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Interrogating the molecular genetics of chronic myeloproliferative malignancies for personalized management in 2021
Ferrata Storti Foundation
Haematologica 2021 Volume 106(7):1787-1793
Tariq I. Mughal,1,2 Bethan Psaila,3 Daniel J. DeAngelo,4 Giuseppe Saglio,5 Richard A. Van Etten6 and Jerald P. Radich7
1Tufts University Medical Center, Boston, MA, USA; 2University of Buckingham Medical School, Buckingham, UK; 3MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; 4Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 5Orbassano University Hospital, Turin, Italy; 6University of California Irvine, Irvine, CA, USA and 7Frederick Hutchinson Cancer Research Center, Seattle, WA, USA
Introduction
Seminal papers over the past four decades have described phenotypic driver muta- tions, such as BCR-ABL1, JAK2, MPL, CALR, KIT and CSF3R, in subsets of myelopro- liferative neoplasms (MPN). These mutations affect cytokine signaling or regulation, and result in malignant hematopoiesis.1-3 Such discoveries and the accompanying bio- logical insights have resulted in successful therapeutic approaches for many people diagnosed with MPN, in particular chronic myeloid leukemia (CML), myelofibrosis (MF) and systemic mastocytosis (SM).4-6 The greatest advance has been in CML, with a significant proportion of patients being able to achieve a major molecular response (MMR or MR3; BCR-ABL1 ≤0.1% on the International Scale) following treatment with an ABL1-tyrosine kinase inhibitor (TKI), leading to these patients having lifes- pans indistinguishable from those of the general population, although the time by which this response milestone should be reached remains controversial.7 Qualified success with significant symptomatic benefit and modest gains in survival have also been achieved in people with MF and SM, following treatment with JAK inhibitors and KIT inhibitors, respectively.6 Some of these achievements have been facilitated by the rational integration of next-generation sequencing (NGS) assays, high-sensi- tive polymerase chain reaction (PCR) assays on DNA or RNA (sensitivity 0.01%- 0.1%), and single-cell analyses, in efforts to improve personalized treatment approaches.8 Such efforts have opened a new era of precision medicine for diverse malignancies in which relatively non-specific and often toxic drugs are being replaced by safer and better tolerated agents whose mechanism of action is precisely defined, and for which the treatment algorithm is guided by individual genetic information. Here we examine how molecular testing in MPN can shape diagnosis, monitoring, and treatment algorithms and enable more precise early identification of targeted therapy resistance, particularly in CML (Figure 1). We also discuss the potential impact of persistent or new clonal hematopoiesis on the molecular testing of individ- uals with MPN and the potential impact on measurable residual disease. This manu- script describes some of the current highlights and challenges related to genetic test- ing in MPN in 2021.
Clinically validated tests for detecting and monitoring BCR-ABL1 and KIT mutations
For patients with CML, a qualitative reverse transcriptase PCR, conducted at diag- nosis on peripheral blood cells, enables precise identification of BCR-ABL1 tran- scripts. Once TKI therapy has commenced, quantitative reverse transcriptase PCR, which adheres to the well-established International Scale, is used for sensitive and accurate monitoring of the levels of BCR-ABL1. However, this has inherent limita- tions with regard to its lower limit of detection and quantification of BCR-ABL1 tran- scripts, problems which became important as TKI that were more powerful, com- pared to imatinib, were developed.9 This, in turn, affected the definition and identi- fication of deep molecular response (DMR), defined as a greater than 4 (MR4), 4.5 (MR4.5) or 5 (MR5) log reduction in BCR-ABL1 transcripts on the International Scale, below the standardized baseline (Figure 2). DMR is now recognized to be of consid- erable clinical importance to prospectively identify patients likely to remain in remis- sion after discontinuing TKI therapy. Indeed, several current CML guidelines advo-
Correspondence:
TARIQ MUGHAL
tariq.mughal@tufts.edu
Received: September 2, 2020. Accepted: January 13, 2021. Pre-published: March 4, 2021.
https://doi.org/10.3324/haematol.2020.267252
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