Myelodysplastic syndromes/myeloproliferative overlap neoplasms

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are haematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) that display a paradoxical bone marrow phenotype hallmarked by myeloid proliferation in the context of bone marrow dysplasia and ineffective haematopoiesis. The unfolding MDS/MPN genomic landscape has revealed numerous mutations in signalling genes, such as CBL, JAK2, NRAS, KRAS, CSF3R, and others involving the spliceosome complex. These observations suggest that comutation of genes involved in dysplasia and bone marrow failure along with those of cytokine receptor signalling may, in part, explain the dual MDS/MPN phenotype. The respective MDS/MPN diseases are identified by the type of myeloid subset which predominates in the peripheral blood. Currently there are no standard treatment recommendations for most patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic endpoints and standardized response criteria for clinical trials.

Essential thrombocythaemia

Essential thrombocythaemia is a classic myeloproliferative neoplasm characterized by thrombocytosis, increased risk of thrombotic and/or haemorrhagic complications, and a trend to transformation to myelofibrosis and acute leukaemia. Mutations in JAK2, CALR, and MPL genes besides bone marrow histology are crucial elements of diagnosis. Treatment is aimed to prevent the appearance of thrombotic complications that are the main cause of morbidity and mortality. Accordingly, thrombosis risk stratification is of the utmost importance to select the appropriate treatment. Antiplatelet therapy as primary antithrombotic prophylaxis in low-risk patients should be tailored according to the existence of extreme thrombocytosis and presence of JAK2V617F mutation and/or cardiovascular risk factors. Cytoreductive treatment options are discussed with reference to results of randomized clinical trials. Practical approach to unusual and risk situations as surgery, pregnancy, and paediatric essential thrombocythaemia are also reviewed.

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) was recognized in the 1970s by Janet Rowley to be a genetically simple malignancy; resulting as a consequence of a balanced translocation between chromosome 9 and 22. This provided vital insights into the molecular aberration, in the 1990s, which ushered in the current ‘precision medicine’ era, not only for patients of CML, but for cancers in general. As a result, today, a personalized treatment algorithm is available for all newly diagnosed patients with CML. Treatment involves a choice of three first-line orally administered tyrosine kinase inhibitors (TKIs) and two effective next-line TKIs that should be used based on risk stratification, comorbidities, the side effects profile, and the BCR-ABL1 genotype. Regardless of the initial choice of TKI, the vast majority of patients achieve a durable complete cytogenetic remission, with a lifespan approaching that of the general population. In most instances the medication must be continued indefinitely, and a principal challenge now, is to develop strategies to stop TKIs safely and effectively. Challenges remain in how to achieve optimal monitoring of patients with CML on treatment and in achieving a better understanding of the mechanisms and treatment of patients with advanced phase disease. This chapter addresses these questions as well as the concomitant topical issues in CML.

Prognostic factors of chronic myeloid leukaemia

Two decades following the successful introduction of the ABL tyrosine kinase inhibitors in clinics for the treatment of patients with chronic myeloid leukaemia (CML), the principal objective of treatment in chronic phase (CP) is survival, preferably without life-long therapy. In tandem, the methodology and tools for assessing the prognosis of the newly diagnosed patient with CML in CP has evolved substantially. Prior to the era of tyrosine kinase inhibitors (TKIs), risk assessment depended more on the response to treatment than on baseline characteristics. The Sokal score, introduced in 1984, was the first one dividing patients into three risk categories based on a mathematical formula taking into account the patient’s age, and baseline characteristics like blast cell count, spleen size, and platelet count. This, and the several other subsequent risk stratification methods developed during the chemotherapy and interferon-alpha era, have remained useful in the first-line TKI treatment, and identifies a variable proportion of high-risk patients with lower response rates and worse outcomes. In second line, the most important risk factors are the absence of haematologic or cytogenetic response on first line, the presence of hematologic toxicity the development of additional cytogenetic abnormities (ACA), and the development of BCR-ABL1 kinase domain mutations. In this chapter, we address the prognosis of CML and the various methods for risk stratification.

Haematopathology of classic myeloproliferative neoplasms

The classification of the World Health Organization (WHO) continues to advocate the diagnostic importance of bone marrow (BM) morphology in the diagnostic workup of myeloproliferative neoplasms (MPN). In this regard, distinctive histological BM patterns characterize specific subtypes of MPN and are the key to a meaningful clinical and molecular-defined risk stratification of patients. In this regard, the morphological denominator includes a characteristic megakaryocytic proliferation along with variable changes in the granulopoiesis and erythropoiesis. Importantly, diagnosis of MPN requires absence of relevant dysgranulopoiesis or dyserythropoiesis. In terms of clinical practice, the concept of precursor stages provides the possibility of an early intervention by appropriate therapeutic regimens that might prevent fatal complications like thrombosis and haemorrhage, especially in early stages of polycythaemia vera or in primary myelofibrosis. However, the WHO classification is not aimed to capture all biological true cases of MPN or guarantee a complete diagnostic specificity and thus might be in need of continuous improvement following clinical experience.

History of the myeloproliferative neoplasms

The history of haematological malignancies appears to have begun in the sixteenth century as a result of astute clinical observations and the invention of medical microscopy. In the nineteenth century, the use of aniline-based dyes to stain human tissues facilitated the initial recognition of leukaemias, lymphomas, and myelomas as distinct nosological entities. The first detailed description of what is now referred to as chronic myeloid leukaemia, appeared in 1845, and the other ‘classic’ myeloproliferative neoplasms thereafter. Major progress in the therapy and the understanding of these malignancies, however, did not occur until the mid-twentieth century. Since the mid-1990s, these efforts have accelerated remarkably, resulting in the successful introduction of molecularly targeted therapies, and along with increased affordability and reliability of genomic profiling, have helped to usher in the era of precision medicine. In this chapter, we present a brief history of the biological and therapeutic milestones pertaining to myeloproliferative neoplasms.

Stem cell transplantation for BCR-ABL1-positive and negative myeloproliferative neoplasms

The indication to allogeneic stem cell transplantation has changed in the treatment strategy of chronic myeloid leukaemia (CML) and myelofibrosis (MF). The introduction of tyrosine kinase inhibitors has confined the indication to transplant only to the very few CML patients who fail the medical treatment or progress to a blastic phase of the disease. Nonetheless, a distinct group of CML patients still require allogeneic transplant that remains a curable treatment options even for these otherwise incurable patients. On the other hand, the allogeneic transplant activity for myelofibrosis is growing despite the persistent concern about the non-relapse mortality that remains significantly high in most studies and never below 20%. The availability of the new treatment option represented by JAK2 inhibitors hold promise not only for improving the quality of life but also the transplant outcomes of MF patients. However, their use poses new challenges for the most wise and appropriate selection of patients to transplant.

Myelofibrosis

The World Health Organization (WHO) classification defines myelofibrosis (MF) to comprise of the three principal subtypes, primary myelofibrosis, post-polycythaemia vera myelofibrosis, and post-essential thrombocythaemia. Each subtype appears to exhibit a similar pathogenesis, clinical presentation, evolution, and treatment. The critical driver mutations involved in the pathogenesis are be JAK2, MPL, or CALR; mutations in the splicing machinery genes, the epigenome, transcription factors, and dysregulation in the haematopoietic stem cell niche also play pathogenetic roles. Myelofibrosis is a progressive disease, often evolves from a precursor disease state without any clinical symptoms and few laboratory anomalies, to more advanced stages with substantial symptom-burden. Janus kinase (JAK) inhibitors, such as ruxolitinib, afford significant symptomatic benefit, but no major impact on the JAK2 allelic burden, and many patients are offered a risk-adapted approach.

Polycythaemia vera

Polycythaemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis and associated with burdensome symptoms, risk of thrombohaemorrhagic complications, and transformation to myelofibrosis and acute myeloid leukaemia. Diagnostic criteria are very recently revised by the World Health Organization (WHO) based on haemoglobin and haematocrit levels, bone marrow morphology consistent with trilineage proliferation and presence of the JAK2 V617 mutation. Cytoreductive therapy is indicated in patients at increased risk of thrombosis. Hydroxyurea (HU) remains the most commonly used first-line cytoreductive therapy and interferon (IFN) is used either at failure of HU or in selected patients as first-line therapy. A recent phase 3 trial has shown the superiority of the JAK1/2 inhibitor ruxolitinib in comparison to best available treatment in HU-intolerant or resistant patients.

Molecular risk stratification of myeloproliferative neoplasms

Recent advances in understanding the molecular landscape of chronic myeloproliferative neoplasms (MPN) have remarkably improved the diagnostic approach to these disorders. The three phenotypic driver mutations, involving JAK2 (V617F, exon 12 mutations), MPL, and CALR, are major diagnostic criteria in the World Health Organization (WHO) classification, and point to different risk categories. Subclonal mutations in genes of the epigenetic regulation and the spliceosome deserve major prognostication significance and contribute to identify categories of patients with different survival and risk of leukaemia. This chapter will address these aspects and elucidate how mutational analysis may contribute to advanced assessment of MPN patients, as well as its the impact on prognosis for those with MPN.