Recently published in the Journal of Clinical Oncology, work from the Hourigan Lab (National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD) has provided evidence that intervention on acute myeloid leukemia (AML) genomic measurable residual disease (MRD) can improve clinical outcomes.1
Complete remission in AML: not complete
Challenges remain in this era of rapid therapeutic advances; despite the best anti-leukemic and supportive therapies, patients with AML classified as being in complete remission (CR) frequently relapse. More sensitive methods of measuring disease burden better reflect the risk of relapse.
MRD is the term used to describe the malignant cells remaining in patients following treatment, which are below the level of routine morphological detection used in defining CR.2,3 Estimates of MRD status in those in CR can be made by detecting tumor-specific DNA, RNA or proteins, such testing is primarily performed using molecular methods or multidimensional flow cytometry.4-8
A prior meta-analysis found that AML patients who are in CR but have an MRD positive status prior to allo-SCT were found to have a higher relapse rate and poorer survival compared to those who were MRD negative.8 The next question was whether anything could be done to impact outcomes?
Is AML MRD just fate, or is it treatable?
The BMT CTN 0901 trial compared reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens in patients with myeloid malignancies who were in CR.9 Accrual ceased early due to an increased relapse risk in the group who received RIC.10
This led to the Hourigan Lab hypothesizing that the impact of conditioning intensity would be greatest in those who had an MRD positive status pre-transplant. MRD was not tested for in the trial and blood samples were frozen, making them unsuitable for the primary methods of detecting MRD; flow cytometry and quantitative (q)PCR.11-13
Samples to test for detectable mutations at initial diagnosis were not available, so the group had use multiple methods of error-correction and ultra-deep next-generation DNA sequencing in order to determine MRD in these pre-transplant remission samples. The impact of the detectable mutation depended upon which gene it was located on. However, the results revealed that patients in CR but with detectable mutations in one of ten AML-associated genes prior to allo-SCT had a significantly increased risk of relapse and worse survival if randomized to RIC rather than MAC. This is particularly highlighted by the finding that all patients with SF3B1, IDH1, IDH2 and non-ITD FLT3 mutations randomized to RIC relapsed vs. no relapses in those who received MAC.1
Implications & the future
MAC appears preferable for patients who were NGS positive for MRD prior to allo-SCT; MRD negativity had no impact on survival with MAC vs. RIC.
This topic is obviously an area of great interest. The paper was highlighted as the top article of the month of January by Stem Cell Evidence, a collection of high-quality research relevant to hematopoietic stem cell transplantation produced by the NHS Blood and Transplant Systematic Review Initiative.17 Further, a recent review of allogeneic transplant for AML from the Memorial Sloan Kettering Cancer Centre cites data from the study as one of their four key points.18
There is undoubtedly more to learn in this area:
“Not all MRD as defined by NGS was treatable – why was this? Could targeted therapy do better? How does NGS correlate with MRD as measured by flow cytometry or qPCR? What impact do later graft-versus-leukemia effects have? Will the results be different in those transplanted with myelodysplastic syndrome?” — Chris Hourigan, Study Author
In addition, how outcomes can be improved in MRD positive patients with AML who are unsuitable for MAC should be addressed. The BMT CTN 1506 trial will look at the role of the FLT3 inhibitor gilteritinib as maintenance following allo-SCT for FLT3-ITD AML14, while in the UK the AMADEUS and COSI trials, which are part of the IMPACT network, will assess oral azacitidine and other therapeutic interventions to improve transplant outcomes for AML and MDS.15,16
When approached for comment by VJHemOnc, Academic Director of the Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK, and Professor of Haemato-Oncology at the University of Birmingham, said:
“Dr Hourigan and colleagues are to be congratulated on delivering such an important randomized trial, which provides pivotal information concerning the choice of conditioning regimen in adults with AML. Their data, whilst requiring confirmation, particularly in studies in which flow-based MRD technologies are used, confirms the importance of providing an infrastructure for the efficient delivery of randomized transplant trials. It is only through the prospective integration of MRD, genetics and clinical outcomes that we are likely to accelerate the improvement in outcomes after allogeneic transplant for AML that our patients so richly deserve. It is for this reason that the UK IMPACT transplant trials network was established in 2017.” — Charles Craddock, Chief Investigator of AMADEUS and COSI
With further knowledge we could intervene at the MRD stage and improve outcomes for patients with AML, and future randomized trials will address exactly that question.
Written by Cally Cameron Smith
Hourigan CS, Dillon LW, Gui G et al. J Clin Oncol. 2019 Dec 20. Impact of Conditioning Intensity of Allogeneic Transplantation for Acute Myeloid Leukemia with Genomic Evidence of Residual Disease.
Ossenkoppele G, Schuurhuis GJ. MRD in AML: time for redefinition of CR? Blood. 2013 Mar 21; 121(12): 2166-2168.
Ravandi F, Walter RB, Freeman SD. Evaluating measurable residual disease in acute myeloid leukemia. Blood Adv. 2018 Jun 12; 2(11): 1356-1366.
van Dongen JJ, van der Velden VH, Brüggemann M, et al. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. 2015 Jun 25; 125(26): 3996-4009.
Cloos J, Harris JR, Janssen JJWM, et al. Comprehensive Protocol to Sample and Process Bone Marrow for Measuring Measurable Residual Disease and Leukemic Stem Cells in Acute Myeloid Leukemia. J Vis Exp. 2018 Mar 5; (133).
Schweighofer CD, Hallek M, Wendtner CM. Eradication of minimal residual disease in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2008 Jan; 3(1): 54-60.
Nyvold CG. Critical methodological factors in diagnosing minimal residual disease in hematological malignancies using quantitative PCR. Expert Rev Mol Diagn. 2015 May; 15(5): 581-4.
Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018 Mar 22; 131(12): 1275-1291.
Buckley SA, Wood BL, Othus M, et al. Haematologica. 2017 May;102(5):865-873. Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis.
gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT01339910. Reduced Intensity Regimen vs Myeloablative Regimen for Myeloid Leukemia or Myelodysplastic Syndrome (BMT CTN 0901). Available from: https://clinicaltrials.gov/ct2/show/NCT01339910. [Accessed 9 Jan 2020].
Scott BL, Pasquini MC, Logan BR, et al. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes.
Köhnke T, Sauter D, Ringel K, et al. Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse. Leukemia. 2015 Feb;29(2):377-86.
Hubmann M, Köhnke T, Hoster E, et al. Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse. Haematologica. 2014 Aug;99(8):1317-25.
gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02997202. A Trial of the FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/Internal Tandem Duplication (ITD) Acute Myeloid Leukemia (AML). Available from: https://clinicaltrials.gov/ct2/show/NCT02997202. [Accessed 8 Jan 2020].
gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT04173533. Randomised Study of Oral Azacitidine vs Placebo Maintenance in AML or MDS Patients After Allo-SCT (AMADEUS). Available from: https://clinicaltrials.gov/ct2/show/NCT04173533. [Accessed 9 Jan 2020].
com [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier ISRCTN12434060. An international randomised clinical trial of therapeutic interventions with the potential to improve outcome in adults with acute myeloid leukaemia and high-risk myelodysplasia undergoing allogeneic stem cell transplantation. Available from: http://www.isrctn.com/ISRCTN12434060. [Accessed 9 Jan 2020].
com [Internet]. United Kingdom. NHS Blood and Transplant Systematic Review Initiative. Funded by the four UK Blood Services and Oxford Biomedical Research Centre. Available from: http://www.stemcellevidence.com/article/31860405. [Accessed 27 Jan 2020].
Gomez-Arteaga A and Gyurkocza B. Recent Advances in Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia. Curr Opin Hematol. 2020 Jan6; [Epub ahead of print].