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ASH 2019: Leukemias EU
Key Leukemia Trials From ASH 2019: A European Perspective

Released: January 24, 2020

Expiration: January 22, 2021

Michael Heuser
Michael Heuser, MD
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In this commentary, I give an overview of the most interesting presentations at the 2019 ASH annual meeting relating to the management of acute leukemias, including data that I believe are likely to change clinical practice in the European healthcare community.

APR-246 Plus Azacitidine in TP53-Mutant Myelodysplastic Syndromes (MDS)/Acute Myeloid Leukemia (AML)
APR‑246 is an investigational p53 activator that induces apoptosis in TP53-mutant cancer cells. The combination of APR-246 and azacitidine was evaluated in a phase Ib/II trial in 55 patients with TP53-mutated higher-risk MDS, MDS/myeloproliferative neoplasms, or oligoblastic AML with a blast count ≤ 30% who had not received previous treatment with hypomethylating agents (HMAs). Among 45 evaluable patients, the CR rate was 53% (primary endpoint), including marrow CR with hematologic improvement in 18%, and an ORR of 87%, which is remarkable for a cohort in which 85% of patients had a complex karyotype and 100% were p53 mutated. Median OS was 10.8 months, which is also remarkable in this population. So far, APR-246 is restricted to TP53‑mutated patients, and it is not clear whether it is active in patients with wild‑type TP53. A phase III trial is ongoing in patients with TP53-mutated MDS, and we will be looking forward to that study’s results.

AG221‑AML‑005: Enasidenib Plus Azacitidine vs Azacitidine Alone in Newly Diagnosed AML With IDH2 Mutations
AG221‑AML‑005 is an ongoing phase II randomized study comparing enasidenib plus azacitidine with azacitidine monotherapy in 101 patients with newly diagnosed AML with IDH2 mutations who were ineligible for intensive chemotherapy and had no history of treatment with HMAs. In this interim analysis, the primary endpoint of ORR was reported in 71% of patients receiving enasidenib plus azacitidine vs 42% in the azacitidine monotherapy group (P = .0064), including CR observed in 53% vs 12% of patients, respectively (P = .0001). It is important to note that time to CR was longer with the combination therapy vs monotherapy (5.5 vs 3.7 months, respectively), but duration of response was twice as long with enasidenib plus azacitidine vs azacitidine alone (24 vs 12 months, respectively). IDH differentiation syndrome occurred in 18% (n = 12) of patients receiving enasidenib plus azacitidine, which requires careful monitoring and prompt treatment. Overall, the combination of enasidenib plus azacitidine is a promising strategy for patients with the IDH2 mutation, who have a remarkably good prognosis with use of available and novel treatments.

CPX‑351 Genetic Analysis
An earlier phase III study of CPX‑351, a liposomal formulation of cytarabine and daunorubicin, showed improved efficacy compared with standard 7+3 chemotherapy in 309 patients aged 60-75 years with newly diagnosed high-risk or secondary AML. This subset analysis of the phase III study examined the genetic dispositions of 184 patients with available blood or bone marrow samples. As expected, 33% of patients had a TP53 mutation and 57% had secondary‑type mutations. There were no significant differences in CR/CR with incomplete blood count recovery (CRi) or transplantation rates according to gene mutation and treatment arm when the comparison was restricted to genes mutated in ≥ 20% of patients. The only variable that correlated with longer OS in the multivariate analysis was CPX‑351 use (P = .026), whereas older age, performance status 1/ 2, previous HMA treatment, unfavorable cytogenetic risk, mutations in RUNX1 or TP53, or mutations in activated signaling genes were correlated with shorter OS. I think these subgroup analyses will not change our current practice, although they might suggest that TP53‑mutated patients do not seem to benefit from CPX‑351 and that considerations such as performance status and eligibility for intensive chemotherapy should be carefully evaluated in this patient population with difficult-to-treat disease when making treatment decisions.

QUAZAR AML-001: CC-486 as Maintenance Therapy in First-Remission AML
QUAZAR AML‑001 was a randomized, placebo-controlled phase III trial evaluating an oral azacitidine, CC‑486, as maintenance therapy in 472 patients with de novo or secondary AML in first CR/CRi after induction chemotherapy who were ineligible for stem cell transplant.  After a median follow-up of 41.2 months, the primary endpoint of median OS was 24.7 months in the CC-486 arm compared with 14.8 months in the placebo arm (HR: 0.69; P = .0009), with similar benefit with CC-486 seen across subgroups and with regard to relapse‑free survival. This is the first placebo-controlled study of maintenance therapy in AML, and I expect that it will change the standard of care for this population once CC-486 becomes available in Europe. In my experience, once we decide that a patient with AML should receive intensive chemotherapy, most will proceed to allogeneic transplantation; this study is relevant for the smaller proportion of patients who would receive intensive chemotherapy but not be candidates for allogeneic transplantation.

A few studies not discussed above that were of interest in AML included targeting CD70 with the antibody cusatuzumab combined with azacitidine in a small, dose-escalation phase I trial in older patients with treatment-naive AML, which suggested promising efficacy in these patients with CR/CRi in 10 of 12 patients. Results from a study of the PD-L1 inhibitor durvalumab combined with azacitidine in unfit patients with AML, however, were disappointing but insightful, showing that the regimen did not improve OS compared with azacitidine alone. It continues to be unclear whether there is a role for checkpoint inhibitors in AML.

M16‑106: Venetoclax and Navitoclax for R/R Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma
Turning to ALL, M16‑106 was a multicenter, open‑label, dose-escalation phase I trial of venetoclax plus navitoclax and chemotherapy, conducted in 45 adult and pediatric patients with relapsed/refractory ALL or lymphoblastic lymphoma. Nine percent of patients discontinued due to treatment‑related adverse events, and 7 patients experienced dose-limiting toxicities including delayed count recovery, liver injury, intestinal ischemia, and increased bilirubin. The overall rate of CR/CRi/CR with incomplete platelet recovery was 49%, with 29% of patients achieving a measurable residual disease–negative response. Overall, this was an encouraging result with a good response rate in heavily pretreated patients and with acceptable toxicity. An expansion cohort is exploring whether venetoclax treatment can be reduced to a 21‑day dosing scheme with 50-mg navitoclax to alleviate the prolonged count recovery.

Hyper‑CVAD Plus Ponatinib in Philadelphia Chromosome–Positive ALL
The combination of hyper‑CVAD and ponatinib in adults with newly diagnosed Philadelphia chromosome–positive ALL who were either untreated or had received a maximum of 2 previous treatment cycles was assessed in a single‑arm phase II study.  The initial dose of ponatinib was reduced to 30 mg/day or 15 mg/day after an excess risk of venous thromboembolism was observed with the higher 45-mg/day dose. After a median follow-up of 44 months, the 3‑year OS was 78%, and the 3‑year event‑free survival was 71%. It was also remarkable that all patients achieved a CR, and 86% achieved a complete molecular response. Nineteen patients (22%) received stem cell transplantation (SCT) in first remission, and the patients with SCT had a 3‑year OS of 66%, whereas patients without SCT had a 3‑year OS of 90%—an interesting result, although we cannot draw any firm conclusions about this observation. It is possible that the stronger inhibitory effect of ponatinib against the BCR‑ABL kinase and its activity against the T315 mutation in BCR‑ABL improves the response rate and OS in this cohort. However, this was a nonrandomized study and these findings need confirmation in a randomized study.

Key Leukemia Takeaways From ASH 2019
The 2019 ASH annual meeting provided new insights into novel agents and treatment combinations for leukemia. It is becoming increasingly clear that the future standard therapy in patients ineligible for intensive chemotherapy in AML will be azacitidine/venetoclax, and so novel agents should be evaluated against that combination. The standout practice‑changing finding in AML was the QUAZAR study demonstrating the efficacy of maintenance treatment with oral azacitidine. I am hopeful that the new agents and combinations discussed here for both AML and ALL will bring further benefit to our patients in the near future.

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Which leukemia studies at the 2019 ASH annual meeting did you find most interesting? Please answer the polling question on your screen and share your thoughts in the comments box.

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