Novel and Emerging Treatment Strategies for Acute Myeloid Leukemia

Presenter: Eunice S. Wang

Acute myeloid leukemia (AML) remains difficult and challenging to treat. Recognition that AML is a genomically heterogeneous disease has given rise to several new targeted therapies (eg, inhibitors of FLT3 and IDH1/2). Because the genomic landscape of AML evolves as the disease progresses, genomic testing is advised at diagnosis and at recurrence or relapse. In addition to targeted inhibitors, several emerging therapies directed at immune responses and p53 are on the horizon. Despite these advances, the 5-year overall survival rate for AML is 28.3%. The hope is that novel combinations and emerging strategies will move the survival bar higher for patients with AML in the near future.

Despite the advent of novel targeted therapies and promising emerging strategies, acute myeloid leukemia (AML) remains difficult and challenging to treat. With a median age at diagnosis of 68 years, the incidence of AML is increasing as the general population ages. The “7 + 3 regimen” of cytarabine + anthracycline has been the backbone of AML treatment for 40 years; however, there have been 9 new drug approvals since 2017, said Eunice S. Wang, MD, Chief, Leukemia Service, and Professor of Oncology, Roswell Park Comprehensive Cancer Center.

“The treatment of AML is complex because it is a highly biologically diverse malignancy characterized by many malignant clones. The difficulty lies in successfully eradicating new clones at diagnosis as well as those that evolve as the disease progresses,” Dr. Wang explained to listeners at the virtual NCCN 2020 Virtual Annual Conference. “Due to the biological diversity of AML, it is essential for newly diagnosed patients to undergo comprehensive genomic assessment that includes cytogenetics [to detect gene fusions] and molecular profiling [no gene fusions]. This allows us to optimally select therapy for all subtypes of disease, including those that do not respond well to standard chemotherapy.”

The assumption has been that it is essential to start aggressive treatment upfront immediately for newly diagnosed AML. “With new therapies, we now know that many individuals with AML have disease that responds better to targeted therapy compared with standard cytotoxic therapy. This outweighs the urgency to start immediately,” she said. “Many of the novel drugs are specifically tailored for AML biology, and it makes sense to wait for genomic testing results.” Results of a recent study of >2,200 patients with newly diagnosed AML (median age, 59 years)1 confirmed that it is safe and feasible to delay upfront chemotherapy for up to 15 days while waiting for genomic testing results, with no adverse effects on outcome. These findings held true for both younger (aged ≤60 years) and older patients (aged >60 years).

Dr. Wang reminded listeners that it is also essential to repeat genomic analysis at recurrence. “Multiple studies have shown significant clonal evolution throughout the disease course. At 12 months, the genomics of the disease can be completely different than at the time of diagnosis,” she emphasized. “Clinicians need to be aware of what the best treatment is at each disease stage.”

Since 2017, a number of new targeted therapies have been approved for the treatment of subsets of patients with AML based on disease biology, specifically the unique cytogenetic, molecular, and flow cytometric features of their disease (Figure 1).

Figure 1.
Figure 1.

Targeted therapy based on AML biology.

aMidostaurin

bQuizartinib, crenolanib, gilteritinib.

cAPR-346; anti-CD47+Aza.

dCD123 ADC; CD123 BiTe; CD123 CART.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 7.5; 10.6004/jnccn.2020.5012

FLT3 Inhibitors

FLT3 is the most commonly mutated gene in patients with newly diagnosed AML and consists of 2 types: FLT3-ITD mutations occur in approximately 25% of cases, and FLT3-TKD mutations occur in approximately 10%. FLT3 mutations occur more frequently in younger patients (aged ≤60 years), patients with de novo AML, and in association with diploid cytogenetics. FLT3-ITD is known as an independent predictor of shorter disease-free survival and overall survival (OS).2 Currently, it is not clear whether the presence of FLT3-TKD confers poor prognosis; however, this gene mutation frequently arises following prior therapy as a harbinger of chemoresistance, Dr. Wang noted.

Numerous oral tyrosine kinase inhibitors against FLT3 (also known as FLT3-TKIs) are in development. The first-generation FLT3-TKIs (lestaurtinib, midostaurin, sorafenib) are multikinase targeted agents that were repurposed as treatment for other cancers. In general, they are much less potent and inhibitory than the second-generation FLT3-TKIs (quizartinib, crenolanib, gilteritinib) and frequently interact with other drugs. Second-generation FLT3-TKIs are much more potent inhibitors of mutant FLT3 but are also associated with certain unique side effects, including QTc prolongation, myelosuppression, gastrointestinal effects, rash, and other complications.

Incorporation of FLT3-TKIs into treatment of patients with FLT3-mutant AML (either newly diagnosed or relapsed/refractory) is now standard of care. The phase III RATIFY study performed in younger patients (aged 18–60 years) with newly diagnosed FLT3-mutant AML found that individuals receiving midostaurin in combination with the 7 + 3 regimen achieved significantly longer survival compared with those receiving placebo and chemotherapy alone (P=.009). Median OS was 74.7 months with the combination versus 25.6 months for placebo.3 “More recent phase II studies suggest that the newer generation of more potent specific FLT3-TKIs may further improve on the results with midostaurin plus chemotherapy,” Dr. Wang continued. Preliminary results of these trials (presented in abstract form) demonstrate complete remission (CR) rates of 84% to 93% compared with historical 59% remission rate following midostaurin and 7 + 3 chemotherapy. Multiple phase III studies currently evaluating quizartinib, crenolanib, and gilteritinib plus 7 + 3 regimen compared with midostaurin plus 7 + 3 are ongoing.

Single-agent FLT3-TKI therapy has been shown to be superior to chemotherapy alone for treatment of relapsed/refractory FLT3-mutant AML. The randomized phase III QUANTUM-R trial in patients with relapsed/recurrent AML characterized by FLT3 mutations demonstrated that oral quizartinib modestly improved OS over salvage chemotherapy.4 Results of the large randomized phase III ADMIRAL study demonstrated that gilteritinib was superior to high- or low-dose chemotherapy in a similar patient population.5 Although grade ≥3 hematologic toxicity can occur in 12% to 20% of patients treated with FLT3-TKI therapy alone, depending on the drug, in general, tolerability of a once-daily oral FLT3-TKI is overall much improved and can be administered in the outpatient setting as opposed to high-dose intensive salvage chemotherapy, she continued. Rare side effects of gilteritinib include differentiation syndrome, QTc interval prolongation, and pancreatitis. Because responses and side effects of drug can take up to 7 weeks to emerge, long-term monitoring for several months may be needed for these individuals.

Some early studies suggest that the effectiveness of FLT3-TKIs can be improved in both the upfront and relapsed setting by adding other chemotherapy regimens.6 Early results of studies performed in frail elderly patients suggest that gilteritinib as well as other TKIs (sorafenib, midostaurin) can be safely combined with low-dose chemotherapy (azacitidine, decitabine), providing yet another combinatorial regimen to be considered in appropriate patients. Lastly, based on current data, Dr. Wang provided some guidance on how to select the most appropriate FLT3 inhibitor for an individual patient and in consideration of each agent’s unique side-effect profile4,710 (Figure 2). In general, she stated, second-generation TKIs and novel combinations incorporating these TKIs will likely supplant midostaurin and intensive chemotherapy in the future, she said. “We look forward to incorporating these new FLT3-TKIs, but we need to monitor for the different toxicities as we consider long-term treatment and treatment of particularly older patients.”

Figure 2.
Figure 2.

How to select the best FLT3 inhibitor.

Abbreviations: chemo, chemotherapy; gen, generation; GI, gastrointestinal; HMA, hypomethylating agent; HSCT, hematopoietic stem cell transplantation; N/V, nausea and vomiting; R/R, relapse/refractory; TKI, tyrosine kinase inhibitor.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 7.5; 10.6004/jnccn.2020.5012

Targeting IDH Mutations

IDH mutations are found much less frequently than FLT3 mutations in patients with AML. IDH1 mutations occur in up to 5% to 10% of patients, and IDH2 mutations in 10% to 15%. Two IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor), are currently available for treatment of patients with newly diagnosed (ivosidenib) or relapsed/refractory (ivosidenib and enasidenib) IDH-mutant AML. “These oral drugs achieve low CR rates but result in clinical benefit (reflected by incomplete responses and stable disease) in up to 40% of patients, with prolonged survival lasting more than 19 months,” Dr. Wang told listeners.

Unique toxicities of IDH1/2 inhibitors include possible life-threatening differentiation syndrome occurring in 4% of patients with ivosidenib and in 7% with enasidenib. This potentially lethal adverse event can develop at any time during the first 3 months of treatment, with symptoms that can mimic those of fungal or bacterial pneumonia. Systemic treatment with corticosteroids is recommended, and hydroxyurea is often used to reduce the WBC count until symptoms resolve.11,12

“Neither of these drugs is ultimately curative, however, and resistance develops over time from the emergence of novel therapy–resistant AML clones. Therefore, there is much interest in combining both IDH inhibitors [ivosidenib and enasidenib] with standard chemotherapy for upfront treatment in IDH-mutated AML,” she said. “One study in progress is evaluating ivosidenib or enasidenib with intensive 7 + 3 regimen in younger patients with newly diagnosed IDH1-mutant AML. Long-term results are expected soon. Other trials have investigated IDH1 and IDH2 inhibitors in combination with azacitidine and have shown promising early response rates of 70%; however, confirmatory results for OS are needed.”

Venetoclax

“Of the most impact in the treatment of older patients with AML is venetoclax, a potent small molecule inhibitor targeting the BCL-2 anti-apoptotic pathway,” Dr. Wang said. “Single-agent venetoclax has resulted in low response rates in AML, but venetoclax plus low-dose chemotherapy (azacitidine) has rapidly become the standard of care for older adults with AML. Median survival is 14.7 months compared with 9.6 months for azacitidine alone. This combination is particularly useful for secondary AML.” One clinical caveat is that rates of myelosuppression and febrile neutropenia with infections were significantly higher for the combination regimen than for azacitidine alone, with many patients requiring close monitoring and frequent transfusions.13 Based on encouraging results of a phase Ib trial, the phase III VIALE-A trial comparing venetoclax + azacitidine versus azacitidine alone has completed accrual (ClinicalTrials.gov identifier: NCT02993523). This trial enrolled patients with newly diagnosed AML who were considered unfit for intensive chemotherapy. Importantly, it was announced in late March 2020 that this trial had met its primary endpoint, with significantly longer OS achieved in the venetoclax + azacitidine arm compared with the azacitidine alone arm.13 A similar phase III VIALE-C trial of venetoclax + low-dose cytarabine versus placebo and low-dose cytarabine in older adults with newly diagnosed AML who are unfit for intensive chemotherapy did not meet the primary OS endpoint for statistical significance. However, median survival was 7.2 months for the combination versus 4.1 months for placebo, and complete remission rates were 27.3% versus 7.4%, respectively.13 Responses were seen within the first 2 cycles of therapy. The most frequent grade ≥3 adverse events were febrile neutropenia and thrombocytopenia attributable to venetoclax. “Be aware of this complication in elderly individuals with baseline cytopenias at presentation,” she said.

An important question is whether this combination can be a bridge to stem cell transplantation (SCT) in older patients who are initially ineligible for transplant. “Stabilization with this regimen may allow these patients to undergo SCT,” she said. In a recent study,14 31 of 304 patients (10%) treated with venetoclax-based therapy successfully proceeded to SCT. Of these 31 patients, 68% (n=21) were alive 12 months posttransplant. Furthermore, of those 31 patients, 55% (n=17) experienced a posttransplant remission of ≥12 months, and of these 17 patients, 71% (n=12) remained in remission for ≥2 years, for a 12-month OS rate of 84%.

Additional studies are evaluating combining venetoclax with the 7 + 3 regimen (NCT03709758) and other chemotherapy regimens before (NCT04102020) and subsequent to allogeneic SCT (NCT04161885). Triple therapies with venetoclax, a hypomethylating agent, and a third agent such as antibody drug conjugates (SL401 [NCT03113643] and IMGN632 [NCT04086264]), FLT3 inhibitors (quizartinib [NCT03661307] and gilteritinib [NCT04140487)], and pevonedistat (NCT04266795) are also actively being studied.

Other Approaches

Other early-phase clinical trials suggest that novel inhibitors of other components of the apoptosis pathway may be worth pursuing for AML therapy. Examples of these drugs include APR-246 (for p53-mutant AML), idasanutlin (active in wild-type p53), AMG167/AMG197 (inhibitors of MCL-1), and alvocidib (inhibitor of CDK9, leading to MCL-1 inactivation).

Additionally, maintenance therapy with oral azacitidine has shown promise in reducing risk of relapse and prolonging survival of patients with AML in morphologic remission, according to a recent international randomized study.15 Patients who were older and fit for chemotherapy but were not eligible for SCT received 7 + 3 induction chemotherapy followed by consolidation chemotherapy, and then while in CR were randomized to receive either 12 months of oral azacytidine or placebo. A significant survival benefit was observed in patients receiving oral azacitidine over observation alone at a median follow-up of 41.2 months (P=.0009). Median OS was 24.7 months for the maintenance arm (n=246) versus 14.8 months for placebo (n=234); the risk of death was reduced by 31% (hazard ratio, 0.69; 95% CI, 0.55–0.86). “Although this approach was promising and obviously prolonged survival, again no patients were cured, and survival continued to trend downward over time. Maintenance therapy with oral azacitidine overall was well tolerated but was associated with more side effects compared with placebo, such as nausea, vomiting, diarrhea, constipation, and neutropenia,” Dr. Wang reported.

Emerging Therapies

In general, multiple prior studies of immune checkpoint inhibitors in patients with AML have been somewhat disappointing. The rate of adverse immunologic events is high (20%–30%), and there is currently no clear role for checkpoint inhibitors in unselected patients with AML. Whether specific patients with AML or biological subsets would benefit from such approaches remains to be determined, and many research groups are continuing to pursue such questions.

Recent clinical trials suggest that a more promising approach may be to target novel specific antigens expressed on leukemic cells, such as CD33, CD70/CD27, and CD47, with novel antibodies. Treatment with an anti-CD47–directed monoclonal antibody (magrolimab) in combination with azacitidine has led to very high response rates, particularly in patients with AML with a poor prognosis. Antibody drug conjugates and several bispecific antibodies are also being explored in various settings for AML therapy, including eradication of minimal residual disease.

“After all of this work and all these new agents, surely we must have found a cure for AML. Unfortunately, despite groundbreaking paradigm-changing therapies, median OS for an AML diagnosis remains dismal, ranging from 12 to 18 months in most patients,” she said. “The future of treating AML will rely on combinations of approved chemotherapy and targeted agents, novel mechanistic agents, and immunotherapy. I do think that over the next few years, we can do better.”

References

  • 1.

    Röllig C, Kramer M, Schliemann C, Time from diagnosis to treatment does not affect outcome in intensively treated patients with newly diagnosed acute myeloid leukemia [abstract]. Blood 2019;134 (Suppl 1):Abstract 13.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Litzow MR, Ferrando AA. How I treat T-cell acute lymphoblastic leukemia in adults. Blood 2015;126:833841.

  • 3.

    Stone RM, Larson RA, Dohner H. Midostaurin in FLT-3 mutated acute myeloid leukemia. N Engl J Med 2017;377:1303.

  • 4.

    Cortes J, Khaled S. Martinelli G, . Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukemia (QuaNTUM-R): a multicenter, randomized, controlled, open-label, phase 3 trial. Lancet Oncol 2019;20:984997.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Perl AE, Marinelli G, Cortes JE, Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 2019;381:17281740.

  • 6.

    Esteve J, Schots R, Del Castillo TB, Multicenter, open-label 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3-mutated acute myeloid leukemia patients ineligible for intensive induction chemotherapy: findings from the safety cohort [abstract]. Blood 2018;132(Suppl 1):Abstract 2738.

    • Search Google Scholar
    • Export Citation
  • 7.

    Stone RM, Mandrekar SJ, Sanford BL, Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454464.

  • 8.

    Ravandi F, Alattar ML, Grunwald MR, Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood 2013;121:46554662.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Perl AE, Altman JK, Cortes J, Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol 2017;18:10611075.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Wang ES, Tallman MS, Stone RM, Low relapse rate in younger patients ≤ 60 years old with newly diagnosed FLT-3 mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. Blood 2017;130:566.

    • Search Google Scholar
    • Export Citation
  • 11.

    DiNardo CD, Stein EM, deBotton S, Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018;378:23862398.

  • 12.

    Stein EM, DiNardo CD, Pollyea DA, . Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017;130:722731.

  • 13.

    Dinardo C, Jonas BA, Pullarkat V, A randomized double-blind placebo-controlled study of venetoclax with azacitidine vs azacitidine in treatment-naive patients with acute myeloid leukemia ineligible for intensive therapy: VIALE-A. Presented at the European Hematology Association (EHA) 25th Annual Congress; June 11–21, 2020; Frankfurt, Germany.

  • 14.

    Pratz KW, DiNardo CD, Arellano M, Outcomes after stem cell transplant in older adult patients with acute myeloid leukemia treated with venetoclax-based therapies [abstract]. Blood 2019;134(Suppl 1):Abstract 264.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Wei AH, Dohner H, Pocock C, The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia in first remission [abstract]. Blood 2019;134(Suppl 2):Abstract LBA-3.

    • Crossref
    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Disclosures: Dr. Wang has disclosed that she has received consulting fees from AbbVie, Inc.; Astellas Pharma US, Inc.; Daiichi-Sankyo Co.; Jazz Pharmaceuticals Inc.; Kite Pharma; Celyad; Stemline; and Pfizer Inc.; and has received honoraria from Stemline and Pfizer Inc.

Correspondence: Eunice S. Wang, MD, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263. Email: eunice.wang@roswellpark.org
  • View in gallery

    Targeted therapy based on AML biology.

    aMidostaurin

    bQuizartinib, crenolanib, gilteritinib.

    cAPR-346; anti-CD47+Aza.

    dCD123 ADC; CD123 BiTe; CD123 CART.

  • View in gallery

    How to select the best FLT3 inhibitor.

    Abbreviations: chemo, chemotherapy; gen, generation; GI, gastrointestinal; HMA, hypomethylating agent; HSCT, hematopoietic stem cell transplantation; N/V, nausea and vomiting; R/R, relapse/refractory; TKI, tyrosine kinase inhibitor.

  • 1.

    Röllig C, Kramer M, Schliemann C, Time from diagnosis to treatment does not affect outcome in intensively treated patients with newly diagnosed acute myeloid leukemia [abstract]. Blood 2019;134 (Suppl 1):Abstract 13.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Litzow MR, Ferrando AA. How I treat T-cell acute lymphoblastic leukemia in adults. Blood 2015;126:833841.

  • 3.

    Stone RM, Larson RA, Dohner H. Midostaurin in FLT-3 mutated acute myeloid leukemia. N Engl J Med 2017;377:1303.

  • 4.

    Cortes J, Khaled S. Martinelli G, . Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukemia (QuaNTUM-R): a multicenter, randomized, controlled, open-label, phase 3 trial. Lancet Oncol 2019;20:984997.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Perl AE, Marinelli G, Cortes JE, Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 2019;381:17281740.

  • 6.

    Esteve J, Schots R, Del Castillo TB, Multicenter, open-label 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3-mutated acute myeloid leukemia patients ineligible for intensive induction chemotherapy: findings from the safety cohort [abstract]. Blood 2018;132(Suppl 1):Abstract 2738.

    • Search Google Scholar
    • Export Citation
  • 7.

    Stone RM, Mandrekar SJ, Sanford BL, Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454464.

  • 8.

    Ravandi F, Alattar ML, Grunwald MR, Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood 2013;121:46554662.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Perl AE, Altman JK, Cortes J, Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol 2017;18:10611075.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Wang ES, Tallman MS, Stone RM, Low relapse rate in younger patients ≤ 60 years old with newly diagnosed FLT-3 mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. Blood 2017;130:566.

    • Search Google Scholar
    • Export Citation
  • 11.

    DiNardo CD, Stein EM, deBotton S, Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018;378:23862398.

  • 12.

    Stein EM, DiNardo CD, Pollyea DA, . Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017;130:722731.

  • 13.

    Dinardo C, Jonas BA, Pullarkat V, A randomized double-blind placebo-controlled study of venetoclax with azacitidine vs azacitidine in treatment-naive patients with acute myeloid leukemia ineligible for intensive therapy: VIALE-A. Presented at the European Hematology Association (EHA) 25th Annual Congress; June 11–21, 2020; Frankfurt, Germany.

  • 14.

    Pratz KW, DiNardo CD, Arellano M, Outcomes after stem cell transplant in older adult patients with acute myeloid leukemia treated with venetoclax-based therapies [abstract]. Blood 2019;134(Suppl 1):Abstract 264.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Wei AH, Dohner H, Pocock C, The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia in first remission [abstract]. Blood 2019;134(Suppl 2):Abstract LBA-3.

    • Crossref
    • Search Google Scholar
    • Export Citation
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