The treatment of acute myeloid leukemia (AML) has been rapidly evolving in the past few years. Since 2017 eight new drugs have been approved by the United Stated Federal Drug Administration (FDA) for various subsets of AML patients in first line and relapsed/refractory settings (DiNardo and Wei table 2,3). Several of these treatments have been registered and are reimbursed in the Israeli Health System (Table 1). In January 2020 Courtney DiNardo and Andrew Wei published an informative review regarding the treatment of AML in this new age of novel agents.1 They present clinical cases and debate the various treatment options available for them, providing practical recommendations based on the literature and their experience and judgement. Here I review the relevance of this information to the care of Israeli AML patients in light of treatment options available in 2020.
F.C. TABS.: Dosage should be ajust. individ. See lit. Tmt. of pts. with Chron. Lymphoc. Leukem./Small Lymphoc. Lymphoma with or without 17p deletion, who have received at least one prior ther. Acute Myeloid Leukem.: in comb. with a hypomethylating agent/comb. with low dose cytarabine is indicated for newly diagnosed pts. with AML who are ineligible for intensive chemother. C/I: Concom. use with strong CYP3A inhib. at init. and during ramp-up phase is contraind. in pts. with CLL/SLL due to the potent. for incr. risk of tumor lysis syndr. Concom. use with St. John’s wort.
Treatment of elderly AML patients
DiNardo and Wei present a case of a 75 year old woman with presenting with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, progressive fatigue and dyspnea, a high WBC count with 76% peripheral blasts and 94% blasts in the bone marrow. Immunophenotyping was positive for CD33, the karyotype showed trisomy 13, and molecular profiling showed mutations in RUNX1, ASXL1 and SRSF2. The biochemistry panel showed mildly elevated serum LDH and creatinine. Treatment options relevant to Israeli patients were discussed as follows:
Intensive chemotherapy, with or without Gemtuzumab Ozogamicin (GO)
Certain subsets of elderly patients may be eligible for intensive chemotherapy. Patients with a good performance status, few comorbidities, and favorable features of their leukemia (e.g. inv16 or t(8;21)) can indeed benefit from this modality, but represent a very small proportion of elderly AML patients2.
The addition of GO to intensive chemotherapy has shown clinical benefit in a meta-analysis of five randomized trials, particularly in patients with AML with favorable cytogenetics3. Very few of the patients included in this meta-analysis were older than 70 years old, with only one of the trials recruiting patients of this age group. As such, little is known about the benefit of such treatment in elderly patients.
In the case discussed, DiNardo and Wei rightfully state that the patients' poor performance status, renal dysfunction, and poor prognostic features discourage treatment with intensive chemotherapy with or without GO.
Low dose cytarabine
As hypomethylating agents (HMA) alone were never reimbursed in the Israeli health care system for AML patients, the only option for low-intensity treatment for unfit AML patients until recently was sub-cutaneous low dose cytarabine (LDAC). In the UK MRC NRCI AML14 unfit arm, only 18% of patients treated with LDAC achieved complete remission (CR) none of which were with unfavorable features4. In the current age of novel treatments this treatment can rarely be justified.
Venetoclax in combination with hypomethylating agents or low dose cytarabine
Venetoclax, an oral inhibitor of B-cell lymphoma 2 (BCL-2), was administered in combination with LDAC or HMAs in two recent phase Ib/phase Ib/II trials5,6. CR/CR with incomplete count recovery (CRi) was achieved in 54% in combination with LDAC and 67% in combination with HMAs – azacitidine or decitabine. It is worthy of note that the patient population in both studies were different and may partially explain the slight difference in outcomes. Also of note is the low early death rate in both trials (3-6%), and median overall survival outcomes which compare favorably to outcomes with any other treatment option in the elderly. Due to these considerations, DiNardo and Wei recommend treating the patient in case with venetoclax and azacitidine.
Management of patients treated with venetoclax based regimens
Practical recommendations regarding the treatment of AML patients based on the clinical experience of the authors, clinical trial data, and the venetoclax prescribing information brochure are summarized in table 4 of the review by DiNardo and Wei.
Several points are worth of mention:
* Target doses of venetoclax are 400 mg per day for 28 days with azacitidine 75 mg/m2 on days 1-7 or decitabine on days 1-5. Alternatively, venetoclax is given at a target dose of 600 mg/day for 28 days with low dose cytarabine 20 mg/m2/day on days 1-10.
* Most patients will eventually receive care in an ambulatory setting. In this setting, "5-2-2" dosing regimen of azacitidine (five days of daily azacitidine on week 1, a two day weekend with no azacitidine, followed by two days of azacitidine on week 2) is most practical.
* Patients presenting with baseline renal dysfunction, established spontaneous tumor lysis syndrome (TLS), a high burden of disease, or AML subgroups with high sensitivity to venetoclax based treatment (NPM1 or IDH mutated AML) are at high risk for life threatening tumor lysis syndrome upon initiation of treatment during cycle 1. Measures to reduce this risk described in the table include hydration and administration of allopurinol prior to initiation of treatment, cytoreduction using hydroxyurea in patients with WBC counts over 25,000 x 109/L, a standard dose ramp up of venetoclax in the first days of treatment, and careful monitoring of serum creatinine, uric acid, and electrolyte levels during the ramp up phase of treatment. Treatment should be suspended until TLS resolution if clinical TLS occurs. The authors recommend hospitalizing patients for the initial ramp up phase of treatment to manage TLS risk, as was done in the clinical trials of venetoclax based regimens.
* The authors recommend adjusting the dose if inhibitors of CYP3A4 are used concomitantly. This is especially relevant if azoles and ciprofloxacin are used as antimicrobial prophylaxis or treatment. Dosing should also be adjusted in patients with severe hepatic impairment, and no literature or recommendations exists regarding patients with severe renal impairment.
* One of the most important issues is management of myelosuppression. While many of the patients will present with disease related cytopenias, by day 21-28 of a significant subset of patients will have achieved at least a bone marrow morphologic leukemia free state (MLFS). This subgroup of patients can benefit from treatment interruption, administration of G-CSF, and initiation of the next cycle of treatment only after recovery of a neutrophil count over 0.5 x 109/L and a platelet count over 50 x109/L. Patients with excess of blasts on day 21-28 should continue to cycle 2 of treatment on day 29 of cycle 1 without interruption regardless of the peripheral cell count. This stresses the importance of a bone marrow examination at day 21-28 of each cycle until achievement of at least a MLFS. Patients with no meaningful responses after 3-4 cycles should be given alternative treatment options if available.
* After achievement of CR/CRi, cell counts should be monitored and future myelosuppression should be managed by administration of GCSF, reduction of venetoclax treatment duration per cycle in future cycles, and/or delay of the subsequent cycle as described in table 4. Balancing the risk of myelotoxicity and the risk of relapse is of paramount importance. Robust clinical data to guide dosing decisions is currently lacking, and it is recommended to follow the expert opinion suggested by Wei and DiNardo.
Treatment of patients with mutation in Flt3
The authors describe a case of a 36 year old male with normal karyotype AML with mutation in NPM1 DNMT3A, and high allelic ratio Flt3-ITD. As characteristic of AML patients with Flt3 mutations, he presents with a high WBC count and an aggressive disease course. In the case presented, induction treatment is given with the 7+3 protocol (cytarabine 200 mg/m2 on days 1-7 and daunorubicin 60 mg/m2 on days 1-3) and midostaurin 50 mg x2 per day on days 8-21, as given in the RATIFY trial.
As of yet, midostaurin is the only drug approved by the FDA and reimbursed in the Israeli health care system as an addition to intensive chemotherapy for the treatment of Flt3-mutated AML. This is based on the results of the phase III RATIFY trial, in which Flt-3 mutated AML patients under the age of 60 were given midostaurin 50 mg x2 per day or placebo for 14 days in every induction or consolidation cycle, initiated a day following completion of chemotherapy, and as maintenance for 12 months in patients who did not undergo stem cell transplant. Addition of midostaurin to intensive chemotherapy produced improved overall survival and event free survival rated than placebo treatment7.
This highlights the importance of a rapid molecular assessment to discover Flt-3 mutations at diagnosis, as this is a targetable mutation.
Of note, although not related to the case presented, there is scarce data from clinical trials regarding the outcome of elderly AML patients with Flt3 mutations. Patients over the age of 60 were not included in the Ratify trial, and patients over the age of 70 were not recruited to the phase 2 AMLSG trial which examined addition of midostaurin to induction and consolidation chemotherapy8. Elderly unfit AML patients with mutated Flt3 tend to respond well to the combination of venetoclax and hypomethylating agents, exhibiting a CR/CRi rate of 72% and a median OS that was not reached during a 15.2 follow up5. This data is based on analysis of only 18 patients, but nevertheless is remarkable. Data on combination of venetoclax and Flt-3 inhibitors is lacking and therefore no recommendation can be given.
Treatment of AML relapse after hypomethylating agents:
In the third case, the authors present an elderly woman with relapse of AML after two years of successful treatment with azacitidine (initiated before venetoclax was approved for AML). At relapse, molecular testing was positive for mutation in IDH1.
AML progressing after treatment with HMAs has a dismal prognosis, with median overall survival outcomes of 2-4 months9. Even with treatment with intensive chemotherapy for fit patients after HMA failure has limited efficacy. Only approximately a third of patients will respond to treatment and the median OS of treated patients is about half a year10.
Patients previously treated with HMAs for myelodysplastic syndrome (but not AML) were included in the phase I/II trial of venetoclax in combination with LDAC, but only one third achieved CR/CRi and the median OS was less than six months6.
The only novel agent available in Israel in the relapse setting is GO. This agent was tested in AML patients who relapsed after treatment with intensive chemotherapy. In this patient population, 26-33% of patient achieved CR/CRp in clinical trials, and a median OS of 8.4 months was observed13.
Once again, it is encouraged to attempt to enroll such patients to clinical trials.
The past few years have seen a burst of innovative drugs receiving FDA approval for the treatment of acute myeloid leukemia. Only a fraction of these treatments have been approved and are reimbursed in Israel. These new agents have revolutionized our approach to patients suffering from AML. As little data exists to guide clinical decisions, Dr. Andrew Wei and Dr. Courtney DiNardo's informative "How I treat" review provides practical tips to enable safe and efficient management and care of acute myeloid leukemia patients in the era of new drugs.
*Dr Moshe received honorarium from Abbvie for the preparation of this review.
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