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ASH 2018: New AML Data
Promising Developments in AML From ASH 2018

Released: December 27, 2018

Expiration: December 26, 2019

Gary J. Schiller
Gary J. Schiller, MD
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The 2018 ASH conference featured the latest clinical data on several promising investigational, as well as recently approved, treatments for acute myeloid leukemia (AML). Below, I highlight the studies most clinically relevant to me on targeted therapies and immunotherapies in both frontline and progressive disease.

Targeted Therapies in Patients Ineligible for Conventional Chemotherapy
Older patients with AML who are unfit for conventional chemotherapy have long represented an unmet medical need in AML. Shortly before ASH 2018 convened, the FDA approved 2 promising approaches for these patients combining the proapoptotic BCL-2 inhibitor venetoclax with hypomethylating agents (HMAs), and pairing glasdegib, an oral inhibitor of the hedgehog pathway, with low-dose cytarabine (LDAC).

At ASH 2018, we saw updated phase Ib results on first-line venetoclax plus either azacitidine or decitabine in 115 patients with AML who were ineligible for intensive therapy. Responses were rapid and deep, with a median time to first response of < 2 months and a CR/CRi rate of 71% with venetoclax plus azacitidine and 74% with venetoclax plus decitabine. Grade ≥ 3 febrile neutropenia occurred in 39% of patients treated with venetoclax plus azacitidine and in 65% with venetoclax plus decitabine. The FDA gave accelerated approval to venetoclax for newly diagnosed AML in November 2018 in combination with an HMA or LDAC in patients aged 75 years or older or who were unfit for intensive induction chemotherapy.

Glasdegib was also approved by the FDA in November 2018 in combination with LDAC for first-line AML in patients aged 75 years or older or who were unfit for intensive induction chemotherapy. At ASH 2018, Westley and colleagues presented a cross-trial analysis comparing glasdegib plus either LDAC, azacitidine, or decitabine among patients with AML unfit for intensive chemotherapy. Using indirect treatment comparison methods, the investigators observed a nonsignificant trend toward improved response rates when glasdegib was combined with LDAC. A separate cross-trial analysis by the same investigators observed no consistent differences in survival with glasdegib plus LDAC vs venetoclax plus LDAC in older patients with AML ineligible for intensive chemotherapy. Both venetoclax and glasdegib induce remission, but some patients may experience myelosuppression similar to that which is associated with cytotoxic chemotherapy. Time on therapy, however, was not long, and the reasons for discontinuation of treatment will need to be evaluated, as well as the duration of response and whether hematopoietic recovery can occur with continued treatment.

Moving Targeted Agents Into Frontline Disease
Targeted agents currently approved by the FDA in the relapsed/refractory setting also showed efficacy in the frontline setting according to data at ASH 2018. Stein and colleagues presented updated phase I results assessing standard induction and consolidation therapy combined with either the mutant IDH1 inhibitor ivosidenib or the mutant IDH2 inhibitor enasidenib in previously untreated, IDH1-mutated or IDH2-mutated AML. Among the 153 enrolled patients, the median age was approximately 63 years and 63% to 70% had de novo AML. In the ivosidenib plus chemotherapy cohort, 71% achieved a CR as best overall response and 88% achieved measurable residual disease (MRD) negativity by flow cytometry; in the enasidenib plus chemotherapy cohort, the CR rate was 56% and the MRD negativity rate was 45%. Both regimens were well tolerated.

We also saw data on gilteritinib, an oral kinase inhibitor approved by the FDA in November 2018 as monotherapy for relapsed/refractory FLT3-mutated AML both in FLT3-ITD and, to a lesser degree, in FLT3-TKD. Updated phase I results were presented at ASH 2018 on gilteritinib combined with induction and consolidation chemotherapy followed by gilteritinib maintenance in patients with newly diagnosed AML, of whom 54.5% had an FLT3 mutation. Results suggest that this approach was highly effective, with a CR/CRi rate of 66.7% in FLT3-mutated AML.

New Developments in Immunotherapy
There were several interesting studies presented on BiTE constructs and CAR T-cell therapies in the AML space. CD33 is an antigen against which bifunctional monoclonal antibodies, as well as DARTs, have been directed. CD123 is another antigen that may lend itself for the development of CAR T-cells. But in both cases, the antigens are not completely discrete and are not entirely isolated to the leukemia clone, and there is both the risk of severe and prolonged myelosuppression, as well as cytokine release syndrome that has, of course, complicated the development of these agents outside the AML setting, such as in acute lymphoblastic leukemia and other diseases. Thus, we still need to determine the optimal setting, frequency of dosing, and ways to ameliorate the toxicity associated with these approaches.

At ASH 2018, Ravandi and colleagues presented data from the first-in-human phase I study of AMG 330, an anti–CD33-CD3 BiTE construct, in 35 patients with heavily pretreated relapsed/refractory AML. Serious adverse events were observed in 66% of patients, with cytokine-release syndrome being the most common. At the target dose, 2 patients achieved a CR and 1 patient a CRi; a fourth patient at a lower dose achieved a morphologic leukemia-free state. These results are interesting for this novel approach. Promising activity was seen as well in this setting with the novel CD33-targeted antibody–drug conjugate IMGN779.

Also in the setting of relapsed/refractory AML, we saw activity with the novel CAR T-cell therapy CYAD-01—which is based on the NKG2D receptor specific for the ligands MICA, MICB, and ULBP1-6 expressed across multiple malignancies.

Although immune checkpoint inhibitors lack single-agent activity in AML, there were interesting data presented on checkpoint inhibitors combined with other agents. For example, a phase II trial assessed idarubicin and cytarabine plus the PD-1 inhibitor nivolumab in newly diagnosed AML and high-risk myelodysplastic syndrome. This combination was associated with a trend toward prolonged median OS compared with a contemporary cohort treated with idarubicin and cytarabine alone (18.54 vs 13.2 months, respectively; P = .2). Combination approaches with immune checkpoint inhibitors may thus warrant further exploration in AML.

Your Thoughts?
Which studies presented at ASH 2018 will have the greatest effect on your clinical practice? Please share your thoughts in the comments box!

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