doses);
• via IV at 25 mg/m2 every 48 hours (7 doses); or
• via IV at 25 mg/m2 on Monday and Wednesday and IM at 50 mg/m2 on Friday (6 doses).
  

Treatment-related adverse events (TRAEs) of grade 3 or higher were seen in 55% of patients but none led to death. A total of 22 patients receiving IM injection (13%) and 20 patients in the IV group (33%) had a TRAE that led to discontinuation. Most common in the IM cohort was pancreatitis; in the IV cohort, hypersensitivity.

Authors noted that treatment-related discontinuation rates with IV Rylaze were greater than with the IM formulation, mostly due to greater likelihood of hypersensitivity and infusion-related reactions along with nausea and vomiting. The authors said that although several dosing schedules can be effective, the intramuscular formulation offered more sustained serum ASP activity, “therefore providing flexibility to patients and physicians.” 

References
1. Maese L, Loh ML, Choi MR, et al. Efficacy and safety of recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL): complete follow-up of the Children’s Oncology Group (COG) AALL1931 Study. Blood. 2023;142(suppl 1):1498. doi:10.1182/blood-2023-172577.
2. Ben-Ari E. FDA approval of Rylaze will address drug shortage for childhood ALL. National Cancer Institute. July 29, 2021. Accessed December 20, 2023. https://www.cancer.gov/news-events/cancer-currents-blog/2021/fda-rylaze-asparaginase-childhood-leukemia