Chronic Myeloid Leukemia: Diagnosis and Treatment

Dear Colleagues,

Because the main causative genetic alteration of Ph+ Chronic Myeloid Leukemia (CML) has been identified, and researchers have been able to develop tyrosine kinase inhibitors (TKIs) effective on BCR-ABL1, the prognosis of this disease has improved dramatically. Life expectancy of CML patients now approaches that of the general population. The advances we have seen in the last two decades have also been due to the introduction of standardized molecular monitoring of the BCR-ABL1 trancript, based on the quantitative PCR technique. In fact, today, molecular monitoring plays an essential role in the management of CML patients, leading the majority of clinical decisions.

This continuous improvement has led to increasingly challanging treatment goals. The possibility of leaving without treatment has become an option for some patients, with a substantial inpact on quality of life, particularly for young women who want to have a family, but also for elderly patients who present with several comorbidities. In the last 15 years, different studies have analyzed the outcome of patients with sustained deep molecular remission (DMR) who discontinued TKIs, reporting rates of treatment-free remission (TFR) ranging from 33% to 66%, depending on the definition of molecular relapse. More recently, reports on TKI discontinuation in the real life settings have included hundreds of patients. Some criticisms have emarged—for istance, treatment response for patients with atypical transcripts cannot be measured using the standard molecular methods that are used for p210 BCR-ABL1; thus, ideally, these patients are not eligible for attempting drug discontinuation. The application of new technologies such as digital (d)PCR in these rare cases is required. Interest in dPCR is also growing due to its higher accuracy in the detection of minimal residual disease (MRD) and, therefore, in a possible better prognostication of relapse after stopping treatment.

Unfortunately, not all patients fulfil the criteria for stopping treatment, and we all know that TKIs do not work for everyone. Approximately half of patients do not optimmally respond or become resistant or intolerant to TKIs over time, requiring alternative approaches. There is a paucity of literature on the long-term outcome of patients who achieve a complete cytogenetec response (CCyR) but never achieve a major molecular remission (MMR). Trasnsplant is still an option for CML patients; however, except for patients in blast crisis, indications for bone marrow transplantation need to be supported by more evidence.

Many molecules are being tested in clinical trials. Cancer immunology, particularly NK and T cell-mediated immune responses, and myeloid-derived suppressor cells and Treg-mediated immune suppression can play important roles in inducing and mantaining remission. Immunotherapy is still considered an optional combination therapy for the eradication of the disease as Interferon for a long time in CML history.

Management of CML in advanced phases is still a topic of concern because survival after prograssion is dimal. There are no validated markers to predict blast crisis. Risk scores, such as Sokal and ELTS, are only based on clinical parameters. It is desirable that in the future, a combination of clinical and gene expression signatures may contribute to tailoring a selection of frontline treatments in the chronic phase to avoid progression.

Dr. Carmen Fava
Guest Editor

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• prognostic factors
• new techniques for MRD monitoring
• atypical transcripts
• long term outcome
• new and combination therapies
• genetic signature