Improving Survival Rates in Patients with Relapsed and Refractory Acute Myeloid Leukemia

Page 1

SPECIAL REPORT

Improving Survival Rates in Patients with Relapsed and Refractory Acute Myeloid Leukemia

Molecular Subtypes of Acute Myeloid Leukemia and the Prevalence of FLT3 Mutation Clinical Guidelines and Standards of Care for the Treatment of AML Urgent Need for More Targeted Agents for Relapsed and Refractory AML Patients The Evolving Role and Development of New Targeted Therapies

Published by Global Business Media


TAKE A STAND FOR LONGER SURVIVAL XOSPATA Is the First Oral Monotherapy to Deliver Superior Overall Survival vs Salvage Chemotherapy in Relapsed or Refractory FLT3m+ AML1*

In the final analysis, XOSPATA delivered superior overall survival vs salvage chemotherapy1: †

36

% reduced risk of death

with XOSPATA (n=247) vs salvage chemotherapy (n=124)

• 9.3 months median OS (95% CI: 7.7, 10.7) vs 5.6 months with salvage chemotherapy (95% CI: 4.7, 7.3) HR=0.64 (95% CI: 0.49, 0.83); P=0.0004

The efficacy of XOSPATA was established on the basis of CR‡/CRh,§ the duration of CR/CRh (DOR), and the rate of conversion to transfusion independence at the first interim analysis1

21% CR/CRh

(95% CI: 14.5, 28.8; n=29/138)

• The median DOR was 4.6 months with XOSPATA (range: 0.1 to 15.8||; n=29/138) — DOR was defined as the time from the date of either first CR or CRh until the date of a documented relapse of any type. Deaths were counted as events

• Among patients in the XOSPATA arm who were transfusion dependent at baseline (n=106), 31.1% became transfusion independent with XOSPATA during any 56-day post-baseline period (n=33/106) — Transfusion independence is defined as patients who were dependent on RBC and/or platelet transfusions at baseline and became independent of RBC and platelet transfusions during any 56-day post-baseline period

Gilteritinib (XOSPATA) is the ONLY Category 1 recommendation for patients with relapsed or refractory AML with a FLT3 mutation in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) 2

• XOSPATA was evaluated in a Phase 3, open-label, multicenter, randomized clinical trial compared with a prespecified salvage 1,3 chemotherapy in 371 adult patients with relapsed or refractory FLT3m+ AML

• The efficacy of XOSPATA was based on an interim analysis and a final analysis1: — The first interim analysis evaluated the endpoints of CR/CRh, the DOR, and the rate of conversion from transfusion dependence to transfusion independence in 138 patients treated with XOSPATA — The final analysis evaluated the endpoint of OS and was measured from the date of randomization until death by any cause *FLT3 mutation status: FLT3-ITD, FLT3-TKD, and FLT3-ITD-TKD.1 † The OS endpoint was measured from the date of randomization until death by any cause in the final analysis, which included 371 patients randomized 2:1 to receive XOSPATA or a prespecified salvage chemotherapy regimen.1 ‡ CR defined as normal marrow differential with <5% blasts, ANC ≥1.0 x 109/L and platelets ≥100 x 109/L, no evidence of extramedullary leukemia, and must have been RBC and platelet transfusion independent.1 § CRh defined as marrow blasts <5%, partial hematologic recovery, ANC ≥0.5 x 109/L and platelets ≥50 x 109/L, no evidence of extramedullary leukemia, and could not have been classified as CR.1 || Response was ongoing.1 AML=acute myeloid leukemia; ANC=absolute neutrophil count; CI=confidence interval; CR=complete remission; CRh=complete remission with partial hematologic recovery; FLT3=FMS-like tyrosine kinase 3; HR=hazard ratio; ITD=internal tandem duplication; m+=mutation-positive; NCCN=National Comprehensive Cancer Network; OS=overall survival; RBC=red blood cell; TKD=tyrosine kinase domain.

References: 1. XOSPATA [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.2.2020. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed 09-05-2019. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 3. Astellas. XOSPATA. Data on File.

Please see adjacent pages for Brief Summary of Full Prescribing Information, including BOXED WARNING.


Indication XOSPATA is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test.

Important Safety Information Contraindications XOSPATA is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials.

WARNING: DIFFERENTIATION SYNDROME Patients treated with XOSPATA have experienced symptoms of differentiation syndrome, which can be fatal or life-threatening if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, or renal dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

Warnings and Precautions Differentiation Syndrome (See BOXED WARNING) 3% of 319 patients treated with XOSPATA in the clinical trials experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with XOSPATA included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as 2 days and up to 75 days after XOSPATA initiation and has been observed with or without concomitant leukocytosis. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt XOSPATA until signs and symptoms are no longer severe. Posterior Reversible Encephalopathy Syndrome (PRES) 1% of 319 patients treated with XOSPATA in the clinical trials experienced posterior reversible encephalopathy syndrome (PRES) with symptoms including seizure and altered mental status. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XOSPATA in patients who develop PRES. Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). 1% of the 317 patients with a post-baseline QTc measurement on treatment with XOSPATA in the clinical trial were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with XOSPATA, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration. Pancreatitis 4% of 319 patients treated with XOSPATA in the clinical trials experienced pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis. Embryo-Fetal Toxicity XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA

and for at least 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

Adverse Reactions Fatal adverse reactions occurred in 2% of patients receiving XOSPATA. These were cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis. The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%). 7% discontinued XOSPATA treatment permanently due to an adverse reaction. The most common (>1%) adverse reactions leading to discontinuation were aspartate aminotransferase increased (2%) and alanine aminotransferase increased (2%). The most frequent (≥5%) grade ≥3 nonhematological adverse reactions reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/ malaise (6%). Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (9%), hypersensitivity (8%), pancreatitis (5%), cardiac failure (4%), pericardial effusion (4%), acute febrile neutrophilic dermatosis (3%), differentiation syndrome (3%), pericarditis/myocarditis (2%), large intestine perforation (1%), and posterior reversible encephalopathy syndrome (1%). Lab Abnormalities Shifts to grades 3-4 nonhematologic laboratory abnormalities in XOSPATA treated patients included phosphate decreased (14%), alanine aminotransferase increased (13%), sodium decreased (12%), aspartate aminotransferase increased (10%), calcium decreased (6%), creatine kinase increased (6%), triglycerides increased (6%), creatinine increased (3%), and alkaline phosphatase increased (2%).

Drug Interactions Combined P-gp and Strong CYP3A Inducers Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases XOSPATA exposure which may decrease XOSPATA efficacy. Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers. Strong CYP3A inhibitors Concomitant use of XOSPATA with a strong CYP3A inhibitor increases XOSPATA exposure. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity. Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor Concomitant use of XOSPATA may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient.

Specific Populations Lactation Advise women not to breastfeed during treatment with XOSPATA and for 2 months after the last dose.

© 2019 Astellas Pharma US, Inc. All rights reserved. 077-0869-PM 10/19 Printed in USA. XOSPATA, Astellas, and the flying star logo are registered trademarks of Astellas Pharma Inc.

See the full story at XospataHCP.com


XOSPATA® (gilteritinib) tablets for oral use The following is a brief summary of full Prescribing Information. Please see the package insert for full prescribing information. WARNING: DIFFERENTIATION SYNDROME Patients treated with XOSPATA have experienced symptoms of differentiation syndrome, which can be fatal or life-threatening if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, or renal dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution. INDICATIONS AND USAGE XOSPATA is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test. DOSAGE AND ADMINISTRATION Patient Selection Select patients for the treatment of AML with XOSPATA based on the presence of FLT3 mutations in the blood or bone marrow. Information on FDAapproved tests for the detection of a FLT3 mutation in AML is available at http://www.fda.gov/CompanionDiagnostics. Recommended Dosage The recommended starting dose of XOSPATA is 120 mg orally once daily with or without food. Response may be delayed. In the absence of disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for a clinical response. Do not break or crush XOSPATA tablets. Administer XOSPATA tablets orally about the same time each day. If a dose of XOSPATA is missed or not taken at the usual time, administer the dose as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours. Dose Modification Assess blood counts and blood chemistries, including creatine phosphokinase, prior to the initiation of XOSPATA, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Perform electrocardiogram (ECG) prior to initiation of treatment with gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt dosing or reduce dose for toxicities. CONTRAINDICATIONS XOSPATA is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials. WARNINGS AND PRECAUTIONS Differentiation Syndrome Of 319 patients treated with XOSPATA in the clinical trials, 3% experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with XOSPATA included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as 2 days and up to 75 days after XOSPATA initiation and has been observed with or without concomitant leukocytosis. Of the 11 patients who experienced differentiation syndrome, 9 (82%) recovered after treatment or after dose interruption of XOSPATA. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt XOSPATA until signs and symptoms are no longer severe.

Posterior Reversible Encephalopathy Syndrome (PRES) Of 319 patients treated with XOSPATA in the clinical trials, 1% experienced posterior reversible encephalopathy syndrome (PRES) with symptoms including seizure and altered mental status. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XOSPATA in patients who develop PRES. Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). Of the 317 patients with a post-baseline QTc measurement on treatment with XOSPATA in the clinical trial, 1% were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration. Pancreatitis Of 319 patients treated with XOSPATA in the clinical trials, 4% experienced pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis. Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety profile of XOSPATA is based on 319 patients with relapsed or refractory AML treated with gilteritinib 120 mg daily in three clinical trials. The median duration of exposure to XOSPATA was 3.6 months (range 0.1 to 43.4 months). Fatal adverse reactions occurred in 2% of patients receiving XOSPATA. These included cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis. The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%). Of the 319 patients, 91 (29%) required a dose interruption due to an adverse reaction; the most common adverse reactions leading to dose interruption were aspartate aminotransferase increased (6%), alanine aminotransferase increased (6%) and fever (4%). Twenty patients (6%) required a dose reduction due to an adverse reaction. Twenty-two (7%) discontinued XOSPATA treatment permanently due to an adverse reaction. The most common (>1%) adverse reactions leading to discontinuation were aspartate aminotransferase increased (2%) and alanine aminotransferase increased (2%). Overall, for the 319 patients, the most frequent (≥10%) all-grade nonhematological adverse reactions reported in patients were transaminase increased (51%), myalgia/arthralgia (50%), fatigue/malaise (44%), fever (41%), mucositis (41%), edema (40%), rash (36%), noninfectious diarrhea (35%), dyspnea (35%), nausea (30%), cough (28%), constipation (28%), eye disorders (25%), headache (24%), dizziness (22%), hypotension (22%), vomiting (21%), renal impairment (21%), abdominal pain (18%), neuropathy (18%), insomnia (15%) and dysgeusia (11%). The most frequent (≥5%) grade ≥3 nonhematological adverse reactions reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%). Shifts to grades 3-4 nonhematologic laboratory abnormalities included phosphate decreased (14%), alanine aminotransferase increased (13%), sodium decreased


(12%), aspartate aminotransferase increased (10%), calcium decreased (6%), creatine kinase increased (6%), triglycerides increased (6%), creatinine increased (3%), and alkaline phosphatase increased (2%). Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (9%), hypersensitivity* (8%), pancreatitis* (5%), cardiac failure* (4%), pericardial effusion (4%), acute febrile neutrophilic dermatosis (3%), differentiation syndrome (3%), pericarditis/ myocarditis* (2%), large intestine perforation (1%), and posterior reversible encephalopathy syndrome (1%). *Grouped terms: cardiac failure (cardiac failure, cardiac failure congestive, cardiomegaly, cardiomyopathy, chronic left ventricular failure, and ejection fraction decreased), hypersensitivity (anaphylactic reaction, angioedema, dermatitis allergic, drug hypersensitivity, erythema multiforme, hypersensitivity, and urticaria), pancreatitis (amylase increased, lipase increased, pancreatitis, pancreatitis acute), pericarditis/myocarditis (myocarditis, pericardial hemorrhage, pericardial rub, and pericarditis).

DRUG INTERACTIONS Combined P-gp and Strong CYP3A Inducers Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases gilteritinib exposure which may decrease XOSPATA efficacy. Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers. Strong CYP3A Inhibitors Concomitant use of XOSPATA with a strong CYP3A inhibitor increases gilteritinib exposure. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity. Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor Concomitant use of gilteritinib may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, XOSPATA can cause fetal harm when administered to a pregnant woman. There are no available data on XOSPATA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, administration of gilteritinib to pregnant rats during organogenesis caused adverse developmental outcomes including embryo-fetal lethality, suppressed fetal growth, and teratogenicity at maternal exposures (AUC24) approximately 0.4 times the AUC24 in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data In an embryo-fetal development study in rats, pregnant animals received oral doses of gilteritinib of 0, 0.3, 3, 10, and 30 mg/kg/day during the period of organogenesis. Maternal findings at 30 mg/kg/day (resulting in exposures approximately 0.4 times the AUC24 in patients receiving the recommended dose) included decreased body weight and food consumption. Administration of gilteritinib at the dose of 30 mg/kg/day also resulted in embryo-fetal death (post implantation loss), decreased fetal body and placental weight, and decreased numbers of ossified sternebrae and sacral and caudal vertebrae, and increased incidence of fetal gross external (anasarca, local edema, exencephaly, cleft lip, cleft palate, short tail, and umbilical hernia), visceral (microphthalmia; atrial and/or ventricular defects; and malformed/absent kidney, and malpositioned adrenal, and ovary), and skeletal (sternoschisis, absent rib, fused rib, fused cervical arch, misaligned cervical vertebra, and absent thoracic vertebra) abnormalities. Single oral administration of [14C] gilteritinib to pregnant rats resulted in transfer of radioactivity to the fetus similar to that observed in maternal plasma on day 14 of

gestation. In addition, distribution profiles of radioactivity in most maternal tissues and the fetus on day 18 of gestation were similar to that on day 14 of gestation. Lactation Risk Summary There are no data on the presence of gilteritinib and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Following administration of radiolabeled gilteritinib to lactating rats, milk concentrations of radioactivity were higher than radioactivity in maternal plasma at 4 and 24 hours post-dose. In animal studies, gilteritinib and/or its metabolite(s) were distributed to the tissues in infant rats via the milk. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with XOSPATA and for 2 months after the last dose. Females and Males of Reproductive Potential Pregnancy testing Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating XOSPATA treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose of XOSPATA. Males Advise males of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose of XOSPATA. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the 319 patients in clinical studies of XOSPATA, 43% were age 65 years or older, and 13% were 75 years or older. No overall differences in effectiveness or safety were observed between patients age 65 years or older and younger patients. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with gilteritinib. Gilteritinib was not mutagenic in a bacterial mutagenesis (Ames) assay and was not clastogenic in a chromosome aberration test assay in Chinese hamster lung cells. Gilteritinib was positive for the induction of micronuclei in mouse bone marrow cells from 65 mg/kg (195 mg/m2) the mid dose tested (approximately 2.6 times the recommended human dose of 120 mg). The effect of XOSPATA on human fertility is unknown. Administration of 10 mg/kg/day gilteritinib in the 4-week study in dogs (12 days of dosing) resulted in degeneration and necrosis of germ cells and spermatid giant cell formation in the testis as well as single cell necrosis of the epididymal duct epithelia of the epididymal head. Animal Toxicology and/or Pharmacology In the 13-week oral repeated dose toxicity studies in rats and dogs, target organs of toxicity included the eye and kidney. Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Revised: 05/2019 222317-GLT Rx Only © 2019 Astellas Pharma US, Inc. XOSPATA® is a registered trademark of Astellas Pharma Inc.

077-0610-PM


SPECIAL REPORT

Improving Survival Rates in Patients with Relapsed and Refractory Acute Myeloid Leukemia

IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA

Contents Foreword

1

Anna Love, M.B.S., Ph.D.

Molecular Subtypes of Acute Myeloid Leukemia and the Prevalence of FLT3 Mutation Clinical Guidelines and Standards of Care for the Treatment of AML Urgent Need for More Targeted Agents for Relapsed and Refractory AML Patients The Evolving Role and Development of New Targeted Therapies

Published by Global Business Media

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org

Molecular Subtypes of Acute Myeloid Leukemia and the Prevalence of FLT3 Mutation

2

Anna Love, M.B.S., Ph.D.

Spliceosome-Complex Genes Myeloid Transcription Factor Mutations Nucleophosmin (NPM1) Status DNA Methylation-Related Genes Tumour Suppressor Genes Chromatin-Modifying Genes Cohesin-Complex Genes Signaling Genes

Publisher Kevin Bell

Clinical Guidelines and Standards 4 of Care for the Treatment of AML

Business Development Director Marie-Anne Brooks

Anna Love, M.B.S., Ph.D.

Editor Anna Love

AML Standards of Care

Senior Project Manager Steve Banks

AML Standards of Care for Elderly Patients PML Standards of Care

Advertising Executives Michael McCarthy Abigail Coombes

Targeted Therapies for AML Molecular Subtypes

Production Manager Paul Davies

Urgent Need for More Targeted Agents for 6 Relapsed and Refractory AMLPatients

For further information visit: www.globalbusinessmedia.org The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated. Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles.

The Role of Stem Cell Transplants in the AML Landscape

Anna Love, M.B.S., Ph.D.

FLT3-Targeted Therapies for the Treatment of AML

The Evolving Role and Development 8 of New Targeted Therapies Anna Love, M.B.S., Ph.D.

Future Outlooks

References 10

Š 2020. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical photocopying, recording or otherwise, without the prior permission of the copyright owner.

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IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA

Foreword

L

eukemia is a relatively rare form of cancer,

high risk and poor outcome.3 The array of leukemic

accounting for roughly 1% of new cancer

subtypes and prevalence of FLT3 mutations in AML

diagnoses each year. Acute myeloid leukemia

highlight the importance of genetic profiling at the

(AML) is the deadliest and most common type of

time of diagnosis for comprehensive prognostics

leukemia, making up approximately one-third of all

and for identifying targetable oncogenic pathways.

leukemia diagnoses. At just over 11,000 deaths a

As FLT3 inhibitors entered the treatment landscape,

year, AML accounts for nearly half the number of

FLT3 profiling at diagnosis shifted from being purely

annual leukemia deaths (23,100).1 In broad terms,

prognostic to being predictive of patient response

AML can be further categorized based on genetic

and overall survival.4

aberrations, clinical manifestations, and patient

With their distinct immunophenotypic profiles,

prior treatment. The World Health Organization

AML and acute lymphoblastic leukemia (ALL) are

(WHO) divides AML into no fewer than two dozen

distinguished through flow cytometry, which is

subtypes with differing prognostic factors.2 Distinct

performed for 99.1% of all AML patients. Karyotyping,

leukemia molecular subtypes are identifiable by

which 98% of AML patients receive, further

immunophenotype, chromosomal mutation, and

distinguishes clonal cytogenetic abnormalities as

gene mutation.

subtypes of AML.5,6 A 2016 survey found that only

The most common AML mutation is the FMS-like

51% of AML patients were tested for FLT3 genetic

tyrosine kinase 3 (FLT3) gene, which is detected in

mutations, ostensibly leaving a significant portion

approximately 30% of AML cases. Of FLT3 mutation

of AML patients with a gap in treatment options.5

subtypes, internal tandem duplication (ITD) is the

However, that gap is quickly closing.

most common, with FLT3-ITDs found in 25% of all AML cases.3 According to the National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN), the FLT3-ITD mutation is associated with

Anna Love Editor

Dr. Anna Love earned her bachelor’s degree in English in 2009, before returning to school in 2011 for post-baccalaureate studies in science. In 2014, Dr. Love completed her master’s degree in biomedical sciences at William Carey College of Medicine. After which, Dr. Love pursued a Ph.D. in molecular biosciences at Middle Tennessee State University with a focus on developmental and cell biology. Dr. Love currently works as a research fellow at Vanderbilt University Medical Center in the Department of Medicine.

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IMPROVING IMPROVINGSURVIVAL SURVIVALRATES RATESIN INPATIENTS PATIENTSWITH WITHRELAPSED RELAPSEDAND ANDREFRACTORY REFRACTORYACUTE ACUTEMYELOID MYELOIDLEUKEMIA LEUKEMIA

Molecular Subtypes of Acute Myeloid Leukemia and the Prevalence of FLT3 Mutation Anna Love, M.B.S., Ph.D.

A

Based on 200 mutational profiles from AML patients in The Cancer Genome Atlas (TCGA) project, 23 genes were found to be recurrently mutated and patients averaged 13 coding mutations

S EVINCED in the introduction, the four main leukemia types: AML, ALL, chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL) have a large array of molecular subtypes. While AML has fewer mutations per exome or genome compared to other cancer types, those mutations combine in such diverse and unique ways that heterogeneity and patient response are highly variable.10 While characterizing all of the AML molecular subtypes has been a difficult undertaking, major advances in understanding the expansive landscape of AML allowed for the identification of new prognostic markers and help set the course for new molecularly targeted treatments.11 Based on 200 mutational profiles from AML patients in The Cancer Genome Atlas (TCGA) project, 23 genes were found to be recurrently mutated and patients averaged 13 coding mutations. From TGCA, nearly all samples had at least one mutation from one of nine distinct functional gene categories.10 The categories and rate of occurrence in TCGA cohort include: transcription factor fusions (18%), gene encoding nucleophosmin (NPM1) (27%), tumour-suppressor genes (16%), DNA methylation-associated genes (44%), signaling genes (such as FLT3) (59%), chromatinmodifying genes (30%), myeloid transcription factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%).12

Spliceosome-Complex Genes Mutations in splicing genes SRSF2, U2AF1, ZRSR2, and SXF3B1 have been recognized in myelodysplastic syndromes (MDS), severe cases of which can become AML.13 Mutated SRSF2 indicate shorter overall survival and more frequent AML progression, and has a high association with RUNX1, a myeloid transcription factor, gene mutation.14

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Myeloid Transcription Factor Mutations Acute myeloid leukemia 1 (AML1) protein, also known as runt-related transcription factor 1 (RUNX1) or core-binding factor subunit alpha-2 (CBFA2), is a protein encoded by the RUNX1 gene.15,16 RUNX1 chromosomal translocations are the most common aberrations found in acute leukemia. AML-1 is a critical regulator of hematopoietic cell development, and when these translocations are present cell production is disrupted.15 RUNX1 mutations are frequently found in radiation-exposed patients with MDS/AML and is associated with poor prognosis. However, the presence of mutated CCAAT enhancerbinding protein alpha (CEBPA), another transcription factor-encoding gene, is associated with a more favorable prognosis for AML patients, indicated by longer remission duration and overall survival than AML patients without CEBPA mutation.17

Nucleophosmin (NPM1) Status AML-carrying nucleophosmin (NPM), a protein encoded by the NPM1 gene that can shuttle cargo from the nucleolus to the nucleoplasm. In a New England Journal of Medicine study, 35.2% of primary AML patients exhibited cytoplasmic accumulation of NPM, a result of NPM1 gene mutation. The presence of cytoplasmic NPM was associated with a normal karyotype and better patient response to induction chemotherapy. This study also reported a high frequency of FLT3-ITDs in CD34- and CD133-negative AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, which is associated with poor outcomes.18

DNA Methylation-Related Genes DNA methylation is an epigenetic posttranslational modification that regulates gene expression and the production of blood cells.


IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA

Quizartinib is a small molecule receptor tyrosine kinase inhibitor for the treatment of acute myeloid

Many cancer types present with alterations in DNA methylation, which lead to genomic instability and aberrant gene expression.19 Hypermethylated tumour suppressor genes become defective, generating a poor outcome. DNA methylation is considered an important marker for early diagnosis, prognosis, and therapeutic decision making in the treatment of AML. Approximately, 25% of AML patients present with a DNA methylation-related mutation.20

Tumour Suppressor Genes The most prevalent tumour suppressor gene across all cancers is TP53. Though its prevalence in AML is significantly lower than in other types of cancer, the presence of TP53 mutations indicates a high resistance to chemotherapy and high risk of relapse. Most AMLs display no genomic TP53 alterations and this may prove to be advantageous as new targeted therapies are developed capable of exploiting unaltered genes.21

Chromatin-Modifying Genes Genes responsible for stem cell development and myeloid/lymphoid cell lineage have been found to be fused to incorrect chromatinmodifying enzymes.15 Additional sex combs-

like 1 (ASXL1) mutations are regularly found in MDS, AML, chronic myeloid leukemia, chronic myelomonocytic leukemia, and myeloproliferative neoplasms. ASXL1 interacts with retinoic acid receptors and is a putative driver of chromatin remodeling.16

Cohesin-Complex Genes The cohesin complex is a multiprotein ring that aligns and stabilizes replicated chromosomes prior to cell division. STAG2 mutations within the cohesin complex are frequently found in AML, as well as, in solid tumours and are found in Ewing’s Sarcoma, bladder cancer, and glioblastoma.22

Wild-type FMS-like tyrosine kinase 3 (FLT3) receptors have been found at the mRNA and/or protein level in 93% of AML patients, 87% of T-cell acute lymphoblastic leukemia, and nearly 100% of B-cell ALL patients

Signaling Genes Wild-type FMS-like tyrosine kinase 3 (FLT3) receptors have been found at the mRNA and/ or protein level in 93% of AML patients, 87% of T-cell acute lymphoblastic leukemia, and nearly 100% of B-cell ALL patients.23 Genotyping of colonies and relapse samples suggest that signaling gene mutations are a result of clonal interference, which is pervasive in cancers but has unclear mechanisms and prognostic impact.24 Due to its mutational frequency, FLT3-targeted therapies are at the forefront of AML personalized treatment.

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Clinical Guidelines and Standards of Care for the Treatment of AML Anna Love, M.B.S., Ph.D.

A

The first line of therapy to induce remission for AML patients, excluding those with the acute promyelocytic leukemia (APL) subtype, is typically intensive chemotherapy using cytarabine plus an anthracycline drug, such as daunorubicin or idarubicin

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CUTE MYELOID leukemia (AML) contains a relatively large number of molecular subtypes, indicating a broad range of clinical standards of care for optimal treatment. Molecular profiling at the time of diagnosis is essential for targeting these individualized subt ypes. Common point mutations include: FLT3 (28% prevalence), NPM1 (27% prevalence), DNMT3A (26% prevalence), IDH1/2 (20% prevalence), NRAS/KRAS (12% prevalence), RUNX1 (10% prevalence), TET2 (8% prevalence), TP53 (6-8% prevalence), and CEBPA (6% prevalence). Oncogenic fusions are also associated with AML; these include PML-RARA (9% prevalence), AML1-ETO (410% prevalence), and CBFB-MYH11 (5% prevalence). Chromosomal losses or deletions such as loss of chromosome 5 or 5q deletions (7-8% prevalence) and loss of chromosome 7 or 7q deletions (10% prevalence) are also seen in AML patients.36

AML Standards of Care AML treatments are delivered in three phases, remission induction, consolidation, and maintenance. The first line of therapy to induce remission for AML patients, excluding those with the acute promyelocytic leukemia (APL) subtype, is typically intensive chemotherapy using cytarabine plus an anthracycline drug, such as daunorubicin or idarubicin. These intensive induction therapies are optimal for patients under 60 years of age lacking certain comorbidities, which would make them poor candidates for intensive chemotherapy regimens. Along with these first-line chemotherapies, clinicians may add midostaurin for FLT3- mutant or gemtuzumab ozogamicin for CD33-positive AML patients. In some instances, including hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia, cladribine is added to the remission induction therapy phase. If the patient has high levels of leukemia cells in the blood, leukapheresis to treat the leukostasis may precede chemotherapy.37

During the consolidation phase, the standard treatment plan for AML patients under 60 years of age includes multiple cycles of cytarabine and/or either allogeneic or autologous stem cell transplant. Midostaurin or gemtuzumab ozogamicin may be added to this consolidation phase regimen if it was used during the induction phase. Older patients receive less intensive treatment during the consolidation phase, which may consist of slightly lower high-dose cytarabine, standard-dose cytarabine with or without idarubicin, daunorubicin, or mitoxantrone, and/or non-myeloablative stem cell transplant (mini-transplant). If the older AML patient received mitoxantrone during the induction phase, it may be continued during the consolidation phase.

AML Standards of Care for Elderly Patients For frail or elderly patients, alternate, less intensive standards of care are applied during the consolidation phase. Low-dose cytarabine or demethylating agents like azacitidine or decitabine can be used alone. In addition to lowintensity chemotherapy, targeted agents such as the BCL2 inhibitor, venetoclax, or sonic hedgehog (SHH) pathway inhibitor, glasdegib, can be useful for some AML patients. Patients with known IDH1 or IDH2 mutations can be treated, respectively, with ivosidenib or enasidenib alone. Gemtuzumab ozogamicin may also be used alone if the AML cells are CD33 positive.37

PML Standards of Care PML standards of care are different from other AML subtypes and rely on differentiating agents, like all-trans-retinoic acid (ATRA), which targets RARÎą of the PML-RARÎą fusion protein seen in 8% of AML patients.36 Other PML treatments might include chemotherapy and transfusions of platelets or other blood products. Like AML, PML treatments are administered in three phases, remission induction, consolidation, and maintenance. Usually for induction therapy, ATRA is combined with either: arsenic trioxide (ATO)


IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA

with the addition of gemtuzumab ozogamicin for those with high risk for recurrence, an anthracycline chemotherapy with the addition of cytarabine for those at high risk for recurrence, or anthracycline chemotherapy plus ATO.37 Consolidation therapy consists of either ATRA plus ATO, ATRA plus an anthracycline chemotherapeutic agent, ATO plus an anthracycline chemotherapeutic agent, or chemotherapy alone using anthracycline and cytarabine. Patients with high risk of recurrence are given maintenance therapies, including ATRA alone or ATRA along with chemotherapy, such as 6-mercaptopurine and/or methotrexate.37

Targeted Therapies for AML Molecular Subtypes Targeted therapies for AML allow clinicians to provide a tailored regimen to suit a patient’s molecular profile. With FLT3 being the most prevalent mutation in AML, FLT3 inhibitors currently available include midostaurin and gilteritinib. Midostaurin can be administered with certain chemotherapeutic agents as a first-line treatment, while gilteritinib is indicated for adults who have not responded to initial treatment or with recurrent AML. Gilteritinib can result in a serious but rare complication referred to as differentiation syndrome, treatable with a pause in gilteritinib treatment and a round of steroids such as dexamethasone.37 Similar to other tyrosine kinase inhibitors, a major obstacle for FLT3 therapies is acquired resistance. Studies have shown that using a combination of FLT3 inhibitors can help combat acquired resistance.36 IDH1 and IDH2 mutations occur in approximately 20% of AML patients. Ivosidenib targets IDH1-mutant AML, while enasidenib targets IDH2-mutant AML. Both of these drugs are suitable first-line therapies for IDH1or IDH2- mutant patients who cannot tolerate intensive chemotherapy. Both of these drugs can result in differentiation syndrome. Like with gilteritinib, IDH-targeted drugs should be halted and the patient should be treated with steroids before resuming treatment if differentiation syndrome occurs.37 In 20% of AML patients, DNMT3A is altered, resulting in hypermethylation of important tumour suppressor genes, rendering their tumour suppressor function useless. DNMT3A-mutant patients tend to benefit from hypomethylating agents, such as azacitidine and decitabine, which have generated higher response rates and overall survival, particularly in elderly patients.37 For CD33-positive AML patients, a monoclonal antibody-chemotherapeutic conjugate

gemtuzumab ozogamicin, can be added to first-line chemotherapy treatment. Most AML cells are CD33 positive. By targeting CD33 protein, the monoclonal antibody component of gemtuzumab ozogamicin acts as a homing agent for the cytotoxic component, making it more target specific. As previously mentioned, gemtuzumab ozogamicin is also an appropriate first-line therapy for patients who cannot tolerate intensive chemotherapy or when the patient is no longer responsive to other therapies.37 For patients over 75 years old who cannot tolerate intensive chemotherapy as a first-line therapy, venetoclax in combination with a lessintensive chemotherapeutic agent, such as cytarabine, is the standard of care. Venetoclax inhibits BCL-2, a protein known to promote cancer cell survival. Along with typical side effects, tumour lysis syndrome can occur in these patients. Tumour lysis syndrome occurs when the apoptotic leukemia cell fragments overwhelm the kidneys. Therefore, clinicians are advised to gradually titrate the dose of venetoclax to avoid tumour lysis syndrome.37 In patients with hedgehog pathway mutations or overactivity, glasdegib can be given in combination with less intensive chemotherapy, such as low dose cytarabine, as a first-line therapy for patients 75 years or older who cannot tolerate intensive chemotherapy. Because the hedgehog pathway is essential for fetal development, glasdegib should not be used in patients who are pregnant or who could become pregnant.37

The Role of Stem Cell Transplants in the AML Landscape Stem cell transplants are often used for AML patients who are amenable to higher doses of chemotherapy and radiation for stem cell ablation. Allogeneic stem cell transplant (alloSCT) is the most common type of stem cell transplant, with emphasis placed on the donor human leukocyte antigen (HLA) compatibility. For older patients who cannot tolerate high doses of chemotherapy and radiation, nonmyeloablative transplants (mini-transplants) are available. The second major class of stem cell transplants are autologous stem cell transplants, during which the patient’s own stem cells are removed and frozen while the patient receives high-dose radiation and chemotherapy. After treatment, the stem cells are reintroduced into the patient. Autologous transplants are suitable when the patient does not have an adequate HLA match or for patients in remission.37

Stem cell transplants are often used for AML patients who are amenable to higher doses of chemotherapy and radiation for stem cell ablation. Allogeneic stem cell transplant (allo-SCT) is the most common type of stem cell transplant, with emphasis placed on the donor human leukocyte antigen (HLA) compatibility

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Urgent Need for More Targeted Agents for Relapsed and Refractory AML Patients Anna Love, M.B.S., Ph.D.

Between 50-60% of AML patients over 60 years of age achieve complete remission with standard induction therapies, with only 1020% of patients surviving 4 years or more

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For AML, the terms refractory and relapse are nuanced and have specific markers. Most AML patients achieve disease remission after initial treatment. After receiving two full cycles of intensive induction chemotherapy, residual leukemic cells may remain in the marrow, and these patients are diagnosed with refractory AML. Patients with refractory AML may be candidates for stem cell transplants if they achieve remission. AML patients who reach remission and then have leukemia cells return are diagnosed with relapsed leukemia.25 The treatment landscape for AML has not changed much over the last 30 to 40 years, with the majority of treatment decisions revolving around the intensity of chemotherapy and possible hematopoietic stem cell transplantation (HSCT). Outcomes of this standard of treatment are poor. Between 50-60% of AML patients over 60 years of age achieve complete remission with standard induction therapies, with only 1020% of patients surviving 4 years or more.26 For AML patients with relapsed and/or refractory disease, treatment outcomes are downright dismal. Patients with relapsed/refractory disease have a cure rate of less than 10%, with stem cell transplants being possible for a minority of this subset.26 For older patients, the 10-year disease-free survival rate is approximately 2%.27 Indeed, most patients with AML die from progressive disease after relapse. AML relapse is associated with new point mutations and clonal evolution at the cytogenic level, likely shaped by the chemotherapy received by the patients for initial treatment.28 As it stands, the reliance on standard chemotherapy alone leaves a huge treatment gap in terms of potential initial treatments and possibly promoting disease relapse. Identifying and understanding the molecular complexity and genetic mutations associated with AML and relapsed/refractory AML has led to the development of nonchemotherapeutic treatment

strategies and drugs. Until 2017, no new drugs for AML treatment had been approved for over 50 years, with the exception of gemtuzumab ozogamycin, which was withdrawn from the market in June 2010 and then reintroduced in 2017 after further clinical trials illustrated the benefits outweigh the risks.26 The recent surge in newly approved treatments should be seen as the inevitable culmination of long-term research in one of the most difficult fields of oncological study. The complexity of leukemic diseases makes one-size-fits-all therapies appealing. Theoretically, it is easier to treat a collective disease as one and utilize a monotherapeutic approach. The results of such an approach are apparent only after the fact. In fact, they become glaringly apparent after decades of monotherapies and decades of dismal survivability and prognoses. The interpretations of those results are controversial. One interpretation is that leukemic diseases are inherently difficult to treat because they have a low response rate to traditional chemotherapies. Another interpretation would require looking at all the subtypes of leukemic disease as individual diseases driven by specific mutations and requiring more individualized or targeted treatments.

FLT3-Targeted Therapies for the Treatment of AML FLT3 wild-type (FLT3-WT) receptors being nearly ubiquitous, FLT3 gene mutations are the most common genetic aberrations in AML, occurring in approximately 30% of cases. FLT3 mutations are less common in refractory/relapse AML than in new diagnoses (9% and 26%, respectively), but they have a higher likelihood of recurrence.23 FLT3 internal tandem duplication (-ITD) and tyrosine kinase domain (-TKD) are biomarkers for high risk AML and drug-resistance. When mutated in AML patients, FLT3 ramps up proliferation of hematopoietic stem cells


IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA

Acute myeloid leukemia - blood disorder abstract.

and boosts white blood cell count. Mentioned previously, when FLT3 co-occurs with NPM1 mutations (NPM1 mutations occur in 27% of AML patients), prognosis is particularly poor.29 For relapse or refractory AML patients, further treatment is typically enrollment in clinical trials or salvage therapy. Salvage therapy is a rather broad and macabre term that indicates no other treatment options are available. Gilteritinib (Xospata) was used in a phase 3 trial in exactly this manner. A 2:1 ratio of eligible relapsed or refractory AML patients (247:124) received gilteritinib or salvage chemotherapy, respectively. Median overall survival rates were significantly higher in the gilteritinib group than in the chemotherapy group (9.3 months compared to 5.6 months, respectively). Full or partial hematologic recovery was also significantly higher in the gilteritinib group (34% compared to 15.3% in the chemotherapy group), as was complete remission rates (21.1% in the gilteritinib group compared to 10.5% in the chemotherapy group).30

For allogeneic hematopoietic stem cell transplant (allo-SCT) recipients, the addition of an FLT3 inhibitor may improve overall survivability. Allo-SCT offers the highest potential long-term survivability for patients with intermediate- or high-risk disease, but that is not a high standard. Disease relapse is common in AML post alloSCT, with 50% of patients relapsing and, in the case of early relapse, being unable to tolerate or becoming refractory to follow-up chemotherapy. Two-year survival for relapsed transplant recipients is less than 20%.31 The point at which relapse is detected may make the most difference in patient overall survival. Closely monitoring minimal residual disease (MRD) post-transplant can help catch relapse quickly and greatly improve overall survival. Polymerase chain reaction (PCR) analysis to detect genetic mutations has a high level of specificity and sensitivity that makes it an appropriate choice for MRD monitoring. PCR assays detect leukemiaspecific transcripts such as fusion genes or mutated or overexpressed genes.31,32

Identifying and understanding the molecular complexity and genetic mutations associated with AML and relapsed/ refractory AML has led to the development of nonchemotherapeutic treatment strategies and drugs

For allogeneic hematopoietic stem cell transplant (allo-SCT) recipients, the addition of an FLT3 inhibitor may improve overall survivability.

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IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA

The Evolving Role and Development of New Targeted Therapies Anna Love, M.B.S., Ph.D.

As a monotherapy,

gilteritinib has significant overall survival improvements over salvage chemotherapy in relapse or refractory AML

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Focusing on the prevalence of FLT3-ITD or -ITK mutations in AML, tyrosine kinase inhibitors (TKIs) are a promising subset of targeted therapies that can be used as monotherapy or in combination. TKIs, like gilteritinib, bind to FLT3 at the ATPbinding site, preventing phosphorylation of FLT3 and another signaling protein STAT5.33 FLT3 receptors play a key role in stem cell proliferation, differentiation, and survival.29 A second-generation TKI, gilteritinib is more specific and more potent than first generation TKIs such as midostaurin. Gilteritinib was also the first FLT3 inhibitor to be approved as a monotherapy, showing improved survival over salvage chemotherapy in relapsed/ refractory AML. After decades of little to no advancement in AML treatments, the promise and approval of targeted therapies offers hope for a disease with typically poor outcomes. As a monotherapy, gilteritinib has significant overall survival improvements over salvage chemotherapy in relapse or refractory AML. In the ADMIRAL phase 3 clinical trial, 1-year overall survival of a gilteritinib monotherapy group was 37.1%, compared to 16.7% for the salvage chemotherapy group. Serious adverse effects included cytopenia (anemia, febrile neutropenia, thrombocytopenia), prolonged cardiac ventricular repolarization (9%), pancreatitis (5%), posterior reversible encephalopathy syndrome (1%), and differentiation syndrome (3%). Hemodynamic monitoring and dexamethasone, a standard treatment for differentiation syndrome in acute promyelocytic leukemia, was effective treatment for differentiation syndrome in this instance.29,34 Clinical trials are still underway to determine gilteritinib’s efficacy as a combination treatment with chemotherapeutic medicines. Lab studies with nude mice show a that in combination with low-dose arsenic trioxide (ATO), gilteritinib appears to induce cell apoptosis and inhibit proliferation.35 Gilteritinib stands out from other TKIs in that it offers multi-faceted benefits compared to similar medicines. Lestaurtinib and midostaurin, multitargeted TKIs approved for combination therapy with standard

chemotherapies, show no durable benefit as monotherapies. Similarly, sorafenib lacks enough clinical trial data to support its use as a monotherapy, and quizartinib, while showing positive results as a single agent, had short-lived effective responses.30 In a phase 1-2 open label trial (NCT02014558), 41% of relapse/refractory patients receiving >80mg/day gilteritinib showed a composite complete remission of AML, meaning the leukemia was no longer active and blood levels had normalized.35 Following decades of little to no advancement in the targeted therapies and testing techniques available for AML treatment, the shift forward began in April 2017 with the United States’ Food and Drug Administration (FDA) approval of midostaurin for FLT3-targeted treatment. The FDA then fast-tracked enasidenib in August of 2017, and the combination chemotherapeutic treatment daunorubicin plus cytarabine was approved only days later. In September of 2017, gemtuzumab ozogamicin, a chemotherapeutic treatment with a guiding monoclonal antibody targeting the CD33 antigen present on most AML cells, was reapproved in the UK and in the United States.7 The United States’ standard of care for AML patients has changed rapidly, while the UK lags behind. In the UK intensive chemotherapy remains the frontline treatment option according to the National Health Service (NHS), unless a patient is unfit for intensive chemotherapy.8 Given that the median age of diagnosis ranges from 67 to 70 years, an optimistic prognosis for median overall survival at five years is 10% for those fit enough to undergo intensive treatment. For older patients unfit for intensive chemotherapy, overall survival is a dismal 4 to 10 months.9 Targeted therapies offer less invasive treatment options with equal or better efficacy and prognosis.

Future Outlooks Since 2017, eight new FDA-approved drugs have been introduced to the AML treatment landscape - FLT3 inhibitors midostaurin and gilteritinib, IDH inhibitors ivosidenib and enasidenib, anti-


IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA

Acute myeloid leukemia (AML)

CD33 monoclonal antibody-chemotherapy conjugate gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib, and the BCL-2 inhibitor venetoclax.38 Targeted treatments are not limited to a singular medicine for a singular mutation, but also a particular combination of treatments for a given leukemic subtype. For elderly patients who are unfit for aggressive chemotherapy, DNA-hypomethylating agents may be an appropriate and well-tolerated approach. Initial studies with decitabine as a frontline treatment produced unremarkable results, but a new series of developments has shown that decitabine, a hypomethylating agent, in combination with venetoclax, a BCL-2 inhibitor, results in high rates of complete remission in both frontline settings and modest effects in relapse settings.39 For relapse/refractory patients, the median overall survival was 3 months with a 6- month overall survival rate of 24%. Objective response rate was 24% in patients with diploid/ intermediate-risk cytogenetics, 27% in patients with IDH1 or IDH2 mutations, 50% in patients with RUNX1 mutations, and 15% in patients with adverse cytogenetics. Even though results are modest, combination venetoclax and lowintensity chemotherapy is a relatively safe and well-tolerated alternative therapy option, especially beneficial for patients with IDH1, IDH2 or RUNX1 mutations.38 For patients with chromosomal translocations that result in oncogenic fusion proteins, like PML-RARA, AML1-ETO, MLL-fusions, and CBFBMYH11, a broader class of drugs targeting DNA damage repair may be the new frontier of AML treatment. These DNA damage repair drugs may also treat single point mutations, such as FLT3 and NPM1.40 As is the nature of targeted therapies, DNA repair is likely to be useful

as a monotherapy for only a subset of AML patients with underlying DNA repair defects like secondary leukemias or complex karyotypes.41 As of this report, there are currently 29 treatment clinical trials for adult AML covering combination therapy, cell transplant, marrow transplants, and open- and closed-label trials. The phase 3 VIALE-A trial has shown positive results with combination azacitidine and venetoclax, while the SIERRA phase 3 trial showed a highly effective conditioning agent in Iomab-B prior to stem cell transplant compared to traditional chemotherapy conditioning.42,43 In June 2020, the ASTRAL-1 phase 3 trial ended without meeting its end goal. The trial compared guadecitabine, a DNA hypomethylating agent, to AML patients’ therapy of choice for patients were considered unfit for intensive chemotherapy. ASTRAL-2 and ASTRAL-3 trials are still underway. Leukemic disease being so incredibly complex to map and having limited viable treatment options has created a chasm between the volume of data collected on the disease and the comprehensive information gleaned from it. While the clinical case is that targeted treatments are on the rise, certain co-occurrences lead to better prognosis, and while the treatment landscape is finally changing, the truth for AML patients is that leukemia is a devastating diagnosis. Decades of treatment stagnation has cost countless patient lives. The onus is on researchers and healthcare providers to identify this gap and move to close it rapidly. For many patients, standard AML therapy has, to date, failed to provide cures. For elderly patients with comorbidities contraindicative of intensive chemotherapies, few low-toxicity treatment options are available, leaving them with salvage therapies or palliative care. The absence of viable options speaks to the urgency for new treatments.36

While the clinical case is that targeted treatments are on the rise, certain co-occurrences lead to better prognosis, and while the treatment landscape is finally changing, the truth for AML patients is that leukemia is a devastating diagnosis

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References: Key Statistics for Acute Myeloid Leukemia (AML). Accessed August 25, 2020.

1.

https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html 2.

Acute Myeloid Leukemia (AML) Subtypes and Prognostic Factors. Accessed August 26, 2020.

https://www.cancer.org/cancer/acute-myeloid-leukemia/detection-diagnosis-staging/how-classified.html 3.

Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299-312. doi:10.1038/s41375-018-0357-9

4.

Patnaik MM. The importance of FLT3 mutational analysis in acute myeloid leukemia. Leuk Lymphoma. 2018;59(10):2273-2286.

doi:10.1080/10428194.2017.1399312 5.

Weir EG, Borowitz MJ. Flow cytometry in the diagnosis of acute leukemia. Semin Hematol. 2001;38(2):124-138. doi:10.1016/S0037-1963(01)90046-0

6.

George TI, Tworek JA, Thomas NE, et al. Evaluation of Testing of Acute Leukemia Samples: Survey Result From the College of American Pathologists. Arch Pathol Lab Med. 2017;141(8):1101-1106. doi:10.5858/arpa.2016-0398-CP

7.

Perl AE. The role of targeted therapy in the management of patients with AML. Hematol Am Soc Hematol Educ Program. 2017;2017(1):54-65.

8.

Acute myeloid leukaemia - Treatment. nhs.uk. Published October 20, 2017. Accessed August 27, 2020.

https://www.nhs.uk/conditions/acute-myeloid-leukaemia/treatment/ 9.

Davis JR, Benjamin DJ, Jonas BA. New and emerging therapies for acute myeloid leukaemia. J Investig Med Off Publ Am Fed Clin Res.

10.

2018;66(8):1088-1095. doi:10.1136/jim-2018-000807 Bullinger L, Döhner K, Döhner H. Genomics of Acute Myeloid Leukemia Diagnosis and Pathways. J Clin Oncol. 2017;35(9):934-946.

doi:10.1200/JCO.2016.71.2208 11.

Medinger M, Passweg JR. Acute myeloid leukaemia genomics. Br J Haematol. 2017;179(4):530-542. doi:10.1111/bjh.14823

12.

Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013;368(22):2059-2074. doi:10.1056/NEJMoa1301689

13.

Thol F, Kade S, Schlarmann C, et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood. 2012;119(15):3578-3584. doi:10.1182/blood-2011-12-399337

14.

Gaidzik VI, Teleanu V, Papaemmanuil E, et al. RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features. Leukemia. 2016;30(11):2160-2168. doi:10.1038/leu.2016.126

15.

Di Croce L. Chromatin modifying activity of leukaemia associated fusion proteins. Hum Mol Genet. 2005;14(suppl_1):R77-R84. doi:10.1093/hmg/ddi109

16.

Schnittger S, Eder C, Jeromin S, et al. ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia. 2013;27(1):82-91. doi:10.1038/leu.2012.262

17.

Daneshbod Y, Kohan L, Taghadosi V, Weinberg OK, Arber DA. Prognostic Significance of Complex Karyotypes in Acute Myeloid Leukemia. Curr Treat Options Oncol. 2019;20(2):15. doi:10.1007/s11864-019-0612-y

18.

Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype. N Engl J Med. 2005;352(3) :254-266. doi:10.1056/NEJMoa041974

19.

Figueroa ME, Lugthart S, Li Y, et al. DNA Methylation Signatures Identify Biologically Distinct Subtypes in Acute Myeloid Leukemia. Cancer Cell.

20.

Yang X, Wong MPM, Ng RK. Aberrant DNA Methylation in Acute Myeloid Leukemia and Its Clinical Implications. Int J Mol Sci. 2019;20(18). doi:10.3390/

21.

Barbosa K, Li S, Adams PD, Deshpande AJ. The role of TP53 in acute myeloid leukemia: Challenges and opportunities. Genes Chromosomes Cancer.

22.

Viny AD, Levine RL. Cohesin mutations in myeloid malignancies made simple. Curr Opin Hematol. 2018;25(2):61-66. doi:10.1097/MOH.0000000000000405

23.

Grafone T, Palmisano M, Nicci C, Storti S. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment.

2010;17(1):13-27. doi:10.1016/j.ccr.2009.11.020 ijms20184576 2019;58(12):875-888. doi:10.1002/gcc.22796

24.

25.

Oncol Rev. 2012;6(1):e8. doi:10.4081/oncol.2012.e8 Itzykson R, Duployez N, Fasan A, et al. Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia. Blood. 2018;132(2):187-196. doi:10.1182/blood-2018-03-837781 gknation. Relapsed and Refractory. Published February 26, 2015. Accessed August 30, 2020.

https://www.lls.org/leukemia/acute-myeloid-leukemia/treatment/relapsed-and-refractory 26.

Bose P, Vachhani P, Cortes JE. Treatment of Relapsed/Refractory Acute Myeloid Leukemia. Curr Treat Options Oncol. 2017;18(3):17. doi:10.1007/s11864-017-0456-2

27.

Mims AS, Blum W. Progress in the problem of relapsed or refractory acute myeloid leukemia. Curr Opin Hematol. 2019;26(2):88–95. doi:10.1097/ MOH.0000000000000490

28.

Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481(7382): 506-510. doi:10.1038/nature10738

29.

Zhao J, Song Y, Liu D. Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia. Biomark Res. 2019;7(1):19. doi:10.1186/s40364-019-0170-2 10 | WWW.HOSPITALREPORTS.EU


IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA

30.

Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688

31.

Rautenberg C, Germing U, Haas R, Kobbe G, Schroeder T. Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: Prevention, Detection, and Treatment. Int J Mol Sci. 2019;20(1). doi:10.3390/ijms20010228

32.

Tsirigotis P, Byrne M, Schmid C, et al. Relapse of AML after hematopoietic stem cell transplantation: methods of monitoring and preventive strategies. A review from the ALWP of the EBMT. Bone Marrow Transplant. 2016;51(11):1431-1438. doi:10.1038/bmt.2016.167

33.

Dhillon S. Gilteritinib: First Global Approval. Drugs. 2019;79(3):331-339. doi:10.1007/s40265-019-1062-3

34.

Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014;123(18):2777-2782. doi:10.1182/blood-2013-10-512640

35.

Hu X, Cai J, Zhu J, et al. Arsenic trioxide potentiates Gilteritinib-induced apoptosis in FLT3-ITD positive leukemic cells via IRE1a-JNK-mediated endoplasmic reticulum stress. Cancer Cell Int. 2020;20(1):250. doi:10.1186/s12935-020-01341-5

36.

Karjalainen E, Repasky GA. Chapter Nine - Molecular Changes During Acute Myeloid Leukemia (AML) Evolution and Identification of Novel Treatment Strategies Through Molecular Stratification. In: Pruitt K, ed. Progress in Molecular Biology and Translational Science. Vol 144. Molecular and Cellular Changes in the Cancer Cell. Academic Press; 2016:383-436. doi:10.1016/bs.pmbts.2016.09.005

37.

Typical Treatment of Acute Myeloid Leukemia (Except APL). Accessed September 2, 2020.

https://www.cancer.org/cancer/acute-myeloid-leukemia/treating/typical-treatment-of-aml.html 38.

Guerra VA, DiNardo C, Konopleva M. Venetoclax-based Therapies for Acute Myeloid Leukemia. Best Pract Res Clin Haematol. 2019;32(2):145-153. doi:10.1016/j.beha.2019.05.008

39.

Stahl M, DeVeaux M, Montesinos P, et al. Hypomethylating agents in relapsed and refractory AML: outcomes and their predictors in a large international patient cohort. Blood Adv. 2018;2(8):923-932. doi:10.1182/bloodadvances.2018016121

40.

Gavande NS, VanderVere-Carozza PS, Hinshaw HD, et al. DNA repair targeted therapy: The past or future of cancer treatment? Pharmacol Ther. 2016;160:6583. doi:10.1016/j.pharmthera.2016.02.003

41.

D’Andrea AD. Targeting DNA repair pathways in AML. Best Pract Res Clin Haematol. 2010;23(4):469-473. doi:10.1016/j.beha.2010.09.005

42.

Dr. DiNardo on the Results of the VIALE-A Trial in AML. OncLive. Accessed September 3, 2020.

https://www.onclive.com/view/dr-dinardo-on-the-results-of-the-viale-a-trial-in-aml 43.

Actinium Pharmaceuticals. A Multicenter, Pivotal Phase 3 Study of Iomab-B Prior to Allogeneic Hematopoietic Cell Transplant Versus Conventional Care in Older Subjects With Active, Relapsed or Refractory Acute Myeloid Leukemia (AML). clinicaltrials.gov; 2020. Accessed September 2, 2020. https://clinicaltrials.gov/ct2/show/NCT02665065

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