All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit Know AML.

The AML Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy


Now you can personalise
your AML Hub experience!

Bookmark content to read later

Select your specific areas of interest

View content recommended for you

Find out more

The AML Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the AML Hub cannot guarantee the accuracy of translated content. The AML Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.

Steering CommitteeAbout UsNewsletterContact
You're logged in! Click here any time to manage your account or log out.
You're logged in! Click here any time to manage your account or log out.

"How I treat": case studies to address new challenges encountered in the treatment of AML

Dec 16, 2019

Bookmark this article

The “How I Treat” series in Blood aims to offer diagnostic or therapeutic advice for a disease or several distinct aspects of a single disorder.1 There have been several that have focused on acute myeloid leukemia (AML) covering a range of different topics.2-9 With the numerous new drug approvals by the U.S. Food and Drug Administration (FDA), there are now overlapping treatment options, which whilst welcoming for patients can be challenging for treating physicians.

In a recent “How I Treat” article,10 Courtney DiNardo from the  MD Anderson Cancer Center, Texas, US, and Andrew Wei of the  Alfred Hospital and Australian Centre for Blood Disease, Monash University, Melbourne, AU, highlight the current key issues. These include the identification of mutations at both diagnosis and relapse, deciding which treatment to use from the many therapeutic options, and increasing awareness on how to manage the common complications that are associated with these newer therapies. They go on to present three case studies to demonstrate the use of these newly approved drug options, keeping the aforementioned key issues in mind.

1. A 75-year-old woman with untreated AML


  • Over 6 months has had progressive shortness of breath and fatigue
  • White blood cell (WBC) count 26x109 per L with 79% blasts, hemoglobin 89g/dL, neutrophils 0.76x109 per L, platelets 28x109 per L, bone marrow infiltrated with 94% myeloblasts of CD34+, CD117+, CD13+, CD33+ phenotype
  • Trisomy 13, mutations in RUNX1, ASXL1, and SRSF2
  • Mildly increased serum lactate dehydrogenase (LDH) and creatinine
  • ECOG score 2

Question: Should the patient be treated with intensive chemotherapy (CPX-351, low-dose cytarabine (LDAC) +/- glasdegib or venetoclax) or a hypomethylating agent (HMA) +/- venetoclax?

  • Screening for actionable mutations of FLT3, IDH1 and IDH2 recommended as FLT3 inhibitors are approved for patients ≥75 years – none detected
  • Intensive chemotherapy and CPX-351 contraindicated due to age, baseline renal impairment, and ECOG score
  • Treatment with LDAC or HMA alone results in poor response rates (1811
  • The addition of glasdegib to LDAC improves the overall response rate modestly (27 vs 5%, LDAC + glasdegib vs LDAC alone)12
  • HMA + venetoclax or LDAC + venetoclax achieves response rates of 54-67%, with patients with RUNX1 or SRSF2 mutations having response rates of 81% and 71% respectively13

Treatment: Venetoclax + azacitidine (HMA)

  • Due to risk of tumor lysis syndrome (TLS), patient received hydroxycarbamide, intravenous (IV) hydration, and allopurinol to prevent TLS and lower WBC
  • Treatment began when WBC reduced to <15x109 per L
  • Cycle 1 (28-day cycle): Venetoclax 100mg day 1, 200mg day 2, 400mg days 3-28, then combined with azacitidine 75mg/m2 per day on days 1-7
  • 2-week treatment holiday for platelet recovery
  • Cycle 2 (28-day cycle interrupted): Venetoclax 400mg days 1-28
  • Cycle 3 (21-day cycle): Venetoclax 400mg days 1-21
  • Cycle 4 (14-day cycle): Venetoclax 400mg days 1-14
  • Cycles 5-12: Venetoclax 400mg days 1-14
  • Outcome: Relapsed AML confirmed 30 months after diagnosis, cytogenetic evolution was identified probably in the form of TP53 abnormalities

Side effects

  • Urine infection requiring antibiotics during first cycle
  • Cycle 1: Day 22 posaconazole was administered to increase neutrophil count, venetoclax dose reduced, day 24 granulocyte-colony stimulating factor (G-CSF) given on alternate days due to severe pancytopenia, hypocellular bone marrow and neutrophil count of <0.5x109 per L. Neutrophils recovered after 6 days
  • Cycle 2: During the fourth week, treatment interrupted due to neutrophil count (<0.5x109 per L) and G-CSF intermittently given. Neutrophils recovered after 4 days. Patient also had grade 4 thrombocytopenia
  • Cycle 3: Similar pattern of side effects as cycle 2
  • Cycle 4: Grade 4 thrombocytopenia for shorter period


Due to severe marrow suppression, management should utilize bone marrow assessment in the third week with appropriate dose interruption, delay, and duration reduction, as required. As highlighted in the case study, dose duration reduction from 28-day to 14- or 21-day cycles may be required to prevent cytopenias. DiNardo and Wei recommend using the combination of LDAC/HMA + venetoclax in older unfit patients with NPM1 mutant AML having seen recovery rates of 93% and relapse free survival (RFS) of >4 years.13

2. A 36-year-old man with relapsed FLT3-ITD mutant AML


  • Gingival swelling, low-grade fever, and epistaxis
  • White blood cell (WBC) count 44x109 per L, hemoglobin 68g/dL, platelets 22x109 per L, bone marrow infiltrated with 72% blasts of monocytic phenotype
  • ECOG score 0
  • Normal diploid karyotype
  • Mutations: NPM1, DNMT3A R882 and FLT3-ITD (mutant:wild-type allelic ratio of 0:6)
  • Induction treatment: 60mg/m2 danorubicin days 1-3 and 200mg/m2 daily cytarabine on days 1-7 (7+3), 50mg midostaurin twice daily on days 8-21
  • Consolidation therapy: 3g/m2 high-dose cytarabine twice daily on days 1,3,5 with 50mg midostaurin twice daily on days 8-21
  • Developed neutropenic fever, typhlitis, and pancolitis during first consolidation and relapsed prior to planned hematopoietic stem cell transplantation (HSCT)

Question: Should the patient be treated with intensive salvage chemotherapy or gilteritinib?

  • Previous trials14,15 of salvage chemotherapy vs FLT3 inhibition in patients with FLT3-ITD AML have shown better survival and response rates in patients with relapsed or refractory disease
  • Combination chemotherapy + FLT3 inhibition studies are ongoing but there is preliminary data to suggest that combination treatment of gilteritinib + azacitidine may be suitable for relapsed/refractory AML16

Treatment: Gilteritinib (FLT3 inhibitor)

  • 120mg oral gilteritinib per day for four cycles


  • Complete response (CR) by the end of cycle 3
  • NPM1 and FLT3-ITD mutations were undetectable by the end of cycle 4
  • DNMT3A mutation persisted
  • HSCT in second CR
  • Gilteritinib again at 45 days post-HSCT (120mg daily, reduced to 80mg per day following abnormal liver function tests)
  • Sustained CR at 8 months following HSCT

Side effects

  • Post-transplant gilteritinib had to be held at 3 weeks due to potential liver damage indicated by a rise in alanine transaminase (ALT) and aspartate transaminase (AST) levels to >4x upper limit of normal (ULN), confirmed by biopsy


As an initial treatment option, midostaurin combined with intensive chemotherapy is suggested for younger patients with FLT3 mutant AML.17 DiNardo and Wei note that although both the ELN 2017 classification18 and NCCN AML guidelines19 recommend stratifying AML risk based on FLT3-ITD allelic ratio and NPM1 mutation status, FLT3-ITD allelic ratio is not standardized and should be considered alongside other risk factors. FLT3 inhibitors may also have a role in maintenance therapy, and were used here following HSCT. The authors recommend restarting FLT3 inhibition 30 days after HSCT, following confirmation of no clinically significant graft-versus-host disease (GvHD), infection or other toxicity.

3. A 78-year-old woman with relapsed IDH1 mutant AML


  • History of cytopenias two years prior to elective orthopedic surgery
  • White blood cell (WBC) count 2.3x109 per L with 12% blasts, hemoglobin 8.6g/dL, neutrophils 0.3x109 per L, platelets 114x109 per L, bone marrow 28% myeloblasts
  • Trisomy 8
  • Had initially been treated with azacitidine; CR (on bone marrow analysis) after 5 cycles
  • Relapsed with 37% blasts after nine cycles of therapy
  • Molecular analysis (done at relapse, had not been done before) identified DNMT3A-R882 and IDH1-R132C mutations

Question: Should the patient receive chemotherapy or ivosidenib salvage therapy?

  • Intensive chemotherapy following HMA failure achieves a response rate of 32% and median OS of 6.2 months20 in fit patients
  • Molecular screening (and re-screening) is recommended to enable the identification of actionable mutations

Treatment: Ivosidenib

  • Ivosidenib 500mg orally per day
  • Concurrent use of fluoroquinolone or cephalosporin to prevent increase in QTc interval
  • Four weeks after ivosidenib initiation; WBC increased to 8x109 per L, 45% neutrophils, 10% metamyelocytes, 7% monocytes, and 5% blasts
  • At six weeks, WBC increased to 27x109 per L, patient was admitted and given hydroxycarbamide, antibiotics, furosemide and dexamethasone for potential differentiation syndrome


  • At 3 months: blood counts normal and 3% blasts in bone marrow consistent with CR
  • At 6 months: IDH1 mutation was negative by next generation sequencing (NGS) but detectable by digital PCR
  • 12 months: Patient alive and in ongoing remission

Side effects

  • Electrocardiogram monitoring detected an increase in QTc interval from 450ms to 475ms after two weeks of treatment
  • Patient had shortness of breath (along with pulmonary bilateral infiltrates, 94% oxygen saturation, fever), and leg edema


This particular case study was highlighted as challenging, with a median overall survival (OS) of <5 months in patients who relapsed following treatment with HMAs (azacitidine).21,22 The identification of actionable mutations is particularly important in older patients as IDH1 mutations occur more frequently in that population. With ivosidenib (an inhibitor of IDH1 mutant enzyme), higher response rates were seen in patients who had failed one treatment rather than patients who had failed ≥3 treatments, yet 50% of patients with relapsed or refractory disease who responded to ivosidenib were still alive after 18 months. IDH inhibitor monotherapy is currently advised but there are ongoing trials to determine its role in combination therapies.10 Professors DiNardo and Wei went on to discuss IDH inhibitor complications, and particularly the possible development of differentiation syndrome (DS) that can occur approximately 29 days following IDH inhibitor initiation. As the symptoms (dyspnea, fever, pulmonary infiltrates, hypoxia, pleural or pericardial effusions, peripheral edema, and weight gain) overlap with symptoms of infection and/or progression, the authors highlight the importance of clinician awareness when using these therapies.

In conclusion, the paper highlights how treatment for AML is moving away from the two main options of “curative, intensive” and “palliative, low intensity” treatments to a more diverse range of options. The authors recommend caution in the use of combinations of the newer drugs, unless as part of a clinical trial, so as to avoid unanticipated side effects due to drug interactions.10

  1. Kaushansky K. "How I treat": a new style of clinical review article. Blood. 2000 August 15; 96(4):1205. DOI: 10.1182/blood.V96.4.1205
  2. Tallman M.S. and Altman J.K. How I treat acute promyelocytic leukemia. Blood. 2009 December 10; 114 (25): 5126-5135. DOI: 10.1182/blood-2009-07-216457
  3. Rowe J.M. and Tallman M.S. How I treat acute myeloid leukemia. Blood. 2010 Oct 28;116(17):3147-3156. DOI: 10.1182/blood-2010-05-260117
  4. Zuckerman T. et al., How I treat hematologic emergencies in adults with acute leukemia. Blood. 2012 Sept 6;120(10):1993-2002. DOI: 10.1182/blood-2012-04-424440
  5. Thol F. et al., How I treat refractory and early relapsed acute myeloid leukemia. Blood. 2015 July 16;126(3):319-327. DOI: 10.1182/blood-2014-10-551911
  6. Ossenkoppele G. and Löwenberg B. How I treat the older patient with acute myeloid leukemia. Blood. 2015 Jan 29;125(5):767-774. DOI: 10.1182/blood-2014-08-551499
  7. Röllig C. and Ehninger G. How I treat hyperleukocytosis in acute myeloid leukemia Blood. 2015 May 21;125(21):3246-3252. DOI: 10.1182/blood-2014-10-551507
  8. Ofran Y. et al., How I treat acute myeloid leukemia presenting with preexisting comorbidities. Blood. 2016 July 28; 128(4):488-496. DOI: 10.1182/blood-2016-01-635060
  9. Pratz K.W. and Levis M. How I treat FLT3 mutant AML. Blood. 2017 Feb 2;129(5):565-571. DOI: 10.1182/blood-2016-09-693648.
  10. DiNardo C.D. and Wei A.H. How I treat myeloid leukemia in the era of new drugs. 2019 Nov 25. DOI: 10.1182/blood.2019001239 [Epub ahead of print]
  11. Kantarjian H.M. et al., Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J. Clin. Oncol. 2012;30(21):2670-2677 DOI: 10.1200/JCO.2011.38.9429
  12. Cortes J.E. et al., Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019;33(2):379 DOI: 10.1038/s41375-018-0312-9
  13. Strickland S.A. et al., Cytogenetic and Molecular Drivers of Outcome with Venetoclax-Based Combination Therapies in Treatment-Naïve Elderly Patients with Acute Myeloid Leukemia (AML). Clin Lymphoma Myeloma Leuk. 2018;18(S1):S202. DOI: 10.1010/j.clml.2018.07.052
  14. Cortes J.E. et al., Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-997. DOI: 10.1016/S1470-2045(19)30150-0
  15. Perl A. et al., Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial. Oral Abstract CT184 presented at AACR Annual Meeting 2019.
  16. Esteve J. et al., Open-label study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed flt3-mutated aml patients ineligible for intensive chemotherapy: results from the safety cohort. EHA Library, 2019 Jun 15, DOI: 10.1200/JCO.2017.35.15_suppl.TPS7068
  17. Stone R.M. et al., Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. DOI: 10.1056/NEJMoa1614359
  18. Döhner H. et al., Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.34 gilteritinib +azacytidine r/rAML. DOI: 10.1182/blood-2016-08-733196
  19. Tallman M.S. et al., Acute Myeloid Leukemia, Version 3. 2019, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Canc. Netw. 2019 June; 17(6). DOI: 10.6004/jnccn.2019.0028
  20. Ball B. et al., Evaluation of induction chemotherapies after hypomethylating agent failure in myelodysplastic syndromes and acute myeloid leukemia. Blood Adv. 2018;2(16):2063-2071. DOI: 10.1182/bloodadvances.2018015529
  21. Boddu P. et al., Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis. Blood Adv. 2017;1(17):1312-1323. DOI: 10.1182/bloodadvances.2017008227
  22. Prébet T. et al., Outcome of acute myeloid leukaemia following myelodysplastic syndrome after azacitidine treatment failure. B. J. Haematol. 2012;157(6):764-766. DOI: 10.1111/j.1365-2141.2012.09076.x


Subscribe to get the best content related to AML delivered to your inbox