Revisiting the need for bone marrow examination in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is one of the most genetically visible diseases, credit to Peter Nowell (1928–2016) and David Hungerford (1927–1993), who discovered the Philadelphia chromosome (Ph) in 1960. In 1972, Janet Rowley (1925–2013) uncovered the constitution of Ph, as a reciprocal translocation between chromosomes 9 and 22; t (9;22)(q34;q11.2). In 1984, the Ph chromosome 22 breakpoint site was narrowed to a 5.8 kb “breakpoint cluster region” and subsequently shown to be part of the BCR gene. Around the same time, a new 8.5 kb ABL transcript was described and subsequently identified as a BCRABL1 fusion transcript that translated into a P210 fusion oncoprotein. In 1990, retroviral infection of hematopoietic stem cells with P210 BCR-ABL1was shown to induce CML-like disease in mice. There are currently three popular laboratory techniques for detecting the CML-associated BCR-ABL1 abnormality: karyotype, fluorescence in situ hybridization (FISH) and reverse-transcriptase polymerase chain reaction (RT-PCR). Karyotype and FISH are semi quantitative methods while quantitative RT-PCR is the preferred technique for monitoring minimal residual disease (MRD). Furthermore, the overall accuracy of these methods varies by institution and commercial vendors. At our institution, karyotype is performed on fresh bone marrow aspirates and reported according to the International System for Human Cytogenetic Nomenclature (ISCN) criteria. We utilize a dual-fusion FISH (D-FISH) method to ensure adequate sensitivity and also determine/predict balanced 9;22 translocation (1R1G2F), complex translocation (2R2G1F), and molecular imbalances at the ABL or BCR regions (2R1G1F, 1R2G1F or 1R1G1F). BCR-ABL1 transcript levels are evaluated using quantitative RT-PCR with 0.01% analytical sensitivity and reported using the international scale (IS). Our discussion below assumes availability of adequately sensitive and accurate testing methods. In 1996, imatinib mesylate (IM) was discovered as a small molecule ATP binding site inhibitor of ABL. In 2003, the first results of the international randomized study of interferon and STI571 (IRIS) were published and recently updated in 2017 after 11 years of followup; at 18 months, the complete cytogenetic response (CCyR) rate with IM was 76.2% and progression-free survival 96.7%. At the time of the final analysis of IRIS, 6.9% of IM-treated patients experienced progression into accelerated or blast phase disease while event-free survival at 10 years was> ̴> 80% and overall survival 83%; the cumulative incidence of CCyR at the end of the trial was> ̴> 83% and CCyR loss was documented in 16%; among informative cases, major molecular response (MMR) rate at 10 years was 93% and 63% had MMR 4.5. One of the major lessons learned from IRIS and other similarly mature IM-based studies is the fact that the achievement of CCyR, and not necessarily MMR, was the most relevant milestone for overall survival. In this regard, one has to be acutely aware of the potentially flawed suggestion of an additional survival advantage from early molecular response or MMR, which does not take into account the fact that the comparator arm in such analyses includes patients who ultimately might or might not achieve CCyR; in other words, to be credible, such analysis should be restricted to patients who have otherwise managed to attain CCyR, sooner or later. Since the inception of IRIS, a number of other second generation tyrosine kinase inhibitors (2G-TKIs) have been developed and some have been compared to IM in newly diagnosed patients. To date, however, despite a recurring theme of faster and deeper responses with 2G-TKIs (e.g. nilotinib, dasatinib, bosutinib, ponatinib, radotinib), or higher dose IM (800 mg/day), none of them have shown a significant overall survival advantage over standard dose IM (400 mg/day). Furthermore, the apparently higher drug potency displayed by 2G-TKIs might have been achievable with higher doses of IM. Accordingly, and also considering the better long-term drug safety profile, IM remains the first line drug of choice in chronic phase CML, regardless of risk score, with early switch to 2G-TKI recommended for suboptimal response. Evidence-based guidelines for monitoring TKI treatment response in CML have been formalized by the European LeukemiaNet (ELN) but are seldom adhered to; the 2013 ELN recommendations consider “optimal” response in the presence of 10% peripheral blood (PB) BCR-ABL1 IS or partial cytogenetic remission (PCyR) at 3 months, 1% BCR-ABL1 IS or CCyR at 6 months, 0.1% BCR-ABL1 IS or MMR at 12 months. In a recently published IM-based controlled study that did not include other TKIs, these milestones were achieved by 69%, 61% and 55% of treated patients, respectively. Most recently, the possibility of long and safe treatment-free remissions in about half of TKItreated patients achieving undetectable disease status (MMR 4.5) lasting for at least two years have been reported. Taken together, these observations highlight the prominent role of PB BCR-ABL1 IS monitoring in TKI-treated patients with chronic phase CML. What then is the role of bone marrow (BM) examination and PB FISH? In the 2016 edition of the WHO classification of tumors of haematopoiectic and lymphoid tissues, the authors for the CML section state “most cases of CML can be diagnosed on the basis of PB findings combined with detection of the Ph chromosome and/or BCR-ABL1 by cytogenetic and molecular genetic techniques. However, BM aspiration is essential to ensure sufficient material for a complete karyotype and for morphological evaluation to confirm the phase of disease. BM