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

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

Presentation

• 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

Comments

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

Presentation

• 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 trials^14,15 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

Outcome:

• 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

Comments

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

Presentation

• 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

Outcome

• 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

Comments

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