Courtney D. DiNardo, MD, and Andrew H. Wei, MD, review recently approved therapies for acute myeloid leukemia and the treatment challenges they present.
This material is repurposed from “How I treat acute myeloid leukemia in the era of new drugs,” published in the January 9, 2020 edition of Blood.
The recent wave of new drug approvals for acute myeloid leukemia (AML) by the FDA has resulted in overlapping treatment options, especially in older patients or those considered unfit for intensive chemotherapy and in patients with relapsed or refractory disease. These therapies are a welcome advance for patients with AML but present physicians with new treatment challenges, such as the timely identification of actionable mutations at diagnosis and again at relapse; choosing which drugs to use; and the need for increased awareness of how to anticipate, mitigate, and manage common complications associated with these new agents.
In this overview, Drs. DiNardo and Wei illustrate treatment decisions between these novel agents and management of anticipated drug-related complications through three patient scenarios.
- Since 2017, several novel therapies for AML – venetoclax, midostaurin, gilteritinib, ivosidenib, enasidenib, gemtuzumab ozogamicin, glasdegib, and CPX-351 – have been approved, making treatment decisions and adverse event management more complicated.
- Venetoclax in combination with HMA or LDAC may induce severe marrow suppression leading to significant and prolonged cytopenias. Management requires a combination of dose interruption, dose delay, dose duration reduction, and other supportive care measures.
- The second-generation FLT3 inhibitors quizartinib and gilteritinib are associated with superior response rates and improved OS, compared with chemotherapy, in patients with relapsed/refractory disease.
- In patients with FLT3-mutated disease undergoing transplant, posttransplant outcomes appeared best if maintenance therapy with an FLT3 inhibitor was continued.
- “Treated secondary AML” in the context of HMA failure is a highly challenging scenario, but for patients with an IDH mutation, treatment with an IDH inhibitor results in a median OS of about 9 months. Treatment complications include QT prolongation, indirect hyperbilirubinemia, and differentiation syndrome.
Case 1: An older woman with previously untreated AML
A 75-year-old woman has bone marrow infiltrated with 94% myeloblasts, trisomy 13 karyotype, RUNX1, ASXL1, and SRSF2 mutations, a mildly increased serum lactate dehydrogenase and creatinine, and an Eastern Cooperative Oncology Group (ECOG) performance score of 2. Should this patient receive intensive chemotherapy (7+3 plus or minus gemtuzumab ozogamicin, or CPX-351), low-dose cytarabine (LDAC) plus or minus glasdegib or venetoclax, or a hypomethylating agent (HMA) plus or minus venetoclax?
Case 1 Treatment Selection and Outcome: Whenever possible, enrollment in a clinical trial should be considered, and rapid screening for actionable mutations is recommended. Some older patients benefit from intensive chemotherapy, but given this patient’s age, baseline renal impairment, ECOG status, and a European LeukemiaNet (ELN) 2017 risk classification that suggests <20% likelihood of 2-year survival, the risk of early mortality may be high. Therefore, we would eliminate intensive chemotherapy options.
Complete response (CR) rates for LDAC or HMA alone in AML are low (18%-28%) and these drugs are associated with a relatively slow time to complete response (CR; median = 3-4 months). Glasdegib is one of three recently FDA-approved drugs for use in older or unfit patients with AML, but the overall response rate (ORR) in combination with LDAC is modest (27%).
Venetoclax in combination with either HMA or LDAC for older patients unfit for intensive chemotherapy has been associated with response rates ranging from 54% to 67% and a risk of early mortality <10%. Patients with RUNX1 or SRSF2 mutations were reported to have a CR or CR with incomplete hematologic recovery (CRi) rate of 81% and 71% to venetoclax-based therapy, respectively.
This patient had an elevated risk of tumor lysis syndrome (TLS) at therapy start due to a presenting white blood cell (WBC) count of >25×109/L, elevated lactate dehydrogenase, and baseline renal impairment. She was hospitalized for titrated cycloreduction with hydroxyurea to lower the WBC count and received TLS prophylaxis during the venetoclax dose ramp-up phase. After 48 hours, her WBC count fell to <15×109/L and treatment was initiated.
Severe marrow suppression followed, and the patient was started on posaconazole when the neutrophil count dropped to <0.5×109/L, which necessitated a venetoclax dose reduction due to the pharmacokinetic interaction with CYP3A4 inhibitors.
The patient had persistently low neutrophil counts, but marrow aspirate showed good cytoreduction of blasts and hypocellularity. Therefore, venetoclax was interrupted and granulocyte colony-stimulating factor (G-CSF) commenced on alternate days. Venetoclax cycle 2 was resumed 2 weeks after interruption but neutrophil levels fell again and the patient was given G-CSF and venetoclax for only 21 days in cycles 2 and 3. Starting with cycle 4, venetoclax was given only on days 1 to 14 of each cycle. The patient received 12 cycles of therapy, then elected to cease treatment due to fatigue and ongoing treatment burden. Thirty months after diagnosis, cytopenias developed and a bone marrow confirmed relapsed AML with a monosomy 17p and two new TP53 mutations.
Case 1 Commentary: Venetoclax-based regimens administered to patients with hyperleukocytosis may lead to life-threatening TLS and should be delayed until effective cytoreduction has been achieved with hydroxyurea.
As seen with this patient, venetoclax in combination with HMA or LDAC may induce severe marrow suppression leading to significant and prolonged cytopenias. Bone marrow assessment between days 21 and 28 of cycle 1 is recommended. Management requires a combination of dose interruption, dose delay, dose duration reduction, and other supportive care measures.
Although the effectiveness of various reduction strategies has never been compared, venetoclax dose duration reductions to 14-21 days per cycle is often necessary to prevent recurrent prolonged cytopenias.
Case 2: A young man with relapsed FLT3-ITD–mutant AML
A 36-year-old man presented with gingival swelling, low-grade fevers, and epistaxis, and AML with 72% blasts and monocytic phenotype and an ECOG score of 0. Induction with 7+3 was started. Genomic analysis revealed a normal diploid karyotype with NPM1mut, DNMT3A R882mut, and FLT3-ITD. Midostaurin 50 mg twice daily was commenced on days 8 to 21 of induction. He tolerated induction well and bone marrow assessment at day 28 was consistent with a CR. The patient received consolidation therapy with high-dose cytarabine 3 g/m2 twice daily on days 1, 3, and 5, combined with midostaurin twice daily on days 8 to 21. An allogeneic hematopoietic cell transplant (alloHCT) in first CR was planned.
During first consolidation, the patient developed neutropenic fever complicated by pancolitis resulting in delayed administration of additional therapy. Relapsed AML was detected with peripheral blood leukocytosis (35×109/L) comprising 48% blasts before the second cycle of consolidation could begin. Repeat molecular testing confirmed recurrence of the NPM1, FLT3-ITD, and DNMT3A mutations. Should this patient receive intensive salvage chemotherapy or gilteritinib?
Case 2 Treatment Selection and Outcome: The patient was started on gilteritinib 120 mg/day, with twice-weekly blood counts to monitor for severe differentiation syndrome. By the end of cycle 3, CR was attained with 5% bone marrow blasts, and transition to alloHCT was reinitiated. By the end of cycle 4, neither the NPM1 nor FLT3-ITD mutations were detectable, but the DNMT3A mutation persisted.
The patient proceeded to alloHCT in second CR. Gilteritinib was held 7 days prior to initiation of the transplant preparative regimen and resumed 45 days posttransplant, after confirmation of successful engraftment with sustained neutrophils, sustained platelets, and absence of graft-versus-host disease (GVHD).
Eight months posttransplant, the patient remains in CR. Gilteritinib was used as maintenance therapy given his excellent response and tolerability to gilteritinib as first salvage therapy. Several treatment-related complications may occur with gilteritinib, including severe differentiation syndrome, hepatic impairment, pancreatitis, posterior reversible encephalopathy syndrome, and prolonged QT interval.
Case 2 Commentary: When considering second-line targeted therapies in patients with FLT3-ITD–mutated AML, it is important to repeat FLT3 molecular testing to confirm persistence of the mutation.
Both quizartinib and gilteritinib are associated with superior response rates and improved overall survival (OS), compared with chemotherapy in patients with relapsed/refractory FLT3-mutated AML. Unlike quizartinib, which has activity only against FLT3-ITD, gilteritinib has activity against both FLT3-ITD and FLT3-D835 mutations.
In clinical trials of quizartinib (QuANTUM-R) and gilteritinib (ADMIRAL), posttransplant outcomes appeared best if maintenance therapy with an FLT3 inhibitor was continued in the posttransplant setting. Although neither study included a second randomization, it is recommended that FLT3 inhibitors be restarted as early as 30 days post-alloHCT, once engraftment has occurred and in the absence of clinically significant GVHD, infection, or other toxicity.
Case 3: An older woman with relapsed IDH1-mutant AML and HMA Failure
A 78-year-old woman with a history of unexplained cytopenias for 2 years was diagnosed with AML with 28% myeloblasts and trisomy 8 on cytogenetic analysis. She initially received azacitidine, as venetoclax was not available. After 3 cycles, hematologic improvement was noted, and a subsequent bone marrow biopsy after 5 cycles confirmed CR. After 9 cycles of therapy, she had relapsed AML (37% blasts, recurrence of trisomy 8, and an AML next-generation sequencing (NGS) panel identified DNMT3A, R882H, and IDH1 R132C mutations). Should this patient receive chemotherapy or ivosidenib salvage?
Case 3 Treatment Selection and Outcome: The patient received ivosidenib 500 mg/day. Four weeks into therapy, her WBC count increased to 8×109/L with 45% neutrophils, 10% metamyelocytes, 7% monocytes, and 5% blasts. At 6 weeks, her WBC count increased to 27×109/L with a similar differential. She complained of shortness of breath with peripheral leg edema and was started on hydroxyurea and broad-spectrum antibiotics, furosemide, and dexamethasone 10 mg twice daily for suspected differentiation syndrome. Ivosidenib was continued and her symptoms improved swiftly. She was discharged on a 2-week steroid taper.
At 6 months, she was IDH1 mutation–negative by NGS, but IDH1 mutation–positive by digital polymerase chain reaction (PCR). Twelve months after ivosidenib initiation, the patient was alive and in ongoing remission.
Case 3 Commentary: “Treated secondary AML” evolving from treated prior antecedent hematologic disease in the context of failure of an HMA is a highly challenging scenario, with a median OS of fewer than 5 months; however, in fitter patients who receive intensive chemotherapy, the median OS is ~6.2 months. Treatment with ivosidenib or enasidenib in IDH mutated, relapsed/refractory AML results in a median OS of about 9 months.
Ivosidenib monotherapy can be associated with a QT prolongation while enasidenib-treated patients may develop indirect hyperbilirubinemia. Both drugs can lead to differentiation syndrome, manifesting as dyspnea, culture-negative fever, pulmonary infiltrates, hypoxia, pleural or pericardial effusions, peripheral edema, and weight gain. Because of the long half-life of IDH inhibitors, treatment interruption is not likely to result in rapid resolution of symptoms.
The treatment landscape of AML is undergoing unprecedented change, with 8 new drug approvals since 2017. The treatment paradigm has shifted away from a simple binary distinction between “curative, intensive therapy” and “palliative, lower-intensity” approaches. Instead, the increased diversity of therapeutic options requires a more nuanced treatment algorithm that incorporates mutation-specific targeted therapies, monoclonal antibodies, and apoptosis-inducing small molecules, in addition to improved liposomal delivery of standard therapies.
Combination clinical trials with the recently approved AML agents are ongoing, including trials of 7+3–based chemotherapy with FLT3 inhibitors (crenolanib, gilteritinib, and quizartinib) and other combinations in newly diagnosed and relapsed disease. Caution is advised in unrestrained combination of these new drugs outside of the context of clinical trials, as prevention of unanticipated severe drug-induced toxicities is imperative.