ABSTRACT
Disease Overview
Acute myeloid leukemia (AML) is a bone marrow stem cell cancer that is often fatal despite available treatments. Diagnosis, risk assessment, monitoring, and therapeutic management of AML have changed dramatically in the last decade due to increased pathophysiologic understanding, improved assessment technology, and the addition of at least 12 approved therapies.
Diagnosis
The diagnosis is based on the presence of immature leukemia cells in the blood, and/or bone marrow or less often in extra‐medullary tissues. New biological insights have been integrated into recent classification systems.
Risk Assessment
The European Leukemia Network has published risk classification algorithms for both intensively and non‐intensively treated patients based on cytogenetic and on molecular findings. Prognostic factors may differ based on the therapeutic approach.
Monitoring
Our increasing ability to quantify lower levels of measurable residual disease (MRD) potentially allows better response assessment, as well as dynamic monitoring of disease status. The incorporation of MRD findings into therapeutic decision‐making is rapidly evolving.
Risk Adapted Therapy
The availability of 12 newly approved agents has been welcomed; however, optimal strategies incorporating newer agents into therapeutic algorithms are debated. The overarching approach integrates patient and caregiver goals of care, comorbidities, and disease characteristics.
Keywords: AML diagnosis, AML therapy, AML‐molecular diagnosis and therapy, measureable residual disease in AML, neoplasia‐myeloid leukemias and dysplasias
1. Introduction
Acute myeloid leukemia (AML) is a disease arising from uncontrolled proliferation of clonal hematopoietic cells [1, 2]. It comprises 1% of all new cancer cases in the United States. AML is diagnosed mainly at older age (median age at diagnosis of 68 years) [3] and has an estimated 5‐year OS of 32% (up to 50% in young patients and less than 10% in patients older than 60) [4, 5]. However, these outcomes do not fully encompass the dramatic change in the therapeutic landscape, with the approval of 12 new drugs or combination regimens since 2017 [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21] (Table 1). Furthermore, novel insights regarding AML biology have impacted our ability to diagnose, prognosticate, and monitor patients with AML [2, 22, 23, 24].
TABLE 1.
Drugs and/or combinations recently approved by the FDA for AML with selected trials.
| Drug | Mechanism | Approved indication | FDA approval date | Approved regimen | Other selected trials |
|---|---|---|---|---|---|
| GO [13, 120, 217] | CD33‐directed antibody drug conjugate | ND CD33‐positive AML | 09/01/2017 | ND – combination a with intensive chemotherapy | |
| R/R CD33 positive adults | R/R – monotherapy | ||||
| CPX‐351 [7, 133] | Liposomal daunorubicin and cytarabine | ND t‐AML or AML‐MRC (defined by clinical history, morphologic changes, or cytogenetics) | 08/03/2017 | Monotherapy for induction and consolidation |
|
| Enasidenib [10] | IDH2 inhibitor | R/R IDH2 mutated AML | 01/08/2017 | Monotherapy |
|
| Ivosidenib [8, 9, 15] | IDH1 inhibitor | R/R IDH1‐mutated AML | R/R − 07/20/2018 |
R/R—Monotherapy ND—Combination therapy with azacitidine or monotherapy |
|
| ND IDH1‐mutated AML age ≥ 75 years/comorbidities, not fit for intensive chemotherapy |
ND Monotherapy −05/02/2019 Combination—05/25/2022 |
||||
| Olutasidenib [19, 210] | IDH1 inhibitor | R/R IDH1‐mutated AML | 12/01/2022 | Monotherapy | |
| Midostaurin [6] | FLT3 inhibitor | ND FLT3‐mutated AML | 04/28/2017 | With “7 + 3” and HIDAC consolidation |
|
| Gilteritinib [12] | FLT3 inhibitor | R/R FLT3‐mutated AML | 11/21/2018 | Monotherapy |
|
| Quizartinib [20] | FLT3 inhibitor | ND FLT3‐mutated AML | 07/20/2023 | With “7 + 3” and HIDAC consolidation |
|
| Venetoclax [11, 17, 18, 165] | BCL2 inhibitor | ND‐AML age ≥ 75 years/comorbidities, not fit for intensive chemotherapy | 11/21/2018 | Combination + decitabine, aza or LDAC |
“7 + 3” + ven in AML [141] (NCT03709758) [142] Clad + ven + LDAC/aza in ND‐AML [168] Clad + IDA+ ara‐C + ven in ND‐AML [143] Ven in combination with reduced intensity conditioning for AlloSCT [266] HMA + ven as maintenance therapy post‐AlloSCT (“VIALE‐T,” NCT04161885) or post‐chemotherapy (“VIALE‐M,” NCT04102020) |
| CC486 [14] | Oral DNMT inhibitor | ND‐AML patients aged 55 ≥ as post‐intensive induction therapy in patients who achieved remission | 09/01/2020 | Monotherapy |
|
| Glasdegib [16] | Hedgehog pathway inhibitor | ND‐AML age ≥ 75 years/comorbidities, not fit for intensive chemotherapy | 11/21/2018 | In combination with LDAC |
|
| Revumenib [21, 222] | Menin inhibitor | R/R KMT2A rearranged acute leukemia | 11/15/2024 | Monotherapy |
AUGMENT‐102 (NCT05326516): Chemotherapy + revumenib in R/R AML NCT05886049: 7 + 3+ revumenib in ND AML SAVE (NCT05360160): Decitabine/cedazuridine + venetoclax + revumenib in ND and R/R AML |
Abbreviations: 7 + 3—daunorubicin plus cytarabine; AlloSCT—allogeneic stem cell transplantation; AML—acute myeloid leukemia; AML‐MRC—acute myeloid leukemia with myelodysplastic related changes; ara‐C—cytarabine; ATRA—all trans retinoic acid; aza—azacitidine; CD—cluster of differentiation; clad—cladribine; DNMT—DNA methyltransferase; Ena—enasidenib; FLAG‐IDA—fludarabine, cytarabine, G‐CSF, idarubicin; FLT3i—FLT3 inhibitor; GO—gemtuzumab ozogamicin; HIDAC—high dose cytarabine; HMA—hypomethylating agents; HR—high risk; ICE—Idarubicin, cytarabine, etoposide; ida—idarubicin; IDH—isocitrate dehydrogenase; Ivo—ivosidenib; LDAC—low dose cytarabine; ND—newly diagnosed; R/R—relapse or refractory; t‐AML—therapy related AML; ven—venetoclax.
Approved as a single agent in patients with ND‐AML as well, but rarely used as monotherapy.
2. Updates in Diagnosis
In 2022 the WHO fifth edition [22] and the International consensus criteria (ICC) [23] AML classification systems were published, each integrating novel molecular findings and highlighting biologically‐defined and clinically relevant AML subtypes. We will discuss similarities and differences between the two systems, as well as the challenges and lessons learned since these classifications were introduced.
Of note, acute promyelocytic leukemia (APL), usually associated with a PML::RARA translocation, is a unique clinicopathological AML entity that accounts for 5%–10% of AML [25, 26]. APL is generally initially treated with a combination of all trans‐retinoic acid (ATRA) and arsenic trioxide (ATO), with additional chemotherapy for those with WBC > 10 K/μL. This entity has an excellent prognosis, especially in comparison to other non‐APL AML subtypes [27, 28, 29, 30, 31, 32, 33]. In this review, we will not discuss APL management; AML will refer to non‐APL AML.
Both ICC and WHO fifth edition molecularly defined abnormalities that allow a diagnosis of AML even at relatively low marrow blast counts. In addition to RUNX1::RUNX1T1 and CBFB::MYH11, NPM1 is recognized by both classifications as an AML‐defining mutation, due to the rarity of NPM1 mutations in myelodysplastic syndromes (MDS) and the rapid progression seen in most patients previously defined as MDS with NPM1 mutation [34, 35]. The WHO delineates CEBPA‐mutated AML as an entity including either biallelic CEPBA mutation (irrespective of mutation type) or a monoallelic in‐frame basic leucine zipper region (bZIP) mutated gene. The ICC definition of CEBPA‐mutated AML only requires the presence of the bZIP alteration. This addition is due to the discovery that the in‐frame mutations in C‐terminal bZIP C‐terminus region have distinct clinical and molecular characteristics: younger age, higher white blood cell counts, and enrichment in co‐mutations of GATA2 and NPM1. The presence of bZIP in‐frame mutation is associated with favorable response and improved survival [36, 37, 38]. BCR::ABL1 was added as a formal AML defining lesion, with the requirement of blasts ≥ 20% rather than ≥ 10%, to differentiate from CML in accelerated phase.
The WHO and ICC classifications employ different blast thresholds to define AML in certain situations: There is no minimum threshold in the WHO criteria for AML with defining genetic abnormalities (with the exception 20% required for AML with BCR::ABL1 and AML with CEBPA bZIP mutation); the ICC requires at least 10% blasts in the bone marrow or peripheral blood for defining AML with recurrent genetic abnormalities (with the exception of ≥ 20% in AML with BCR::ABL1 or with prior MDS/MPN, e.g., chronic myelomonocytic leukemia [CMML]). For all other AML subgroups, the 20% blasts threshold was retained by the WHO. However, The ICC introduced a new category of MDS/AML comprising those with 10%–19% blasts in the bone marrow or peripheral blood, in recognition of the similarities in biology and prognosis between such patients and those with ≥ 20% myeloblasts [39, 40, 41, 42]. Whether a patient who has an AML defining‐genetic lesion with a relatively low blast count responds to therapy similarly to those with the same lesion and higher blasts count remains to proven prospectively.
The definition of AML with myelodysplasia related changes (MRC) was not included in either classification system. Instead, both WHO and ICC introduced categories with molecular and cytogenetic abnormalities that define functional secondary ontogeny and are associated with poor prognosis when treated with intensive chemotherapy [43]. However, the definition of “secondary” differs between classifications. The WHO defined AML myelodysplasia‐related (AML‐MR) which includes one of the following: (1) a clinical history of MDS or MDS/MPN, (2) cytogenetics typical of MDS, or (3) molecularly defined based on the presence of one of eight secondary ontogeny defining mutations. In contrast, ICC included two separate entities of secondary AML: molecularly defined (termed AML with myelodysplasia‐related gene mutations) and cytogenetically defined (termed AML with myelodysplasia‐related cytogenetic abnormalities). Furthermore, in the ICC, a clinical history of prior MDS or MDS/MPN is used to annotate the diagnosis of AML, rather than being considered a separate entity. In addition, the molecular and cytogenetic abnormalities considered MDS‐defining differ slightly between the two classifications. For example, a RUNX1 mutation is included as myelodysplasia‐defining in the ICC definition, but not in the WHO 2022 criteria, (Figure 1 and Table 2).
FIGURE 1.
Comparison between WHO fifth versus ICC AML definitions. * ≥ 20% blasts are required for AML definition. Colors reflect similar subgroups between classifications. AML—acute myeloid leukemia; ICC—international consensus classification; MDS—myelodysplastic syndrome; MPN—myelodysplastic neoplasm; WHO—world health organization.
TABLE 2.
Major differences between WHO fifth AML and the ICC AML classifications.
| Major differences in AML classification systems | ||
|---|---|---|
| WHO fifth AML classification | ICC AML classification | Main differences |
| Structure | ||
|
Hierarchical diagnosis of AML with recurrent genetic abnormalities = > mutated TP53 (VAF > 10%) = > AML with myelodysplasia‐related gene mutations = > AML with myelodysplasia‐related cytogenetic abnormalities = > AML NOS | Two groups definition (WHO) versus hierarchical order (ICC) |
| Blast threshold (bone marrow or peripheral blood) | ||
|
AML defined by genetic abnormalities does not require any blast threshold (except for AML with BCR::ABL1, AML with biallelic/single bZIP mutations in CEPBA mutation and AML‐MR which require 20%). AML defined by differentiation requires 20% blasts. |
AML with recurrent genetic abnormalities requires 10% blasts (except AML with BCR::ABL1 or prior MDS/MPN requires 20%). Other subtypes are defined as MDS/AML (blasts 10%–19%) or AML (blasts ≥ 20%). |
Different blasts thresholds. New definition of MDS/AML in ICC criteria. |
| AML‐MR versus AML with myelodysplasia‐related gene mutations/cytogenetic abnormalities (formerly known as part of AML‐MRC definition) | ||
|
Cytogenetic: del(5q)/t(5q); −7/del(7q)/t(7q); del(11q); del(12p)/t(12p); −13/del(13q); del(17p)/t(17p)/iso(17q); idic(X)(q13) or Complex karyotype (≥ 3 abnormalities). Molecular: ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, UAKF2, ZRSR2. Prior history of MDS or MDS/MPN accounts for AML‐MR |
Cytogenetic: del(5q)/t(5q)/add(5q); −7/del(7q); +8; del(12p)/t(12p)/add(12p); iso(17q), −17/add(17p) or del(17p); del(20q); idic(X)(q13) or Complex Karyotype (≥ 3 abnormalities) Molecular: ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 and RUNX1 . Prior history of MDS or MDS/MPN accounts as a qualifier and not a separate group |
Modest difference in molecular and cytogenetic definitions. Significance and interpretation of prior MDS diagnosis |
| Prior History of MDS or MDS/MPN, prior cytotoxic therapy, germline disposition | ||
New definition of secondary myeloid neoplasm (separate from AML defined groups above)—
|
Diagnostic qualifiers in addition to AML group—
|
Different categorization of clinical or pathological characteristics |
Note: Major differences are bolded and highlighted in the right column.
Abbreviations: AML—acute myeloid leukemia; AML‐MR—AML myelodysplasia‐related; AML‐MRC—AML with myelodysplasia‐related changes; ELN—European leukemia network; ICC—international classification; MDS—myelodysplastic syndrome; MPAL—mixed phenotype acute leukemia; MPN—myeloproliferative neoplasm; pCT—post‐cytotoxic therapy; WHO—World Health Organization.
Both classification systems incorporated special consideration for prior cytotoxic exposure and genetic predisposition. In the WHO classification, those were reclassified under a new diagnostic category called secondary myeloid neoplasms encompassing either myeloid neoplasms arising after cytotoxic therapeutics, or those which possess a defined germline predisposition. In the ICC classification, these were considered as qualifiers or annotations to an AML diagnosis rather than a separate diagnostic category (Figure 1).
Therapy‐related AML is traditionally associated with worse prognosis [43], although it was not officially integrated into the ELN prognostic criteria as adverse risk. Recent discoveries demonstrated that mutations in TP53 [44, 45, 46] and related genes such as PPM1D [47, 48] drive chemoresistance and dismal outcomes. Indeed, the biological characteristics of leukemia generally outweigh clinical history. For example, those who develop APL after exposure to chemotherapy for another cancer are expected to do well [49].
With recent advances in molecular diagnosis and analysis, more individuals than previously with myeloid malignancies (even those who present at advanced ages) are now recognized to have an inherited germline predisposition [50]. Thus, it has been advocated that MDS and/or AML patients with certain molecular/cytogenetic lesions, a syndromic presentation with a myeloid malignancy, or a suggestive family history undergo a genetic analysis of unaffected tissue to assess for a germline predisposition [51].
For example, mutations in DDX41 are the most common genetic predisposition in MDS and AML in adults [52, 53], with germline pathogenic variants carrying an increased risk for MDS or AML found in ~1:430 people in European adults [54, 55]. The occurrence of AML in those with a germline mutation in DDX41 is generally thought to involve a “second‐hit” via a mutation in the other allele [56]. AML with DDX41 germline mutations have unique clinical characteristics: male predominance, presentation in the seventh decade, low peripheral blood leukocyte and bone marrow blast counts, and intensive chemotherapy or venetoclax based‐regimen‐responsiveness, yielding a more favorable prognosis than matched patients with wild type DDX41 [57, 58, 59]. Forthcoming discoveries of additional germline predisposition syndromes will likely increasingly impact treatment strategies, such as donor selection for allogeneic stem cell transplant, decisions regarding the choice of the optimal transplant conditioning regimen, or the fashion in which family members are evaluated and monitored [60].
While advances in AML diagnosis could aid in optimizing individualized therapy, the two novel classification systems challenge communication between health care professionals, especially pathologists, treating clinicians, and patients. In the last few years, numerous comparisons between the two classifications have been conducted and there are calls for a unified diagnostic approach [61, 62]. The similarities between the two classification systems exceed the differences. Nonetheless, the clinician has the responsibility to synthesize the biological, clinical, and personal data while considering the available literature to make a treatment decision. Clearly, the diagnosis alone, whether using the ICC or WHO algorithms cannot be the sole factor in such a decision. Further, the ICC recommends that the molecular tests be available in 3–5 days; this goal is aspirational for many centers around the world. While the integration of novel molecular findings is likely to improve diagnostic accuracy and promote biologically‐based therapy, we should also consider the applicability and generalizability of recommendations for the entire healthcare community, as a major goal is to optimize care of patients worldwide.
3. Updates in Risk Stratification
The European leukemia network (ELN) 2022 guidelines incorporate knowledge from novel molecular findings and recent trial results. The main changes compared with the ELN 2017 [63] are (Table 3):
The FLT3 internal tandem duplication (ITD) allelic ratio (AR) is no longer considered in risk classification. Patients with FLT3‐ITD‐mutated AML are assigned to the intermediate group, irrespective of the AR or presence of an NPM1 mutation. The reasons for this change include the effect of FLT3 inhibitors on outcomes of patients with FLT3‐ITD‐mutated AML [6, 12, 20, 64] and integration of MRD into decision‐making [65, 66].
AML with myelodysplasia‐related gene mutations (as delineated by ICC) is now defined as an adverse risk entity, which is delineated by the presence of a pathologic variant in one or more of ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2 genes [2, 43]. These mutations do not confer adverse risk in patients with favorable risk‐defining aberrations.
NPM1‐mutated AML with adverse cytogenetic abnormalities is now classified as adverse risk. This change is based on a meta‐analysis that evaluated additional cytogenetic abnormalities in patients with NPM1‐mutated AML [67]. The exact role of additional molecular abnormalities (other than FLT3‐ITD) in patients with NPM1‐mutated AML is not yet defined; currently, those with concomitant NPM1 and myelodysplasia gene mutations and even TP53 mutations are still considered favorable (although there is conflicting data); However, since publication of the ELN 2022 risk criteria, several studies questioned the favorable impact of NPM1 in the presence of otherwise adverse‐risk defining mutations [68, 69, 70, 71, 72].
The favorable prognosis of CEPBA‐mutant AML depends solely on an in‐frame mutations affecting the bZIP region, irrespective of whether mono‐ or bi‐allelic mutations are present [36, 37, 38].
Additional disease‐defining cytogenetic abnormalities now considered as adverse risk—include t(3q26.2;v) involving the MECOM gene and t(8;16)(p11;p13) associated with KAT6A::CREBBP, as they were also shown to be associated with dismal long term overall survival [73, 74].
AMLs with hyperdiploid karyotypes with multiple trisomies (or polysomies) are no longer considered to be equivalent to a complex karyotype and are excluded from the adverse risk group, as such patients with only numerical cytogenetic changes without structural abnormalities have better survival outcome compared to patients with three or more cytogenetic changes with structural abnormalities [75].
TABLE 3.
ELN 2022 risk classification for patients treated with intensive chemotherapy.
| Risk category | Genetic abnormality |
|---|---|
| Favorable | t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 a |
| inv (16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11 a | |
| Mutated NPM1 without FLT3‐ITD b | |
| bZIP in‐frame mutated CEBPA c | |
| Intermediate | FLT3‐ITD (irrespective of allelic ratio or NPM1 mutation) |
| t(9;11)(p21.3;q23.3)/MLLT3::KMT2A d | |
| Cytogenetic and/or molecular abnormalities not classified as favorable or adverse | |
| Adverse | t(6;9)(p23;q34.1)/DEK::NUP214 |
| t(v;11q23.3)/KMT2A rearranged (excluding KMT2A‐PTD) | |
| t(9;22)(q34.1;q11.2)/BCR::ABL1 | |
| (8;16)(p11;p13)/KAT6A::CREBBP | |
| inv (3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM(EVI1) | |
| t(3q26.2;v)/MECOM(EVI1)‐rearranged | |
| −5 or del(5q); −7; −17/abn(17p) | |
| Complex karyotype (change in definition) e ; Monosomal Karyotype f | |
| Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2 g | |
| Mutated TP53 (variant allele frequency ≥ 10%) |
Abbreviation: ELN—European leukemia network.
Source: Modified from Döhner et al. ELN 2022 recommendations, tab. 6 [24].
The presence of KIT or FLT3 mutations does not alter risk category.
AML with NPM1 and adverse risk cytogenetic abnormalities is defined as adverse risk.
Only in‐frame mutations affecting the basic leucine zipper (bZIP) region of CEBPA, irrespective of whether they occur as monoallelic or biallelic mutations, have been associated with favorable outcomes.
The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse‐risk gene mutations.
Complex karyotype: ≥ three unrelated chromosome abnormalities in the absence of other class‐defining recurring genetic abnormalities; excludes hyperdiploid karyotypes with three or more trisomies (or polysomies) without structural abnormalities.
Monosomal karyotype: presence of two or more distinct monosomies (excluding X or Y), or one single autosomal monosomy in combination with at least one structural chromosome abnormality (excluding core‐binding factor AML).
AML with NPM1 and one of these adverse molecular abnormalities do not alter risk category currently.
However, the guidelines are largely based on intensively treated patients up to 60 years. A recent study generated a prognostic score for older patients, aged 60 and older based on the NCRI‐AML 18 and HOVON‐SAKK cohorts [76]. Four distinct groups (favorable, intermediate, poor and very poor) were identified based on clinical (Male, WBC ≥ 20*109/L cells, age > 65 years) and genetic (monosomal karyotype, TP53, RUNX1, FLT3‐ITD, ASXL1, and DNMT3A mutations) characteristics. The proposed classification improved calibration compared with the ELN 2022 in a derivation and internal validation cohort. In addition, they demonstrated that alloSCT was associated with improved survival in the very poor and intermediate group, a trend toward improved survival in the poor group, and no improvement in the favorable group. In the two latter groups, the benefit of reduced non‐relapse mortality with alloSCT was offset by higher non‐relapse mortality associated with alloSCT. These results should be validated in external cohorts for their generalizability.
However, both of these criteria were derived from patients treated with intensive chemotherapy, with multiple studies demonstrating the limited prognostic role of the ELN 2022 criteria in patients who are treated with less‐intensive therapies, mainly venetoclax‐based regimens [59]. For example, a recent study in patients treated with a hypomethylating agent (HMA) plus venetoclax demonstrated that an AML‐MR mutation does not confer an inferior prognosis [77]. Thus, the ELN‐2022 schema must be considered in the context of the specific treatment received. Based on analysis of the prospective randomized VIALE‐A plus the previous phase Ib trial involving HMA plus venetoclax, a 4‐gene signature risk score classified patients into three prognostic groups: (1) those with TP53 mutations were included in a lower benefit group; (2) those without TP53 but harboring a FLT3‐ITD, NRAS or KRAS mutations were intermediate; (3) those without any of these 4 mutations were favorable (median OS 5.5, 12.1 and 26.5 months, respectively) [78]. A retrospective study based on this classifier demonstrated similar results [79], thereby enabling the development of new ELN risk criteria for patients with AML treated with lesser‐intensive therapies (Table 4) [80]. Nevertheless, one should note that the combination of HMA plus venetoclax is widely used today in a broader and more heterogenous population than was included in the VIALE‐A trial. A recent real‐world study from the UK in patients treated with venetoclax plus azacitidine (n = 587) or low dose cytarabine (LDAC; n = 67) demonstrated that the new ELN 2024 performed better compared to the ELN 2022, (C‐index of 0.568 vs. 0.542) [81]. However, the prognostic value was still sub‐optimal. A large retrospective study in three academic centers (n = 279) suggested a re‐classification: favorable (mutated NPM1, IDH1, IDH2, DDX41, and wild‐type N/KRAS, PTPN11, FLT3‐ITD, TP53), intermediate (mutated FLT3‐ITD, NRAS, or other mutations not classified and wild‐type KRAS, PTPN11, and TP53) and adverse risk (mutated KRAS, PTPN11, or TP53). The reclassification was verified in the external UK cohort (n = 430) [82]. Thus, the generalizability of the ELN 2024 risk criteria is still not clear. Furthermore, although DDX41‐mutated AML is categorized as favorable risk irrespective of co‐mutations, there is limited data on TP53 co‐mutation and its clinical implication.
TABLE 4.
ELN 2024 risk classification for patients treated with less‐intensive chemotherapy.
| Risk category | Genetic abnormality |
|---|---|
| Favorable | Mutated NPM1 (FLT3‐ITD wt , NRAS wt , KRAS wt , TP53 wt ) |
| Mutated IDH2 (FLT3‐ITD wt , NRAS wt , KRAS wt , TP53 wt ) | |
| Mutated IDH1 a (TP53 wt ) | |
| Mutated DDX41 b | |
| Other cytogenetic and/or molecular abnormalities c (FLT3‐ITD wt , NRAS wt , KRAS wt , TP53 wt ) | |
| Intermediate | Other cytogenetic and/or molecular abnormalities c (FLT3‐ITD pos and/or NRAS mut , and/or KRAS mut , TP53 wt ) |
| Adverse | Mutated TP53 |
Note: The classification does not apply to patients with prior hypomethylating agent exposure.
Source: Modified from Döhner et al. ELN 2022 recommendations, tab. 1, [80].
The favorable risk applies specifically to patients treated with azacitidine + ivosidenib, irrespective of the presence of activating signaling gene mutations.
Identification of a DDX41 mutation at near‐heterozygous frequency should prompt consideration of germline DDX41 mutation.
For many cytogenetic and molecular abnormalities, single or as co‐aberrations, no data are currently available; they are tentatively categorized as favorable and intermediate risk depending on the absence or presence of activating signaling gene mutations.
4. Updates in MRD Measurement and Monitoring
MRD (minimal or measurable residual disease) is a biomarker used for prognostic, predictive, monitoring, and response assessment in AML. The two most commonly used technologies to evaluate MRD are multiparameter flow cytometry (MFC) and real‐time quantitative PCR (RT‐qPCR), each of which can detect one malignant cell in 104. While the former may be applicable to most patients with AML, the latter requires the knowledge of specific diagnostic cytogenetic abnormalities or mutations and is commonly available for tracking patients with CBF or NPM1 mutations. Other increasingly used techniques are next‐generation sequencing (NGS) [83, 84] and digital droplet PCR (ddPCR; each of the latter can be sensitive down to about 1/106) [85]. The ELN recommendations from 2021 focus on the standardization of MFC‐MRD and RT‐qPCR MRD thresholds, MRD response definition, and use of MRD in clinical decision‐making [66]. Currently, the level of detection recommended by ELN is 1/103 or lower. However, as measurement becomes more sensitive over time and data from clinical trials are generated, the use and interpretation of MRD assessment is expected to evolve.
The prognostic value of MRD, no matter how measured, is well established, both in patients treated with intensive and less‐intensive chemotherapy. In a study including 346 patients with an NPM1 mutation, MRD measured by RT‐qPCR for this gene with a threshold of 0.1% after two cycles of intensive chemotherapy was found to be an independent prognostic factor (MRD positivity HR for death: 4.38; 95% CI: 2.57 to 7.47; p < 0.001) [86]. Another key trial in 430 intensively treated patients evaluated the utility of MRD in CR after two chemotherapy cycles using an NGS panel with a cut‐off ≥ 0.02% for positivity [87]. Patients with persistent MRD positivity, excluding mutations in DNMT3A, TET2, and ASXL1, which are often present in clonal hematopoiesis, had higher 4‐year relapse rates than those with undetectable MRD (55.4% vs. 31.9%; hazard ratio [HR], 2.14; p < 0.001), as well as worse 4‐year overall survival (41.9% vs. 66.1%; HR for death, 2.06; p < 0.001). In addition, NGS contributed additive prognostic value compared to MFC‐MRD alone, in that patients who were negative by both had the lowest rate of relapse (73% when both were positive, ~50% when either MFC‐MRD or NGS‐MRD were negative and 27% when both were negative, p < 0.001). In a systematic review and meta‐analysis of MRD as prognostic tool in AML among 11 151 patients treated intensively, the average OS HR for achieving MRD negativity was 0.36 (95% CI: 0.33–0.39) and the 5 year OS was 68% versus 34% among patients who achieved MRD negativity versus those who did not [88].
The prognostic value of MRD in non‐intensively treated patients has also been demonstrated. Among patients who were treated with azacytidine and venetoclax in the VIALE‐A trial, in patients who achieved composite complete remission (cCR) defined as complete (CR) or complete responses with incomplete count recovery [CRi]), the achievement of MFC‐MRD negativity (< 0.1%) was associated with better outcomes compared to those who failed to have responses at such a deep level. The median DOR, EFS, and OS were not reached in patients with MRD negativity with 12‐month estimates for DOR, EFS, and OS in this group of 81.2%, 83.2%, and 94.0%. In cCR patients with MRD positivity, the median DOR, EFS, and OS were 9.7, 10.6, and 18.7 months, corresponding to 12‐month DOR, EFS and OS estimates of 46.6%, 45.4%, and 67.9%, respectively. In a COX regression multivariable analysis adjusting for age, cytogenetics and type of AML (de novo vs. secondary), MRD negativity by MFC was independently predictive for improved OS (HR for mortality 0.285; 95% CI: 0.159 to 0.510; p < 0.001) [89]. A recent study among NPM1‐mutated patients treated with HMA + VEN demonstrated that MRD negativity (defined as 0 NPM1 copies per 100 ABL1 at the end of cycle 4) was associated with superior OS and EFS as well as a lower cumulative incidence of relapse than in those who remained MRD positive at that time point (at 2‐year 84% vs. 46%), EFS (at 2‐year 84% vs. 20%) and cumulative incidence of relapse CIR (at 2‐year 72% vs. 10%) [90].
The peri‐transplant setting is a critical time for MRD evaluation. Decisions about the relative utility of consolidation chemotherapy and post‐transplant maintenance often need to be made at this juncture. However, the prognostic importance of MRD detection in the pre‐transplant setting is impacted by diagnostic features. For example, in one study of patients aged ≥ 60 years treated with intensive chemotherapy followed by reduced‐intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloSCT), MRD negativity, measured by NGS and defined as lack of any non‐DNMT3A or TET2 mutation, was associated with better leukemia free survival (LFS) in a univariable model compared with MRD positivity [91]. However, MRD was no longer prognostic in a multivariable model, mainly due to its association with diagnostic genetic characteristics, including MDS‐associated gene mutations, TP53 mutations, and high‐risk karyotype. Similar results emphasizing the impact of baseline cytogenetic and molecular characteristics compared with MRD pre‐transplant was also seen when MRD was measured by MFC [92].
In a study performed in the United States, pre‐alloSCT blood samples were obtained from the CIBMTR biobank and MRD measured by ultra‐deep anchored multiplex PCR‐based NGS‐MRD for FLT3, NPM1, IDH1/2, and KIT with error‐corrected variant calling. Among 822 patients treated with AML who achieved CR and proceeded with alloSCT (371 in the discovery cohort, 451 in the validation cohort), pre‐alloSCT NPM1, and/or FLT3‐ITD negativity was associated with improved OS, RFS, and lower relapse rates (p < 0.001 for all) compared with detectable presence of these mutant genes [84, 93].
The ELN MRD guidelines recommend using qPCR for patients with NPM1 or CBF‐mutated AML (ddPCR or NGS‐MRD may be alternatively used, though paucity of data existed at the time of recommendations). For patients without an NPM1 or CBF mutation at diagnosis, MFC‐MRD, ideally established at diagnosis to define the patient‐specific leukemia‐associated immunophenotype (LAIP) or different from normal (DfN), may be used. The ELN guidelines also address the optimal timing and tissue of MRD assessment. The diagnostic sample should ideally be obtained from the bone marrow aspirate but can be done from peripheral blood in patients with NPM1 or CBF‐mutated AML whose blood has ≥ 20% peripheral blasts. The first post‐treatment MRD should be measured in the marrow after two cycles of therapy (those with NPM1 and CBF mutant AML may have peripheral blood assessment). An end‐of‐treatment MRD measurement from marrow aspirate is also recommended, although lack of data precludes firm therapeutic recommendation based on the result. To evaluate pre‐clinical recurrence in NPM1 or CBF mutant AML, assessments via blood every 4–6 weeks or bone marrow every 3 months are recommended. The MFC‐MRD monitoring frequency should be similar, but data supporting such intervals are lacking, leading the panel to define this as an exploratory recommendation. Moreover, even with such close serial monitoring, surprises are not uncommon. Relapse can occur in up to 30% of patients with MRD negativity [86, 87] and not all patients with MRD positive disease will relapse, especially those with low level PCR‐MRD in patients with NPM1 or CBF mutations [94, 95] (although relapse by flow without clinical relapse was shown to carry the same adverse prognosis as morphological relapse) [96].
While the value of MRD as prognostic marker is well established, there are no guidelines or wide acceptance on MRD utility as a predictive marker to aid in therapeutic decision‐making. However, several studies have demonstrated the use of MRD measurement as a guide to decide between post‐remission alloSCT versus consolidation chemotherapy. A prospective trial suggested that with the persistence of RUNX1::RUNX1T1 transcripts after two cycles of chemotherapy should indicate the need for alloSCT even in this “favorable” subtype of AML [97]. Results from an important recently published study from the United Kingdom may aid in guiding utilization of alloSCT in patients with NPM1‐mutated AML treated with intensive chemotherapy. In 737 patients with NPM1‐mutated AML who were treated on the NCRI AM17 and AML19 studies and achieved remission [98], consolidation with alloSCT in first complete remission (CR1) was beneficial only in those who were MRD positive by PCR (sensitivity 1/10 000) for the NPM1 mutation post‐induction (3‐year OS 61% vs. 24% with vs. without alloSCT, HR 0.39, 95% CI: 0.24–0.64, p < 0.001), but not in those who were MRD negative post‐induction (79% vs. 82% with vs. without alloSCT, HR 0.82, 95% CI: 0.50–1.33, p = 0.4). This was true even in the subset of patients who had concomitant FLT3‐ITD mutation and thus, considered ELN 2022 intermediate risk and traditionally recommended for alloSCT in CR1: 3‐year OS 45% versus 18% with MRD positivity post‐induction; 83% vs. 76% if MRD negativity post‐induction.
MRD detectability during post‐therapy monitoring could prompt early treatment, but will this change disease natural history? In the phase II VALDAC trial 48 patients with an MRD positive relapse (defined as ≥ 1 log) rise in the MRD was measured by RT‐qPCR or dd‐PCR or low‐oligoblastic (defined as 5%–15% blasts) after achieving remission with intensive chemotherapy were treated with LDAC plus venetoclax, to try and eradicate the relapsing clone [99]. By the end of the second cycle, almost half (44%) of the patients with MRD relapse achieved MRD negativity and 70% of those with oligoblastic relapse were able to achieve remission. The median OS was not reached, with an estimated 2‐year OS of 67% in the MRD cohort and 53% in the oligoblastic cohort. Although not randomized, these data suggest for potential role of MRD as a surveillance marker and early intervention in those with low‐burden relapsed disease.
The use of MRD in the peri‐transplant period could help determine which patients should receive targeted maintenance therapy. In the phase III MORPHO trial (detailed below, under “Gilteritinib” and “Post‐remission therapy”), maintenance gilteritinib post‐alloSCT in patients with FLT3‐ITD AML improved relapse‐free survival (RFS) compared with placebo only in patients who had MRD detected using a sensitive PCR‐based assay for FLT3‐ITD prior to or post‐alloSCT (HR, 0.515 [95% CI: 0.316 to 0.838]; p = 0.0065), but not in those without detectable MRD (HR, 1.213 [95% CI: 0.616 to 2.387]; p = 0.575).
Overall, MRD clearly has a role in the determination of prognosis after initial chemotherapy, in both patients destined to receive an alloSCT and in those that will be treated with consolidation chemotherapy. MRD testing is also emerging as predictive test to provide therapeutic guidance in various time‐points—post‐induction, pre‐ and post‐alloSCT; however, as there is still no standardized method for MRD measurement and no solid prospective data guiding the integration of results into clinical management, we do not routinely utilize MRD for surveillance and decision‐making in every patient with AML, but we do consider the MRD findings in selected patients as part of the decision to perform allogeneic stem cell transplant in first complete remission. For patients without a useful molecular diagnostic mutation at diagnosis, we routinely employ flow cytometry, using DfN MRD technology, which generally uses a 0.02% cut‐off [100]. For detection of NPM1 mutations or CBF translocations, we use PCR measurement, as previously mentioned [86, 101].
5. Updates in Response and Outcomes Evaluation
The ELN 2022 response criteria retained the ELN 2017 definitions of CR, CRi, partial remission (PR) and marrow leukemia free state (MLFS), with the addition of a new response category: CR with partial hematological recovery (CRh), which is defined by bone marrow blasts < 5%, absence of peripheral blasts or extramedullary disease and partial count recovery with ANC ≥ 500/μL and platelets ≥ 50 000/μL. CRh was used as post hoc analysis required by the FDA for enasidenib approval [10] and has been used since as an endpoint in other clinical trials; however, the exact role of CRh in predicting survival is yet to be defined [102]. ELN 2022 also integrated MRD status into response definitions. If MRD negative response is achieved, all CR subtypes (i.e., CR, CRi, and CRh) should be annotated with MRD status as well, (i.e., CRMRD−, CRiMRD−, and CRhMRD−). The definition of relapse remains bone marrow leukemia blasts ≥ 5%, any reappearance of peripheral leukemic blasts in two samples 1 week apart or new extra‐medullary disease. A new definition of MRD failure or relapse is based on one of the following (if repeated within 4 weeks to validate the results in a second consecutive sample from the same tissue source, preferably bone marrow): conversion from MRD negativity to positivity by any method or copy number increase by quantitative PCR by a factor of 10. The cutoff for MFC‐MRD negativity is < 0.1% for CD45‐expressing cells using either LAIP or DfN immunophenotype. MRD negativity by qPCR is defined as cycling threshold (Ct) ≥ 40 in ≥ 2 of 3 replicates. Due to low relapse risk when the end of treatment NPM1 or CBF AML qPCR is less than 2%, only values above that level are considered positive [66, 94, 95, 101]. However, the recent findings of NPM1 MRD positivity prognostic value [71, 90, 98] have not been incorporated into these guidelines and will possibly impact the threshold for MRD positivity in patients with NPM1‐mutated AML.
The incorporation of MRD as an endpoint also created new definitions for time‐to‐event outcomes other than OS, such as event free survival (EFSMRD), relapse free survival (RFSMRD) or cumulative incidence of relapse (CIRMRD), reflecting MRD positivity as an event. For proper interpretation of a given study, the MRD sample site (marrow vs. peripheral blood), technique, and sensitivity should be provided. The practical suggestions on the ELN MRD guidelines are highly valuable, appreciated, and reasonable, but it must be recognized that more prospective data will be required to increase the validity and strength of the recommendations. The developers acknowledged that revisions will be required when new data is generated, such as that described above for NPM1 and FLT3‐ITD‐mutated AML.
6. Updates on Treatments in Newly Diagnosed AML
6.1. General Considerations
The classical paradigm to achieve cure in AML is first to induce CR thereby reducing the leukemia burden by several orders of magnitude, followed by post‐remission therapy in the form of chemotherapy and/or alloSCT. The choice of the most appropriate induction and post‐remission therapy is based on multiple parameters, including patient comorbidities, past medical history including prior myeloid disease and/or cytotoxic chemotherapy exposure, AML cytogenetic and molecular risk profile, possibly post‐therapy MRD status, as well as donor availability and patient goals of care [24, 63]. Historically, the first step for deciding on initial treatment is based on patients ‘fitness’ for intensive therapy, with intensive chemotherapy induction being the default for those who are being deemed fit for a highly myelosuppressive/gut‐toxic approach. It is perhaps easier to delineate who should not receive intensive chemotherapy than who should definitively be subject to a long hospitalization with a significant risk of treatment‐related mortality. At this time, age over 75 is thought to be a relative contraindication to intensive chemotherapy, especially based on the known availability of effective less intensive chemotherapy. Other than age, the FDA has adopted a set of stringent criteria (poor hepatic, renal, cardiac, and pulmonary function) to definitively consider a patient unfit for intensive chemotherapy. The criteria, suggested by Ferrara et al. [103], are commonly incorporated into eligibility criteria and were validated in a large cohort of patients for predicting shorter‐term mortality after intensive chemotherapy treatment in AML [104]. However, with multiple therapeutics emerging in recent years, the paradigm has shifted toward “who would benefit from intensive chemotherapy” rather than who is deemed fit. For instance, even a ‘fit’ patient (of any age) with adverse risk biology might not be “appropriate” for intensive chemotherapy due the likelihood of poor outcomes. The dilemma is most prominent in patients aged 60–75 years, which represents the largest age group in AML, many of whom can potentially be treated with either intensive or less‐intensive therapies in the upfront setting. We will elaborate on the various therapeutic possibilities and present our approach, including an updated suggested therapeutic algorithm for patients in this age group.
6.2. Updates on Intensive Therapy for Newly Diagnosed Patients
6.2.1. Updates on Induction Therapy
The backbone of intensive chemotherapy remains an anthracycline‐ and cytarabine‐based approach [105, 106], most commonly as the “7 + 3” regimen using daunorubicin at a dose of 60–90 mg/m2 for 3 days and cytarabine at a dose of 100–200 mg/m2 for 7 days [107, 108, 109, 110]. However, other induction regimens in use include CLAG‐M [111], G‐CLAM [112], IA [113], FLAG‐IDA [114], and lomustine‐IA [115]. Whether any of these are ‘better’ than 3 + 7 alone is unclear, though the addition of either lomustine [115], a nucleoside analog [116], or treatment with FLAG‐IDA [117] have each been suggested to be superior to 3 + 7 in prospective randomized trials; however, the latter was deemed too toxic for general use [118]. Moreover, several drugs were recently approved (in combination with chemotherapy) for patients with newly diagnosed (ND) AML who are fit for intensive chemotherapy (Table 1 and Figure 2). Regarding the dose of daunorubicin, in two large‐randomized trials, 90 versus 45 mg/m2 improved survival among younger [108] and older [109] patients, as well as in patients with specific mutations (NPM1, FLT3, and DNMT3A) [107]. However, there was no benefit in term of survival among 1206 patients with AML when 90 mg/m2 was compared to 60 mg/m2 (although all patients received a second course of daunorubicin 50 mg/m2, which could potentially reduce the beneficial effects of 90 vs. 60 mg/m2) [110]. The two‐step randomized DAUNODOUBLE trial evaluated daunorubicin intensity and the additive value of second induction in 864 patients aged 18–65 years with ND AML treated with intensive chemotherapy [119]. In the first randomization, there was no difference in response or survival in patients treated with 60 mg/m2 compared with 90 mg/m2 (composite CR rates: 90% vs. 89%, p = 0.691; 3‐year OS 65% vs. 58%, p = 0.242, respectively). In subgroup analyses, comparable outcomes were seen across patients with NPM1, FLT3‐ITD, and all ELN 2017 risk groups. In the second randomization, there was no benefit of a second induction among the 389 who achieved a good early response (defined as < 5% blasts in the day‐14 bone marrow evaluation): composite CR rates 87% versus 85%; 3‐year OS 76% versus 75% with one vs. two inductions, respectively.
FIGURE 2.
Treatment algorithm for newly diagnosed patients aged < 60 years with AML fit for intensive therapy. AlloSCT—allogeneic stem cell transplantation; AML—acute myeloid leukemia; AML‐MR—acute myeloid leukemia with myelodysplasia related changes (ELN 2017 definition); CBF—core binding factor; ELN—European Leukemia Network; FLT3i—FLT3 inhibitors; GO—gemtuzumab ozogamycin; HMA—hypomethylating agents; MRD—measurable residual disease; ND—newly diagnosed; t‐AML—therapy related AML; ven—venetoclax.
Gemtuzumab ozogamicin (GO) is a CD33 monoclonal antibody conjugated to the toxin calicheamicin. In an individual patient meta‐analysis of randomized control trials, improved survival was seen among patients with AML when GO was added to 7 + 3 or FLAG‐IDA vs. no GO addition [120]. The benefit was confined to patients with favorable and intermediate cytogenetics (6 years OS of 76 vs. 55% [OR 0.47, 95% CI: 0.31–0.74] and 39 vs. 34% [OR 0.84, 95% CI: 0.75–0.95], respectively). It should be noted, however, that the OS of patients with CBF‐AML not receiving GO in the meta‐analysis was surprisingly low with a 5‐year OS survival of 55%. An OS advantage with GO addition was not seen in any of the individual trials included in the meta‐analysis. These issues, plus the marrow and hepatoxicity of GO, have caused many to question the routine addition of GO to induction therapy. In the ALFA0701 trial which was included in the meta‐analysis, the administration of fractionated dose of 3 mg/m2 on days 1, 4, and 7 with 7 + 3 in patients aged 50–70 years was associated with longer EFS and OS compared with 7 + 3 alone [13]. A post hoc analysis of the ALFA0701 trial demonstrated a benefit for the addition of GO in favorable and intermediate risk groups per ELN 2017 risk criteria [121]. Additional positive trials included in the meta‐analysis (AML‐MRC15 and NCRI‐AML16) employed a single 3 mg/m2 GO dose on the first day of induction [122, 123] and in each subsequent cycle. The AMLSG 09–09 trial was a phase III randomized study not included in the meta‐analysis, which evaluated the addition of GO to idarubicin, cytarabine, etoposide, and all‐trans‐retinoic acid in patients aged 18 years and older (median 58.8) with NPM1 positive‐AML [124, 125]. EFS was not statistically different between the GO arm and the standard arm (HR 0.83, 95% CI: 0.65–1.04, p = 0.1), with higher rates of early deaths in the GO arm (10.3% vs. 5.7%, p = 0.05 and 20% in patients age ≥ 70 years) due to a higher rate of infections. Subgroup analysis revealed a significant EFS improvement in the GO arm in females, patients younger ≤ 70 years, and non‐FLT3‐ITD patients. The impact of GO addition was also beneficial in achieving an MRD negative state defined as a 3‐log reduction measured by quantitative RT‐PCR (56% vs. 41%, p = 0.01) which translated into lower relapse rates in the GO arm versus standard therapy (4‐year cumulative incidence relapse rates 29.3% vs. 45.7%, respectively. p = 0.009) [13].
The AML‐MRC 18 trial evaluated older patients (age ≥ 60 years; n = 852) treated with intensive chemotherapy induction with either single dose GO (at day one) or fractionated two doses (on day one and four) of GO [126]. In the entire cohort, response rates (CR/CRi) and survival rates were similar between those treated with single versus fractionated GO (82% vs. 81%, p = 0.723; 5‐year OS 24% vs. 29%, p = 0.14). However, the rate of MRD negativity in those who achieved CR (measured by MFC at a threshold of 0.1%) was lower in patients treated with single versus fractionated GO dose (41% vs. 50%, p = 0.027). In addition, in a sensitivity analysis excluding patients with either TP53 mutations or adverse risk cytogenetics, a worse OS was observed with single versus fractionated GO dose (5‐year OS 26% vs. 33%, p = 0.045). This advantage was lost when patients were censored at transplant.
The addition of GO to standard AML therapy prolongs survival in patients with cytogenetically favorable (e.g., CBF) [120] AML and may be beneficial by improving EFS in NPM1‐mutated/FLT3‐ITD wild‐type AML [125]. As noted, GO may be administered by various schedules. Our practice, based on an amalgamation of the MRC and French studies is to give one dose of GO at day 1, capped at 4.5 mg/m2 to all patients with CBF AML and strongly consider in younger patients with NPMI mutant/FLT3 mutant WT AML. As the absolute value of the benefit of adding GO to induction chemo in intermediate‐risk patients is small and many of these patients receive SCT in CR1 (and would be subject to a higher risk of sinusoidal obstruction syndrome (SOS) due to prior GO exposure [127]) many US clinicians reserve the use of GO in induction for those with favorable risk cytogenetics.
Midostaurin is a Type I (active in patients with FLT3‐ITD and FLT3‐TKD mutations) first‐generation FLT3 inhibitor, which was approved based on the results from the RATIFY trial [6], that demonstrated improved survival among patients with ND mutant FLT3 AML aged 18–59 treated with 7 + 3 + midostaurin versus 7 + 3 alone. The FDA approved the combination of 7 + 3 + midostaurin for all patients with FLT3‐mutated AML deemed eligible for intensive chemotherapy based in part on data from a non‐randomized trial that included older patients supporting improved outcomes versus historical cohorts in patients aged 60–70 (median OS 22.7 vs. 8.4 months, HR for death 0.47, 95% CI: 0.33–0.67, p < 0.01) [128, 129]. In addition, in a post hoc analysis of the RATIFY trial incorporating FLT3‐ITD allelic ratio and NPM1 mutational status, improved survival with midostaurin was seen across all ELN 2017 risk groups [64]. Resistance was associated with either loss of FLT3‐ITD with the acquisition of mutations in signaling pathways, persistence of FLT‐ITD clones, or other mechanisms [130].
Quizartinib is a highly potent type II (active only in those with FLT3‐ITD mutations) FLT3 inhibitor that is also approved in combination with chemotherapy for patients with ND FLT3‐ITD‐mutated AML. The QUANTUM FIRST trial demonstrated improved OS among 539 patients up to age 75 years with ND FLT3‐ITD‐mutated AML treated with 7 + 3+ quizartinib versus 7 + 3 (median 32 vs. 15 months, HR 0.78, 95% CI: 0.62–0.98, p = 0.03) [20]. There was a slightly higher rate of fatal events in the quizartinib arm (11.3 vs. 9.7%), which may relate to a significant myelosuppressive effect and/or prolonged QTc with quizartinib. Of note, in a subgroup analysis of patients ≥ 60 years, there was no survival benefit for the addition of Quizartinib (HR 0.91, 95% CI: 0.66–1.26).
Crenolinib is a potent type I second‐generation FLT3 inhibitor that was evaluated in a phase Ib‐II trial when added to traditional 7 + 3 [131]. Among 44 patients aged 18–75 treated with this combination, the CR rate was 77%, with a negative MRD state in 89% of those who achieved complete response. The estimated 3‐year OS in the entire group was 58% and was higher in those aged ≤ 60 years (n = 29, 71%) versus > 60 years (n = 15, 33%).
In addition, ongoing trials are also evaluating the 7 + 3 + midostaurin versus 7 + 3 with the more potent FLT3 inhibitors gilteritinib (HOVON 156—NCT04027309, PreECOG—NCT03836209) or crenolanib (NCT03258931).
Overall, there are two approved FLT3 inhibitors with 7 + 3 in patients with ND FLT3‐mutated AML. In those with FLT3‐TKD mutations, we use midostaurin. In patients with FLT3‐ITD mutations, as there are no comparative trials between midostaurin and quizartinib, we evaluate patient co‐morbidities and specific common drug‐associated side‐effects in an effort to individualize treatment. In addition, in patients who are expected to undergo chemotherapy‐only consolidation without alloSCT we favor quizartinib, because this drug was approved for post‐remission maintenance monotherapy, while midostaurin was not.
CPX‐351, a liposomal formulation of daunorubicin and cytarabine, was approved in 2017 for t‐AML, or AML‐MRC. Approval was based on the phase III trial in which 309 patients aged 60–75 were randomized to receive either CPX‐351 or 7 + 3 [7]. Patients either had t‐AML, prior clinical diagnosis of MDS/CMML, or AML with MDS‐related cytogenetic abnormalities. Both CR rates and median OS were higher among patients treated with CPX‐351 versus 7 + 3: 37% versus 26% (p = 0.02) and 9.3 months versus 6 months (HR for death 0.7, [95% CI: 0.6–0.9]), respectively. The median times to platelet (≥ 50 000/μL) and absolute neutrophil counts (≥ 500/μL) recovery were longer with CPX‐351 versus 7 + 3 (35 days vs. 29 days and 36.5 days vs. 29 days, respectively), with similar infection rates (93%) in each arm but higher rates of bleeding were seen in the CPX‐351 arm (all cause—74.5% vs. 59.6%; grade 3–5 11.8% vs. 8.6%). Longer follow up demonstrated that the survival benefit was maintained (median OS 9.3 vs. 6 months, HR 0.7, 95% CI: 0.55–0.91), especially among patients who received a transplant and had been previously treated with CPX −351(52% vs. 23%, HR 0.51, 95% CI: 0.3–0.9) [132, 133]. This latter finding suggests that CPX‐351 lead to remission at lower MRD levels than 3 + 7, but this parameter was not measured during conduct of the trial. Real world evidence also demonstrated the efficacy of CPX‐351 among 188 patients that included 24.5% under the age of 60 [134]. However, the exact role of CPX‐351 in the current AML landscape remains unclear. First, while the initial approval was in a population defined by either clinical or cytogenetic characteristics, recent analysis of outcomes according to molecular subsets suggest a differential benefit CPX‐351 compared with 3 + 7. For example, patients with TP53 mutations did not benefit from CPX‐351 over 7 + 3 [135]. The high‐risk cohort of the UK NCRI AML19 trial enrolled 187 patients with a median age of 56 years and high‐risk MDS/AML (defined by IPSS‐R or adverse cytogenetics) treated with either FLAG‐IDA (n = 82) or CPX‐351 (n = 105) [136]. The OS was similar between arms (HR 0.78, 95% CI: 0.55–1.12, p = 0.12). However, in exploratory analysis of 59 patients harboring one or more MDS‐related gene mutation (as defined by ICC 2022 [23]), those treated with CPX‐351 experienced improved OS compared with FLAG‐IDA (median OS 38.4 months vs. 16.3 months, HR 0.42, 95% CI: 0.21–0.85).
While the FDA approved CPX‐351 for patients of any age, the randomized trial leading to approval was limited to patients aged 60–75 years, a group expected to be enriched for AML with adverse biology, which could potentially benefit from less intensive therapy such as HMA+ venetoclax. A multicenter retrospective study evaluated 395 patients with molecularly defined secondary AML (by WHO fifth edition), treated with either 7 + 3 (n = 167), CPX‐351 (n = 66) or HMA + venetoclax (n = 162) [69]. The response rates (CR/CRi) were similar between treatment groups (56% vs. 44% vs. 56%, p = 0.22, respectively). The median OS was comparable in patients ≥ 60 years (median OS 16, 11, and 15, respectively, p = 0.54) as well as among patients consolidated with transplant (2‐year OS 64% vs. 60% vs. 74%, p = 0.55). In a multivariable regression model controlling for patient, disease, and treatment characteristics, HMA + VEN was superior to 7 + 3 whereas CPX‐351 was not. Another retrospective study compared outcomes of 217 patients who received CPX‐351 versus 437 patients who received HMA + Venetoclax [137]. The OS rates were comparable between groups (13 months for CPX‐351 vs. 11 months for HMA + venetoclax; HR, 0.88; 95% CI: 0.71–1.08; p = 0.22), even after adjusting for different baseline characteristics and with a sensitivity analysis including only patients who were eligible for the CPX‐351 randomized trial. In contrast, the rates of infection (51% vs. 20%, p < 0.0001), febrile neutropenia (90% vs. 54%, p < 0.0001) and length of hospitalization (41 vs. 15 days, p = 0.0004) were higher among patients treated with CPX‐351 versus HMA + venetoclax.
Venetoclax, a BH3 mimetic that selectively inhibits the pro‐apoptotic BCL2 protein and induces apoptosis in acute myeloid leukemia cells, especially in the presence of cytotoxic chemotherapy [138], was approved in combination with HMA or LDAC for ND AML patients not fit for induction with intensive chemotherapy based on age ≥ 75 or in ineligibility for intensive chemotherapy because of significant co‐morbidities [11, 17]. However, several phase I‐II trials are evaluating the efficacy and safety of venetoclax with Fludarabine, cytarabine, idarubicin, and G‐CSF (FLAG‐IDA) or daunorubicin plus cytarabine in the upfront setting. Among 45 patients with ND‐AML, FLAG‐IDA with venetoclax yielded a composite CR rate of 89%, with 93% of CR patients achieving MRD negativity by multiparameter flow cytometry with an estimated 2‐year OS of 76% [139]. The CAVEAT trial demonstrated CR/CRi rates of 72% in 51 patients older than 60 with a seven‐day venetoclax pre‐phase followed by 5 + 2 and venetoclax for an additional 7 days. The CR/CRi rates were remarkably high (97%) among patients with de‐novo AML versus 43% in patients with secondary AML [140]. Among 33 patients aged 18–60 with ND‐AML, venetoclax in combination with 7 + 3 yielded in composite CR rates of 91% with 97% MRD negativity, and 1 year estimated OS of 97% [141]. In an additional phase I trial evaluating 7 + 3 with venetoclax, all 11 evaluated patients achieved CR, most (78%) with MRD negative CR [142]. Venetoclax combined with cladribine, idarubicin, and cytarabine in 50 patients with ND AML resulted in 94% composite complete response, 85% at the level of MRD negativity with a 1 year OS rate of 85% [143]. While these early results are encouraging, these regimens are highly myelosuppressive leading to significant risk of prolonged cytopenia and infections. Thus, until we have longer follow‐up and matched control trials, intensive chemotherapy with venetoclax in the upfront setting should be evaluated only in the context of clinical trials.
Isocitrate dehydrogenase (IDH) mutations occur in 15%–20% of patients in AML [2, 144]. IDH mutations result in the formation of the neomorphic reaction product R‐2‐hydroxyglutarate, an oncometabolite which leads to epigenetic alterations and impaired hematopoietic differentiation similar to those observed when TET2 is mutated [145]. The IDH1 and IDH2 inhibitors ivosidenib and enasidenib were approved as monotherapy for patients with R/R IDH‐mutated AML; ivosidenib was approved in the frontline setting for unfit patients, either as monotherapy or combined with azacitidine (see “non‐intensive therapy for newly diagnosed patients”). Both IDH inhibitors were evaluated in a phase I trial in combination with 7 + 3 in 151 “fit” patients with IDH‐mutated AML. The CR/CRi/CRp rates were 77% with the addition of ivosidenib and 74% with enasidenib [146]; 39% and 23% of patients achieved mIDH1/2 clearance by ddPCR, respectively. Overall, the combination was tolerable with low rates of differentiation syndrome or significant QT prolongation. Prior to the routine adoption of IDH inhibitors plus intensive chemotherapy in the upfront setting, we await the results from HOVON 150, a phase III trial evaluating the benefit of adding IDH inhibitor to 7 + 3 in fit patients with ND IDH‐mutated AML (NCT03839771).
6.2.2. Updates on Post Remission Therapy
After remission is achieved, post‐induction therapy is necessary to achieve a reasonable chance of favorable long‐term outcomes and possibly a cure. Generally, patients with ELN favorable risk score should receive 3–4 cycles of high‐dose chemotherapy, whereas patients within the intermediate or adverse risk are recommended to proceed with alloSCT [23]. This is mainly based on the risk of death from relapse or refractory disease (high in those with non‐favorable subtypes) possibly overcoming the risk of TRM associated with alloSCT. Although most patients with CBF‐AML usually do not proceed with alloSCT while in CR, as mentioned earlier the benefit of alloSCT was demonstrated in a prospective trial evaluating the predictive value of MRD positivity in patients with RUNX1::RUNX1T1 AML after the second consolidation. Patients who had positive MRD (defined by qPCR with less than 3‐log reduction) were offered to proceed with alloSCT and had lower relapse rates, improved disease free survival, and OS when treated with alloSCT versus continuation of chemotherapy [97].
While most agree that adverse‐risk AML patients have the best chance for long term survival if an allogeneic is done during CR1, an analysis based on MRC trials in the UK suggests that the optimal strategy in intermediate‐risk patients is to transplant only in CR2, thereby saving many (especially those with MRD negativity and a relatively low chance of relapse) from unnecessary SCT‐associated morbidity and mortality [147]. On the contrary, a large meta‐analysis of prospective clinical trials evaluating alloSCT at CR1 versus non‐alloSCT treatments demonstrated an OS advantage both in intermediate‐risk (HR 0.83, 95% CI: 0.74–0.93) as well as adverse risk (HR 0.73, 0.59–0.90) groups [148]. Recently, a post hoc analysis study of the AML‐MRC17 plus 19 trials showed that the benefit of transplant may be MRD status dependent [98]. Among 737 patients (median age 52) with NPM1‐mutated AML, patients with MRD positivity measured at CR after 2 chemotherapy cycles had improved survival when consolidated with alloSCT (3‐year OS 61% vs. 24%, p < 0.001). Conversely, those who achieved MRD negativity after two chemotherapy cycles had comparable outcome with versus without alloSCT (3‐year OS 79% vs. 82%, p = 0.4). Notably, the lack of survival advantage with alloSCT among MRD negative patients persisted in the subset of patients harboring a FLT3‐ITD co‐mutation (which are defined in the ELN intermediate‐risk group): 3‐year OS 83% versus 76%, p = 0.6. Of note, the use of FLT3 inhibitors in patients with FLT3‐ITD in those trials was limited.
Our general approach is still to transplant all intensively treated adverse and intermediate patients by ELN 2022 at CR1 who have an available donor and no contraindication. With the ability to safely conduct haploidentical alloSCT, almost all patients have a donor [149]. The exception may be in patients with NPM1 and FLT‐ITD co‐mutations, in which case MRD may direct our decision toward post‐remission chemotherapy alone without alloSCT.
Post‐transplant maintenance therapy may contribute to prolonged survival. In a meta‐analysis of five randomized controlled trials, maintenance therapy versus no therapy post‐alloSCT was associated with improved OS [150]. The use of sorafenib, a first‐generation Type II TKI (active in patients with FLT3‐ITD mutations) was associated with lower relapse rates in the maintenance trials included in the analysis [151, 152, 153, 154, 155]. The phase III MORPHO trial compared post‐alloSCT gilteritinib (Type I second generation FLT3‐inhibitor, see below under “R/R AML”) monotherapy versus placebo in 356 patients with FLT3‐ITD AML who were transplanted at first remission. The RFS was higher in the gilteritinib arm compared with placebo, albeit with borderline statistical significance (HR 0.68, 95% CI: 0.46–1.005, p = 0.0518) [156]. A pre‐specified analysis demonstrated that the benefit of gilteritinib over placebo was driven by patients who had either pre‐ or post‐alloSCT detectable MRD for FLT3‐ITD using a PCR‐based highly sensitive test to (1*10−6): patients with detectable MRD, HR 0.52, 95% CI: 0.32–0.84, p = 0.0065; patients with non‐detectable MRD (HR 1.21, 95% CI: 0.6–2.39, p = 0.575). Additional post‐alloSCT maintenance therapies, such as HMA plus venetoclax (“VIALE‐T”; NCT04161885) are now being evaluated.
For patients with intermediate or adverse cytogenetic risk AML who cannot proceed with alloSCT and/or complete planned post‐remission chemotherapy, maintenance therapy with CC‐486 (“oral azacitidine”) is useful. CC‐486 is an oral hypomethylating agent that was FDA approved as post‐induction therapy based on the results of the phase III QUAZAR AML‐001 trial [14]. The trial enrolled patients aged 55–86 with ND AML who received intensive chemotherapy, achieved complete remission, and were not candidates for alloSCT at the time of screening. Patients received either CC‐486 for 14 days in 28‐day cycles (n = 238) or placebo (n = 234) at the end of 0, 1, or 2 consolidation cycles. The median OS and RFS were better in the CC‐486 vs. placebo group (24.7 vs. 13.8 months, and 10.2 vs. 4.8 months, respectively p < 0.001 for both). There were higher rates of side effects, such as gastrointestinal distress (50%–65% vs. 10%–24%), neutropenia (44% vs. 26%), and infections (17% vs. 8%) in the CC‐486 arm. Adverse events led to drug interruption in 43% of patients. Ad hoc analysis demonstrated improved OS and RFS irrespective of MRD status at first remission, with conversion rates to MRD negativity in 25% of patients receiving CC‐486 [157]. AlloSCT is more accessible in recent years due to use of more tolerated reduced intensity conditioning [158] and an expanded pool of donors due to improved outcomes with haploidentical alloSCT [159, 160]. Moreover, the use of alloSCT is more common in older patients [161] and associated with less morbidity and TRM [162]. Thus, the use of CC‐486 may be limited to only those few patients who are initially deemed fit for intensive therapy but not for transplant.
6.3. Updates on Non‐Intensive Therapy for Newly Diagnosed Patients
Just a few years ago, our ability to treat older patients who are not fit for intensive therapy was limited to mainly supportive care and was associated with a dismal prognosis. While decitabine or azacitidine were commonly used in older patients, it was never clear whether these single agents were better than other available therapies [163, 164]. Several drugs and combination therapies, especially the addition of venetoclax to low‐dose chemotherapy, were recently approved for this group, which revolutionized the treatment paradigm in AML in patients who are not fit for intensive chemotherapy induction (Table 1 and Figure 3). These therapeutic agents promote prolonged survival and promote questioning the paradigm of initial intensive chemotherapy even for selected fit patients (Figure 4).
FIGURE 3.
Treatment Algorithm for Newly diagnosed patients with AML aged 60–75 years eligible for intensive therapy. AlloSCT—allogeneic stem cell transplantation; AML—acute myeloid leukemia; CBF—core binding factors; ELN—European Leukemia Network; FLT3i—FLT3 inhibitors; GO—gemtuzumab ozogamycin; HMA—hypomethylating agents; ITD—internal tandem duplication; MRD—measurable residual disease; ND—newly diagnosed; Ven—venetoclax.
FIGURE 4.
Treatment Algorithm for Newly diagnosed patients with AML ≥ 75 years or unfit for intensive therapy. AlloSCT—allogeneic stem cell transplantation; AML—acute myeloid leukemia; ELN—European Leukemia Network; FLT3i—FLT3 inhibitors; HMA—hypomethylating agents; IDHi—IDH inhibitor; IDH—isocitrate dehydrogenase; MRD—measurable residual disease; ND—newly diagnosed; Ven—venetoclax.
6.3.1. Venetoclax Combination Therapies
In the phase III VIALE‐A trial, azacitidine added to venetoclax improved responses and overall survival (OS) versus azacitidine alone in patients > 75 years old or those with significant comorbidities (composite CR 66.4% vs. 28.3%, p < 0.001; median OS 14.7 vs. 9.7 months, HR 0.66, 95% CI: 0.52–0.85, p < 0.001) [165]. In the VIALE‐C trial, venetoclax was added to LDAC versus LDAC monotherapy. The trial failed to achieve the primary OS endpoint (median OS 7.2. vs. 4.1 months, HR 0.75 95% CI: 0.52–1.07 p = 0.11) [18]. This was partially due to diminished power (fewer patients were enrolled compared to VIALE‐A (211 vs. 431), as well as inclusion of patients who received HMA as prior therapy in the VIALE‐C trial. However, in a post hoc analysis with 6 months additional follow‐up, an OS advantage was seen (8.4 vs. 4.1 months, HR 0.7, 95% CI: 0.5–0.99, p = 0.04) [166]. These regimens are now considered standard of care for older patients or patients not deemed fit for intensive chemotherapy, although a subgroup analysis in patients younger than age 75 who were eligible for the trial based on significant comorbidity did not show a benefit for the doublet over azacitidine. Venetoclax may also be synergistic with other lower‐dose therapies [167]. For example, Kadia et al. reported on the results of venetoclax combined with low‐dose chemotherapy (LDAC combined with cladribine, alternating with azacitidine) in older patients (age ≥ 60 years) or those deemed unfit for intensive chemotherapy [168]. The composite CR rate was 93%, with 84% of remitting patients achieving MRD negativity. With a median follow‐up time of 22 months, the median OS and disease‐free survival were not reached, with an estimated 24‐month OS of 63.5% (95% CI: 52%–78%). It should be noted, however, the inclusion of fit patients aged 60 or older may have accounted in part for the promising results.
As noted earlier, the relative utility of HMA plus venetoclax versus intensive induction in younger patients without co‐morbidities remains unclear. The ability to achieve high CR rates, with the majority having MRD negative responses at acceptable toxicity with HMA plus venetoclax may allow alloSCT, thereby may even lead to better long‐term outcomes [69, 169, 170, 171, 172]. Currently, there is no published data for a prospective comparison between HMA plus venetoclax versus intensive chemotherapy, though an ongoing phase II (NCT04801797) trial is attempting to provide such information. A phase III multicenter randomized trial conducted in nine European countries compared 10‐day decitabine monotherapy with 7 + 3 in 606 patients aged 60 and older with ND AML, a more favorable group generally than studied in the VIALE trial [173]. At a median follow‐up of 4 years, the 4‐year OS was 26% (95% CI: 21%–32%) and 30% (95% CI: 24%–35%) in the decitabine and 7 + 3 groups, respectively (HR 1.04, 95% CI: 0.86–1.26, p = 0.69). The rates of alloSCT were also comparable between groups (40% vs. 39%), as well as Grades 3–5 adverse events (84% vs. 94%) or treatment‐related mortality (12% vs. 14%). Furthermore, the response to the venetoclax and HMA combination is heterogeneous, with decreased response rates in several morphologic, cytogenetic, and molecular subgroups [165, 174, 175]. For example, the duration of response varies greatly, being only a few months in high‐risk TP53‐mutated AML and in AMLs exhibiting monocytic differentiation [174, 175, 176]. Although in VIALE‐A the addition of venetoclax to HMA in TP53‐mutated AML improved composite CR rates (55.3% vs. 0%, p < 0.001), no survival benefit was noted, and the combination regimen caused added toxicity. The lack of survival advantage of adding venetoclax to HMA in this genetic subset of AML was also shown in real world studies [77, 165].
Many investigators have questioned the need to administer 28 days of venetoclax with each chemotherapy course. Several retrospective studies have suggested that venetoclax for 7 or 14 days per cycle may be adequate, especially in frail patients [177, 178, 179]. However, given the absence of prospective data comparing different venetoclax exposure durations, the optimal approach remains to be determined. Since we can evaluate marrow findings within 48 h, we plan to administer a full course of venetoclax, but will truncate the duration if a bone marrow examination done ~3 weeks after therapy initiation shows blast clearance. We further have a low threshold to shorten the duration of venetoclax in subsequent cycles in the setting of prior prolonged myelosuppression and good disease control.
6.3.2. IDH Inhibitors
The oral IDH1 inhibitor ivosidenib was FDA approved as monotherapy in patients with IDH1‐mutated AML, both in ND patients not eligible for intensive therapy [9], as well as in the R/R setting [8]. The phase III AGILE trial evaluated the addition of ivosidenib to azacitidine versus azacitidine in patients with ND IDH1‐mutated AML older than 75 or with comorbidities [15]. Patients were randomly assigned to azacitidine for 7 days in 28‐day cycles (n = 74) versus azacitidine and ivosidenib 500 mg daily (n = 74). The primary efficacy endpoint, EFS, was superior in patients randomized to the doublet compared with azacitidine alone (HR 0.16, 95% CI: 0.16–0.69). The median overall survival was longer in patients who received ivosidenib plus azacitidine (24 months vs. 7.9 months, HR 0.44, 95% CI: 0.27–0.73). Based on these results, the FDA approved this combination for patients with ND IDH1‐mutated AML aged 75 and above or with comorbidities. Thus, there are two effective regimens approved for older adults with ND IDH1‐mutated AML: azacitidine either with ivosidenib or with venetoclax. Favorable outcomes were seen in a combined analysis of data from IDH‐mutated patients on the VIALE‐A [165] and the phase Ib of HMA+ VEN [11] trials [180]. Nonetheless, the number of patients specifically with IDH1 mutations was low (33 in the VIALE‐A and 11 in the phase‐Ib trial). The question of whether to use azacitidine with either venetoclax or ivosidenib remains open; some would prefer to ‘save’ ivosidenib as a salvage therapy (even though few if any patients on the ivosidenib trial had received venetoclax‐based therapies). Moreover, since azacitidine plus ivosidenib may be less myelotoxic than HMA plus venetoclax, some suggest the former therapy might be more appropriate for a more frail patient.
Although not approved for patients with IDH2‐mutated ND‐AML, combination therapy consisting of the IDH2 inhibitor enasidenib plus azacitidine was evaluated in the phase II AG221‐AML‐005 randomized trial [181]. One hundred and one patients (median age 75) were assigned in a 2:1 ratio to azacitidine with (n = 68) or without (n = 33) enasidenib. CR rates were 54% versus 12% (p < 0.0001) in azacitidine + enasidenib versus azacitidine alone. Twelve (18%) patients in the enasidenib group experienced differentiation syndrome and were treated with corticosteroids. The median overall survival was similar between groups (22 months in each), which may be attributed in part to effective salvage therapies, such as enasidenib or venetoclax‐based therapies used in those assigned to the control arms [175]. Based on available data, we use azacitidine plus venetoclax initially in IDH2 mutant unfit AML.
6.3.3. Glasdegib
The critical embryonic signaling hedgehog pathway is overexpressed in myeloid leukemia cells [182]. Based on this observation, the hedgehog pathway inhibitor glasdegib was evaluated in combination with LDAC compared to LDAC alone, in patients with ND AML deemed not fit for intensive chemotherapy, based on age ≥ 75 or having significant comorbidities (BRIGHT AML 1003 study) [16]. Glasdegib was given orally 100 mg/day in 28 days cycles and LDAC was administrated subcutaneous for 10 days at the start of each cycle. The complete remission rates and median OS were 17% versus 2.3% (p < 0.05) and 8.8 versus 4.9 months (HR 0.51, 80% CI: 0.39–0.67, p = 0.0004) in the glasdegib + LDAC versus LDAC alone, respectively. This trial led to the FDA approval of LDAC + glasdegib in ND patients unfit for intensive chemotherapy. Although no direct comparison was performed, the VIALE‐A and VIALE‐C trials demonstrated far superior outcomes with venetoclax combinations compared to glasdegib plus low dose cytarabine, leading to infrequent use of glasdegib in patients with ND AML deemed unfit for intensive chemotherapy. The efficacy of glasdegib with LDAC in the R/R setting was evaluated in a small retrospective study that demonstrated composite CR (CR + CRp) rates of 21% with a median OS of 3.9 months [183]. The phase III BRIGHT AML 1019 trial failed to demonstrate a benefit for addition of glasdegib to 7 + 3 in fit patients or azacitidine alone in unfit patients. In the intensive arm (n = 404), similar OS between 7 + 3 plus placebo versus 7 + 3 plus glasdegib was seen (median OS 20 vs. 17.3 months, HR 1.5, 95% CI: 0.78–1.41, p = 0.749). Similarly, in the non‐intensive arm (n = 325), comparable OS was seen with azacitidine alone or plus glasdegib (median OS 10.9 vs. 10.3 months, HR 0.99, 95% CI: 0.77–1.29, p = 0.969). These results question the role of glasdegib in the treatment of ND AML [184].
6.3.4. Gilteritinib
Gilteritinib is a type 1 s‐generation inhibitor, more potent and specific than midostaurin [185, 186]. Gilteritinib is approved for patients with R/R FLT3‐mutated AML [12] (see R/R AML) based on the ADMIRAL trial (see below). Gilteritinib was also evaluated in combination with other therapies in the upfront setting. In the phase III randomized LACEWING trial, patients with ND FLT3‐mutated AML deemed not eligible for intensive chemotherapy were randomized to azacitidine (n = 49) versus azacitidine with gilteritinib (n = 74) [187]. Although higher composite CR rates were seen with azacitidine + gilteritinib versus azacitidine (58% vs. 26.5%, p < 0.001), the median OS was similar between groups (9.8 months vs. 8.9 months, HR 0.92, 95% CI: 0.529–1.585, p = 0.75). Of note, almost half (44%) of patients in the AZA arm were treated subsequently with a FLT3 inhibitor versus 20% in the gilteritinib plus azacitidine arm, which might have contributed to the perceived lack of success of this combination in FLT3 mutant AML in ND older adults. At present, such patients should receive venetoclax plus azacitidine, although phase I‐II results of doublets (FLT3‐inhibitor plus venetoclax) and triplet combinations (FLT3 inhibitor plus HMA and venetoclax) have been published.
For example, in a phase II trial evaluating the triplet therapy of venetoclax, decitabine and FLT3 inhibitors (sorafenib, gilteritinib, or midostaurin) in ND unfit patients as well as R/R patients, CR rates were 75% and 2‐year OS was 80% among ND patients [188]. A triplet combination of azacitidine, venetoclax, and gilteritinib was evaluated in a phase I‐II trial in patients with FLT3‐mutated ND (n = 30) or R/R AML (n = 22) [189]. The recommended dose of gilteritinib was 80 mg/day, and the CR/CRi rates were 96% in the upfront cohort with MRD negativity (measured by FLT3‐ITD at a threshold of 5*10−5) was 65%. After a median follow‐up of 19.3 months, the median RFS and OS were not reached with an estimated 18‐month OS of 72%. As the data is short‐term and derived from single‐arm studies, triplet combination therapies should be used with caution, and preferably within the context of a clinical trial.
7. Updates on Relapsed and Refractory (R/R) AML
Relapsed or refractory AML remains a therapeutic challenge, with a 5‐year survival of only 10% [190, 191]. Age, duration of CR1, initial cytogenetics and previous alloSCT are prognostic factors for outcome [192]. The general paradigm in R/R AML, at least in patients who are willing to accept more therapy for a relatively small chance of good long‐term outcomes, is salvage therapy [193, 194] consolidated with alloSCT if remission is achieved [195]. However, this concept was challenged in the ASAP trial, which compared patients with R/R AML who had only one previous line of therapy and were assigned to either salvage therapy with cytarabine and mitoxantrone followed by alloSCT (n = 141) or immediate alloSCT (n = 140). The OS was comparable between those treated with immediate alloSCT (4‐year OS of 46% [95% CI: 36%–55%]) compared with salvage therapy followed by alloSCT (4‐year OS of 49% [95% CI: 39%–59%]), p = 0.42 [196]. Given similar OS and complete remission rates at day 56 post‐alloSCT (79% vs. 83%), despite the study not meeting its primary endpoint of non‐inferiority, the results suggest that immediate alloSCT may be a reasonable approach in some patients, especially if very intensive conditioning is used.
In patients who relapse after an alloSCT in CR1, options which may yield responses and potentially improve survival include manipulation of the immune system in order to stimulate graft versus leukemia effect via tapering graft versus host disease prophylaxis [197], administering donor T‐cells Infusion (DLI) [198], addition of immune checkpoint inhibitors [199] or a second alloSCT [200].
There are several targeted therapies for patients with specific mutations that were approved in recent years for patients with R/R AML (Table 1 and Figure 5).
FIGURE 5.
Treatment Algorithm for patients with relapsed or refractory AML. AlloSCT—allogeneic stem cell transplantation; AML—acute myeloid leukemia; DLI—donor lymphocyte infusion; FLT3i—FLT3 inhibitors; GO—gemtuzumab ozogamycin; HMA—hypomethylating agents; IDH—isocitrate dehydrogenase; KMT2Ar—Lysine methyltransferase 2A gene (KMT2A) re‐arranged; MRD—measurable residual disease; R/R—relapse or refractory; Ven—venetoclax.
7.1. Gilteritinib
Gilteritinib is a potent FLT3 ITD and TKD inhibitor [201]. Gilteritinib was approved as monotherapy for patients with R/R FLT3‐mutated AML based on the results of the ADMIRAL trial [12]. Patients with R/R FLT3‐mutated AML were randomized to either gilteritinib monotherapy (120 mg daily, n = 247) or salvage chemotherapy (n = 124). The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; HR 0.64; 95% CI: 0.49–0.83; p < 0.001) and side effects were less common in the gilteritinib group vs. chemotherapy. In a follow up analysis at 24 months, among the 40 patients in the gilteritinib arm who received alloSCT and were treated with gilteritinib as post‐alloSCT maintenance, the cumulative relapse rates were 0% and 18.6% among patients who achieved CR/CRh or composite CR, respectively, which may suggest a role for gilteritinib as post‐AlloSCT in the advanced disease maintenance [202]. Of note, only 12% of patients in the AMDIRAL study had prior FLT3 inhibitor exposure. However, the benefit of gilteritinib in patients with prior exposure to FLT3 inhibitor was demonstrated both in a post hoc analysis of the ADMIRAL and the phase I‐II CHRYSALLIS trial [203], as well in real world data [204, 205]. In a phase Ib‐II trial gilteritinib was combined with venetoclax in 61 patients (56 with FLT3 mutation) with R/R AML [206], with 64% of patients having received prior FLT3 inhibitor therapy. The modified composite CR rate (CR + CRi + CRp + MLFS) was 75% (36% were MLFS). Molecular remission by FLT3 PCR was achieved in 60% of patients and the median OS was 10 months. Grades 3–4 cytopenias were common (80%) with prolonged myelosuppression and adverse events prompting venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. Triplet therapy with HMA, venetoclax, and gilteritinib yielded a CR/CRi rate of only 27% in the R/R setting (with an ORR of 67%—CR + CRi + MLFS and median OS of 10.5 months). Dose reductions due to myelosuppression and infections were common; thus, gilteritinib 80 mg daily was suggested for further studies. Are the myelotoxic regimens of either gilteritinib plus venetoclax or gilteritinib plus venetoclax, and azacitidine better than monotherapy in R/R FLT3‐mutated AML? The doublet or triplet might be appropriate as a bridge to transplant, whereas initial or subsequent monotherapy might be more realistic for long‐term use. A real‐world retrospective study demonstrated comparable response rates and overall survival between gilteritinib monotherapy versus gilteritinib plus venetoclax (53% vs. 65%, p = 0.51, 59% vs. 42%, p = 0.11) [207]. However, early salvage with gilteritinib plus venetoclax versus any other gilteritinib‐based approach was associated with the best outcome (p = 0.031), which suggests that earliest use (i.e., first line for R/R AML) of combination therapy with gilteritinib may be beneficial.
7.2. IDH Inhibitors
The IDH1 inhibitor ivosidenib was approved as monotherapy for patients with IDH1‐mutated R/R AML [8]. Lachowiez et al. presented data from a phase Ib‐II trial in patients with IDH1‐mutated MDS (n = 9), ND‐AML (n = 14) or R/R AML (n = 8) who were treated with venetoclax and ivosidenib +/−azacitidine [208]. The response rates were high (composite CR rate 90%); 63% of AML patients attained MRD negativity. The Median EFS and OS were 36 months (95% CI: 23‐NR) and 42 months (95% CI: 42‐NR), respectively. Although promising, these results should be compared to the outcome in patients treated with either HMA plus venetoclax or ivosidenib alone. It should be noted that the ivosidenib approval for R/R AML was prior to HMA plus venetoclax broad usage. That, alongside a retrospective study demonstrating minimal efficacy of ivosidenib post‐HMA plus venetoclax [209], questions the utility of ivosidenib in patients who were treated with venetoclax‐based therapies.
Olutasidenib is a selective IDH1 inhibitor which was recently approved for R/R IDH1‐mutated AML based on a phase I‐II trial [19, 210]. In the phase I portion of the trial, 78 patients with AML (n = 65; 17 ND and 48 R/R) or intermediate, high, or very high‐risk MDS (n = 13, 7 treatment naïve and 6 R/R) per IPSS‐R received olutasidenib as monotherapy (n = 32) or in combination with azacitidine (n = 46). Among patients with R/R AML who received Olutasidenib monotherapy or combination therapy, 9/22 (41%) and 12/26 (46%) achieved an overall response, respectively. The estimated median OS in R/R AML was 8.7 months (95% CI: 2.5‐non‐reached) with monotherapy and 12.1 months (95% CI: 4.2‐non reached) with combination therapy. The rate of differentiation syndrome was 13%, similar to that associated with other IDH inhibitors [211]. Overall, the CR + CRh rates among 147 patients with R/R IDH1‐mutated AML was 35% (51/147) [212]. In addition, 29/86 (34%) transfusion‐dependent patients became RBC and platelet transfusion independent. A recent small case series of single‐agent olutasidenib described 16 patients with R/R IDH1‐mutated AML who were previously treated with venetoclax based therapy: 4/16 (25%) achieved CR and one (6%) CRh [213]. However, the exact role of this drug is not yet known, as most of the patients on the approval trial received neither HMA plus venetoclax nor HMA plus ivosidenib upfront, each of which is now considered reasonable initial therapy for older patients unfit for intensive chemotherapy.
The IDH2 inhibitor enasidenib was FDA approved for patients with IDH2‐mutated R/R AML based on the results of a phase II single‐arm study [10]. However the phase III trial IDHENTIFY in patients with IDH2‐mutated R/R AML aged ≥ 60 years treated with enasidenib versus either HMA monotherapy, intermediate (0.5–1.5 g/m2) or low dose cytarabine (20 mg BID) or supportive care failed to meet its primary endpoint of OS improvement (median OS 6.5 vs. 6.2 months, HR 0.86, p = 0.23) [214, 215]. There was an improvement in EFS (4.9 vs. 2.6 months, HR 0.68, p = 0.008) and red blood cell transfusion independence (31.7% vs. 9.3%). Combination therapy with enasidenib was also evaluated in a small case series in the R/R setting, either as doublet with azacitidine or triplet therapy, suggesting a possible benefit for the triplet versus the doublet: (1 year OS 67% vs. 20%, HR 0.26, 95% CI: 0.09–0.97, p = 0.08) [216].
7.3. Gemtuzumab Ozogamycin
GO is a CD33 monoclonal antibody conjugated to calicheamicin. It was (re‐)approved for patients with R/R AML as monotherapy at a dose of 3 mg/m2 on days 1, 4, and 7, mainly based on the results from the phase II MYELOFRANCE‐1 trial, which demonstrated 26% CR rates with a median RFS of 11 months [217]. Due to its modest efficacy, as well as association with higher risk of SOS [127] in patients which optimally would proceed with AlloSCT, the use of GO in this setting is limited.
7.4. Menin Inhibitors
11q23 translocations are found in 5%–10% of adults with AML [218] and confer an adverse prognosis, except for the intermediate risk are associated with self‐renewal of hematopoitetic stem cells k t(9;11)(p21.3;q23.3)/MLLT3::KMT2A translocation [23]. These cytogenetic rearrangements are associated with self‐renewal of hematopoitetic stem cells and elicit increased expression of homeobox (HOX) genes, which are also dysregulated in NPM1‐mutated AML [219]. The scaffold protein menin, which is encoded by the MEN1 gene, binds to KMT2A and is crucial for its function [220]. The FDA approved revumenib (SNDX−5613) for R/R KMT2A rearranged AML based on the results of AUGMENT‐101, a phase I single agent clinical trial in KMT2A‐rearranged and NPM1‐mutated R/R AML [221]. The CR/CRh rate were 30% and 22.8% with a median OS of 7 months and 8 months in the entire cohort and in KMT2A rearranged cohort, respectively [21, 222]. Asymptomatic prolongation of the QT interval was identified as the only dose‐limiting toxicity; differentiation syndrome (all grade 2) was reported in 16% of patients. Additional menin inhibitors, as monotherapy and in combination, are now being evaluated (see below “Selected investigational therapies”).
7.5. Venetoclax Plus Chemo Salvage
Intensive chemotherapy‐only regimens for R/R include mitoxantrone plus etoposide and cytarabine, high‐dose cytarabine alone, cytarabine plus clofarabine, or fludarabine plus idarubicin, cytarabine, and G‐CSF. None is clearly “best” [223]. Venetoclax was combined with intensive chemotherapy in an effort to improve outcomes for these challenging to‐treat patients. In a phase Ib/II trial, DiNardo et al. reported results of FLAG‐IDA plus venetoclax in patients with R/R AML. The composite CR rates were 61%–75%, and 1 year OS estimate of 68% [224]. AlloSCT was crucial for long‐term survival, with a landmark analysis in the R/R group demonstrating improved survival among patients consolidated with alloSCT versus chemotherapy alone (median OS not reached vs. 7 months, p = 0.009). As expected, patients with R/R AML harboring TP53 mutation had a dismal prognosis (OS 7 months). As these combinations are highly myelosuppressive, all patients received anti‐bacterial quinolone, anti‐fungal, and anti‐viral therapy prophylaxis, and the length of venetoclax was amended during trial from 14 to 7 days. Real‐world data with this regimen demonstrated invasive bacteremia in half of the patients and fungal infection in one‐third [225]. The substantial risk of infections requires vigilant monitoring and prompt treatment when early signs of such problems occur.
Although not approved for in R/R AML, venetoclax with HMA was evaluated in real‐world studies, with response rates of 31%–60% [226, 227]. Though conclusions are tentative given indirect comparisons, response rates seem higher with HMA and venetoclax compared to HMA alone (16% CRi [228]), but overall survival is similar (6.1–6.8 months vs. 6.7 months, respectively). The phase II VALDAC study prospectively evaluated the utility of venetoclax (600 mg/day) plus LDAC (20 mg/m2/day on days 1–10) in 48 patients (median age 68 years) with AML who previously received intensive chemotherapy, achieved morphologic remission and experienced either MRD relapse (considered as ≥ 1 log10 increase; n = 26) or oligoblastic relapse (defined as 5%–15% bone marrow blasts; n = 22) [99]. AlloSCT at first remission was considered part of the initial therapy. In the MRD cohort by the end of second cycle a log10 reduction was achieved in 69% and overall, 46% achieved MRD negativity. In the oligoblastic cohort, CR/CRh/CRi were achieved in 73%. Overall, 21 (44%) patients were successfully bridged to alloSCT. The estimated 2‐year OS was 67% and 53% in the MRD and oligoblastic cohorts, respectively. Albeit requiring conformation in a larger study, this study demonstrates the importance of MRD surveillance and potential early intervention.
The best salvage for those who fail to respond or progress after HMA plus venetoclax, the most used upfront therapy in unfit older patients with AML, is unclear. A small retrospective study showed dismal outcomes (median OS 4.2 months) with IDH inhibitors or FLT3 inhibitors in the relevant mutational context post HMA plus venetoclax [209]. A recent study by Chin et al. demonstrated that intensive salvage chemotherapy after HMA plus venetoclax yielded CR/CRi rates of 37% and a median OS of 7.2 months. However, it should be noted that the median age of this cohort was 65 (with interquartile range of 50–68) and were fit enough to receive intensive chemotherapy, which represents only a small fraction of patients treated with less‐intensive chemotherapies [229].
8. Updates on Selected Investigational Therapies
Despite marked improvements in AML management, outcomes are still unsatisfactory, especially in patients with high‐risk disease. In the last year, several phase III trials involving the addition of promising drugs to standard therapy failed to yield a new approval.
The combination of azacitidine with the anti‐CD47 monoclonal antibody magrolimab, which binds to a “don't eat me signal” warding off anti‐tumor immunity yielded high response rates, particularly in TP53 mutant MDS/AML [230]. Magrolimab was then tested in prospective randomized trials including magrolimab + azacitidine versus azacitidine in higher‐risk MDS (ENAHNCE, NCT0431388), magrolimab + azacitidine versus venetoclax + azacitidine or intensive chemotherapy in patients with TP53‐mutated AML (ENHANCE 2, NCT04778397) and magrolimab + azacitidine + venetoclax versus placebo + azacitidine + venetoclax in ND‐AML patients not fit for intensive therapy (ENHANCE 3, NCT05079230) but in each study OS on the magrolimab arms was not superior to standard of care [231, 232]. Second, clinical development of the anti‐TIM‐3 antibody sabatolimab, a novel immune checkpoint inhibitor, in AML (STIMULUS‐AML1, NCT04150029) was discontinued after the phase III trial STIMULUS‐MDS2 trial (azacitidine + sabatolimab compared to azacitidine alone in patients with higher risk MDS and CMML) failed to show an OS improvement [233]. Lastly, the E‐selectin inhibitor uproleselan, designed to disrupt the leukemia stem cell‐niche interaction which showed promise in combination with chemotherapy in an uncontrolled trial [234], failed to improve OS in combination with chemotherapy in patients with R/R AML (NCT03616470) [235]. The phase II/III trial of chemotherapy +/‐ uproleselan in ND‐AML older than 60 years (NCT03701308) has completed accrual but results are not yet available.
There are many drugs being developed against novel pathways. Efforts involving monotherapies and combinations directed against two exciting targets: menin, and CD123, are detailed in Table 5. Highly promising results have been demonstrated with menin inhibitors in AMLs harboring either a translocation in the lysine histone methyltransferase KMT2A gene on chromosome 11q23 or a mutation in NPM1 and already lead, as mentioned, to revumenib's approval. Alongside revumenib, a multitude of different menin inhibitors are currently in various stages of clinical trial development either as monotherapy or in combination with chemotherapy or HMA + venetoclax. These include ziftomenib, bleximenib [236], BMF‐219, DS1594 and DSP 5336. A phase I trial of the menin inhibitor ziftomenib in KMT2A‐rarranged and NPM1‐mutated R/R AML (KOMET‐001) demonstrated a CR/CRh rate of 25% [237]. Importantly, MEN1 resistance mutations in response to menin inhibitors have been observed in a significant proportion of patients on early menin inhibitor trials. The spectrum of resistance mutations, as well side effects such as differentiation syndrome, seem to differ based on the specific menin inhibitor used [238, 239]. Ongoing clinical trials will examine the combination of menin inhibitor with intensive chemotherapy, HMA + venetoclax and targeted therapy in both ND and R/R AML.
TABLE 5.
Selected investigational drugs for acute myeloid leukemia.
| Target | Drug | Regimens | Population | Early efficacy outcomes | Selected ongoing trials |
|---|---|---|---|---|---|
| Menin | KO‐539 (ziftomenib) | Monotherapy (KOMET‐001) [237] | KMT2A rearranged or NPM1‐mutated R/R AML | CR/CRh—25% |
KOMET‐007 (NCT05735184): ND‐AML and R/R AML 7 + 3 + ziftomenib aza + ven + ziftomenib KOMET‐008 (NCT06001788): Ziftomenib in combination with FLAG‐IDA, LDAC, or gilteritinib for the treatment of patients with R/R AML |
| JNJ‐75276617 (bleximenib) | Monotherapy [236, 269] | ORR 40%–50% |
As monotherapy (NCT04811560). Combination with chemotherapy (NCT05521087). Combination aza + ven (NCT05453903). |
||
| CD123 | Tagraxofusp | Tagraxofusp + HMA + venetoclax [242] | ND AML not fit for intensive therapy |
ORR—69% CR/CRi—59% |
Phase II in ND AML Tagraxofusp + HMA + venetoclax |
| IMGN632 (Pivekimab sunirine) | Monotherapy [243] | R/R AML |
ORR—21% CR/CRi/CRh—17% |
Phase Ib/II in both ND and R/R AML IMGN632 + HMA + venetoclax |
|
| Flotetuzumab (CD123/CD3) | Monotherapy [244] | R/R AML | CR/CRi/CRh—30% | Phase I trial of second generation MGD024 in R/R AML [270] (NCT05362773) |
Abbreviations: AML—acute myeloid leukemia; aza—azacitidine; CR—complete remission; CRh—complete remission with partial hematologic recovery; CRi—complete response with incomplete count recovery; FLAG‐IDA—fludarabine, cytarabine, G‐CSF, idarubicin; HMA—hypomethylating agent; LDAC—low dose cytarabine; ND—newly diagnosed; ORR—overall response rate; R/R—relapse or refractory; ven—venetoclax.
Multiple immune therapies are under development including antibody‐drug conjugates, bispecific T cell engaging antibodies and chimeric antigen receptor T (CART) cells directed against a multitude of different antigens including CD123, CD33, and CD70 [240, 241]. However, none of the tested immune therapies have yet led to new drug approval yet as clinical trials to date have demonstrated limited efficacy and concerning toxicities such as cytokine release syndrome (CRS) and neurotoxicity.
Tagraxofusp and Pivekimab sunirine are two agents directed toward CD123, the IL3 receptor alpha chain. Tagraxofusp represents a truncated diphtheria toxin bound to IL‐3. Pivekimab sunirine is an antibody‐drug conjugate with an indolinobenzodiazepine pseudodimer antibody drug payload. Tagraxofusp in combination with azacitidine + venetoclax showed a promising CR/CRi rate of 59% in ND‐AML patients with adverse risk ND‐AML (50% with mutations in TP53) [242]. Capillary leak syndrome (CLS) occurred in 18.9% of patients (5 grade 2, 1 grade 3, 1 grade 4). Median overall survival and progression‐free survival were 14 months and 8.5 months, respectively. Pivekimab sunirine was tested as a single‐agent therapy every 3 weeks in patients with R/R AML [243]. Infusion reactions occurred in 31% of patients but they were mainly grade 1/2 (one grade 3 led to discontinuation) and limited to the first cycle; veno‐occlusive disease was observed in 3 patients but at higher doses than the recommended phase II dose which led to a 17% CR/CRi/CRh rate. Both antibody‐drug conjugates are currently being evaluated further in combination with HMA plus venetoclax in larger phase II trials (NCT06456463 and NCT04086264).
Flotetuzumab which binds to CD3ε on T cells and CD123 was the first of the bispecific T cell engaging antibody to be tested in AML in a multicenter, open‐label phase I/II trial in 88 R/R AML patients [244]. Among 30 patients treated at the recommended phase dose, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%. The most frequent adverse events were grade 1–2 infusion‐related reactions and cytokine release syndrome (CRS). A 10‐gene immune signature predicted response to flotetuzumab. An immune‐infiltrated IFN‐γ–dominant tumor microenvironment was associated with a more likely response. However flotetuzumab's development was discontinued in favor of a second generation bispecific T cell engaging antibody named MGD024 [245], which has a longer half‐life, thereby promoting ease of administration and potentially minimizing CRS risk (NCT05362773).
One common issue with CD123 and CD33 targeting approaches is that AML blasts do not have either a truly leukemia‐specific dispensable antigen such as CD19 on B cells. For comparison, antibody‐directed therapy in acute lymphoblastic leukemia has led to the approval of a bispecific antibody, an antibody drug conjugate, and three chimeric antigen receptor T cell products. However, while CD123 and CD33 are abundantly expressed on AML blasts, these antigens are also present on normal hematopoietic stem and progenitor cells which could result in significant myelotoxicity. Second, a recent publication suggests that the cytokines released by activated T‐cells may promote AML growth, suggesting that AML cells may be intrinsically resistant to these approaches [246]. One creative approach to allow CAR T cell persistence without the unwanted prolonged myeloablation effect is to genetically edit out a surprisingly dispensable CAR target antigen (e.g., CD33 or CD45) from a donor allograft using CRISPR/Cas9 technology and then give CAR T cells or an ADC directed against this now “leukemia specific” antigen [247, 248] (NCT04849910).
9. Choosing a Treatment Strategy
A key question in choosing therapy for an AML patient was traditionally the consideration of eligibility or “fitness” for an intensive 3 + 7‐type regimen. However, the availability of genetically targeted therapies and especially the broad usage of less‐intensive therapies, has shifted the dilemma to the relative likelihood of benefit from intensive chemotherapy. For example, it may be that perfectly fit patients with mutated‐TP53 may not benefit from intensive chemotherapy regimen [249] or even the addition of venetoclax to HMA [77]. Thus, the therapeutic decision is based on patient age, comorbidities, goals of care, disease characteristics, and perhaps on physician experience. We herein provide some principles that could guide the clinicians thinking about how to treat an AML patient.
9.1. Disease and Treatment‐Driven
The most common cause of death in patients with AML is persistent/relapsed disease.
Certain AML subtypes may have differential responses to different therapy modalities (e.g., TP53‐mutated AML is poorly responsive to chemotherapy, subtypes with monocytic differentiation may be less responsive to HMA plus venetoclax, and AML with AML‐MR mutations may be more sensitive to venetoclax based therapies.).
Consider whether the patient may become eligible for alloSCT.
Many treatment options, particularly newly approved drugs which present regulatory and financial challenges, may be only available to a subset of AML patients, based on geographic and resource considerations.
9.2. Patient‐Driven
Goals of care should be discussed early on and guide the decision on best treatment for the patient.
Age by itself should not solely guide any treatment modality, especially if curative intent is pursued.
A comprehensive evaluation of comorbidities should be conducted prior to the decision on treatment strategy. AML‐related comorbidities should not be an absolute contraindication to aggressive (or any) therapy.
Older patients should undergo some form of Geriatric Assessment. Although there is no standard assessment [250], such evaluations can reveal vulnerabilities that are not detected in routine clinical practice [251], predict morbidity, mortality, and therapeutic toxicities [252, 253, 254, 255] and increase the rates of goals of care/end of life discussion [256].
Our proposed therapeutic algorithms are based on our experience and our interpretation of the available data. They should be considered a framework for the busy clinician.
10. Conclusion
In recent years, our knowledge about AML has expanded exponentially. Through novel pathophysiological discoveries, the therapeutic landscape has changed dramatically. As we enter the era of personalized medicine in AML with numerous smaller cohorts that vary by disease, treatment, and response characteristics, we should aim as a community to collaborate regarding data and clinical trials.
Ethics Statement
The authors have nothing to report.
Conflicts of Interest
R.M.S. reports grants and personal fees from Abbvie, personal fees from Actinium, grants and personal fees from Agios, personal fees from Argenx, grants from Arog, personal fees from Astellas, personal fees from AstraZeneca, personal fees from Biolinerx, personal fees from Celgene, personal fees from Daiichi‐Sankyo, personal fees from Elevate, personal fees from Gemoab, personal fees from Janssen, personal fees from Jazz, personal fees from Macrogenics, grants and personal fees from Novartis, personal fees from Otsuka, personal fees from Pfizer, personal fees from Hoffman LaRoche, personal fees from Stemline, personal fees from Syndax, personal fees from Syntrix, personal fees from Syros, personal fees from Takeda, from Trovagene, outside the submitted work. M.S. reports consulting and personal fees from Curtis Oncology, Haymarket Media, Boston Consulting; Membership on advisory board of Novartis, Kymera. S.S. do not have conflicts of interest to declare.
Acknowledgments
The authors have nothing to report.
Contributor Information
Shai Shimony, Email: shai_shimony@dfci.harvard.edu.
Richard M. Stone, Email: richard_stone@dfci.harvard.edu.
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