Approximately 90 percent of acute myeloid leukemia (AML) patients diagnosed with the disease after 60 years of age will ultimately experience a relapse after having initial remission using intensive chemotherapy. Consequently, there is a tremendous unmet need for addressing AML in those patients having either relapsed or refractory disease.
With the increased understanding of underlying disease state mechanisms and our immune system, new targeted chemotherapy and immunotherapy approaches have been developed for the treatment of many forms of cancer.
Recently, Hagop Kantarjian, MD, and Naval Daver, MD, both at the University of Texas, MD Anderson Cancer Center in Houston, were interviewed concerning some of the relevant targeted chemotherapy and immunotherapy strategies for treating AML. In this interview, Kantarjian was queried on targeted chemotherapies while Daver commented on the immunotherapeutic treatments.
FMS-Like Tyrosine Kinase 3 Inhibitors
Midostaurin—This staurosporine derivative exerts its effects via inhibition of multiple protein kinases, including FMS-like tyrosine kinase 3 (FLT3). In preclinical studies, midostaurin was shown to inhibit FLT3 receptor signaling and cell proliferation, as well as promote programmed cell death in leukemic cells having either internal tandem duplication and tyrosine kinase domain mutated FLT3 receptors or overexpressing wild-type FLT3.
“In April 2017, midostaurin was approved by the FDA for use in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of newly diagnosed FLT3-mutation-positive (FLT3+) adult AML patients,” stated Kantarjian, who is Professor and Chair of the Department of Leukemia at MD Anderson. “Patients are considered eligible for this treatment if their AML is confirmed to be FLT3+ using the simultaneously approved companion diagnostic FLT3-mutation assay.”
This approval was based on the results obtained in a phase III clinical trial (NCT00651261) that compared standard chemotherapy plus midostaurin or placebo in newly diagnosed, treatment-naïve AML patients. The overall survival benefit for the midostaurin group was significant relative to those who received only chemotherapy, with a hazard ratio (HR) for death of 0.78 (p=0.009). Additionally, the event-free survival was significantly longer for the midostaurin group (HR for event or death, 0.78, p=0.002)(N Engl J Med 2017; doi:10.1056/NEJMoa1614359).
“Approximately 30 percent of AML patients harbor mutations in their FLT3 gene,” Kantarjian noted.
Quizartinib: Quizartinib is a potent, selective, and orally bioavailable FLT3 inhibitor currently being evaluated in clinical studies for the treatment of AML. This inhibitor specifically targets forms of the enzyme that have internal tandem duplication (ITD) mutations.
In a first-in-human phase I study (NCT00462761), quizartinib was tested in relapsed/refractory AML patients irrespective of their FT3-ITD mutation status (J Clin Oncol 2013;31:3681-3687).
“For those patients having FLT3-ITD-driven disease, the response rate was 53 percent,” Kantarjian commented. “The maximum-tolerated dose was determined to be 200 mg/day as a result of grade 3 QT prolongation that was the dose-limiting toxicity.”
The phase III QuANTUM-R study (NCT02039726) is evaluating the use of quizartinib as a stand-alone therapy versus standard chemotherapy in adults with FLT3-ITD mutation-positive relapsed/refractory AML without prior FLT3 inhibitor treatment. In this study, patients were randomized in a 2:1 fashion to receive either quizartinib or investigator's choice of standard chemotherapy. Data presented at the European Hematological Association Congress in June 2018 showed a significant overall survival (OS) advantage for quizartinib (median OS-27.0 weeks) relative to standard chemotherapy (median OS-20.4 weeks). These data afforded a HR of 0.76 (p=0.0177).
Based on the results obtained in this study, in August 2018, the FDA granted quizartinib breakthrough therapy designation. “This was the first instance where FLT3 inhibitor monotherapy showed superior survival to standard chemotherapy in FLT3-ITD mutation-positive patients,” Kantarjian noted
Isocitrate Dehydrogenase Inhibitors
Enasidenib—Isocitrate dehydrogenase 2 (IDH2) is an enzyme located in the mitochondria that catalyzes the oxidative decarboxylation of isocitrate to afford α-ketoglutarate. However, neomorphic mutations to the conserved residues R140 and R172 result in the reduction of α-ketoglutarate to give (R)-2-hydroxyglutarate (R-2-HG). Preclinical studies showed that α-ketoglutarate-dependent enzymes were competitively inhibited with elevated levels of R-2-HG, resulting in aberrant hypoxia, DNA, and histone hypermethylation, as well as chromatin modifications.
Enasidenib is an orally dosed, first-in-class inhibitor of these mutated forms of IDH2. When asked about the mechanism of action for this compound, Kantarjian noted, “Enasidenib does not appear to be cytotoxic, but rather seems to function as a differentiation agent.
“Bone marrow blasts from patients with mutant-IDH2 AML, when exposed to enasidenib ex vivo, produce mature and fully functioning neutrophils with conserved mutant IDH2 allele frequency, indicating that the mature cells evolved from blast cells with mutated IDH2.
“Approximately 9-13 percent of AML patients have mutated forms of IDH2 present,” he added.
In August 2017, the FDA approved the use of enasidenib for the treatment of patients with relapsed or refractory AML with specific IDH2 mutations, as determined by the concurrently approved companion diagnostic. In rendering their decision, the FDA cited the results obtained in a phase I/II trial (NCT01915498) that evaluated the use enasidenib in patients with relapsed or refractory AML having assay-confirmed IDH2-mutated disease (Blood 2017;130(6):722-731). Regarding the results for that trial, Kantarjian noted, “Median OS with enasidenib was especially promising, at 9.3 months among all patients with relapsed/refractory AML, and 8.0 months in those having received two or more prior anti-cancer treatments.
“As a comparison,” Kantarjian added, “an OS of only 3.3 months was obtained in a phase III trial for the treatment of a similar patient population with one or more of seven available salvage therapies.”
Ivosidenib—Like IDH2, isocitrate dehydrogenase 1 (IDH1) also catalyzes the oxidative conversion of isocitrate to α-ketoglutarate. However, this enzyme is primarily found in the cytoplasm and the peroxisomes, whereas the IDH2 isoform is found in the mitochondria. Mutation of the R132 residue also results in neomorphic activity, providing the reduction product R-2HG.
Ivosidenib is a first-in-class orally bioavailable selective inhibitor of IDH1 with specific mutations to the R132 residue. In July 2018, the FDA approved ivosidenib for the treatment of adults with relapsed or refractory AML with specific mutations to IDH1, as per confirmation from the concurrently approved diagnostic assay. In approving this therapy, the FDA cited results obtained in a phase I trial (NCT02074839) evaluating the safety, pharmacokinetic, pharmacodynamic, and clinical activity of ivosidenib in adults (i.e., 18 years or older) with IDH1-mutated AML (N Engl J Med 2018;378:2386-2398).
“In the 125 patients that comprised the primary efficacy population, the rate of complete remission or complete remission with partial hematologic recovery was 30.4 percent, the rate of complete remission was 21.6 percent, and the overall response rate was 41.6 percent,” Kantarjian noted. “Transfusion independence was attained in 35 percent of the patients.”
B-Cell Lymphoma 2 Inhibitors
Venetoclax—Venetoclax is a small molecule inhibitor of the apoptosis regulatory protein B-cell lymphoma 2 (Bcl2). Currently, venetoclax has FDA approval in the U.S. for the treatment of relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma alone or in combination with rituximab in patients having or lacking the 17p deletion who had received at least one prior therapy. In preclinical studies, venetoclax showed potent efficacy against AML cell lines and primary patient samples, as well as in xenograft models.
In January 2016, the FDA granted breakthrough therapy designation for venetoclax in combination with hypomethylating agents (HMAs) for use in treatment-naïve AML patients who are ineligible to receive standard induction therapy (i.e., high-dose chemotherapy). This designation was supported by data from M14-358 (NCT02203773), a phase Ib trial that evaluated venetoclax in combination with an HMA, such as azacitidine or decitabine, in AML patients 60 years or older who were not eligible for standard induction therapy.
Later, in July 2017, the FDA granted the breakthrough designation for combination of venetoclax with low-dose cytarabine (LDAC). In their letter, the FDA noted results obtained in the M14-387 trial (NCT02287233), a phase I/II study that tested venetoclax in combination with LDAC in treatment-naïve AML patients 60 years or older who were ineligible to receive intensive chemotherapy.
In July 2018, a supplemental new drug application was filed in the U.S. with the FDA for the combination of venetoclax with either an HMA or LDAC as a first-line therapy for patients with AML who are ineligible for intensive chemotherapy.
“In this application, the results obtained in the M14-358 and the M14-387 studies were cited,” Kantarjian noted.
“No single standard of care currently exists for older patients with AML, as there are no FDA-approved therapies for those patients who are not able to receive standard induction therapy/intensive chemotherapy.”
When asked if venetoclax had been approved by the FDA for the treatment of AML, he replied, “There are ongoing clinical trials evaluating that compound in AML; however, as yet, no approvals have been granted.”
When asked about the state of targeted chemotherapies in the treatment of AML, Kantarjian replied, “Clearly, steady progress is being made with regards to these targeted chemotherapies.
“FDA approvals have been granted to therapies that target FLT3, IDH1, and IDH2 mutations in AML patients. In terms of applicability, roughly one-third of AML patients have FLT3 mutation-driven disease while nearly one-fifth harbor mutations of IDH1, IDH2, or IDH1 and IDH2.
“The findings for FLT3 inhibitors are particularly exciting,” he stated. “Midostaurin has received FDA approval in combination with standard chemotherapy for the treatment of FLT3-positive AML, and with quizartinib, for the first time, FLT3-inhibitor monotherapy showed improved survival relative to standard chemotherapy, and as a result, that compound has recently received breakthrough therapy designation from the FDA.
“Additionally, a new drug application has been filed for another FLT3 inhibitor, gilteritinib, for the treatment of adults with relapsed/refractory FLT3 mutation-positive AML.”
Concerning the Bcl2 inhibitor, Kantarjian noted, “Although FDA approval has not yet been granted to venetoclax, the developments there are exciting, as this therapy could potentially be relevant to all AML patients. And I would not be surprised in the near future to see new treatment strategies utilizing combination chemoimmunotherapy.”
Gemtuzumab Ozogamicin—This therapy is an antibody-drug conjugate (ADC). ADCs like gemtuzumab ozogamicin (GO) consist of a toxin that is covalently bound to an antibody; in principle, the toxin is preferentially delivered to cancer cells via targeting by the antibody. In this instance, the antibody, which recognizes the surface protein CD33 present on roughly 90 percent of patients' leukemic cells, is coupled to a calicheamicin-based cytotoxic agent.
Accelerated approval was granted by the FDA in 2000 for use of GO as a stand-alone therapy in elderly CD33+ AML patients who had relapsed after first-line therapy. A subsequent U.S. confirmatory co-operative group clinical trial showed GO in combination with induction chemotherapy conferred no improvement in survival while having an association with increased risk for adverse events and early death. Consequently, in 2010, the treatment was voluntarily withdrawn by its manufacturer.
FDA approval was granted in September 2017 to GO for treatment in combination with chemotherapy for newly diagnosed adult CD33+ AML patients, as well as a stand-alone therapy in those patients with relapsed or refractory CD33+ AML who were 2 years or older.
For the combination approval, the FDA cited results from the ALFA-0701 study (NCT00927498) in which newly diagnosed patients received induction chemotherapy with or without GO. Using the protocol outlined in the study, the median event-free survival was 17.3 months in the patients receiving GO, as compared to 9.5 months for those who did not, providing an HR of 0.56 (95% CI: 0.42-0.76).
In their decision to approve GO as a stand-alone therapy for adult or pediatric patients, two separate studies were referenced. In the AML-19 study (NCT00091234), patients either a) older than 75 years or b) 61-75 years old with a WHO performance status of 0-2 or were unwilling to receive intensive chemotherapy were randomized in a 1:1 manner to either GO or best standard care (BSC). Those patients receiving GO had a median estimated OS of 4.9 months, while patients receiving BSC had a median OS of 3.6 months, affording a HR of 0.69 (95% CI: 0.53-0.90).
The second trial cited was the phase II MyloFrance-1 study. In that single-arm study, patients received a single course of GO with cytarabine consolidation. Of these patients, 26 percent achieved complete remission (CR), while the median relapse-free survival was 11.6 months.
“The recommended dose of GO in both frontline and the salvage setting is the fractionated dose of 3 mg/m2, given on days 1,4, and 7 with 3+7 induction per the ALFA-0701 regimen; the benefit of GO when added to frontline therapy was most prominent among newly diagnosed AML with favorable (core-binding factor: inv(16) and t(8:21)) AML,” noted Daver, who is Associate Professor in the Department of Leukemia at MD Anderson. “Some benefit was also seen in patients with intermediate cytogenetics. Patients with adverse cytogenetics did not have benefit and the addition of GO to induction therapy is not strongly recommended.”
Vadastuximab Talirine—Another ADC that targets CD33 is vadastuximab talirine (VT), which consists of an anti-CD33 antibody that is bound to molecules of the DNA-crosslinking pyrrolobenzodiazepine dimers via cysteine residues.
In a phase I study (NCT01902329), safety, clinical activity, and pharmacokinetic data for VT was evaluated in relapsed or refractory AML patients (Blood 2018;131(4):387-396). The CR plus complete remission with incomplete hematologic recovery (CRi) was 28 percent. Of the patients responding, 50 percent attained minimal residual disease status.
For the phase III Cascade trial (NCT02785900), the combination of VT or placebo plus HMAs azacitidine or decitabine were evaluated in newly diagnosed adult patients with AML.
“However, in June 2017, that trial had to be stopped early due to a signal for increased mortality on the VT-containing arm of the study,” Daver noted. “Consequently, VT is no longer in clinical development,” he further commented.
Flotetuzumab—This dual-affinity re-targeting protein is an antibody-based therapy that has the ability to target two different cellular surface proteins simultaneously. In this particular case, flotetuzumab recognizes CD3, a surface protein normally expressed on T cells and CD123 (the α-chain of the interleukin-3 receptor heterodimer), which is often overexpressed on AML blast and leukemic stem cells (LSCs). By binding to both these substrates, it is thought that the immune system's T cells can be directed selectively to leukemic cells which tend to overexpress CD123. Regarding its mechanism, Daver explained, “Bispecific Abs function by bringing T cells in close proximity to AML blasts, resulting in T-cell activation and T-cell mediated death of the blasts.”
A phase I dose-escalation trial (NCT02152956) is evaluating flotetuzumab in both relapsed or refractory AML patients (89% of study participants) as well as those having myelodysplastic syndrome (MDS, 11% of study participants) (Blood 2017;130:637). In that study, the maximum tolerated dosing schedule obtained was 500 ng/kg/day, while the ORR was 43 percent in patients treated at or above the maximum tolerated dose level, thus showing anti-leukemic activity; additionally, the safety profile was manageable.
“This agent is also being evaluated in an expanded phase II multicenter study in relapsed AML,” Daver commented.
SL-401—This therapy is a recombinant fusion protein consisting of the catalytic and translocation domains of diptheria toxin bound to IL3 via a linker molecule. “Similar to other ADCs, SL-401 functions by targeting CD123 on the surface of mature blasts and LSCs and is internalized, releasing the toxic payload, resulting in death of the blasts or LSCs,” Daver noted.
In preclinical studies, SL-401 showed significant survival improvement in murine patient-derived AML xenograft models (Haematologica 2018; doi:10.3324/haematol.2018.188193). Additionally, SL-401 displayed activity against normal hematopoietic progenitors in studies using normal cord blood and healthy marrow. These findings would seem to indicate the potential use for SL-401 as a “bridge-to-transplant” before allogeneic hematopoietic stem cell transplantation in patients with AML or MDS.
Currently, SL-401 is being evaluated in a phase I/II study (NCT02113982) as consolidation therapy in adverse risk AML patients in first complete remission.
When asked to elaborate on what he thought were the most promising approaches for AML utilizing ADCs, Daver replied, “For ADCs, those conjugated to chemical toxins hold more promise, as we believe that the toxicity profile and the risk of cytokine release, capillary leak, possibly veno-occlusive disorder (VOD) will be lower with chemical toxins.
“Among the ADCs currently being evaluated, the CD123-targeting IMGN632 is showing encouraging single-agent activity in relapsed AML as a single agent; clinical data will be presented at ASH 2018,” he noted.
“SL-401 is showing exciting activity in BPDCN, but thus far, it has shown limited activity as a single agent in relapsed AML, but is being evaluated in combination with azacitidine in relapsed AML.”
When the topic of the discussion turned to immune checkpoint (ICP) antibodies, Daver noted, “The combination of ICP antibody nivolumab with the HMA azacitidine has shown overall response rates of 35 percent (CR/CRi 24%) in relapsed AML with median two prior salvages. The overall response rate was especially high, at 52 percent, in prior HMA-naïve relapsed AML treated with azacitidine and nivolumab.
“The median overall survival with this regimen was 10.4 months in salvage 1 AML, which is encouraging. Pre-therapy bone marrow CD3+ infiltrate was an important biomarker for response and may be used to select patients for future trials,” Daver stated.
Concerning bispecific antibodies, he observed, “Flotetuzumab was the first bispecific Ab to show single-agent activity in relapsed AML and is being evaluated in an expanded multicenter phase II study. Other bispecific Abs, such as AMG 330 (CD3 x CD33) and XmAb (CD3 x CD123), are in clinical development and may be agents to look out for in relapsed AML.
“For AML, targeting of CD33 has been utilized as a therapeutic strategy,” Daver continued, “since it is expressed in >95 percent of AMLs, is expressed on a majority of the AML mature blasts as well as LSCs, and has limited pulmonary, GI, and vascular expression, resulting in limited toxicity to these organs.”
Regarding the negatives for this strategy, he stated, “The cons are that CD33 is expressed on non-leukemic hematopoietic stem and progenitor cells, which means that collateral myelosuppression (especially neutropenia) is frequently seen with CD33-based therapies conjugated to potent toxins. The other issue that has been noted with GO and vadastuximab, especially when used in the peri-transplant setting, was the occurrence of VOD of the liver. This was thought to be likely due to CD33 expression on liver Kupffer cells and possibly hepatocytes.
“VOD was seen in 4-5 percent of patients treated with GO at the prior unfractionated dose of 9 mg/m2 with much lower incidence at the 3mg/m2 fractionated dose, but is a life-threatening complication if not treated rapidly.”
“I believe immune therapies will play a major role in therapy of AML and will complement targeted therapies,” Daver stated. “GO is approved and should be added to induction in all core-binding factor AML and considered for intermediate risk cytogenetic AML.
“ICP-based therapies, especially combinations of HMAs with a PD-1 inhibitor are showing encouraging activity in relapsed AML and are being evaluated in multiple phase II trials and a phase III study in frontline older AML.
“CTLA4 inhibitors have shown encouraging single-agent activity in postSCT relapsed AML and in post-HMA MDS and may be further synergistic when combined with PD1 inhibition,” Daver commented.
“Bispecific Abs are showing single-agent activity and one of the major mechanisms of resistance to bispecific therapy appears to be up-regulation of PD-1; consequently, combinations of bispecific Abs with PD-1 inhibitors may further enhance responses, but toxicities must be assessed.”
Regarding the potential implications of increased immunotherapy use in AML, Daver stated, “I see more and more use of immune therapies in novel combinatorial approaches for AML in the near future. However, immune agents have unique toxicities; awareness and rapid management of these toxicities will be very important with increased usage of these therapies in AML.”
Richard Simoneaux is a contributing writer.
A Glance at AML Therapeutic Approaches
- Midostaurin was approved in 2017 for the treatment of newly diagnosed FLT3+ adult AML patients based on findings from a phase III clinical trial (NCT00651261).
- Quizartinib is being evaluated in the phase III QuANTUM-R study (NCT02039726).
- Enasidenib was approved in 2017 for R/R AML with specific IDH2 mutations based on a phase I/II trial (NCT01915498).
- Ivosidenib received approval in 2018 for adults with R/R AML with specific mutations to IDH1.
- Venetoclax is being studied in ongoing clinical trials evaluating the compound in AML; however, no approvals have been granted yet.
- Gemtuzumab ozogamicin was granted approval in 2017 for treatment in combination with chemotherapy for newly diagnosed adult CD33+ patients, as well as a stand-alone therapy in patients 2 years or older with R/R CD33+ AML.
- Vadastuximab talirine (VT) was evaluated in a phase I study (NCT01902329) for R/R AML. A phase III study (NCT02785900) had to be stopped early due to increased mortality in the VT-containing arm.
- Flotetuzumab is being evaluated in a phase I dose-escalation trial (NCT02152956) in R/R AML patients, as well as an expanded phase II study for relapsed AML.
- SL-401 is being analyzed in a phase I/II study (NCT02113982) as consolidation therapy in adverse risk AML patients in first complete remission.