Case-based Roundtable on Management Approach for Newly Diagnosed Chronic Myeloid Leukaemia (CML) Patients

Bone marrow (BM) studies

Although BM evaluation is not required for establishing the diagnosis of CML, BM aspirate and biopsy at diagnosis are recommended for the following reasons:

1. Conventional karyotyping: At diagnosis, 10–12% of CML chronic phase (CP) have chromosomal abnormalities other than Ph chromosome, which have been clubbed under additional cytogenetic abnormalities (ACA). They have been subdivided into major and minor route ACA. The major route ACA such as trisomy 8, a second Ph, isochromosome 17q, or trisomy 19 have been associated with poor prognosis.^[3] Newer studies have reemphasised the importance of carrying out conventional karyotyping at diagnosis.^[4]

2. BM aspirate differential count is essential for determining the disease stage. PB and BM blasts between 10 and 19% are diagnostic of accelerated phase (AP) disease, while blasts over 20% are diagnostic of blast crisis.

3. Trephine biopsy is required to assess the degree of fibrosis which may be seen in up to 40% of patients at diagnosis.^[5] The presence of fibrosis was considered to be the marker of AP; however, with the advent of tyrosine kinase inhibitors (TKIs), the prognostic significance of the degree of fibrosis at presentation is debatable.^[6] Usually, patients with significant fibrosis do not tolerate higher doses of imatinib and there are reports of the development of BM fibrosis after prolonged imatinib therapy.^[7]

Molecular diagnosis

Signature reciprocal translocation [(t9; 22) (q34:q11.2)] results in the generation of BCR ABL fusion transcript which is pathognomic of CML. Genetic testing for the Philadelphia chromosome, the BCR-ABL1 fusion gene, or the fusion mRNA gene product is done by conventional cytogenetic analysis (karyotyping), fluorescence in situ hybridisation (FISH) analysis, or by reverse transcription polymerase chain reaction (RT-PCR). The transcript generated from the BCR-ABL fusion gene is dependent on the site of breakage in BCR. PCR is the most sensitive technique and it is recommended that multiplex PCR which detects the presence of different transcripts (p210, p190, and p230) be done at initial diagnosis for all cases. We do not recommend FISH testing for diagnosing CML. Although not essential, it is recommended that quantification of BCR ABL1 transcripts according to the IS be done before initiation of TKI therapy as the kinetics of decline of these transcripts is emerging as an important decision-making tool.^[8]

Prognostic scores

Various scoring systems have been devised to predict disease outcomes in CML. Sokal score which takes into account spleen size, PB blasts, age, and platelet counts is the most widely used prognostic too at presentation.^[9] EUTOS long-term survival score (ELTS) was derived from survival data that reflect the treatment of CML with TKIs and it provides the best discrimination for the probability of CML-specific death.^[10] We recommend that Sokal and ELTS scores be calculated and documented for all patients at presentation.

Case

Mrs. AK underwent BM examination and was found to have 100% Ph chromosomes on karyotyping. She fell into the ‘low-risk’ category as per Sokal scoring. She is concerned about treatment duration and wants to know the effect of the disease and its treatment on her future plans for pregnancy.

With the availability of multiple TKIs, there is a greater responsibility on physicians to discuss various treatment options with patients and their relatives and select the best TKI wisely. Imatinib changed the way CML is treated over the past two decades. Although the second- and third-generation TKIs are available in the market, imatinib remains the initial choice in the majority of patients and is the most cost-effective treatment option. Patients treated upfront with imatinib have probabilities of 65–70% for CCyR at 12 months, 50–55% for MMR at 2 years, and 45–50% for MR4 at 5 years.^[11] In all of the randomised studies of imatinib versus a 2GTKI, it is clear that the 2GTKI induces deeper responses more rapidly than imatinib and probably in a higher proportion of patients.^[12,13] However, whether this translates into better survival rates has never been clearly shown in any of the studies. To summarise, if the goal is to attempt treatment-free remission (TFR) at the earliest, it is prudent to use the second-generation TKI at the onset for achieving faster and deeper molecular response.

Patient-related factors

The decision to choose appropriate TKI is not straightforward due to a multitude of patient-related factors.

Drug-related factors

TKIs are associated with multiple adverse events largely due to the inhibition of off-target tyrosine kinases. Each of the drugs has a specific adverse event profile that should be known to prescribing physician when choosing first-line therapy. Imatinib is generally regarded as the safest of the TKIs, having been in use for more than 20 years, with no significant long-term irreversible adverse effects. In contrast, the newer generation TKIs have individual risk profiles with more serious complications, and data for long-term adverse events are not there. Major potentially life-threatening side effects of newer generation TKIs have been summarised in [Table 2].

Making the ‘right’ choice in clinical practice

Due to more than 2 decades of experience with imatinib and the wide availability of low-cost generics, it is hard to go wrong in choosing imatinib for all patients with CML-CP. However, approximately half of the patients treated initially with imatinib will have changed their drug at least once 8 years later and will presumably remain on their second or subsequent choice of drug for the rest of their lives.^[11] In young patients who are desirous of TFR at the earliest, the second-generation TKIs would be a more attractive proposition. If decision-making is purely on ‘biological grounds’ and not on ‘economic grounds,’ the second-generation TKIs may be considered in certain indications which are summarised in [Table 3].