Tuesday, March 28, 2023
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Associate Professor of Medicine
Clinical Director of Leukemia Services
Robert H. Allen MD Chair in Hematology Research
Division of Hematology
University of Colorado School of Medicine
Denver, Colorado
Peer Reviewer
This activity has been peer reviewed and the reviewer has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Celgene; Jazz; Pfizer
Received grants for clinical research from: Takeda
This activity is intended for hematology/oncology specialists.
The goal of this activity is to provide clinicians with expert insight on optimal approaches to induction therapy in older or unfit patients who are not candidates for intensive induction chemotherapy.
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As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.
Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.
Associate Professor of Medicine
Clinical Director of Leukemia Services
Robert H. Allen MD Chair in Hematology Research
Division of Hematology
University of Colorado School of Medicine
Denver, Colorado
Peer Reviewer
This activity has been peer reviewed and the reviewer has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Celgene; Jazz; Pfizer
Received grants for clinical research from: Takeda
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Could you provide an overview of induction therapy?
Daniel A. Pollyea, MD, MS: Induction therapy in AML refers to the therapeutic attempt to induce a remission and is typically used in the context of a newly diagnosed patient.[1] For decades, the term "induction therapy" has uniformly been used to describe a very intensive chemotherapy regimen. In the United States, this most often refers to the 7+3 regimen consisting of an anthracycline and cytarabine.[2] Despite attempts over the years, few, if any, improvements were made upon this regimen.[1] This has changed very recently and we now can add midostaurin to the classic 7+3 regimen for patients with an FLT3 mutation or use a newer, repackaged version of 7+3 (CPX-351) for patients with secondary AML (AML from an antecedent MDS or CMML or treatment-related AML) or de novo AML with MDS-related changes (AML-MRC). In addition, we have several new lower-intensity therapies that can induce a remission with considerably less toxicity than classic intensive regimens.[2,3] These developments are making induction chemotherapy more successful and more accessible to patients who would otherwise not be candidates for an intensive chemotherapy approach.
Do you think intensive induction chemotherapy should be used in all eligible patients?
Dr Pollyea: I think intensive induction chemotherapy is appropriate for many patients with newly diagnosed AML, but may not be the best option for all eligible patients. While current standards of care are still largely driven by historical practices, the emergence of effective, lower-intensity induction regimens raises the question of whether these newer options would also be appropriate for some patients who are technically eligible for more aggressive chemotherapy.[2] For instance, unfavorable-risk cytogenetics are common in older patients with AML and these patients have historically responded poorly to standard intensive chemotherapy regimens.[4] New lower-intensity regimens that have demonstrated efficacy in high-risk disease may be a good option for these fit older patients with unfavorable cytogenetics, despite their eligibility for intensive induction, because they may work, regardless of adverse biological features.[2,4]
What factors do you weigh when considering whether a patient should receive intensive induction therapy or a less intensive regimen?
Dr Pollyea: Despite extensive efforts to define criteria for selection of induction therapy in patients with AML, there is not currently a universal metric to guide these decisions. Current NCCN® Guidelines include age, ECOG performance status, functional status, and comorbid conditions as important factors that should be carefully weighed when choosing between intensive and less-intensive induction regimens.[2] Patient fitness and frailty are often assessed subjectively based on observation, but can also be evaluated objectively according to organ function and other comorbidities.[5] A consensus panel developed criteria to help identify patients with AML who could be considered unfit for intensive chemotherapy, including age > 75 years, ECOG performance status ≥ 3 not related to leukemia, congestive heart failure or cardiomyopathy, pulmonary disease, renal insufficiency, liver cirrhosis or disease, active infection resistant to therapy, or substantial mental illness.[6] Cytogenetics, patient preferences and goals, and social support system are also important factors to consider.[5] All the available information should be examined collectively and decisions made based on clinician experience, objective data, and the ever-changing treatment landscape.
How has the management of older patients changed in recent years?
Dr Pollyea: The majority of patients with AML are over the age of 65 and many can benefit greatly from available systemic therapies. Even those who appear very frail or sick often have symptoms related to their leukemia that will improve upon receipt of an effective induction regimen. Analysis of over 8000 elderly patients with AML from the SEER database published a few years ago showed that 60% of patients > 65 years of age did not receive chemotherapy within 3 months of their diagnosis.[7] While we have improved our management of older patients with AML since then, it is important to remain aware of emerging induction regimens that can now be used in a wider variety of patients and give frail/unfit patients a closer look to ensure they are offered optimal treatment options.
What are the options for a patient with AML when considering less intensive induction therapy?
Dr Pollyea: There are a number of lower intensity induction regimens now recommended in current NCCN Guidelines® for AML, expanding the treatment options for patients that are older or unfit and may not be good candidates for intensive chemotherapy (Table).[2,8-16] It is important to consider both the efficacy of these regimens and the toxicities, particularly in older and unfit patients who may have more difficulty tolerating treatments.
|
Regimen |
Phase |
Patient population |
N |
CR/CRi |
Median OS |
1-year OS |
|---|---|---|---|---|---|---|
|
Decitabine vs BSC or LDAC[8] |
3 |
≥ 65 years old, poor or intermediate-risk AML |
485 |
25.6% vs 10.3% |
7.7 vs 5.0 mos HR 0.85; P = .108 |
NR |
|
Azacitidine vs standard care*[9] |
3 |
≥ 65 years old, > 30% BM blasts |
488 |
27.8% vs 25.1%; P = .5384 |
10.4 vs 6.5, HR 0.85; P =.1009 |
46.5% vs 34.2% |
|
Venetoclax + decitabine or azacitidine[10] |
1b |
≥ 65 years old, AML ineligible for intensive chemotherapy |
145 |
67% |
17.5 mos |
59% |
|
Venetoclax + LDAC[11] |
1/2 |
≥ 60 years old, AML ineligible for intensive chemotherapy |
82 |
54% |
10.1 mos |
NR |
|
Glasdegib/LDAC vs LDAC[12] |
2 |
≥ 55 years old, AML unsuitable for intensive chemotherapy |
116 |
26.9% vs 5.3% |
8.3 vs 4.3 mos HR 0.46; P =.0002 |
39.5% vs 9.5% |
|
Gemtuzumab ozogamicin vs BSC[13] |
3 |
> 60 years old, AML unsuitable for intensive chemotherapy |
237 |
27% for GO |
4.9 vs 3.6 mos HR 0.69; P =.005 |
24.3% vs 9.7% |
|
Ivosidenib[14] |
1 |
IDH1-mutant AML ineligible for intensive chemotherapy |
34 |
48.5% |
12.6 mos |
63.0% |
|
Ivosidenib + azacitidine[15] |
1b |
IDH1-mutant AML ineligible for intensive chemotherapy |
23 |
69.6% |
NE |
82.0% |
|
Enasidenib[16] |
1/2 |
IDH2-mutant AML ineligible for standard therapy |
39 |
21% |
11.3 mos |
NR |
BSC = best supportive care; BM = bone marrow; GO = gemtuzumab ozogamicin; LDAC = low dose cytarabine; NE = not estimable; NR = not reported
*Standard care included best supportive care, low-dose cytarabine, or standard induction chemotherapy
HMA Monotherapy
Single-agent HMAs have demonstrated efficacy and tolerability in older patients with newly diagnosed AML. Phase 3 trials have demonstrated a survival benefit with decitabine over best supportive care or LDAC[8] and with azacitidine over standard of care.[9] The most common grade 3/4 AEs observed in the phase 3 trials of single-agent azacitidine or decitabine include febrile neutropenia, neutropenia, thrombocytopenia, pneumonia, anemia, and leukopenia.[8,9]
Venetoclax-Based Regimens
More recently, the oral BCL-2 inhibitor venetoclax demonstrated significant anti-leukemic activity and synergy when combined with hypomethylating agents or LDAC, including in patients with high-risk AML. In a phase 1b study in older patients with treatment-naive AML who were ineligible for intensive induction, venetoclax plus either decitabine or azacitidine induced a CR/CRi in 67% of patients, including 60% in those with poor-risk cytogenetics and 65% in those 75 years of age or older.[10] In that study, the median OS was 17.5 months overall but was not reached in the cohort that received venetoclax at a dose of 400 mg. The most common AEs were nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased WBC count.[10] Grade 3/4 event were primarily hematologic, including neutropenia, leukopenia, and anemia. No TLS was reported.
In a phase 1/2 study of older patients with newly diagnosed AML, venetoclax plus LDAC produced a CR/CRi rate of 54% with a median time to first response of 1.4 months and duration of remission of 8.1 months.[11] CR/CRi was observed in patients with genetic mutations including TP53 (30%), IDH1/2 (72%), FLT3 (44%), and NPM1 (89%). About one-third of patients with CR/CRi attained MRD-negativity. Among patients who were RBC or platelet transfusion dependent at baseline, 48% and 60%, respectively, were transfusion independent during venetoclax treatment. The median OS in this study was 10.1 months. Common grade 3/4 AEs observed with venetoclax + LDAC included febrile neutropenia, thrombocytopenia, WBC count decrease, neutropenia, anemia, and several reports of grade 3 TLS.[11]
While venetoclax plus HMAs is less intensive than standard induction chemotherapy in older patients with AML, these combinations have been associated with hematologic AEs, including worsening of baseline neutropenia.[10.11.12] Close patient monitoring with frequent response assessments, including MRD assessment, and growth factor support should be carefully considered and can improve tolerability.[12] Dose reductions or interruptions may be required. Venetoclax dose modifications should also be considered when concomitant strong or moderate CYP3A inhibitors are used, as this can increase the likelihood of therapy-associated AEs.
Glasdegib
The oral hedgehog pathway inhibitor glasdegib was recently approved in combination with LDAC in patients with untreated AML or high-risk MDS unsuitable for intensive chemotherapy.[13] Among patients with AML, the addition of glasdegib to LDAC has demonstrated a significant 4-month improvement in median OS and an increase in CR/CRi rate from 5.3% to 26.9% compared with LDAC alone. Patients with poor cytogenetic risk also appear to benefit from this combination. The most common grade 3/4 AEs include anemia, febrile neutropenia, thrombocytopenia, pneumonia, and fatigue.[13]
Gemtuzumab Ozogamicin
The CD33-targeted antibody GO has demonstrated efficacy as induction therapy in older patients with AML ineligible for intensive chemotherapy.[14] In a phase 3 trial, GO was associated with an improvement in median OS when compared to BSC (4.9 vs 3.6 months; HR 0.69; P =.005). GO is particularly effective in patients with high CD33 expression and in those with favorable or intermediate cytogenetic risk. GO is generally well tolerated; the most common nonhematologic grade 3/4 AEs are infection, febrile neutropenia, bleeding, and fatigue.[14]
IDH Inhibitors
The IDH1 inhibitor ivosidenib has demonstrated single-agent activity in patients with IDH1-mutant AML, with a CR/CRi rate of 48.5% and median OS of 12.6 months.[15] Grade 3/4 AEs primarily consist of thrombocytopenia, anemia, fatigue, nausea, and diarrhea.[15] Six patients reported differentiation syndrome, which resolved in all patients without the need for dose reductions or treatment discontinuations. The combination of ivosidenib and azacitidine has shown a high CR/CRi rate of 69.6% and a corresponding high rate of IDH1 mutation clearance.[16] The ongoing phase 3 AGILE study is currently investigating this combination.[17]
The IDH2 inhibitor enasidenib is also included in current NCCN Guidelines® for the treatment of patients with newly diagnosed IDH2-mutated AML.[2] Enasidenib showed early efficacy in a phase 1/2 trial in older patients ineligible for intensive induction therapy, with a median OS of 11.3 months and a CR/CRi rate of 21%.[18] The most common grade 3/4 AEs associated with enasidenib included anemia, indirect hyperbilirubinemia, IDH differentiation syndrome, thrombocytopenia, TLS, and leukopenia.
How do you select among the available options to tailor therapy for individual patients?
Dr Pollyea: All of these approaches are reasonable for patients who are not candidates for intensive chemotherapy. The lack of randomized clinical trial data directly comparing the lower intensity induction regimens makes treatment selection challenging. In my own practice, I tend to use venetoclax-based regimens for patients over the age of 60 based on the tolerability and rapid responses observed in clinical trials across the landscape of AML risk groups.[2,10,11] Other regimens are certainly appropriate, particularly if there is a concern regarding a specific AE or comorbidity. Patients with IDH1 or IDH2 mutations may also be considered for upfront ivosidenib or enasidenib, respectively, to exploit this genetic mutation early in the disease course.
What are some important ongoing questions?
Dr Pollyea: There are 3 key issues:
1. Can we predict patients unlikely to respond to a specific therapy so we can better select a treatment and avoid unnecessary toxicity? Addressing this problem will require continued exploration of AML biology and the identification of predictive biomarkers.
2. Can we extend the use of these highly effective, less intensive regimens to more fit patients and thereby spare some patients the highly toxic standard 7+3 regimen? This is particularly relevant for patients with high-risk disease in whom intensive chemotherapy may not be effective.[4] Previous trials of lower-intensity induction regimens have focused on older, unfit patients. An ongoing phase 2 trial is evaluating venetoclax plus azacitidine in adults ages 18-59 with newly diagnosed AML.[19]
3. How can we better manage relapsed AML? As more effective induction regimens yield better survival outcomes for older, unfit patients, a longer-term treatment approach will be needed. Active, tolerable treatment options for relapsed/refractory AML will become increasingly necessary in the coming years.
