Episode 118: AML Series, Pt. 4 - AML Induction: Approach to Initial Management
In this week’s episode, we continue onto part two of our three-part discussion on AML induction, this week focusing on selecting our up-front regimen.
Be sure to check out last week’s episode, as this one builds on that one. Also, if you have not done so, please do check out our hemepath series to ensure you can more easily follow along with this conversation!
How should we interpret next generation sequencing (NGS) reports?
How we use NGS reports differs depending on where in the disease course we are
Initial report: Used for risk stratification and treatment options
Pay attention to “Tier I” and “Tier II” mutations (a.k.a. known or likely to be pathogenic) AND those with a variant allele frequency >10% (clinically significant), or specific mutations (i.e. FLT3)
Later, use the NGS to look for molecular evidence of residual disease
Post definitive consolidation therapy and transplant: any variant allele frequency is indicative of disease
What is the “7 + 3” regimen?
7= continuous cytarabine infusion over 7 days
3 = daily daunorubicin for 3 days
What is the history behind the 7 + 3 regimen (why do we do it)?
Arabinoside cytosine (Ara C or cytarabine) when it enters the cell, is activated by deoxycytidine kinase
In the bloodstream, Ara C is quickly converted into Ara U (deactivated and renally cleared)
If given continuously, Ara C reaches a steady state and is pumped into the cell to its active form, causing cytotoxicity
In 1973 (cool), a study out of Roswell Park with this regimen showed:
Impressive 70% CR rate with the 7 + 3 regimen
In 1982, the CALGB group changed the daunorubicin dose from 30 mg/m2 to 45 mg/m2 with improved CR rates
In 2009, E1900 study further increased the dose of daunorubicin from 45 mg/m2 to 90 mg/m2 with improved CR rates and OS in patients < 60 y/o
A European collaborative with dose increases to 90 mg/m2 in patients over 60 y/o found:
More rapid response and higher response rate in all patients
Improved CR rate in 60-65 y/o patients
Note: this was with double induction
What is idarubicin?
Idarubicin is a novel anthracycline which was introduced into the regimen as 7 + 3i to replace daunorubicin
Idarubicin was 4-8 time more potent and had better CNS penetration
What is the history of using idarubicin in AML?
In 2010, a randomized study, ALFA-9801, showed:
Improved CR rate with 7 + 3i (83% vs. 70%)
No improvement in relapse incidence, EFS or OS
Toxicity was higher with 7 + 3i
Idarubicin has also been used in the IA regimen:
IA: idarubicin + high dose (1500 mg/m2 instead of 100 mg/m2) continuous cytarabine
This regimen was thought to be an option to 7 + 3 therapy with promising results from a single center (MD Anderson) trial.
However, in 2023, a randomized phase III trial, SWOG S1203 showed:
No differences in EFS or OS for either group
Significantly greater toxicity in IA groups compared with the 7 +3 group
The 7 + 3 regimen has been able to stand the test of time for the last 50 years. When do we deviate from 7+3 therapy?
The cytogenetic testing tells us 3 things:
Is the patient a favorable risk?
If the patient is at favorable risk: Give 7 + 3 + GO
GO = gemtuzumab ozogamicin, an antibody-drug conjugate
Antibody against CD33 (on blasts)
Is this AML related to an MDS?
Consider CPX-351/Vyexos
Does this patient have a FLT3 mutation?
Give 7 + 3 + a FLT3 inhibitor (midostaurin or quizartinib)
In instances 1 and 3, with the addition of therapy, daunorubicin dose of 60 mg/m2 was used to limit toxicity.
How do we choose between the doses of daunorubicin (90 mg/m2 or 60 mg/m2)?
If therapy in addition to the 7 + 3 is used, these regimens were tested with 60 mg/m2 were used to limit toxicity as above. Without additional therapy, there is some evidence for non-inferiority of 60 mg/m2 when compared to 90 mg/m2, but it is complicated.
In 2022, the dauno double study out of Germany was presented comparing daunorubicin dosing of 60 mg/m2 with 90 mg/m2
Primary endpoint: good response defined as < 5% blasts on day 14 marrow biopsy
The 60 mg/m2 was not inferior to 90 mg/m2 for the primary end point
Rerandomization was done for double induction vs. single induction for those without a good response showing no difference in EFS or OS.
*Note: End point was at day 14 instead of CR after count recovery. Additionally, we did not get EFS or OS from dose differences.
Why do we get the day 14 bone marrow biopsy?
AML is an aggressive disease, and early biopsy may allow for changing of the regimen if a significant number of blasts are present (usually looking for < 5% blasts).
There is little evidence that the day 14 bone marrow biopsy is a good surrogate value for EFS or OS.
The best evidence was a retrospective study was done at Duke on 74 patients which evaluated the day 14 biopsy:
3 responses recorded
No evidence of disease: <5% blasts
Indeterminate response: 5-20% blasts
Residual disease: >20% blasts
45 had no evidence of disease; 3/45 observed had evidence of disease at the end of treatment marrow
11 had indeterminate response (1 underwent reinduction); 1/10 observed had evidence of disease at the end of treatment marrow
18 had residual disease (15 underwent reinduction); 1/3 observed had evidence of disease at the end of treatment marrow
Takeaway: It is not clear if the day 14 bone marrow biopsy is a good surrogate marker for CR at the end of treatment marrow. However, if no evidence of disease is seen, it may be reassuring.
What regimens could be appropriate for reinduction?
5 + 2 regimen:
5 days of continuous cytarabine and 2 days of daunorubicin
Similar to the double induction used in Europe
Venetoclax based regimens are also available especially for debulking
References:
Yates JW, Wallace HJ Jr, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973 Nov-Dec;57(4):485-8. PMID: 4586956
Yates J, Glidewell O, Wiernik P, Cooper MR, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood. 1982 Aug;60(2):454-62. PMID: 6953986.
Fernandez HF, Sun Z, Yao X, Litzow MR, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. doi: 10.1056/NEJMoa0904544. PMID: 19776406; PMCID: PMC4480917.
Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. doi: 10.1056/NEJMoa0901409. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. PMID: 19776405.
Pautas C, Merabet F, Thomas X, Raffoux E, et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. 2010 Feb 10;28(5):808-14. doi: 10.1200/JCO.2009.23.2652. Epub 2010 Jan 4. PMID: 20048183.
Garcia-Manero G, Podoltsev NA, Othus M, Pagel JM, et al. A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML. Leukemia. 2024 Jan;38(1):58-66. doi: 10.1038/s41375-023-02073-x. Epub 2023 Nov 7. PMID: 37935977.
Röllig C, Steffen B, Schliemann C, Mikesch J, et al. Single Versus Double Induction with "7+3" Containing 60 Versus 90 Mg Daunorubicin for Newly Diagnosed AML: Results from the Randomized Controlled SAL Dauno-Double Trial. Blood 2022; 140 (Supplement 1): 523–525. doi: https://doi.org/10.1182/blood-2022-157126
Morris TA, DeCastro CM, Diehl LF, Gockerman JP, et al. Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia. Leuk Res. 2013 Jan;37(1):28-31. doi: 10.1016/j.leukres.2012.09.016. Epub 2012 Oct 7. PMID: 23046833; PMCID: PMC3753071.
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Joshua Zweigle, Ronak Mistry
Social media management: Ronak Mistry
We are proud to partner with HemOnc.org!
Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org
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