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ClinicalThought
Expert Selections From ASH 2020: Acute and Chronic Myeloid Leukemias

Released: March 03, 2021

Expiration: March 02, 2022

Jorge Cortes
Jorge Cortes, MD
Eunice S. Wang
Eunice S. Wang, MD
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The virtual 2020 ASH conference produced a number of exciting presentations of clinical interest for healthcare professionals treating patients with leukemia. In this ClinicalThought, Jorge Cortes, MD, and Eunice S. Wang, MD, discuss their top 3 choices of the most clinically significant studies in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML).

Targeting CD47 in AML With Magrolimab

Eunice S. Wang, MD
Magrolimab is a first-in-class macrophage immune checkpoint inhibitor that targets CD47, a “don’t eat me” signal expressed at high levels in many cancers, including AML, as a means by which malignant cells evade macrophage. By blocking CD47, magrolimab restores macrophage phagocytosis of malignant cells and may act synergistically with azacitidine, which can also induce prophagocytic signals in preclinical studies. Sallman and colleagues presented preliminary results from an ongoing phase Ib trial of magrolimab plus azacitidine in a cohort of individuals with newly diagnosed AML considered ineligible for intensive chemotherapy.

Patients received a priming dose of magrolimab at 1 mg/kg followed by 30 mg/kg weekly in combination with a 7-day regimen of azacitidine. The primary endpoints were safety and efficacy with secondary endpoints including the pharmacokinetics, pharmacodynamics, and immunogenicity. The trial’s protocol was amended early to preferentially enroll patients with TP53‑mutated disease. In this cohort analysis, 73% of patients had the TP53 mutation.

Early results showed that no maximum tolerated dose was reached, and the overall tolerability was excellent, with no significant increase in rates of cytopenias, infections, or immune-related adverse events (AEs) from baseline. Fewer than 5% of patients required dose modification or discontinuation due to drug-related AEs. The all-cause mortality rate was just below 5% at 30 days and < 10% at 60 days.

This regimen was associated with the unique AE of on-target anemia. Aged red blood cells express surface CD47, leading to on-target hemolytic anemia occurring mostly with the first magrolimab infusion. Despite this initial decrease in hemoglobin levels due to on-target hemolytic anemia, most patients had improvement in their transfusion frequency and hemoglobin levels over several months of magrolimab-based therapy.

Regarding efficacy, 63% of all patients in this cohort achieved a response, with a CR rate of 42% and a CR with incomplete hematologic recovery rate of 12%. Although these are impressive data and comparable to the efficacy of venetoclax/azacitidine in a similar patient population, a key difference is that this regimen was associated with efficacy regardless of TP53 mutation status. The transfusion independence rate was 68% during the course of therapy, again regardless of TP53 mutation status.

The median OS was particularly impressive at 12.9 months in the TP53-mutated cohort. This compares favorably with a median OS of 5.2-7.2 months with frontline venetoclax plus hypomethylating agents in similar patients with TP53-mutated AML. The median OS was 18.9 months in patients with wild-type TP53, although this cohort had only 16 patients enrolled in this preliminary OS analysis. This compares favorably with the results of the VIALE A trial, which reported a median OS of 14.7 months following upfront venetoclax/azacitidine in older unfit individuals with AML.

Jorge Cortes, MD:
I was impressed by these results, particularly for the patients with TP53-mutated AML, because we currently lack effective therapies for that population. Even venetoclax/azacitidine has poor efficacy in TP53-mutated disease, as you discussed. I was struck by the ORR being as high as 69% in those with TP53-mutated AML, with 45% achieving CR. As you mentioned, it is important to emphasize that this regimen is not specific to those with TP53 mutation. Magrolimab simply is not affected by TP53 status, unlike chemotherapy and other agents.

These results will change our care for those with TP53-mutated disease. The question is: What should we do for patients with wild-type TP53? Our standard of care is venetoclax plus either azacitidine or another hypomethylating agent, which is quite effective. That being said, the safety profile seems to be very favorable for magrolimab plus azacitidine, particularly given its lower rates of myelosuppression. We could also try combining the backbone of venetoclax/azacitidine with magrolimab.

I am not that concerned about the anemia observed in this trial. We are accustomed to observing anemia in patients with AML when starting chemotherapy, with transfusion frequency increasing during the initial cycles. We saw here that, over time, approximately two thirds of patients became transfusion independent. We would simply need to support patients through that first to second month of therapy with magrolimab plus azacitidine.

Eunice S. Wang, MD:
I agree. I believe that magrolimab will likely be a transformative agent for AML. Moreover, magrolimab is the first immunotherapeutic treatment of AML or myelodysplastic syndrome to demonstrate response rates > 50%. I was also struck by the high response rates in those with TP53-mutated AML. Recent data suggest that TP53-mutated AML is associated with an immunosuppressive microenvironment, which may explain why there are such high response rates in that patient population.

Regarding the preliminary OS benefit, these data compare very favorably with the VIALE-A data on venetoclax/azacitidine, as we discussed. Another important point of contrast is the difficulty of administration and toxicity management requirements. I have treated patients with this combination on this clinical trial, and our center was able to administer magrolimab plus azacitidine in the ambulatory setting. Admissions were necessary only for patients who might have, for example, experienced an acute drop in hemoglobin levels because of hemolytic anemia. By contrast, the profound myelosuppression with venetoclax/azacitidine requires us to hospitalize many of our older patients for at least the first week, and potentially much longer, for daily transfusion support and monitoring for tumor lysis syndrome.

ASCEMBL: STAMP Inhibitor Asciminib for Patients With Chronic-Phase CML

Jorge Cortes, MD:
There were many interesting studies on CML at the conference. One standout was a late-breaking abstract on the phase III ASCEMBL trial, evaluating the investigational tyrosine kinase inhibitor (TKI) asciminib. Instead of targeting the ATP-binding pocket of ABL1, like other TKIs, asciminib is a first-in-class inhibitor of STAMP (specifically targeting the ABL myristoyl pocket), binding to the myristoyl pocket and restoring inhibition of BCR-ABL1.

ASCEMBL is a multicenter, open-label phase III trial that recruited patients with chronic-phase (CP) CML who had received ≥ 2 previous TKIs with resistance or intolerance to the most recent TKI. Patients were randomized to receive 40 mg twice daily of asciminib or 500 mg daily of bosutinib. The primary endpoint is the rate of major molecular response (MMR) at 24 weeks. Patients with the T315I mutation were excluded because bosutinib is not active against T315I, yet asciminib is. The efficacy of asciminib against the T315I mutation in CML was discussed in another presentation at ASH, which you can review here.

Asciminib significantly improved the rate of MMR at 24 weeks vs bosutinib (25.5% vs 13.2%, respectively; 95% CI: 2.19-22.30; P = .029). Subgroup analyses of the 24-week MMR rate indicated a benefit with asciminib across all subsets.

There was slightly more thrombocytopenia with asciminib (28.8% vs 18.4% with bosutinib), but bosutinib exhibited higher rates of gastrointestinal toxicity, rash, and elevated liver function tests. In ASCEMBL, there were more arterial occlusive events with asciminib (myocardial ischemia, coronary artery disease, ischemic stroke, and mesenteric artery embolism/thrombosis) vs bosutinib (3.2% vs 1.3%, respectively), not surprising with the low association of bosutinib with this risk. These are important AEs that must be closely monitored for and managed in this population.

Eunice S. Wang, MD:
I consider this to be a landmark study establishing asciminib as the next BCR-ABL inhibitor likely to be approved by the FDA for CP-CML. A doubling of MMR rates as early as 24 weeks is pretty impressive and will likely lead to regulatory approval. I was also impressed by the excellent tolerability of asciminib. The only AE of concern is thrombocytopenia, as opposed to the multiple AEs commonly associated with bosutinib noted above.

In my practice, I mainly use bosutinib in older patients at risk for long-term cardiovascular and/or vascular arterial events. Thus, the data demonstrating that there was only a slight increase in the number of arterial occlusive events reassured me that, given there was a twofold improvement in efficacy and not a massive increase in arterial occlusive events, I could potentially use asciminib in some of my patients currently receiving bosutinib.

Jorge Cortes, MD:
I agree. I expect that, assuming it is approved, asciminib will be a very welcome addition to management of CP-CML. Regarding the use of bosutinib as the control, I consider bosutinib to play a role more in the first and second line. I suspect that bosutinib was selected as the control for this study because it has prospective trial data in the third-line setting. Nonetheless, was bosutinib the most appropriate control, or should the study have used ponatinib? My thoughts are that because of the arterial occlusive event concerns with ponatinib, its use would have led to more exclusions and issues with eligibility. That being said, ideally we will have a head-to-head comparison of asciminib vs ponatinib.

Optimal Dosing for Ponatinib in Relapsed/Refractory CP-CML

Jorge Cortes, MD:
Ponatinib is a very effective drug for treating CP-CML, but it comes with the increased risk of arterial occlusive events, which can preclude some patients from receiving this agent. Data have suggested a correlation between the dose of ponatinib and the incidence of these events. This dose-response relationship was the rationale behind the randomized phase II OPTIC trial, which is evaluating whether doses lower than the standard could maintain efficacy while decreasing the risk of toxicities in patients with CP-CML that is either resistant or intolerant to ≥ 2 TKIs or with a BCR-ABL1 T315I mutation. At ASH 2020, my colleagues and I published an interim analysis of OPTIC.

The trial recruited 283 patients with CP-CML and ≥ 2 previous TKIs or with a T315I mutation. Patients were randomized to a starting ponatinib dose of 45 mg/day (standard), 30 mg/day, or 15 mg/day, with patients in the first 2 arms reducing their dose to 15 mg/day upon achieving ≤ 1% BCR-ABL1IS. The primary endpoint was the rate of patients achieving ≤ 1% BCR-ABL1IS at 12 months.

The 12-month rate of patients achieving ≤ 1% BCR-ABL1IS was markedly higher in patients who received the 45-mg starting dose. The rate was 48% in the 45-mg group, dropping to 35% with 30 mg and 23% with 15 mg. This dose-response trend is particularly pronounced in patients with a T315I mutation, where the rate was 60% with 45 mg, 25% with 30 mg, and only 6% with 15 mg. Patients with the most refractory disease had the greatest benefit. In those who had only a complete hematologic response to the last previous TKI, the response rate was 43% with 45 mg, 22% with 30 mg, and 15% with 15 mg. Those who had received ≥ 3 previous TKIs exhibited response rates of 49%, 30%, and 22%, respectively. Overall, the 45-mg starting dose was associated with higher response rates, particularly in those with the most challenging disease.

This study had an independent adjudication committee who reviewed all arterial occlusive events and determined whether they met the criteria for an arterial occlusive event per American College of Cardiology/American Heart Association criteria. The committee was blinded to the dose, any dose modification, and the investigator’s opinion on causality. Thus, I would consider the data on adjudicated treatment-emergent arterial occlusive events to be quite robust.

Overall, the rate of adjudicated arterial occlusive events was relatively low (2% to 6%). I was surprised that there was not much of a difference between the 45-mg and 30-mg dose arms. Looking at patients who had received ≥ 3 TKIs, the rate was 6% with 45 mg, 5% with 30 mg, and 2% with 15 mg. For those less heavily pretreated (≤ 2 TKIs), the rates were 5%, 3%, and 0%, respectively. We observed a slight dose response for this event, but the overall rate of these events is relatively low—perhaps because the mandatory dose reduction once the patient achieved a response was reducing the risk of arterial occlusive events. Ponatinib in CP-CML was also examined at ASH 2020 in a comparison of the OPTIC and PACE trials here. 

Eunice S. Wang, MD:
I consider these to be very important results with great applicability to patients we are seeing in practice. Many clinicians have had reservations about using the 45-mg dose in practice, given the AE profile of ponatinib. It was informative that the study enrolled patients with common cardiovascular risk factors—hypertension, diabetes, and hypercholesterolemia. These results support the dose-response relationship for efficacy, with the highest response rate of 48% occurring with the 45-mg starting dose. That is the standard dose, and these data also provide reassurance that the risk of vascular and occlusive events does not markedly increase when a patient starts ponatinib at 45 mg.

Although this is only a phase II trial, these results support the safety and tolerability of the 45-mg starting dose and provide an option for patients with very difficult-to-treat disease (eg, ≥ 2 TKIs or T315I mutation). These data also indicate that a starting dose of 15 mg or 30 mg is insufficiently active. Overall, this approach reminds me of the induction strategy we use in other malignancies, and I anticipate this trial having direct implications for our use of ponatinib in this difficult-to-treat population.

Share Your Thoughts
Which presentations did you find most compelling from ASH 2020? Answer the polling question and join the conversation by posting a comment in the discussion section.

Be sure to see more CCO coverage of other leukemia topics and download CCO’s ASH 2020 leukemia conference coverage slides and expert analysis, as well as other hematologic topics.

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