Episode 126: AML Series, Pt 12 - Treatment of patients with relapsed/refractory disease
This week, we round out our AML series with a detailed discussion about the approach to management of relapsed and refractory disease. This has been a VERY long road going through all management of AML. We hope that you have continued to build on our discussions week-to-week. An exciting treatment paradigm that is ever-evolving!
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What is “primary induction failure” in AML?
Primary induction failure which is also known as “primary refractory AML” differs based on intensive induction with anthracycline-based chemotherapy vs. less intensive induction
The European Leukemia Network (ELN) provided guidance on these definitions in 2022:
For patients undergoing intensive induction, primary induction failure is defined by persistent disease with >5% blasts after two courses of intensive induction (recall that this is the European SOC)
For patients undergoing less intensive induction, there is less of a consensus and based on an arbitrary amount of time after starting therapy (anywhere from 90-180 days)
This is because some less intensive induction regimens can take 2-4 cycles before achieving a CR
In reality, many of our patients who are hospitalized for weeks will not achieve a CR after intensive induction therapy and this differs based on ELN risk group
There was a pivotal validation study for the ELN 2022 risk stratification published in 2023:
Over 1100 patients from AML trials conducted in European countries between 1999-2012 who underwent intensive induction with cytarabine-based chemotherapy were included
There was second validation cohort of over 1100 patients from the German-Austrian AML study group trials to confirm key findings
There were differing CR rates based on risk group
Favorable had nearly 75% CR rate
Intermediate had about 66% CR rate
Adverse had 45% CR rate
About 15% of patients were reclassified from the ELN 2017 risk stratification
Patients who had both TP53 mutated AML and complex karyotype had a 5 year overall survival of 0% (?should we reclassify these patients as very unfavorable risk?!)
What is a good framework for treatment options in patients with refractory AML?
Caveats:
We don’t have robust randomized data in this setting and overall the prognosis for these patients is poor
The best thing to do is refer for consideration of a clinical trial which may not be feasible for all patients
After that, intensive reinduction, regardless of targeted mutation status, it is reasonable to consider a round of intensive induction with regimens such as: FLAG, FLAG-Ida, CLAG, and CLAG-M (more below)
You can also consider HMA + venetoclax in lieu of intensive reinduction or the addition of venetoclax to intensive reinduction with FLAG-Ida-Ven
If patients have primary refractory disease after two courses of intensive induction or relapse after achieving a prior remission with or without allo transplant, consider HMA + venetoclax therapy or (ideally) targeted therapies
Recall: targeted mutations with therapies includes IDH1, IDH2, and FLT3
Recently, a menin inhibitor for the KMT2A rearrangement (translocation 11q23) was approved
What are the alternative intensive reinduction strategies for patients with AML?
As we discussed in our consolidation episode, high dose cytarabine was effective for achieving CR in the relapsed and refractory setting at doses ranging from 1 g/m2 up to 7.5 g/m2 in a dose finding study published in 1983
This is led to high-dose cytarabine as a key component of the backbone for salvage intensive regimens for AML
There were also studies that showed efficacy of single agent or combinations of etoposide and an alternative anthracycline mitoxantrone in the relapsed/refractory setting
This led to the development of the regimen MEC, which we don’t see used very often in the modern treatment paradigm
MEC stands for mitoxantrone, etoposide, and intermediate dose cytarabine at 1 g/m2
Cr rates ranged from 20% up to 60%
In addition to the use of etoposide and mitoxantrone, there was significant work done in the lab to understand how to augment the effect of high dose cytarabine in AML
Remember that cytarabine is cytosine with the arabinoside sugar attached and is an inactive prodrug
It has to enter the cell and be converted into its active form by an enzyme. Essentially this means “ara-C → ara-CTP” due to phosphorylation
The goal was to figure out how to upregulate that enzyme to have higher amounts of activated ara-CTP
There was a pivotal study published in JCO in 1993 that showed the addition of the purine antimetabolite, Fludarabine, prior to high dose cytarabine infusion increased the accumulation of active cytarabine in leukemia cells (AKA fludarabine potentiates the effects of cytarabine)
During this time period, there was an alternative purine antimetabolite known as cladribine which was also shown to be effective
There was then a subsequent study that showed using G-CSF also increases activity of the enzyme and pushes quiescent AML cells into the S phase which allowed for more optimal cytotoxicity of the ara-CTP which was incorporated into DNA to cause apoptosis
The CL and FL are cladribine or fludarabine
The A and G are for high dose cytarabine and G-CSF
Really the goal of these regimens is to augment the efficacy of high doses of cytarabine
There was also a push to add an alternative anthracycline to the CLAG and FLAG which gave us CLAG-M and FLAG-Ida
The M for mitoxantrone (https://pubmed.ncbi.nlm.nih.gov/18076637/)
The Ida for idarubicin (https://pubmed.ncbi.nlm.nih.gov/9432047/)
For all of these regimens, the CR rates ranged depending on which small study you looked at from 20% up to 70%
There was never randomized study evaluating differences in MEC, CLAG, FLAG, CLAG-M, or FLAG-Ida so it really was dealers choice
There was a thought that the addition of anthracycline would augment CR rates and lead to improved MRD negativity but there are conflicting results from retrospective studies when looking at CLAG-M or FLAG-Ida vs. CLAG or FLAG respectively
Study that showed CLAG-M better than CLAG or MEC (https://pubmed.ncbi.nlm.nih.gov/32951486/)
Study that showed FLAG better than FLAG-Ida (https://pubmed.ncbi.nlm.nih.gov/30887181/)
Overall expectation of CR somewhere around 30-50% is reasonable in the relapsed/refractory setting for AML
What is the role for venetoclax in the salvage setting?
Venetoclax has really broadened our treatment options in AML
Remember from episode 125 that venetoclax is a BH3 mimetic that inhibits the anti apoptotic protein BCL-2 which is overexpressed in AML cells and thus activates apoptosis
We noted previously that single agent venetoclax has little activity in AML with CR rates around 10% and should be combined with chemotherapy or HMA
Given the new standard of care in unfit patients from HMA + venetoclax, this regimen has been used in the relapsed/refractory setting and can be a good strategy for patients with a concern for chemo refractory disease like in our case
There have been conflicting reports on the efficacy in the relapsed/refractory setting and most have been retrospective in nature
One of the largest trials was a single center phase II study from MD anderson that looked at decitabine x 10 days + venetoclax
The study included both newly diagnosed and relapsed/refractory patients who were not eligible for intensive induction chemotherapy
Over 80 patients with relapsed/refractory AML were included
It is important to note that 70% of the relapsed/refractory patients had already received HMA therapy and about one third of these patients had a TP53 mutation
The composite CR rate was roughly 40% in the relapsed/refractory patients despite prior HMA use
There was another real world multicenter study from 11 centers in France presented at ASH 2023
They included 146 patients with relapsed/refractory AML
The composite CR rate was 44% confirming the findings seen the phase 2 study in a real world setting
One other very important single center retrospective study from City of Hope looking at HMA+Ven for 32 patients who all had TP53 mutations showed a composite CR rate of 50%
Another important intensive venetoclax based regimen is FLAG-Ida-Ven developed by the MD Anderson group
This regimen added venetoclax on to the regimen of FLAG-Ida
There was a phase 1b/II study with 59 patients who had relapsed/refractory AML
The composite CR rate was an astounding 66%
To summarize, HMA + venetoclax and FLAG-Ida-Ven are both reasonable options in the relapsed/refractory setting and there has yet to be a reported randomized trial run for these patients
What are the salvage treatment options for patients with relapsed FLT3 AML?
The drug of choice in this setting is gilteritinib which is a FLT3-inhibitor that was approved based on the phase 3 randomized ADMIRAL trial
This study included 371 patients who were randomized 2:1 to gilteritinib monotherapy vs. salvage chemotherapy (either MEC, FLAG-Ida, LoDAC, or Azacitidine)
It is important to note that HMA + venetoclax was not an option as it was approved years after this study was published
The composite CR rate was 34% vs. 15% and there was improved median OS at 9 months vs. 6 months
Notably at 2 year follow up, the survival rate was 20% in the gilteritinib arm with most patients undergoing allogeneic transplant
Another caveat is that only 13% of patients had received a FLT3 inhibitor in induction given that the RATIFY trial was published in 2017 and the ADMIRAL accrued from 2015 to 2018
We still don’t know if HMA + ven, gilteritinib monotherapy, or potentially a triplet of HMA + ven + gilteritinib is ideal in this setting
What about IDH1 and IDH2 mutated AML in the relapsed/refractory setting?
For IDH1 AML, the options are ivosidenib (NEJM 2018 article) or olutasidenib (Lancet Haematology 2023 article)
“I” in ivosidenib looks like a 1 so that’s how I remember that it is for IDH1 mutated AML
For IDH2 AML, the option is enasidenib (n is like a “2” on it’s side)
As we discussed episode 125, the IDH mutations are gain of function and leads to an excess of the compound 2-HG which ultimately leads to hypermethylation, a block in differentiation, and inhibition of apoptosis
When you inhibit the IDH mutation, normal differentiation is restored and there is a risk of differentiation syndrome as the blasts can rapidly differentiate into mature neutrophils
The median time to response for these therapies is around 3-4 cycles so it is important to continue with treatment for several months before determining if the patient is refractory
Given the hypermethylation, you will also see the addition of hypomethylating agents to these therapies though there is no good evidence behind this practice
See links included above to review these studies. Overall, in these studies there was an ORR ~ 46%, composite CR rates ~ 20%, and OS ~ 9 months. Roughly one third of patients will achieve transfusion independence.
It’s important to know that these patients did not have prior venetoclax therapies given the time of accrual.
We do have a phase 3 randomized trial of enasidenib vs. conventional treatments in older adults. Can we go over that study?
This is called the phase III IDHentify study published in Blood 2022
The study enrolled 319 patients with relapsed/refractory AML with about 75% of patients receiving prior intensive chemotherapy
This was an open label study that randomized patients 1:1 to either enasidenib monotherapy or conventional therapy (including either azacitadine monotherapy, intermediate dose cytarabine, low dose cytarabine, or best supportive care)
There was no difference in OS with median 6.5 months vs. 6.2 months
Notably 12% of patients in the control arm dropped out before receiving any therapy
The composite CR rate was 30% in the enasidenib arm vs. 6% in the control arm
Transfusion independence occurred in 30% compared to 10% in the control arm
Differentiation syndrome occurred in 14% of patients on the enasidenib arm
Hot off the press at the time of this recording is the FDA approval of revumenib, known as a menin inhibitor that can be considered for patients with a KMT2A rearrangement. What does this drug do and what should we know about the approval process?
Remember these are patients who have a translocation involving the chromosome 11q23 which is known as a KMT2A rearrangement
Recall this is also what you will see is associated with anthracycline related AML
This rearrangement leads to upregulation of something called the HOX gene which blocks cell differentiation and promotes leukemia persistence
The KMT2A-HOX gene interaction is mediated by a scaffolding protein called menin
A similar mechanism is found in NPM1 mutated AML
There was then a push to develop an inhibitor of menin which is where we got to this new drug called revumenib
In August of 2024, there was a phase 2 study called AUGMENT-101 including pediatric and adult patients with relapsed/refractory KMT2A rearranged or NPM1 mutated AML
All patients were heavily pretreated and received revumenib monotherapy given every 12 hours as a capsule or liquid in 28 day cycles
There was a composite CR rate of 23% with median time to CR of 1.9 months
Differentiation syndrome was common occurring in a little over 25% of patients
This was a big improvement as 75% of these patients had received prior venetoclax treatment and the KMT2A rearrangement is associated with chemotherapy refractory disease
We anticipate future studies to move this further up in the treatment paradigm.
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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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