Episode 120: AML Series, Pt 6 - AML Consolidation: Therapeutic Approaches
This week, we move to our next phases of therapy for AML, which are consolidation and maintenance. Be sure to check out our prior episodes for a discussion on initial workup and how we incorporate recurrent genetic abnormalities into how we think about AML. Check out figure 1 from this paper for a helpful diagram!
Let’s recap the steps for treatment of AML:
Phase 1: Induction
We give high doses of chemotherapy to induce a morphologic remission (defined by <5% blasts in the bone marrow after count recovery)
Phase 2: Consolidation
We know that we have some leukemic cells left over after induction and we need to do more to prevent relapse.
We give less intense cytarabine based treatment to maintain and deepen our remission
For favorable risk patients, we stop here
Phase 3: Maintenance
This is where allogeneic stem cell transplant comes in
We ablate the patients bone marrow with very high doses of chemotherapy and transplant another person’s stem cells
The patient will then have a new immune system which we call a graft
This graft will fight any residual leukemia that was left behind in something called graft vs. leukemia effect (i.e. GVL)
We have to balance this GVL with the graft attacking the patients body which is called graft vs. host disease (i.e. GVHD) which requires immune suppression
The goal is to minimize immune suppression as much as possible to allow for optimal GVL while also not flaring GVHD which can lead to significant morbidity and mortality
Who do we consider for an allogeneic transplant?
First: Is the patient patient fit or unfit for intensive chemotherapy induction and stem cell transplant for curative intent?
This is often very subjective (more in the future)
Can use the HCT-CI score so that you can risk stratify but there is a significant amount of clinical judgment
Let’s focus on patients who are fit for intensive induction and transplant:
We then risk stratify patients based on the ELN 2022 risk groups into favorable, intermediate, and adverse
In general, patients who are intermediate to adverse risk are taken to transplant
What are the common cytogenetic abnormalities seen with therapy-related AML?
Our advice: always look these up, but these are a favorite for board question writers; clinically, this is used to risk stratify patients
For anthracyclines, we often see a rearrangement involving 11q23, which is known as a KMT2A or MLL rearrangement
You will hear that this occurs 2-3 years after treatment which helps remember the q2 3
MLL stands for mixed lineage leukemia
For alkylating agents and radiation, we often see deletion in chromosome 5 or 7 and potentially a TP53 mutation
You will hear that this occurs 5-7 years after therapy which helps you remember 5 and 7
Where did our approach to consolidation come from?
Bottom line:You definitely need cytarabine consolidation but there is no good prospective evidence on the optimal dosing approach
Recall from episode 118 where we discussed that the 7+3 standard of care came from a pivotal study published in 1973 with CR rates around 60-70%
After that time, there was uncertainty on the role of post-remission consolidation and there were two pivotal cooperative group trials run in the early 1980’s
One was run by the ECOG group in the United States called E3483
Here, patients who achieved remission after induction and did not have a matched sibling allo transplant donor were randomized to one cycle of high dose cytarabine, maintenance chemotherapy, or observation
The observation arm was terminated early because every patient had relapsed by 18 months with the vast majority relapsing within the first 6-12 months
Another similar trial was done the German AML group in 1978 and showed the same results for the observation arm so at that point we knew that patients needed some form of post remission therapy
These studies also showed that with durable remissions occurred in less than 20% of patients with consolidation and maintenance
Around this time, high dose of cytarabine was effective in achieving CR in patients with relapsed and refractory disease (link)
Several doses were studied ranging from 1 g/m2 up to 7.5 g/m2
Length of time on cytarabine was associated with increased toxicities so q12h dosing over six days was considered the maximum
Cerebellar toxicity was noted much more commonly in patients at doses above 3 g/m2 so this was the maximum dose limit chosen
After that time, the CALGB group in the United States worked to identify the optimal cytarabine dosing in consolidation which led to a pivotal randomized trial published in NEJM 1994
The study included patients who achieved a CR after induction 7+3 (note that daunorubicin doses were suboptimal at 45 mg/m2 in patients younger than 60 and 30 mg/m2 in those older than 60 because the trial with 90 mg/m2 had not been done yet)
They were randomized in consolidation to:
Continuous cytarabine for 5 days at 100 mg/m2
Continuous cytarabine for 5 days at 400 mg/m2
High dose cytarabine at 3 g/m2 given every 12 hours on Day 1, 3 and 5 which is what we now call “HiDAC”
Each patient got 4 cycles of consolidation followed by monthly low dose cytarabine subcutaneously and monthly daunorubicin at 45 mg/m2 for 4 courses
This study showed HiDAC was superior to the other consolidation strategies with 4 year DFS of 46%
At the time, only young patients (often younger than 45) who typically had matched sibling donors were transplanted with a 4 year DFS of around 52%
This led to HiDAC consolidation x 4 cycles followed by monthly daunorubicin and low dose subcutaneous cytarabine x 4 courses as an option for standard of care
One important limitation of HiDAC is for patients above the age of 60
After 4 years of opening the trial, these patients were excluded due to severe ocular toxicity, neurotoxicity, and infectious complications
This showed us that 3 g/m2 is not a good dose for older patients
Notably only about 50% of young patients could tolerate all 4 cycles but this was in an era without dose adjustment for renal function and G-CSF support
There was another important CALGB study published in Blood 2005 that demonstrated the efficacy of HiDAC x 3 cycles without further chemotherapy
In this study patients received 7+3 with dauno at 45 mg/m2 who had a CR after induction
Patients were randomized to HiDAC x 3 cycles at a dose of 3 g/m2 vs. HiDAC x 1 cycle followed by intensification with cytoxan + etoposide x 1 cycle and then mitoxantrone plus AZQ (diaziquone) x 1 cycle
3 cycles was chosen for HiDAC to mirror the treatment length of time as opposed to the 4 cycles in the prior study
There was no difference in DFS or OS between these two approaches with similar results to the earlier trial with 4 cycles followed by more anthracycline based consolidation
This led to HiDAC x 3 cycles to become an option as a standard of care in consolidation
One of the most important findings in this study was that there was a tremendous benefit of HiDAC seen in those who had favorable risk cytogenetics which was defined by CBF AML with t(8;21), inv(16), or t(16;16) with 5 year OS around 70%
A few years later in 2011 there were two studies, one run in Japan and one run by the French group, which randomized patients to HiDAC x 3 cycles vs. multiagent chemotherapy consolidation without high doses of cytarabine
The Japanese trial showed no difference in DFS or OS but noted a higher rate of neutropenia and infections with HiDAC because, at that time, G-CSF support was not being used
The French trial showed no difference in DFS or OS but a much better toxicity profile with HiDAC compared to chemotherapy
Last thing is what about chemotherapy + HiDAC vs. HiDAC
This was answered in German trial published in 2013 called the AML 2003 trial
Patients were randomized in consolidation to HiDAC x 3 cycles vs. HiDAC + anthracycline based chemotherapy
There was no difference in 3 year DFS or OS but much higher toxicity in the combination arm
This again showed that HiDAC consolidation was the standard of care
What is the data behind G-CSF use and the condensed Day 1, 2, 3 schedule in consolidation vs. 1, 3, 5?
After establishing HiDAC consolidation as the standard of care for patients younger than 60, there were still 2 unanswered questions:
How do we decrease rates of febrile neutropenia and prolonged myelosuppression associated with HiDAC?
What is the standard for patients >60 years of age?
G-CSF was incorporated into many trial protocols as a means to minimize the duration of myelosuppression
The NCCN guidelines for many years did not recommend G-CSF support outside of clinical trials given concern for stimulation of leukemic blasts leading to relapsed AML for those who had achieved a CR and lack of prospective evidence of efficacy
There was a Cochrane meta analysis from 19 randomized trials in AML published in 2012 that did not show a benefit in infections or survival with the use of G-CSF for AML treatments
This was limited because of the inclusion of induction, consolidation, salvage, or conditioning prior to autologous transplant studies with a majority having multi agent chemotherapy arms
It was still unclear whether there was a benefit in HiDAC consolidation arms with a recovered marrow
There was then a pivotal study from the German-Austrian AML study group published in Blood Cancer Journal 2017 that showed the efficacy of incorporating routine G-CSF in consolidation and HiDAC dosed on consecutive days
This was a sub cohort study from multiple randomized trials running at the time in Germany and Austria
Patients randomized to a consolidation arm either received:
HiDAC consolidation 3 g/m2 q12h on Days 1, 2, and 3
HiDAC consolidation 3g/m2 on Days 1, 3, and 5
In addition, they either received pegfilgrastim or no growth factor
There were 392 patients who got HiDAC on consecutive days and 176 patients who got HiDAC on Day 1, 3, and 5
When comparing schedules, the consecutive Day 1-3 group had significantly lower infections and transfusions with faster count recovery
The use of G-CSF was associated with significantly lower infections and faster count recovery
There was also reduced hospitalization and length of stay with the condensed schedule and G-CSF
Most important, there was no difference in relapse free survival or overall survival which really shows that this schedule and the use of G-CSF is safe
Our take: The 2017 study is helpful but the counter argument could be made that it wasn’t a randomized comparison. It was an interesting subcohort analysis of prospective trials but not perfect. This leaves it up to the provider to determine what they think is best without ideal evidence. G-CSF support is routinely used but you may see variation in the dosing schedule.
What about the data for doses lower than 3 g/m2, such as the 1.5 mg/m2?
We knew that toxicity was high in the 3 g/m2 dosing and many older patients could not tolerate the dose
In addition, cytarabine was cleared in part by the kidneys so additional dose reductions are very important for patients with renal dysfunction which is common in older adults
One of the largest studies was done in the United Kingdom from 2002-2009 in the AML15 trial published in JCO 2013
There were 657 patients in CR after induction who were randomized to either conventional HiDAC at 3 g/m2 q12h on Day 1,3,5 or an Intermediate Dose HiDAC at 1.5 g/m2 (also sometimes called IDAC) q12h on Day 1,3,5
There was no difference in overall survival
The higher dose arm had higher hospital days, antibiotic use, and transfusion needs
There was a trend towards higher relapse with IDAC but the study was not powered for this endpoint and it was not statistically significant
Although not definitively proven that IDAC is non inferior to HiDAC in this study, it provided some of the best prospective evidence that it is better tolerated and likely has non inferior outcomes
There were 10 randomized phase 3 trials from 1994 - 2016 that looked at a variety of doses and combinations of cytarabine in consolidation but there were no prospective trials comparing 3 g/m2 to 1.5 or 1 g/m2
In 2017, there was a network meta analysis that looked at these 10 trials to compare HiDAC (defined by cytarabine 2 g/m2 or higher) and IDAC (defined by 1-2 g/m2)
Keep in mind that may of these trials combined cytarabine with multiagent chemotherapy in consolidation
There was fairly complex statistical methodology to perform indirect comparisons with dosing and the authors concluded that the addition of other chemotherapy agents was non contributory
The problem with that is that we know that combination consolidation approaches and differential use of allogeneic transplant would greatly affect the results
All those limitations aside, the meta analysis showed that there was no difference in hematologic toxicities but there was inferior DFS for IDAC when compared to HiDAC with a HR or 0.87
The benefit for HiDAC was most pronounced for patients with CBF AML and favorable risk cytogenetics
Based on the large UK study and this network meta analysis, some people believe that HiDAC is superior to IDAC to prevent relapse but there is no good prospective trials ot actually answer this question
Patients above the age of 60 should really be treated with the 1.5 g/m2 dosing but you could go either way for younger patients
You may want to use 3 g/m2 for favorable risk cytogenetics given great outcomes and chance of cure
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: 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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