Updates on the Treatment of Acute Myeloid Leukemia

Lauren Ooka, PharmD BCOP
Clinical Pharmacist Specialist, Bone Marrow Transplant/Hematology
Franciscan Health Indianapolis
Indianapolis, IN

Bradley Yelvington, PharmD BCOP
Clinical Pharmacist, Adult Malignant Hematology
Vanderbilt University Medical Center
Nashville, TN

Acute myeloid leukemia (AML) is a hematologic malignancy that impairs normal hematopoiesis and leads to anemia, neutropenia, and thrombocytopenia.¹ This disease is expected to make up only 1.1% of all new cancer cases in 2018, yet it will account for 1.8% of all cancer deaths. Five-year overall survival (OS) rates from 2008 to 2014 were low, at only 27.4%.²

Despite the poor outcomes associated with AML, an increased understanding of the disease, and significant advances in treating other hematologic malignancies, standard treatment of AML had remained relatively unchanged for decades.³ Since 2017, however, the U.S. Food and Drug Administration (FDA) has approved five new drugs for the treatment of AML, potentially changing the treatment landscape for a disease that has proven difficult to treat.

Gemtuzumab Ozogamicin
Gemtuzumab ozogamicin (GO, Mylotarg) is a CD33-directed antibody drug conjugate linked to a cytotoxic antibiotic, calicheamicin. CD33 expression can be variable but is present on 40% or more leukemic blasts in three-fourths of patients.⁴ GO was originally approved in May 2000 for relapsed CD33-positive AML in older patients but was subsequently removed from the market because of lack of efficacy and increased toxicity, including early death. Several studies investigating fractionated GO dosing established better safety and efficacy, resulting in its reapproval in September 2017. GO is now indicated for treating newly diagnosed CD33-positive AML either as a single agent or in combination with 7+3 and in the relapsed or refractory setting as a single agent.⁵

ALFA-0701 was a phase 3 study that compared 7+3 (daunorubicin 60 mg/m² on days 1–3 and cytarabine 200 mg/m² on days 1–7) to 7+3 with GO (3 mg/m² [maximum dose 5 mg] on days 1, 4, and 7) in patients 50–70 years of age with previously untreated AML. A second induction could be given with daunorubicin 60 mg/m² on days 1–2 and cytarabine 1,000 mg/m² every 12 hours on days 1–3. Consolidation courses consisted of daunorubicin 60 mg/m² for 1 day (first course) or 2 days (second course), with cytarabine 1,000 mg/m² every 12 hours on days 1–4 with or without GO 3 mg/m² (maximum dose 5 mg) on day 1. The primary end point of event-free survival (EFS) was significantly longer in the GO arm, with a median EFS of 15.6 versus 9.7 months and a 2-year EFS of 40.8% versus 17.1% (p = .0003). The secondary end point of OS was also significantly prolonged in the GO arm, with a median OS of 34 months versus 19.2 months and a 2-year OS of 53.2% versus 41.9% (p = .0368). In a subgroup analysis, patients with favorable or intermediate-risk cytogenetics seemed to gain the most benefit from the addition of GO. Patients in the GO arm experienced more prolonged cytopenias, required more platelet transfusions, and had more liver toxicity (13% vs. 6%, p = .10). Three patients developed veno-occlusive disease (VOD), resulting in two deaths.⁶

The AML-19 trial compared GO (6 mg/m² on day 1 followed by 3 mg/m² on day 8, then 2 mg/m² on day 1 every 4 weeks for up to 8 cycles) to best supportive care (BSC) as front-line treatment in patients older than 60 years with AML who were unable to undergo intensive induction chemotherapy. The primary end point of OS was significantly prolonged in the GO arm, with a median OS of 4.9 months versus 3.6 months (p = .005). The benefit was greater in patients with more than 80% CD33-positive blasts. Grade 3 or higher liver toxicity was slightly higher in the GO arm (7.2% vs. 6.1%), but no cases of VOD were reported.⁷

The Mylofrance-1 trial studied single-agent GO (3 mg/m² on days 1, 4, and 7 for 1 course) in 57 patients with AML in first relapse. Overall response rate (ORR) was 33.3%, with 26% achieving complete response (CR) and 7% achieving complete response with incomplete platelet recovery (CRp). Median OS was 8.4 months, with a 1-year relapse rate of 57.4% and median relapse-free survival of 11 months. No episodes of VOD were reported, even in the three patients receiving an allogeneic stem cell transplant after GO treatment.⁸

Major considerations for pharmacists include monitoring for liver toxicity, avoiding concomitant hepatotoxic medications, and recommending appropriate dosing schedule based on indication.⁵

Midostaurin
Midostaurin (Rydapt) is an oral tyrosine kinase inhibitor approved by the FDA in 2017 for the treatment of FLT3-positive AML. Although it is used for its effects on FLT3, it can also affect KIT receptor, platelet-derived growth factor receptor (PDGFR) alpha/beta, vascular endothelial growth factor receptor 2 (VEGFR2), and other PDGFRs.9 In a study evaluating the mutational status of patients with cytogenetically normal AML, FLT3-ITD mutations were found in 31% and FLT-TKD in 11%. Although FLT3-ITD mutation is associated with poor outcomes, prognostic implications of a FLT3-TKD mutation are not as clear.¹⁰

The RATIFY trial (CALGB 10603) randomized 717 patients with FLT3 mutations to receive standard chemotherapy plus either midostaurin or placebo. Patients with both ITD (77.4%) and TKD (22.6%) mutations were included. Patients with FLT3-ITD mutations were also stratified based on high (29.8%) or low (47.6%) ratio of mutant to wild-type alleles. Midostaurin was given at a dose of 50 mg twice daily on days 8–21 of induction (7+3 with daunorubicin 60 mg/m2 on days 1–3 and cytarabine 200 mg/m² on days 1–7) and consolidation (high-dose cytarabine 3,000 mg/m² every 12 hours on days 1, 3, and 5) chemotherapy. The primary outcome of median OS was significantly longer in the midostaurin group: 74.7 months compared to 25.6 months in the placebo group (p = .009). Adverse events were similar between groups, with more grade 3 or greater rash (14% vs. 8%) and anemia (93% vs. 88%) in the midostaurin group and more grade 3 or greater nausea (6% vs. 10%) in the placebo group.¹¹

Major considerations for pharmacists include management of drug interactions (e.g., with CYP3A4 inhibitors and inducers), recommendations for monitoring (e.g., with electrocardiograms for QT prolongation and for signs and symptoms of rare but serious pulmonary toxicity (interstitial lung disease and pneumonitis), and patient counseling (e.g., regarding the drug’s moderate emetogenic potential and the need to take it with food).¹⁰

Liposomal Daunorubicin/Cytarabine
Liposomal daunorubicin/cytarabine (Vyxeos) received FDA approval in 2017 for the treatment of therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).¹² This agent, also known as CPX-351, is a liposomal combination of cytarabine and daunorubicin in a fixed 5:1 molar ratio, which was shown to be optimally synergistic in vitro.¹³ This formulation was also compared to standard, or “free,” chemotherapy in animal models, where it was shown to increase drug exposure in the bone marrow and preferentially affect leukemia cells over normal bone marrow cells.¹⁴

On the basis of this preclinical data and a subsequent randomized phase 2 trial that showed higher remission rates and improved OS and EFS with CPX-351 compared to 7+3 (daunorubicin 60 mg/m² on days 1–3 and cytarabine 100 mg/m2 on days 1–7) in patients with secondary AML, a phase 3 trial was initiated.¹⁵ This study compared CPX-351 to traditional 7+3 chemotherapy in 309 patients 60–75 years of age with high-risk or secondary AML. CPX-351 was given at the FDA-approved dose of daunorubicin 44 mg/m² (cytarabine 100 mg/m²) on days 1, 3, and 5 for induction and at the same doses on days 1 and 3 only for a second induction if necessary. The dose used for consolidation was 29 mg/m² of daunorubicin (65 mg/m² cytarabine) on days 1 and 3. This was compared to standard 7+3 therapy. A second induction could be given if needed in the traditional treatment group with 5+2 (cytarabine 100 mg/m² over 5 days and daunorubicin 60 mg/m² on days 1 and 2). The primary outcome of median OS was significantly longer in the CPX-351 group at 9.56 months compared to 5.95 months with 7+3 therapy (p = .003). The benefit of CPX-351 was maintained across all age groups and subtypes of AML. Adverse events were similar between groups; however, median times to neutrophil (35 vs. 29 days) and platelet (36.5 vs. 29 days) recovery were longer with CPX-351 compared to 7+3. This finding did not correspond with an increase in infection-related events but may have been related to an increase in bleeding events (all grades: 74.5% with CPX-351 vs. 59.6% with 7+3; grades 3–5: 11.8% vs. 8.6%).¹⁶

Major considerations for pharmacists include look-alike and sound-alike precautions (black-box warning for confusion with other chemotherapy), oversight of complicated admixture, and recommendations for monitoring (e.g., bleeding, cumulative anthracycline toxicity).¹²

Enasidenib and Ivosidenib
Isocitrate dehydrogenase (IDH) enzymes, including IDH1 and IDH2, are responsible for the conversion of isocitrate to alpha-ketoglutarate as part of the citric acid cycle within the cells of the body, including myeloid cells. Mutant IDH reduces alpha-ketoglutarate to beta-hydroxyglutarate. This results in gene hypermethylation, which halts myeloid differentiation and allows immature myeloid blasts to proliferate. By blocking mutant IDH, enasidenib and ivosidenib restore myeloid differentiation.¹⁷

Enasidenib (Idhifa) was approved in 2017 for the treatment of relapsed and refractory AML with an IDH2 mutation, which is present in about 10%–15% of AML cases.¹⁸ In a phase 1/2 study, enasidenib was investigated in adult patients with relapsed or refractory IDH2-mutated AML treated with enasidenib 100 mg by mouth (PO) daily (N = 109). The most common grade 3–4 treatment-related adverse events included hyperbilirubinemia (8%), IDH differentiation syndrome (IDH-DS) (7%), anemia (7%), and thrombocytopenia (5%). IDH-DS had a median time to onset of 48 days with a range of 10–340 days. Diagnosis of IDH-DS is often made by excluding other causes and should be suspected in patients with new or worsening respiratory symptoms, infiltrates or opacities on chest imaging, pleural or pericardial effusions, peripheral edema, rapid weight gain, or increased serum creatinine.¹⁹ Management includes systemic corticosteroids and dose interruption if symptoms persist beyond 48 hours after initiation of steroid treatment.²⁰ Ten patients in the study required dose interruption for IDH-DS without requiring permanent discontinuation of the drug. Hyperbilirubinemia was predominantly indirect, not associated with intrinsic liver toxicity, and was thought to be due to altered bilirubin metabolism by UGT1A1 inhibition. Adverse events generally decreased over time as treatment continued. ORR was 38.5% (median duration 5.6 months) with a CR or CR with incomplete count recovery (CRi) rate of 26.6% (median duration 8.8 months). Median time to first response was 1.9 months, with a median time to CR of 3.7 months. Ten percent of patients went on to receive allogeneic stem cell transplant. Median OS was 9.3 months, with an estimated 1-year survival rate of 39%. For patients with CR or partial response (PR), median survival was 19.7 months or 14.4 months, respectively. The phase 3 IDHENTIFY study comparing enasidenib to conventional care in late-stage IDH2-mutant AML is ongoing.¹⁹

Ivosidenib (Tibsovo) was approved in 2018 for the treatment of relapsed or refractory AML with a susceptible IDH1 mutation, an abnormality that occurs in 6%–10% of patients with AML. Approval was based on a phase 1 dose escalation and expansion study of ivosidenib 500 mg PO daily in 179 patients with relapsed or refractory AML. ORR was 41.6% (median duration 6.5 months) with a CR rate of 21.6% (median duration 9.3 months) and CR or CRi rate of 30.4% (median duration 8.2 months). The median time to response varied according to the type of response but ranged from 1.9 to 2.8 months. The most common grade 3–4 treatment-related adverse events in patients with relapsed or refractory AML treated with ivosidenib 500 mg daily were QT interval prolongation (7.8%), IDH-DS (3.9%), anemia (2.2%), thrombocytopenia (1.7%), and leukocytosis (1.7%). IDH-DS occurred in 10.6% overall in the relapsed or refractory AML population, with 5% of these cases being grade 3 or higher. Median time to onset of IDH-DS was 29 days (range 5–59 days). Treatment included glucocorticoids, diuretics, and hydroxyurea (in cases of concomitant leukocytosis), but no patients permanently discontinued ivosidenib because of IDH-DS.²¹

Major considerations for pharmacists include the need to educate patients on IDH-DS signs and symptoms (including possible late onset), QTc monitoring with ivosidenib, and the need for adequate duration of treatment prior to assessing disease status.^18-21

Conclusion
The FDA approvals in treatment of AML since 2017 are changing the treatment paradigm for this disease in both the front-line and relapsed and refractory settings. Changes are likely to continue as new and more selective FLT3 inhibitors are being investigated, IDH inhibitors are being studied in the up-front setting in combination with standard chemotherapy, the role of venetoclax is being elucidated, and other new agents are being explored. As knowledge of molecular mutations continues to grow, these targets may be exploited to provide new therapies and improve outcomes in a disease state with historic 5-year OS rates less than 30%.

References

1. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood. 2005;106:1154-1163.
2. SEER Cancer Stat Facts: Acute Myeloid Leukemia. Bethesda, MD: National Cancer Institute. Available at https://seer.cancer.gov/statfacts/html/amyl.html
3. Watts J, Nimer S. Recent advances in the understanding and treatment of acute myeloid leukemia. F1000 Faculty Rev. 2018:1196.
4. Godwin CD, Gale RP, Walter RB. Gemtuzumab ozogamicin in acute myeloid leukemia. Leukemia. 2017;31;1855-1868.
5. Mylotarg (gemtuzumab ozogamicin) for injection [product information per FDA]. Philadelphia, PA: Pfizer, Inc.; 2018.
6. Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukemia (ALFA-0701): A randomised, open-label, phase 3 study. Lancet. 2012;379:1508-1516.
7. Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: Results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34:972-979.
8. Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: A prospective study of the alfa group. Leukemia. 2007;21:66-71.
9. Rydapt (midostaurin) capsules [product information per FDA]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2018.
10. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18);1909-1918.
11. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454-464.
12. Vyxeos liposome (daunorubicin and cytarabine liposome) for injection [product information per FDA]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2017.
13. Tardi P, Johnstone S, Harasym N, et al. In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy. Leuk Res. 2009;33:129-139.
14. Lim WS, Tardi PG, Dos Santos N, et al. Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed ratio cytarabine:daunorubicin formulation in bone marrow xenografts. Leuk Res. 2010;34:1214-1223.
15. Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123:3239-3246.
16. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36:1-9.
17. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: Mechanisms, models, and clinical opportunities. Cancer Discov. 2013;3(7):730-741.
18. Stein EM, Tallman, MS. Emerging therapeutic drugs for AML. Blood. 2016;127(1):71-78.
19. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
20. Fathi AT, DiNardo CD, Kline I, et al. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol. 2018;4(8):1106-1110.
21. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398.