Insights From the 62nd ASH Annual Meeting and Exposition

Meeting Insights
Laura Michaelis, MD

 

Insights From the 62nd ASH Annual Meeting and Exposition

Laura Michaelis, MD

Practice Community

Milwaukee, Wisconsin

Practice Niche

Hematologic Malignancies

Hospital and Institutional Affiliations

Medical College of Wisconsin

Question

What were the most clinically impactful abstracts presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition?

Answer

One of the most important abstracts presented this year was an abstract in the plenary session that discussed how patients of African American descent had worse outcomes when treated for acute myeloid leukemia (AML), even when data were normalized for subtype of disease.1

This type of data has been presented in the AML community in various forms before, but the fact that this was selected for the plenary was a statement. It draws attention to the fact that hematologic malignancies, like other health conditions, are marked by disparities that are bigger than the diseases and are part of a real problem of systemic racism in the delivery of health care. The fact that ASH chose this to be in the plenary is a pivot point for the society. We need to figure out ways to better deliver care to all members of society and focus on those who are prevented from getting good care because of systemic inequities.

Another big trend this year in AML was [expanded] information on the use of novel doublet therapies in older patients or those not fit for cytotoxic therapies. Abstracts were presented on combining FLT-3 inhibitors with hypomethylating agents2,3 and on the use of novel retinoic acid receptor agonists with hypomethylating agents.4,5 One of the other interesting novel agents was KO-539, an MLL inhibitor that I thought looked intriguing.6 Finally, we saw new data on already approved drugs, like liposomal daunorubicin/cytarabine. The 5-year follow-up on that pivotal study was encouraging.7

There was also a lot of data on adding venetoclax or targeted agents like FLT3 inhibitors to cytotoxic therapy. One exciting example was the data from MD Anderson on the safety and early efficacy adding venetoclax to a fludarabine-based cytotoxic induction regimen.8 Finally, there were multiple abstracts utilizing immunotherapies, like bi-specific antibodies in myeloid disease, a phenomenon that is only just gaining steam in AML.

Question

In one presentation,9 coronary artery disease was found to be more common in patients with IDH1-mutated AML, and in another presentation,10 a TP53 mutation was shown to be associated with inferior response to frontline DEC10-VEN in patients with AML. How has sequencing in this disease setting evolved?

Answer

Molecular testing is now done routinely for patients with AML. For many years, this testing was done to understand the best consolidation therapy. When midostaurin was approved, it became very important to understand on a molecular basis whether someone was FLT3-positive. It was important to know that by day 8, because that is when the study [that led to the approval] started targeted therapy.11

Now, we have targeted agents used in the front-line setting for fit patients, including midostaurin, and less fit patients, [such as] IDH inhibitors. We are waiting longer to treat patients, especially less fit patients, because we want to get the IDH1/2 tests turned around. At our center, it still takes about 14 days to get a full molecular panel back. Sometimes it takes 30 days. We are accruing data though that shows we will need those results even sooner. That is going to be a real challenge.

Question

Race was determined to be a driver of survival disparity in young patients with AML.1 What is the best way to encourage the use of molecular diagnostic tests for patients who may not have easy access to such tools?

Answer

It needs to become standard that these tests are paid for by insurers and in the uninsured setting, and that doctors who treat AML understand the prognostic and therapeutic utility of these tests. That requires education and setting standards for reimbursement that don’t penalize the patients and allow them to start therapy.

There also needs to be some rational use. It is not necessarily rational to do a full molecular panel for someone with relapsed/refractory disease. Standards should be set by independent organizations, either the FDA or [National Comprehensive Cancer Network], about when it is appropriate and useful to have these tests sent out.

The good side is that these tests are going to get less expensive and faster as time goes on. In 2 to 3 years, maybe sooner, knowing the molecular test of your myeloid mutation is going to be as routine as knowing the cytogenetics.

Question

A poster12 on early postinduction mortality in patients with AML deemed fit determined that disease-specific mutations (in RUNX1 and TET2) were associated with early posttreatment mortality. What is the best way to approach mortality risk in fit patients?

Answer

We have been trying to figure out predictors of treatment-related mortality (TRM) for a long time. There have been a number of calculators developed to try to predict the danger of intensive therapy, and there has been significant research on the usefulness of geriatric assessments in older populations.

In the fit population, we understand that higher-risk disease, [defined as] disease that presents with extramedullary involvement or very high blast counts, portends a more difficult course. These data are interesting because they may mean we need to think about molecular mutations when we are considering TRM calculations. In general, I don’t think it is a surprise that the worse disease impacts the body in a more devastating way in a younger patient.

Michaelis has received research funding from JAZZ Pharmaceuticals and has been an advisor to Celgene.

References

  1. Bhatnagar B, Zhao Q, Fisher, JL, et al. Poor treatment outcomes of young (<60 years) African American patients (pts) diagnosed with acute myeloid leukemia (AML) (Alliance). Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 6.
  2. Yilmaz M, Kantarjian HM, Muftuoglu M, et al. Quizartinib with decitabine +/- venetoclax is highly active in patients (pts) with FLT3-ITD mutated (mut) acute myeloid leukemia (AML): clinical report and signaling cytof profiling from a phase Ib/II trial. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 26.
  3. Wang ES, Montesinos P, Minden MD, et al. Phase 3, multicenter, open-label study of gilteritinibm gilteritinib plus azacytidine, or azacytidine alone in newly diagnosed FLT3 mutated (FLTmut+) acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 27.
  4. Stein EM, De Botton S, Cluzeau T, et al. Initial results from a biomarker-directed phase 2 trial of SY-1425, a potent and selective RARα agonist, in combination with azacitidine in relapsed/refractory acute myeloid leukemia. Blood. 2020;136(Suppl 1):6-7. doi:10.1182/blood-2020-1364602
  5. De Botton S, Cluzeau T, Vigial CE, et al. SY-1425, a potent and selective RARα agonist, in combination with azacitidine demonstrates a high complete response rate and rapid onset of response in RARA-positive newly diagnosed unfit acute myeloid leukemia. Blood.2020;136(Suppl 1):4-5. doi:10.1182/blood-2020-134600
  6. Wang ES, Altman JK, Pettit K, et al. Preliminary data on a phase 1/2A first in human study of the menin-KMT2A (MLL) inhibitor KO-539 in patients with relapsed or refractory acute myeloid leukemia. Blood. 2020;136(Suppl 1):7-8. doi:10.1182/blood-2020-134942
  7. Lancet JE, Uy GL, Newell LF, et al. Five-year final results of a phase 3 study of CPX-351 versus 7+3 in older adults with newly diagnosed high-risk/secondary acute myeloid leukemia (AML): outcomes by age subgroup and among responders. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 635.
  8. Lachoiez C, Konopleva M, Kadia TM, et al. Interim analysis of the phase 1b/2 study of the BCL-2 inhibitor venetoclax in combination with standard intensive AML induction/consolidation therapy with FLAG-IDA in patients with newly diagnosed or relapsed/refractory AML. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 332.
  9. Kattih B, Shirvani A, Klement P, et al. IDH mutations are associated with an increased risk of coronary artery disease and cardiotoxicity in patients with established AML. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 389.
  10. Kim K, Maiti A, Kadia TM, et al. Outcomes of TP53-mutant acute myeloid leukemia with venetoclax and decitabine. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 693.
  11. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi: 10.1056/NEJMoa1614359
  12. Haydu JE, Flamand Y, Vedula RS, et al. Distinct clinical and genetic factors predict early versus late mortality in AML patients undergoing induction chemotherapy. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 1911.