Jacob M. Rowe, MD

The FLT3 inhibitor midostaurin, the antibody-drug conjugate gemtuzumab ozogamicin, CPX-351(liposomaldaunorubicin and cytarabine), and the IDH2 inhibitor enasidenib are among the novel agents approved for use in the clinic this past year. This year, 2018, already has seen the regulatory approval of the BCL2 inhibitor venetoclax in the form of breakthrough designation and the IDH1 inhibitor ivosidenib received full FDA approval. Much remains to be learned about how best to use these drugs to improve patient outcomes and how best to employ and interpret next-generation sequencing to determine measurable residual disease (MRD) levels that can more accurately predict risk of relapse.

Keywords:AML; Acute myeloid leukemia; FLT3; Enasidenib; Gemtuzumab; Histone deacetylase; IDH; Ivosidenib; MRD; Measurable residual disease; Midostaurin; Venetoclax

In the past year, several novel agents have been approved by the US Food and Drug Administration (FDA) for use in patients with acute myeloid leukemia (AML): the FLT3 inhibitor midostaurin, the antibody-drug conjugate gemtuzumab ozogamicin, CPX-351 (liposomaldaunorubicin and cytarabine), and the IDH2 inhibitor enasidenib. This year already has seen the regulatory approval of the IDH1 inhibitor ivosidenib. And a likely approval for AML in 2018 is the BCL2 inhibitor venetoclax, which has already been granted breakthrough designation. Already approved for use in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in combination with rutixumab, venetoclax has also shown promise in AML, particularly with low-dose cytarabine. In a phase 1/2 study of the combination in treatment-naïve elderly patients unfit for intensive chemotherapy, 1-year follow-up showed 38 of 61 patients still responding, for a complete response (CR) and CR with incomplete blood count recovery (CRi) rate of 62% (Figure 1) [1]. Not surprisingly, the response was dependent upon the molecular markers of the disease. All patients with an NPM1 mutation achieved CR/CRi, while patients with TP53 mutations had the lowest CR/CRi rates (Figure 2). Impressive results with venetoclax and hypomethylating agents in AML have also been reported [2]. Based on the data of these two studies a supplemental New Drug Application (sNDA) has just been submitted to the FDA. As with Tarceva the IDH2 inhibitors, impressive data are being reported for the IDH1 inhibitor ivosidenib in relapsed or refractory AML [3]. Over 20% of treated patients are achieving complete remission with a median duration of over 9 months (Table 1). And early trials of ivosidenib in combination with standard chemotherapy are already underway in newly diagnosed AML and are confirming the agent’s easy tolerability [4]. As a result of these data, the FDA recently approved ivosidenib for relapsed or refractory AML. gamma-alumina intermediate layers

A considerable number of trials and much information has been gathered regarding the use of FLT3 inhibitors in AML, mostly for advanced disease. One of the best registries for data on leukemia is the Swedish AML Group, which reported the prevalence, or survival, of AML patients in January 2014 [5]. Comparing surviving AML patients diagnosed between 2011 and 2013 with those survivors diagnosed between 1997 and 2010, it is clear there are very few long-term survivors who are positive for FLT3-ITD (Table 2). These data need to be cautiously interpreted, as they include all ages, comorbidities, and other patient characteristics. The point is, however, that this is a group with a particularly poor prognosis. FLT3-ITD mutation occurs in 30% of young adults. Data from the Cancer Genome Atlas Research Network show that out of 200 AML patients, almost 60 are FLT3 positive [6] . Data reported by Stone et al show the benefit of midostaurin for patients who received the inhibitor throughout induction, consolidation, and maintenance.Of note, the long-term survival in the placebo group was surprisingly good (Figure 3) [7]. In addition, the RATIFY Study does not allow conclusions on the value of the addition of midostaurin as maintenance therapy [8].This has led to an FDA approval of midostaurin that does not include maintenance therapy, in contrast to a broader approval by the European regulator EMEA. The question is whether the next-generation FLT3 inhibitors will further improve the outcome in newly diagnosed patients. We know that FLT3 inhibitors have been tested in advanced disease, but for newly diagnosed patients, trials are underway using quizartinib, crenolanib, gilteritinib, and ponatinib.

And data on ibrutinib in AML may be forthcoming soon.Measurable residual disease (MRD) During this period, continued refinement of MRD detection technology has occurred and it is being increasingly used in AML. Flow cytometry and polymerase chain reaction (PCR) have been the mainstay of detection in most institutions, although next-generation sequencing (NGS) has greater sensitivity. One caveat, however, is important: we need to be aware of over interpretation. In this regard, the HOVON-SAKK collaborative study group (Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research) examined MRD by NGS in a cohort of 482 younger (<65 years) AML patients [9]. The investigators noted that 89% had somatic driver mutations present at diagnosis that persist in morphologic remission and may not be associated with a risk of relapse. Rather, these persistent mutations of DNMT3A, TET2, and ASXL1 represent clonal hematopoiesis of unknown significance. Only the other mutations are reliably predictive for relapse. In this trial, using NGS only in persistent mutations other than DNMT3A, TET2, and ASXL1, the predictive value at diagnosis was impressive. Knowing how to interpret and use NGS is of utmost importance. As can be seen, substantial progress has been made in 2018 in the Antiviral immunity treatment of patients with AML. Yet there is still much to learn and a long way to go to improve the outcome of the majority of patients with AML.