Episode 121: AML Series, Pt 7 - AML Consolidation and Maintenance: Role of Allogeneic Transplant
This week, we continue our discussion on consolidation and maintenance therapies for AML, this time highlighting the role of allogeneic stem cell transplants. This episode builds on our prior episode, so if you have not listened to this just yet, we highly recommend doing so!
What about the number of cycles of consolidation therapy?
No good evidence on the optimal number of cycles
NEJM 1994 article discussed last time showed that that only 50% of patients could tolerate HiDAC at 3 g/m2 dose q12h on Day 1,3, and 5 for 4 cycles so we often proceed with 3 cycles of therapy based on other trial data
There was an Intergroup US trial (more below) that compared one cycle of HiDAC vs. auto transplant in consolidation
That one cycle of therapy was effective so there is an argument for fewer cycles of consolidation; however, this has never been answered in a prospective fashion!
Allogeneic stem cell transplant plays an important role in the consolidation of patients with intermediate and high risk AML. What are the fundamental takeaways regarding allo transplants?
AML was the prototypical disease to cure with allogeneic transplant
Initially, high rates of complications including graft-versus-hose disease and severe infections
In allo transplants, conditioning chemotherapy is used to completely get rid of the native marrow so that the new non-self donor stem cells can engraft and function optimally
The non-self donor stem cells then lead to a “graft vs. leukemia effect” where the graft (the donor cells) can attack any residual leukemia cells to deepen the response
This chemotherapy is more toxic than the conditioning for an autologous transplant where you are just giving higher dose intensity chemotherapy to get rid of chemosensitive malignancy and then get rescued with your own stem cells
Over time, there were newer reduced intensity conditioning regimens developed (“RIC”) as opposed to myeloablative conditioning (“MAC”)
RIC regimens allowed for transplant to expand into older patients
At the same time, improvements in management of immunosuppression allowed for transplantation with matched unrelated donors
This treatment modality is the only curative option for many patients with AML
The whole process of allogeneic transplant from donor search, conditioning therapy, management of acute complications, and balancing GVHD and GVL is incredibly complex. Why not use auto transplants instead?
One of the pivotal studies looking at consolidative autologous transplant vs. chemotherapy was published in NEJM 1998
Patients who were in remission after induction chemotherapy were randomized to one cycle of HiDAC vs. autologous stem cell transplant with Busulfan/cyclophosphamide conditioning if a matched sibling donor was not available
There was no difference in survival between the two groups
It's important to note that relapse occurred in 60% of patients who had HiDAC who were then salvaged with either auto or allo transplant
Treatment related mortality was 20% in patients who had received an allogeneic transplant and 14% in patients who got an autologous transplant which highlights how much higher transplant related mortality was in that era compared ot our modern era of therapy
This showed that consolidation chemotherapy seems to be just as effective as auto transplant
Ultimately, the role of autologous transplant was abandoned and has not been reevaluated in the modern era but likely only offers a modest relapse benefit compared to consolidation HiDAC
Why don’t we proceed with allo transplants in patients with favorable risk disease?
One of the best studies that showed a benefit of transplant in intermediate to adverse risk patients but not favorable risk patients was a meta analysis published in JAMA 2009
The study included 24 trials with over 6000 patients and about 3600 patients also had cytogenetic risk information
Allogeneic transplant had improved relapse free survival and overall survival in patients with intermediate and adverse risk cytogenetics
Allogeneic transplant was not associated with improved survival compared to other consolidative approaches for favorable risk patients
There was another study from the European bone marrow transplant registry published in JCO 2008 that showed no difference between autologous transplant consolidation vs. allogeneic transplant consolidation for patients with favorable risk AML transplanted in first CR
Both of these studies serve as the foundation for why patients with favorable risk disease are treated with consolidation HiDAC as opposed to allo transplant in consolidation
Let’s take a patient case who has NPM1 mutated AML and undergoes 7+3+GO induction chemotherapy. They have a morphologic CR on the bone marrow biopsy. They are favorable risk so typically we defer transplant but in the current era how might MRD testing change management for this case?
Remember: per ELN 2022, the presence of NPM1 mutation without FLT3 ITD is considered favorable risk and if there is a co-mutation then the patient is considered intermediate risk
There were two prospective randomized trials run in the UK called AML17 and AML19 where both NMP1 and FLT3 status were known
Patients got a double induction per their standard of care and then had bone marrow and peripheral blood NPM1 PCR tested for MRD
There was no benefit for allo transplant compared to consolidation HiDAC in CR for those who were MRD negative (3 year OS 79% vs. 82%)
There was significant OS benefit for allo transplant compared to consolidation HiDAC in CR for those who were MRD positive (3 year OS 61% vs. 24%)
We should incorporate MRD for NPM1 mutated patients and will be evaluated further using other MRD techniques in clinical trials moving forward
The big question remains on the FLT3 ITD MRD status and what if they patients had received a FLT3 inhibitor in induction for those with co mutation
It is likely they would have done even better as patients in the RATIFY trial with co-mutated NPM1 seemed to not benefit from consolidative allo transplant
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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