Induction therapy for acute myeloid leukemia: still nothing beyond 7+3?

In the last 50 years, induction therapy for acute myeloid leukemia (AML) has not significantly changed since the introduction of the “7+3” scheme, with low dose cytarabine and an anthracycline (1). Despite complete remission (CR) rates with conventional induction being quite favorable, long-term survival is still dismal (2), with the partial exception of younger/fit patients who can proceed to allogeneic hematopoietic cell transplant (HCT). This has prompted extensive investigations on possible modification to AML therapy, with special focus on induction and consolidation phases.

A recent work from Garcia-Manero et al. explored the role of higher doses of cytarabine and the histone deacetylase (HDAC) inhibitor vorinostat in AML (3). The authors randomized 738 younger (18–60 years) newly diagnosed patients to receive induction therapy with either classical 7+3, high dose cytarabine and idarubicin (IA), or IA plus vorinostat (IA-V); the main finding of the study was that no significant differences in CR, event-free survival (EFS), or overall survival (OS) were observed among the three arms.

The almost identical CR rates in the three cohorts suggest a lack of efficacy of both higher dose cytarabine and addition of vorinostat, though two different anthracyclines (i.e., daunorubicin 90 mg/m² or idarubicin 12 mg/m²) were used. Even in the classical 7+3 arm, the effect on EFS and OS could have been partially impacted by different consolidation strategies, as patients in the arm 7+3 received high-dose cytarabine, while those in IA and IA-V received intermediate-dose IA ± V. This potential bias is of relevance in the favorable cytogenetic subgroup (i.e., AML with core binding factor mutations, n=96, 13%), in which the inferior EFS with IA compared to DA might have been strongly conditioned by the peculiar sensitivity of these leukemias to higher cytarabine doses. Moreover, data on patients proceeding to allogeneic HCT have not been reported.

However, the paper from Garcia-Manero et al. is a source of reflection on various open issues on AML therapy.

Anthracycline and cytarabine dose in induction therapy

Regarding the daunorubicin dose, two randomized clinical trials proved the advantage of the escalated dose of 90 mg/m² compared to the standard 45 mg/m² dose, in terms of prolonged OS in both younger and elderly patients (4,5), thus recommending the higher dose as a standard of care. However, the randomized AML17 trial enrolled 1,206 AML or high-risk myelodysplastic syndrome patients, mainly <60 years, randomized to receive 90 or 60 mg/m² combined with cytarabine as induction chemotherapy (6). The study showed that there was no difference in CR rate, while early mortality was 2-fold higher in the 90 mg/m² arm (10% vs. 5%) and that 2-year OS was almost identical (59–60%) in the two cohorts.

Idarubicin is a common substitute of daunorubicin, also in the study from Garcia-Manero et al., but the equipotency of the two drugs has not been defined. Usually, a 1:5 dose ratio is used (e.g., 12 mg/m² idarubicin to 60 mg/m² daunorubicin). However, data from a meta-analysis and in vitro test on cell lines and AML samples support an equipotent ratio around 1:4 (7), suggesting a potential underdosage of idarubicin in the clinical practice.

Even the best dose of cytarabine, the second cornerstone of AML induction, has been investigated in the last years. Ten years ago, an EORTC/GIMEMA trial enrolled 1,942 AML patients up to 60 years of age, randomized to induction therapy with daunorubicin, etoposide, and either standard (100 mg/m² for 10 days) or high (3,000 mg/m² for 8 doses) cytarabine (8). CR rate and OS were superior in the high-dose group, with a more relevant benefit in patients younger than 46 years and in those with adverse cytogenetic/molecular abnormalities and with secondary AML. A more recent Australian retrospective study on 416 patients with intermediate- or poor-risk cytogenetic AML showed greater CR rate with high-dose cytarabine induction (90% vs. 78%, P<0.01) but similar OS (48% vs. 43%) or disease-free survival (DFS) (39% vs. 45%), while DFS was positively affected by higher cytarabine doses in the consolidation phase (9). Similarly, a Finnish trial failed to detect any significant difference in CR rate and long-term outcomes between induction with standard dose cytarabine, combined with idarubicin and thioguanine, and intermediate (1,000 mg/m² for 8 doses) dose cytarabine combined with idarubicin alone in 356 AML patients (median age 53 years) (10).

Addition of a third drug to the 7+3 backbone

The addition of a third agent to the standard 7+3 regimen to enhance therapeutic effectiveness has been tested in many trials over the last decades. Earlier studies with etoposide or thioguanine failed to prove any benefit, while gemtuzumab ozogamicin, a drug-conjugated anti-CD33 monoclonal antibody, showed encouraging results in favorable- or intermediate-risk AML (11).

Purine analogs, such as fludarabine and cladribine, are promising additions to induction treatment due to their ability to increase cytarabine’s cellular uptake and their direct antileukemic activity, which involves incorporation into the DNA of AML blasts.

A phase 3 Polish Adult Leukemia Group trial compared standard 7+3 induction therapy with cytarabine and daunorubicin 60 mg/m² (DA), versus DA in combination with fludarabine (25 mg/m² for 5 days) or with cladribine (5 mg/m² for 5 days) in 652 AML patients <60 years old (12). CR rate and 3-year OS were superior with DA + cladribine compared to the other two arms, though results in the latter were found to be inferior to those previously published with the same schemes.

Beyond its synergistic effect with cytarabine on myeloid cells, fludarabine has been demonstrated to overcome multidrug-resistance, a mechanism responsible of poor response and increased relapse rate in AML (13). The MRC AML15 trial compared 7+3 ± etoposide with a fludarabine-based induction comprising two courses of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida) (14). Although CR rates, relapse risk and OS were superior in the FLAG-Ida, increased myelosuppression, resulting in a lower rate of treatment completion, was observed in the fludarabine arm. This enhanced toxicity was partially resolved by limiting fludarabine to only the first induction course. Favorable results, in terms of higher CR rates and longer OS, of fludarabine- or clofarabine-based induction chemotherapy over standard 7+3 were reported by a randomized phase 2 study from MD Anderson Cancer Center (MDACC), that also suggested superior outcomes with fludarabine in patients aged <50 years (15). Nonetheless, also in this cohort, relapse remains the major cause of poor survival, possibly due to overexpression of multidrug-resistance proteins, among which an increasing interest is focused on ABCG2, whose effect seems not to be overcome by either fludarabine or clofarabine (16).

In the very last years, several drugs have been approved for newly diagnosed AML patients fit for intensive chemotherapy, among which venetoclax seems the most promising (17). Though initial results show encouraging CR rates, infectious toxicity is a matter of warning and long-term results are still scarce.

Potential role of HDAC inhibitors in AML

HDACs are involved in chromatin modification; their action closes the chromatin structure, resulting in impaired or blocked binding of transcription factors and, subsequently, gene transcription. It has been hypothesized that HDAC inhibitors lead to a de-repression of silenced tumor suppressor genes, thus displaying an anti-leukemic activity (18).

Valproic acid (VPA), an anticonvulsant drug, has been shown to have activity against neoplastic cells through the inhibition of HDAC, particularly HDAC2. Despite this convincing rationale, the results of VPA activity, alone or in combination with ATRA, were quite poor; in a study of 58 AML patients unfit to receive intensive chemotherapy the response rate was around 15% (19). Partially conflicting results were reported on the efficacy of combining VPA with cytarabine and decitabine; however, the overall activity of these regimens was quite low (20).

The first and most extensively studied HDAC inhibitors were hydroximates, nonselective inhibitors targeting class I and II HDAC. Panobinostat (LBH589) showed a potent anti-leukemic activity in cell lines and primary AML samples, but a negligible effect as a single agent in two clinical trials (21). Combined therapy of panobinostat with various drugs, including hypomethylating agents (HMAs) and other inhibitors, again demonstrated anti-AML effects, but this translated into only a few early-phase clinical trials and yielded disappointing results in terms of the lack of benefit from adding panobinostat (22). However, promising results were reported by a phase Ib/II trial combining panobinostat with cytarabine + idarubicin in induction and, as monotherapy, in maintenance of elderly AML patients (23).

Over 20 years ago, vorinostat showed activity in acute promyelocytic leukemia cell lines and murine models (24), but the effect of monotherapy in relapsed or newly diagnosed high-risk AML was minimal (25), suggesting its use in combination. A phase II study from MDACC in 2012 added vorinostat to IA, revealing higher CR rates compared to the standard arm without any significant increase in toxicity (26). Regarding combinations with HMAs, no advantage was reported with azacytidine in elderly patients with relapsed or refractory AML (27). However, better results were observed with concurrent use of vorinostat and decitabine ± cytarabine in elderly patients with untreated or relapsed/refractory AML (28).

In summary, though the large multicenter trial recently presented by Garcia-Manero and colleagues suggests that intensive induction and/or addition of vorinostat does not improve outcomes of younger AML patients, with the notable exception of those with core binding factor abnormalities (that benefit from consolidation with higher dose cytarabine), various approaches are feasible to finally attain the long-awaited improvement in AML therapy. Beyond the optimization of anthracycline and cytarabine dosages, the addition of novel drugs—including newer HDAC inhibitors and small molecules targeting the numerous molecular abnormalities of leukemic blasts—may represent a promising field for both younger and elderly patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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