Rapid Growth of Targeted Therapies in AML Spurs Need for More Learning

Harry P. Erba, MD, PhD

Prior to 2017, the treatment of acute myeloid leukemia (AML) had been stagnant for several decades, with many patients experiencing poor outcomes if they were unfit to undergo intensive therapy.¹ The advent of next-generation sequencing, however, led to the identification of several cytogenetic and molecular markers that both aided prognostication and prompted the development and approval of 8 novel agents over the past 3 years. These include targeted therapies for specific AML subpopulations (Timeline²).^1-3 Collectively, these agents have improved outcomes for patients with AML.

During a recent OncLive Peer Exchange^® program, a panel of leukemia experts provided an overview of these agents and shared their perspectives on how clinicians can incorporate them into their clinical practice. “We have growing opportunities to individualize treatment options,” emphasized moderator Harry P. Erba, MD, PhD.

Although the rapid pace of approvals in AML means better outcomes for patients, it also means clinicians are tasked with ensuring that the information is streamlined to their teams. “Given the pace of these new agents and the rapid approval over the past 2 years, I think it’s essential that information be communicated to all of the individuals that are involved in making the diagnosis of AML,” Eunice Wang, MD, said. “Specifically, [this includes] the hematopathologist, the flow cytometrists, [and] the cytogeneticists, because I think in the past there was no urgency.”

FLT3 Inhibitors

Approximately 20% to 30% of patients with newly diagnosed AML have FLT3 mutations.¹ Many patients with AML (~25% of all cases) have the FLT3—internal tandem duplication (FLT3-ITD) subtype, which is associated with a high relapse rate and poor outcomes in the setting of a high mutant to wild-type FLT3 allelic ratio.^1,4 Less commonly (≤10% of AML cases), patients have the FLT3—tyrosine kinase domain (FLT3-TKD) subtype, the prognostic impact of which is still unclear.^1,4

Currently, 2 FLT3 inhibitors are FDA approved for patients with AML: midostaurin (Rydapt) and gilteritinib (Xospata). Another agent, quizartinib, received a breakthrough therapy designation and priority review as a treatment for patients with relapsed/refractory (R/R) AML and an FLT3- ITD mutation, but it was ultimately rejected by the FDA over concerns that its benefit may not outweigh its risks; however, quizartinib gained approval in Japan as a treatment for adult patients with R/R FTL3-ITD—positive AML.⁵

Midostaurin

Midostaurin is a first-generation multitargeted tyrosine kinase inhibitor (TKI).⁴ It was approved by the FDA based on data from the phase III CALGB 10603 (RATIFY) trial (NCT00651261), which randomly assigned adult patients aged <60 years with newly diagnosed AML and FLT3-ITD or FLT3-TKD mutations (N = 717) to standard 7 + 3 chemotherapy (cytarabine on days 1-7 and daunorubicin on days 1-3) with midostaurin (n = 360) or standard 7 + 3 chemotherapy with placebo (n = 357).⁶

“At 4 years, 51% of patients were still alive with midostaurin compared with 44% who received standard 7 + 3 [plus placebo],” Erba said. He also noted that patients who went on to transplant following first remission after midostaurin had better overall survival (OS) than patients who went on to transplant after just 7 + 3 with placebo. No significant difference in OS was observed between the 3 FLT3 subtypes (ie, high allelic ratio ITD, low allelic ratio ITD, TKD).⁵

Based on the data, midostaurin plus 7 + 3 has become the standard of care in newly diagnosed AML. The National Comprehensive Cancer Network (NCCN) guidelines now recommend that FLT3 mutation status be determined quickly following an AML diagnosis so that midostaurin can be added on day 8 to up-front intensive chemotherapy.⁷

Gilteritinib

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Gilteritinib was approved in the R/R setting by the FDA based on an interim analysis of data from the phase III ADMIRAL trial, which randomly assigned 371 previously treated patients 2:1 to single-agent gilteritinib (n = 247) or 1 of 4 prerandomization- selected salvage chemotherapy regimens (n = 124), 2 of which were intensive and 2, low intensity.^2,9 “[All patients had] an FLT3 mutation because the prior studies in the phase I/II setting showed very limited activity in patients who didn’t have the target mutation,” Perl explained.

“The [ADMIRAL] study showed a higher response rate in the gilteritinib arm [and] a better survival, with a median overall survival of 9.3 months [compared with] a median overall survival of 5.6 months in the chemotherapy arm,” Perl said.⁹ Furthermore, he explained, there was a higher rate of transplantation in the gilteritinib arm, and the patients who underwent transplantation and then resumed gilteritinib after engraftment had some of the study’s best OS results. Based on these data, gilteritinib became the first FLT3 inhibitor approved as single-agent therapy in adults with relapsed or refractory AML with an FLT3 mutation, and it has an NCCN category 1 recommendation for this indication.^2,7

Although OS is improved with gilteritinib compared with salvage chemotherapy, Perl noted that many patients who respond eventually progress. “The overall survival for the study population as a whole, if you follow them for several years, really does drop down quite low, so the best way to develop these drugs, I think, is by moving to the front line, and those studies are ongoing,” Perl said. He mentioned the phase II/III trial (NCT02752035), which is examining tgilteritinib alone, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3-positive AML.¹⁰

IDH Inhibitors

Isocitrate dehydrogenases are enzymes that are essential for cellular metabolism.¹¹ In AML, mutations have been identified in 2 genes that encode isocitrate dehydrogenases: IDH1 and IDH2. These mutations cause amino acid changes in conserved residues, leading to neomorphic enzymatic function and production of the oncometabolite 2-hydroxyglutarate, causing DNA hypermethylation, aberrant gene expression, cell proliferation, and abnormal differentiation.¹¹ “IDH is a really exciting new target. Somewhat unexpectedly and fairly recently, we became aware that IDH was a recurrent mutation in upward of 15% of our patients,” Daniel Pollyea, MD, MS, said.

The FDA has approved 2 IDH-based therapies: ivosidenib (Tibsovo) for patients with IDH1 mutations and enasidenib (Idhifa) for patients with IDH2 mutations.² “Both are approved in the relapsed/refractory setting as a single agent,” Pollyea said. “Ivosidenib is also approved…as a single agent [for a patient with a new diagnosis].” He noted that both agents can be very effective: “About 30% of patients experience remissions. Other patients who fall short of that have improvement with respect to transfusion requirements—fewer or independence from transfusions.”

Ivosidenib

Based on data from the single-arm, multicenter AG120-C-001 study (NCT02074839), ivosidenib was approved for patients with newly diagnosed AML with IDH1 mutations.¹² The study included 28 patients aged ≥75 years who had comorbidities precluding the use of intensive induction chemotherapy (ie, severe cardiac or pulmonary disease, significant hepatic impairment, ECOG status of ≥2).

Patients were treated with ivosidenib 500 mg orally daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation. Two of the 28 patients (7.1%) underwent stem cell transplantation after receiving ivosidenib. Twelve of the 28 patients (42.9%) achieved a complete remission (CR) or CR with partial hematologic recovery (CRh), and 7 of the 17 transfusion-dependent patients (41.2%) achieved transfusion independence lasting ≥8 weeks.¹²

Ivosidenib was previously approved in the R/R setting based on data from the R/R arm of the AG120-C-001 study, which included 174 adults with IDH1 mutations who received ivosidenib 500 mg orally daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation.¹³ Of these patients, 21 (12%) received stem cell transplantation after ivosidenib treatment. The CR + CRh rate was 32.8% (95% CI, 25.8%-40.3%).¹³

Enasidenib

Enasidenib was approved in the R/R setting for patients with IDH2 mutations based on data from the open-label, single-arm, multicenter AG221-C-001 study (NCT01915498).¹⁴ The study treated 199 patients with IDH2 mutations with enasidenib 100 mg orally daily. After a median follow-up of 6.6 months, 23% of patients had a CR or CRh lasting a median of 8.2 months. Of these, 19% had a CR lasting a median of 8.2 months and 4% had a CRh lasting a median 9.6 months. At the initiation of the trial, 157 patients required transfusions. During at least one 56-day time period on enasidenib, 53 patients (34%) no longer required transfusions. Additionally, 32 of the 42 patients (76%) who did not require transfusions at the start of the trial had maintained transfusion independence.¹⁴

Differentiation Syndrome

A concern with ivosidenib and enasidenib is the risk of differentiation syndrome, a rapid differentiation of myeloid cells that can lead to a potentially fatal systemic inflammatory response. “About 10% of the time we see this,” Pollyea said. He noted that, unlike with acute promyelocytic leukemia, it may not present immediately but be delayed; however, with proper recognition and implementation of supportive care measures, patients can go on to have very good outcomes.

Jorge E. Cortes, MD, emphasized that not all differentiation syndromes present with an increase in white cell and blast counts. This point is important to remember for 2 reasons, he said: so that differentiation syndrome is properly managed to ensure the safety of the patient and so that it is not mistaken for progression. “[We need to] recognize differentiation syndrome because the patient may still benefit from therapy. Once you manage [differentiation syndrome], you can go back to the therapy and that patient may still respond. We need to be careful not to take them off prematurely,” he said.

Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin (Mylotarg; GO) was withdrawn from the US market in 2010 because increased early deaths were observed in patients with newly diagnosed AML who received GO in combination with intensive chemotherapy.¹⁵ In 2017, the FDA reapproved GO for newly diagnosed and R/R CD33-positive AML based on new efficacy and safety data observed in several trials of GO administered on a fractionateddosing schedule.^15,16

“The trial that I focus on the most is the ALFA-0701 study,” Erba said. ALFA-0701 (NCT00927498) is a multicenter, randomized, open-label phase III study that included 271 patients aged 50 to 70 years with newly diagnosed, de novo AML.¹⁶ Patients were randomly assigned 1:1 to receive standard 3 + 7 with GO (n = 135) or without GO (n = 136) on days 1, 4, and 7.

“In the 2 arms there was no difference in response rate, but the event-free survival [EFS] was significantly better with gemtuzumab,” Erba said. Using estimated median EFS was 17.3 months for patients receiving GO compared with 9.5 months for those receiving chemotherapy alone (HR, 0.56; 95% CI, 0.42-0.76).¹⁶ Erba said that at 5 years, the trend in OS benefit was still observed but mostly seen in the intermediate-risk group.

Evolving Treatment Landscape

The panelists also examined several drug types under investigation. Cortes provided insights into a new class of agents that target CXCR4, which has been found to be overexpressed in >20 human cancers, including AML, and is associated with tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance.¹⁷

A promising agent targeting CXCR4 being examined in clinical trials is CX-01, a low anticoagulant heparin derivative. A 3-arm study is comparing 7 + 3 chemotherapy alone, 7 + 3 with a lower dose of CX-01 (0.125 mg/kg/ hr), and 7 + 3 with a higher dose of CX-01 (0.25 mg/kg/hr).¹⁸ The composite CR rate (CR + CRh) was highest in those who received the higher dose of CX-01; 89% of those patients achieved a composite CR compared with 58% of those receiving just 7 + 3 and 50% of those given the lower dose of CX-01.18 “It’s a small study, preliminary but attractive,” Cortes said. Participants were fit patients aged >59 years with newly diagnosed AML.

The panelists thought several immunotherapies also show promise, including bispecific monoclonal antibodies, checkpoint inhibitors, and chimeric antigen receptor T-cell therapy.

Cortes said a challenge with bispecific monoclonal antibodies in AML has involved the difficulty of finding safe and effective agents, but several now in development target CD33, CD123, and some novel targets, such as 12A. One such agent, XmAb14045, which targets CD3 and CD123, is being investigated in patients with R/R AML (NCT02730312).¹⁹ Cortes said that these agents are still early in development but are on their way. “Things are going to look good, and we’re going to have to integrate all of these different approached to improve the outcome of our patients,” he said optimistically.

Gilteritinib, a second-generation FTL3 inhibitor, is active against AML with FLT3-ITD and FLT3-TKD mutations.^1,4 “[It is] active against both of these mutations by virtue that it is a type 1 inhibitor,” Alexander E. Perl, MD, MS, said. Type 1 inhibitors bind to the active conformation of their protein kinase targets.⁸

References

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16. FDA approves gemtuzumab ozogamicin for CD33-positive AML. FDA website. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-gemtuzumab-ozogamicin-cd33-positive-aml. Published September 1, 2017. Accessed October 26, 2019.
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19. PH 1 Study to Evaluate Safety and Tolerability of XmAb14045 in Patients With CD123-expressing Hematologic Malignancies. clinicaltrials.gov/ct2/show/NCT02730312. Updated August 27, 2019. Accessed October 26, 2019.