Myeloid Malignancies

In addition to chemotherapy, which remains the basic treatment, the treatment panel for acute myeloid leukaemia (AML) has expanded considerably in recent years. Clinicians now have a large choice of therapies: targeted therapies (anti-IDH1/2, anti-FLT3, and anti-BCL2 therapies, among others), drugs targeting epigenetic mechanisms, kinase inhibitors (FLT3, MAPK, and JAK2, etc.), immunotherapies (monoclonal antibodies linked or not to a toxin, dual/bispecific), and cellular immunotherapies. Moreover, despite its toxicities, allogeneic transplantation often remains an effective final therapeutic alternative. However, most patients are refractory or relapsed (R/R) after several lines of therapy. Thus, there is a clinical need in AML R/R patients, and CAR-T cells may be an option and can find a place in the treatment to reduce tumour burden and clinical evolution of the disease (Fig. 18.1, modified from Roussel et al. (2020)).


I. Introduction
In December of 2013 the WTC Clinical Centers of Excellence (CCEs) requested that the WTC Health Program review certain myeloid disorders in terms of their status as malignancies. 1 MDS is one type of a group of myeloid malignancies. Therefore, based on the CCEs' request, the Administrator reviewed the available scientific literature and authoritative disease classification sources pertaining to the malignancy of myeloid neoplasms.
The term "myeloid" includes all cells belonging to the granulocyte (i.e., neutrophil, eosinophil, basophil), monocyte/macrophage, erythroid, megakaryocyte, and mast cell lineages. Myeloid malignancies are clonal diseases of hematopoietic stem or progenitor cells. 4 These malignancies can be present in the bone marrow and peripheral blood. They result from genetic and epigenetic alterations that perturb key processes such as self-renewal, proliferation and impaired differentiation. 5,6 Some myeloid disorders, such as the myeloid leukemias, have long been considered malignant while other myeloid disorders have been considered non-malignant or preleukemia blood disorders which may become malignant over time. However, recent scientific findings indicate that these "pre-leukemia" blood disorders are actually forms of slow-growing blood cancers. 7,8 Based on the morphology, cytochemistry, immunophenotype, genetics, and clinical features of myeloid disorders, the World Health Organization (WHO) categorizes myeloid malignancies into five primary types: (1) acute myeloid leukemia; (2) myelodysplastic syndromes (MDS); (3) myeloproliferative neoplasms (MPN); (4) myelodysplastic and myeloproliferative (MDS/MPN) neoplasms; and (5) myeloid neoplasms associated with eosinophilia and abnormalities of growth factor receptors derived from platelets or fibroblasts. The types and subtypes of myeloid malignancies are identified in Table 1 in the Appendix.

A. Myelodysplastic Syndrome and Myeloproliferative Neoplasms
The primary risk factor for MDS is age. The majority of secondary MDS cases occur after treatment for other cancers with radiation therapy or chemotherapy that employs alkylating agents or topoisomerase inhibitors. In addition, several environmental and/or occupational exposures have been associated with increased rates of MDS or cytogenetic abnormalities associated with MDS including pesticides 9 , benzene 10 , organic solvents 11 , semi-metals 12 , and inorganic dusts 13 .
Studies of occupations identified increased incidence of MPN among poultry workers, commercial pressmen, petroleum refinery workers, agricultural workers, cooks/waiters and clerks. Studies of associations with exposure to chemicals such as benzene, petroleum solvents, hair dyes, and pesticides have produced inconsistent results. 14

B. Myeloid Malignancies Other Than AML, MDS and MPN
Information on associations of environmental or occupational exposures for other myeloid malignancies was not found in a Medline search of the relevant medical literature.

III. Clinical and Pathologic Features
The clinical and pathologic features of myeloid malignancies vary according to type.
Acute myeloid leukemia. AML results from the clonal expansion of myeloid blasts in the peripheral blood, bone marrow or other tissue. It is caused when either the myeloid stem cells produce abnormal myeloblasts which do not become healthy white blood cells or too many myeloid stem cells become abnormal red blood cells or platelets. As a result, leukemic blasts, or immature cell forms, accumulate in the bone marrow, peripheral blood, and occasionally in other tissues, and the production of normal red blood cells, platelets, and mature granulocytes are reduced a variable amount. The increased production of malignant cells, along with a reduction in these mature elements, results in a variety of systemic consequences including anemia, bleeding, and an increased risk of infection. 13 Myelodysplastic syndromes. MDSs are a spectrum of bone marrow failure disorders that share the common pathologic feature of cytological dysplasia. They progress to acute myeloid leukemia (AML) in about 30% of patients. MDSs are classified according to features of cellular morphology, cellular and molecular genetics, immunophenotyping, etiology, and clinical presentation. The seven subtypes of MDSs are listed in Table 1 in the Appendix.
The morphological classification of MDSs is largely based on the percent of myeloblasts in the bone marrow and blood, the type and degree of myeloid dysplasia, and the presence of ring sideroblasts. MDSs remain among the most challenging of the myeloid malignancies to diagnose and classify, particularly in cases in which the blast percentage is not increased in the peripheral blood or bone marrow. 13 Myeloproliferative Neoplasms. MPNs are clonal hematopoietic stem cell disorders characterized by proliferation of one or more of the myeloid lineages. The subtypes of myeloproliferative malignancies are identified in Table 1.
Each of these disorders involves dysregulation at the multipotent hematopoietic stem cell (CD34) and clonal myeloproliferation and the absence of dyserythropoiesis, dysgranulopoiesis and monocytosis. Abnormal proliferation among this type arises from specific genetic rearrangements or mutations affecting protein tyrosine kinases or related molecules which produce constitutively active signal transduction pathways. 15 Myeloid neoplasms associated with eosinophilia and abnormalities of growth factor receptors derived from platelets or fibroblasts. These malignancies arise by forming abnormal fusion genes that encode altered surface or cytoplasmic proteins that activate signal transduction pathways. 13,18 The subtypes of myeloid neoplasms associated with eosinophilia and abnormalities of platelet or fibroblast growth factor receptors are listed in Table 1 in the Appendix. Although eosinophilia is characteristic of each subtype, the clinical presentation of each subtype varies. 13,19

IV. Classification
The WTC Health Program uses the International Classification of Diseases Version 9 (ICD-9) coding system for carcinogenic and non-carcinogenic health condition classification. Under the ICD-9 coding system, myelodysplastic and myeloproliferative neoplasms are considered pre-leukemia blood disorders, and therefore were not considered by the WTC Health Program as malignancies. However, since the ICD-9 coding system was developed by the WHO, substantial scientific progress has been made in understanding the behavior of these malignancies. As a result, these health conditions-formerly classified not to be malignancies -are now consider to be malignancies in the newer coding systems such as the International Classification of Diseases for Oncology (ICD-O), which is used for cancer classifications by cancer registries and by the ICD-9 replacement, ICD-10.
In 2000, the World Health Organization (WHO) changed the behavior code for myelodysplastic and myeloproliferative conditions in the ICD-O from 1 (i.e., "uncertain whether benign or malignant") to 3 (i.e., "malignant"). Based on the underlying science that led to the changes in the ICD-O coding system, these neoplasms became reportable to population-based cancer registries, such as the Surveillance, Epidemiology, and End Results (SEER) Program in 2001.
In 2008, the WHO updated the Classification of Tumours of the Haematopoietic and Lymphoid Tissues, a worldwide consensus of hematologic malignancies. The WHO classification system uses the available information on morphology, cytochemistry, immunophenotype, genetics, and clinical features to define clinically meaningful diseases. In this classification system myeloid neoplasms are characterized as malignant.
In making decisions on coverage of myeloid neoplasms, the WTC Health Program is decreasing its reliance on older disease classification systems, such as the ICD-9 coding system, and increasing its reliance on newer authoritative sources, such as ICD-O and ICD-10 coding systems. In addition the WTC Health Program is increasing its reliance on mature scientific information available in the published literature whose significance has been widely acknowledged. This changed emphasis will allow the WTC Health Program to make certification decisions based on more current scientific information.

V. Incidence of Myeloid Malignancies
The other myeloid neoplasms occur at much lower frequencies, but individual incidence rates for each type have not been published. The combined age-adjusted incidence rate for MDSs, MPNs and chronic myelomonocytic leukemia for 2006-10 was 7.8 per 100,000 persons. 22,24 All other myeloid malignancies are very rare, and their precise incidence is unknown at this time.
However, based on the reported incidence of the malignant myeloid malignancies in general, it is reasonable to assume that the combined age-adjusted incidence rate for all myeloid malignancies in the U.S. is less than 15 per 100,000 persons.

VI. Summary of Evidence
Recent scientific advances and authoritative classification sources characterize myeloid neoplasms as slow-growing blood cancers or malignancies. Based on this evidence, the WTC Health Program considers MDSs, MPNs, MDS/MPN, and myeloid neoplasms associated with eosinophilia and abnormalities of growth factor receptors derived from platelets or fibroblasts, to be eligible for coverage under the rare cancers category of covered WTC-related health conditions. Acute myeloid leukemia (AML) is eligible for coverage because it is included in the List of WTC-related health condition.

VII. Certification of Myeloid Malignancies for WTC Health Program Coverage
The WTC Health Program bases coverage decisions for cancer on the WHO disease classification systems. However, classification systems change over time, and even the latest classification systems may not be based on the most recent scientific evidence and diagnostic criteria that contribute to identifying conditions. Consequently, the WTC Program Administrator has determined that reliance on classification systems can inappropriately constrain the decisions of the WTC Health Program and can result in undesired denial of coverage.
Two conditions which have been affected by the reliance on classification systems are Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPN). These disorders had been considered pre-leukemia blood disorders and were not classified as malignant conditions. However, they demonstrate clonal proliferation behavior which is a characteristic used to distinguish between benign and malignant conditions, and the scientific evidence indicates they should be considered forms of slow-growing blood cancers.
To inform certification decisions of myeloid neoplasms the WTC Health Program will use authoritative sources, such as the WHO disease classification system, and mature scientific information available in the published literature whose significance has been widely acknowledged. The WTC Health Program considers MDS, MPN, MDS/MPN, and myeloid neoplasms associated with abnormalities of growth factor receptors to be malignant cancers which can be covered under the rare cancers category of covered WTC-related health conditions. AML is listed as a covered WTC-related health condition.
When a physician from the Clinical Center of Excellence, or the Nationwide Provider Network, determines a neoplasm to be a "myeloid malignancy", the WTC Health Program will consider the myeloid malignancy for certification as a type of leukemia or as a "rare cancer." Each determination of a myeloid neoplasm/malignancy as a WTC-related health condition must be considered for certification under (1) the minimum latency requirements for lymphoproliferative and hematopoietic cancers (including all types of leukemia and lymphoma), 25 and (2) the exposure requirements specified by the WTC Health Program in the WTC-3 Certification Request form.