Episode 124: AML Series, Pt 10 - Allogeneic transplant for AML
In today’s episode, we welcome back Dr. Amar Kelkar for part 2 of our two-part discussion on allogeneic transplant. In this episode, we build on our prior discussion regarding transplant, this time focusing on transplant for the treatment of AML.
Be sure to listen to episode 123 for part 1 of this important discussion!
What are different conditioning regimens used in allogeneic transplant?
They are selected according to age, comorbidities, disease resistance.
Myeloablative conditioning (MAC): This typically incorporates higher doses of busulfan and/or total body irradiation (TBI).
Reduced intensity conditioning (RIC): Typically includes lower doses of busulfan and/or TBI
Non-myeloablative (NMA): lowest doses of chemotherapy and radiation doses.
Lower transplant related mortality (TRM) allows elderly patients.
What is “TBI”?
Stands for total body irradiation
It is one of the original ablative regimens.
TBI regimens have lowest rates of graft rejection
In sickle cell disease and non malignant disease: increased risk of secondary malignancies if they got RIC/NMA. Adding TBI may decrease this risk.
Using MAC in non-malignant conditions reduces the risk of secondary malignancies.
What important trials inform our decision regarding optimal conditioning regimens?
Long term data showed that patients who received MAC were at higher risk of late TRM compared with those who received RIC; however, because of the exceedingly high rates of relapse in the RIC arm, overall survival remained significantly better for patients who received MAC.
Among patients with MDS or AML eligible for either MAC or RIC regimens, long-term follow up demonstrates a survival advantage for patients who received MAC.
A randomized trial of the European Society of Blood and Marrow Transplantation provides evidence that RIC resulted in at least a 2-year relapse-free survival and overall survival similar to MAC in patients with MDS or secondary acute myeloid leukemia. However they closed accrual early.
In general:
<60-65 years with robust performance status: favor MAC
>60-65 years: lose net benefit from GVL effect, lose NRM benefit.
RIC/NMA is better to decrease the risk of TRM and other adverse effects like veno-occlusive disease.
What are common methodologies to test for minimal residual disease (MRD)?
Caveat: there is a lack of high-quality data and what we know is pieced together from smaller studies
For myeloid diseases, we often use flow cytometry-based MRD testing
For lymphoid diseases, we often use PCR-based MRD testing
MRD testing in AML:
For NPM1: NPM1 specific PCR, flow cytometry is also available.
For FLT3: PCR testing
What is the role of MRD testing in transplant decision making?
If MRD +ve: transplant to help.
If MRD -ve: minimal difference between using MAC and RIC (based on several small individual studies)
FLT3: if MRD+, they will benefit from transplant
FLT3: if MRD-ve transplant is not beneficial unless they have secondary mutations that elevate the risk.
What is the role of maintenance study post transplant?
In general, this is used in a case-by-case discussion. The goal of transplant is to replace the marrow and thus the leukemic cells, therefore further treatment should not be warranted. However, in higher risk cases, this may be needed. The studies that inform maintenance options are:
SORMAIN ph 2 trial
Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD–positive AML. ~30% difference in 18 mo survival. Lots of GI toxicity.
This is a negative study, as it just missed the cut off. Worse survival initially in the treatment arm. Results of the phase III MORPHO trial showed a benefit of the FLT3 inhibitor gilteritinib as maintenance therapy after transplantation for patients with FLT3-ITD acute myeloid leukemia with measurable residual disease. It is better tolerated compared to sorafenib in terms of side effects.
What is graft versus host disease (GVHD) and types?
Acute (<6 mos) more commonly 30-90 days and drops off in incidence beyond 6 months.
Chronic (>6 mos) peak at 1 year and drop off >2-3 years (unless if given DLI in relapsed cases).
What are the clinical manifestations of GVHD?
Acute (T-cell mediated): skin (maculopapular rash), gut, liver (elevated direct bili, transaminases)
Chronic (B & T-cell mediated): skin, eyes, mouth, dry syndrome due to scarring, leads to morbidity, chronic GI webbing, bronchiolitis obliterans (lung)
What is the treatment for GVHD?
Steroids in 1st line both in acute and chronic settings
Ruxolitinib can be used in the acute setting for steroid refractory cases
3 FDA approved drugs in 2nd and 3rd line for chronic GvHD:
Ruxolitinib (NOTE: This is the only option for BOTH chronic and acute GVHD)
Others in clinical trials:
CSF1R inhibitors
Inhaled systemic systemic for lung GVHD
What is haplo transplant and role of post transplant cyclophosphamide (PTCy)?
PTCy has been explored since the 1980s.
Recent trial in 2023: Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide/tacrolimus/mycophenolate mofetil than among those who received tacrolimus/methotrexate.
Much less risk of GVHD especially in Haplo.
What are the donor choices while evaluating for transplant?
1st choice MRD
2nd choice MUD
3rd choice: Haplo and MMUD ⅞ equivalent; Use age, donor specific criteria for tie breaker.
In general, there is no set age cut off for haplo donors but ideally, <60-65 years.
What are some of the factors that have contributed to racial and minority disparities in transplant?
Check out Dr. Kelkar’s recent publication on this topic
Fewer donors in ethnic minorities
Limited access (geographic, insurance based)
What steps are being taken to address these disparities?
Expanding donor databases (even internationally)
Gaps closing in some like non hispanic black population.
Shedding light on eliminating implicit biases and improving clinical trial diversity.
About our Guest:
Dr. Amar Kelkar, MD, FACP is a Stem Cell Transplantation Physician at the Dana-Farber Cancer Institute and an Instructor in Medicine at Harvard Medical School in Boston, MA. Dr. Kelkar attended medical school at St. George’s University School of Medicine, after which he completed residency at University of Illinois College of Medicine Peoria. He then went to University of Florida in Gainesville, Florida for his hematology/oncology fellowship and then to the Dana-Farber Cancer Institute for his bone marrow transplant fellowship.
The crew behind the magic:
Show outline: Ronak Mistry, Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Srijan Valasapalli, 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
Have some extra time and want to make some extra money? Click here to get paid to participate in market research surveys!
