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AML at ASH 2018
My Selections for Key AML Abstracts at ASH 2018

Released: December 03, 2018

Expiration: December 02, 2019

Farhad Ravandi
Farhad Ravandi, MD
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The ASH conference in San Diego has introduced a number of exciting new studies with clinical relevance for treating your patients with acute myeloid leukemia (AML). Below, I highlight a few of the key studies, focusing on 3 broad treatment strategies: targeted therapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation (HSCT).

Targeted Therapy
Targeted therapy, either as monotherapy or in combination with cytotoxic agents, is playing an increasing role in AML treatment.

Phase III QuANTUM-R Quizartinib Study (Abstract 563)
This report is final data from the randomized, controlled phase III QuANTUM‑R trial presented at the European Hematology Association meeting. Patients with FLT3 ITD–mutated relapsed/refractory (R/R) AML after standard induction therapy with or without HSCT were randomized 2:1 to receive either quizartinib 60 mg or one of 3 preselected investigator’s choice standard salvage chemotherapy combination regimens (low‑dose cytarabine, intermediate-dose cytarabine, or more intensive FLAG‑IDA regimen). Previous therapy with midostaurin was allowed, which is important because many patients now receive midostaurin for frontline induction therapy.

Median follow-up of the 367 patients was 23.5 months with the treatment groups having very well–balanced baseline characteristics. Median OS was 6.2 months with quizartinib and 4.5 months with the standard-of-care chemotherapy (HR: 0.76; 95% CI: 0.58-0.98: P = .01).

This is an important study because oral monotherapy is improving survival in a patient population with difficult-to-treat refractory or short first remission relapse FLT3-mutated AML. Outcomes are extremely poor in this group of patients—even poorer than other patient populations of R/R AML—so use of a single oral agent with improvement in outcome is a significant therapeutic advance. FDA approval is anticipated for quizartinib in this specific setting based on these results.

Venetoclax Combined With HMAs (Abstract 285)
This presentation is an update of the open‑label, dose-escalation and dose-expansion phase Ib trial of venetoclax in combination with hypomethylating agents (HMAs) for patients with previously untreated AML who were not eligible for intensive chemotherapy because of comorbidities or advanced age. Venetoclax was given daily on a 3‑day ramp-up dosing, from 100 to 200 to 400 mg, with standard dosing of decitabine (ven/dec) or azacitidine (ven/aza).

In total, 115 patients were treated with 400-mg venetoclax (84 with azacytidine and 31 with decitabine) with median ages of 75 and 72 years, respectively. Approximately 25% of patients had secondary AML and a significant proportion (39% to 48%) had poor‑risk cytogenetics. Reasonable tolerability was reported across patient groups, with grade ≥ 3 febrile neutropenia (44%), anemia (28%), and pneumonia (25%) being the leading adverse events.

Rates of rapid and deep responses were very high in this study for this patient population.CR plus CR with incomplete hematologic recovery (Cri) was 70% for ven/aza and 74% for ven/dec. Time to first response appears to be rapid, at approximately 1‑2 months (1‑2 cycles). Responses were seen in both patients with poor‑risk cytogenetics and those with TP53-mutated AML—a bit higher with ven/dec. Notably, lower response rates were seen in other studies in patients with FLT3-mutated AML treated with FLT3 inhibitors. This is significant because there is obviously future potential to combine these two drugs with an FLT3 inhibitor. The rate of MRD negativity was considerable with this nonintensive regimen—47% with ven/aza and 39% with ven/dec.

This is a combination that was just approved in the United States by the FDA for patients age 75 years or older or with comorbidities that make them ineligible for intensive chemotherapy. It will likely also be evaluated in older patients who are fit for intensive chemotherapy because if outcomes are as positive as in this trial, clinicians may also want to use it in fit, older patients to avoid subjecting them to unnecessary risks and adverse events associated with intensive chemotherapy.

Combination Strategies With Other Targeted Agents (Abstract 564 and Abstract 560)
Both abstracts 564 and 560 are results of phase I trials of targeted therapy in combination with induction and consolidation therapy in newly diagnosed AML. Abstract 564 highlights trial results of the addition of the potent FLT3 inhibitor gilteritinib to chemotherapy in this patient setting, and abstract 560 discusses outcomes from a trial of the IDH inhibitors ivosidenib or enasidenib in patients with previously untreated IDH1-mutated or IDH2-mutated AML. All of these agents demonstrated safety when combined with chemotherapy, with positive responses in first-line AML.

These are exciting potential strategies that may be employed in the future to improve outcomes for our patients with AML.

Immunotherapy and Antibody-Based Therapies
Immunotherapy and antibody‑based therapies are novel research strategies that are still in their infancy for AML. One strategy is using bispecific antibodies that have been shown to be effective in acute lymphoblastic leukemia (ALL), with the drug blinatumomab approved for patients with relapsed ALL as well as for patients with MRD-positive ALL after induction therapy. This has led to the investigation of similar strategies for AML.

AMG 330 (Abstract 25)
This first‑in‑human phase I study of AMG 330, an anti–CD33‑CD3 bispecific T-cell engager (BiTE) antibody construct, evaluated this agent for patients with R/R AML. AMG 330 was given by continuous IV infusion, initially with single-patient cohorts for the first 3 doses then 3‑6 patients per cohort. Step‑up dosing was introduced after the fifth patient cohort along with preadministration of dexamethasone, not previously allowed, to help mitigate cytokine-release syndrome (CRS), a known adverse event with these T-cell–activating strategies.

In total, 35 patients were enrolled in 12 cohorts with a target dose range of 0.5‑480 mcg/day. All patients had heavily pretreated relapsed disease, with 40% previously treated with HSCT. Serious adverse events were seen in two thirds of patients, with CRS being the most common. Dose‑limiting toxicities of grade 2 CRS and grade 4 ventricular fibrillation with the target dose of 480 mcg led to the selection of 240 mcg as the maximum target dose.

To date, patients have achieved CR and CRi with AMG 330, so there is early evidence of activity with this strategy, which is exciting because this is a completely new modality in treating AML.

In addition, abstracts 26 and 27 discuss the new anti-CD33 antibody–drug conjugate IMGN779 and anti-CD123 antibody–drug conjugate IMGN632, respectively. Both are being developed in phase I trials and have shown activity in patients with relapsed/refractory AML.

Flotetuzumab (Abstract 764)
This presentation is an update of the expansion cohort of the study of the CD123‑CD3 bispecific DART antibody flotetuzumab for R/R AML initially presented at ASH 2017. Flotetuzumab was administered as a 7-day/week continuous infusion, with CRS as the main observed potential toxicity. Reported responses were 31% at the recommended phase II dose of 500 ng/kg/day in patients with primary refractory disease, but no response in patients with relapsed disease. This study supports the potential viability of the DART antibody concept in AML, suggesting the likelihood that we will see other agents using this strategy. Another presentation (abstract 763) spotlights XmAb14045, a bispecific long half‑life antibody that does not need to be given by continuous infusion, providing easier administration. Treatment was administered weekly in 28-day cycles in patients with R/R AML. Although a phase I study, there is evidence of responses in a number of patients who have been treated with this bispecific antibody.

Allogeneic HSCT
Two important abstracts at ASH will focus on outcomes of patients who underwent allogeneic HSCT.

Gemtuzumab Ozogamicin and VOD (Abstract 28)
In a follow-up of the French randomized phase III ALFA-0701 study, which showed improved outcomes with the addition of gemtuzumab ozogamicin 3 mg/m2 on Days 1, 3, and 5 to 7 + 3 chemotherapy in patients with de novo AML, patients who went on to receive an allogeneic HSCT had similar outcomes post transplantation between the gemtuzumab ozogamicin arm (n = 32) and the control arm (n = 53). Of significance, the use of gemtuzumab ozogamicin was not associated with excessive veno‑occlusive disease (VOD) after transplantation.

This is an important study because we have always been concerned about using gemtuzumab ozogamicin due to a reported concern of increased VOD risk. In this retrospective analysis of approximately 80 patients, it appeared that the addition of gemtuzumab ozogamicin was not associated with significant VOD following transplantation.

Sorafenib After Allogeneic HSCT (Abstract 661)
This last presentation is a randomized double‑blind placebo‑controlled study conducted at 14 centers in Germany and Austria, involving 83 patients with FLT3 ITD–mutated AML (median age: 54 years), who had received an allogeneic HSCT and were then randomized to receive either sorafenib or placebo following transplantation. Median follow-up was 42 months and median relapse-free survival was 30.9 months for the placebo group vs not reached in the sorafenib group, corresponding to a 2‑year relapse-free survival of 53.3% and 85%, respectively.

This is clear evidence that patients with FLT3 ITD–mutated AML should have maintenance sorafenib after allogeneic HSCT because it reduces the risk of relapse.

Conclusion
At ASH 2018, there are several AML abstracts that are showing maturing data with targeted drugs, including FLT3 inhibitors and IDH inhibitors as well as venetoclax. I think the randomized QuANTUM study of quizartinib vs chemotherapy in relapsed AML being positive for survival is very significant. We are also beginning to learn how to combine targeted agents that are now approved and available with either hypomethylating agents or other treatment strategies. The area of immune‑based therapy for AML is beginning to further advance particularly with the introduction of various bispecific antibodies; there may be a role for these immune‑based strategies in the future.

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