Episode 117: AML Series, Pt. 3 - AML Induction: Definitions and Overview
In this week’s episode, we start our three-part discussion on AML induction, this week focusing on key definitions and an overview of treatment.
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!
When you see “blasts” on a smear, what does all this mean?
This means that a tech or pathologist looked at the morphology and felt that it was consistent with a blast but you need to confirm with flow cytometry
Remember that flow gives us the immunophenotype to confirm if this is a myeloblast or lymphoblast
Also flow can help identify potential APL patients as they often have a characteristic immunophenotype that is CD33+, CD34-, and HLA DR-
We also really want to make sure this patient does not have APL and review the blast for morphologic characteristics of APL while also discussing with our pathology colleagues
If there is any concern for APL by morphology, then remember to start ATRA immediately which we discussed in our intro to APL episode previously
If there is concern for AML, then what do we do next?
Assess for tumor lysis syndrome and DIC
Remember the best treatment for TLS is prophylaxis so start continuous IVF and allopurinol 300 mg BID
If you reviewed the smear and talked to pathology with morphology consistent with a blast, then start hydroxyurea for cytoreduction to hold things off while you obtain further diagnostic studies.
Usually 1 g q12h is sufficient and remember this will take a day or so to really start working
The weight based dosing is 50 - 100 mg/kg per day.
Get a bone marrow biopsy to confirm the diagnosis, obtain cytogenetics, and obtain molecular data for risk stratification and treatment planning
Get a PICC line in anticipation for chemotherapy and frequent lab monitoring
Order an transthoracic echo to assess ejection fraction in anticipation of possible use of anthracyclines
If the CBC suggests that there is a rising white blood cell count, with the majority being blasts, what should we do next?
We always want to rule out leukostasis which would require emergent cytoreduction with chemotherapy or leukapheresis
Leukostasis can be seen with high levels of circulating blasts but is very rare if there are significant numbers of mature lymphocytes like in CLL
We often need a blast count greater than 50K but this isn’t always true
Leukostasis results partially from the inability from increased blood viscosity from leukemic blasts that plug the microvasculature resulting in tissue ischemia
There is also a significant contribution of excessive cytokine production and adhesion molecules that mediate blast and endothelial cell interactions which leads to endothelial damage and hemorrhage
Clinical signs include any CNS symptoms (blurry vision, headache, dizziness, gait disturbances, etc), dyspnea with hypoxia and imaging showing diffuse infiltrates, and more rarely myocardial ischemia, gut ischemia, or limb ischemia
We have the bone marrow biopsy results and they are consistent with acute leukemia. Cytogenetics and molecular testing are still in process. So now what?
After we have obtained our diagnostic testing and ruled out leukostasis, the next step is to determine whether the patient is fit for intensive chemotherapy or not which is extremely subjective
Often patients above the age of 75 are not candidates for intensive induction
Intensive induction chemotherapy involves the use of an anthracycline so we need to make sure they have a normal EF which is why we obtained the TTE
Molecular and cytogenetic testing varies by center but in general we get some components early and comprehensive components later
Patients will have a FISH panel sent for common MDS and AML chromosomal rearrangements
The key things that would change treatment are t(15;17), inv16, or t(8;21)
The 15;17 is diagnostic of APL and changes treatment approach
Inv16 and t(8;21) are found in something called core binding factor AML which is favorable risk and changes treatment
Patients will also have molecular mutation panel sent and potential single gene testing sent looking for targetable mutations that could influence front line therapy
This often looks for NPM1, FLT3-ITD, FLT3-TKD, IDH1, IDH2, and bZip in-frame CEBPA mutation
After about 2 weeks, we can get the karyotype and next generation sequencing
How do we risk stratify patients?
The cytogenetic and molecular studies allow us to risk stratify these patients for both prognosis and treatment planning
There are 3 risk groups based on these studies defined by the European Leukemia Network which had an updated classification in 2022:
Favorable risk
Intermediate risk
Adverse risk
These are essentially the same concept of staging in solid tumors
The biggest thing to know is that, in general, favorable risk patients do not need an allogeneic transplant for cure
These risk groups were determined from many studies looking at predictors of poor survival in pooled analysis of prospective trials and retrospective studies
Let’s focus on patients fit for intensive therapy (we will discuss less fit patients in a future discussion). The goal for a patient fit for intensive therapy is curative intent.
You should think about treatment in three phases:
Phase 1: Induction
We give high doses of chemotherapy to induce a morphologic remission which is 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 chemotherapy to maintain and deepen our remission
For favorable risk patients, we generally stop here
Now we can assess for measurable residual disease (i.e. MRD) which can tell us if we need to move to phase 3 even for favorable risk patients
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
We can’t given them their own stem cells back (autologous), not only because we want this graft vs. leukemia effect, but it is likely that their native stem cell harbor the mutations that led to a block in differentiation and resulting cancerous myeloblasts
How do we define responses to therapy?
Complete response: After intensive chemotherapy, cell counts have recovered and the marrow shows <5% blasts. We define count recovery as platelets >100 and neutrophils >1000.
Morphologic leukemia free state: After intensive chemotherapy, counts have not yet recovered but a marrow is performed and there are not leukemia cells
Composite complete response: Patients got high doses of chemotherapy, but they have incomplete marrow recovery (i.e., either their platelets or neutrophils have yet to recover), but there are still no signs of blasts
References:
https://ashpublications.org/blood/article/140/12/1345/485817/Diagnosis-and-management-of-AML-in-adults-2022
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
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