Immunotherapy and Myeliod Metaplasia

Authors:
Allen T ,Khoni NS ,Morampudi S
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Abstract

The past few decades have witnessed significant advances in our understanding of the etiology, diagnosis and treatment of Myeloproliferative disorders (MPDs). Although the causes of chronic MPDs remain unknown, Janus kinase 2 (JAK 2) gene mutation is found to be associated. Myelofibrosis with Myeloid metaplasia (MMM) is a rare MPD, characterized by splenomegaly, immature peripheral blood granulocytes and erythrocytes, and teardrop-shaped red blood cells. The identification of the JAK2–V617F mutations in chronic MPDs has stimulated a great deal of effort in screening and developing specific inhibitors for clinical use. Currently, immunotherapies options for MMM include kinase inhibitors, anti-fibrotic therapy, stem cell transplantation, mTOR inhibitor and immunomodulators. While allogeneic stem cell transplantation is curative, rest of the treatment are mostly supportive. This review contributes to existing knowledge of recent therapeutic advances by encapsulating various immunotherapeutic modalities. However, further research is mandated on the effects of such modalities in combination with immunotherapy to witness improved quality of life and better prognosis in patient.

Keywords: MPDs; Myeloid metaplasia; Kinase inhibitors; Stem cells; Immunomodulators

Introduction

Myeloproliferative disorders (MPDs) are classified according to the most affected type of blood cells. There are four main types of MPDs, namely, Polycythemia Vera (PV), Essential thrombocythemia (ET), Myelofibrosis with Myeloid metaplasia (MMM), and Chronic myelomonocytic leukemia (CMML).

MMM (also known as chronic idiopathic myelofibrosis, myelosclerosis with MMM, and idiopathic myelofibrosis) is a rare myeloproliferative disorder, characterized by splenomegaly, immature peripheral blood granulocytes and erythrocytes, and teardrop-shaped red blood cells [1]. The cause of death in MMM includes leukemic transformation (LT) that occurs in 8% to 23% of patients in the first 10 years of diagnosis [2,3]. Annually, it occurs in about 1.5 out of every 100,000 people in the United States. The disease affects both men and women and is usually diagnosed in people over the age of 50. However, MF can occur at any age.

Etiology/Predisposing Factors

The causes of chronic MPDs remain unknown. However, a mutation of a particular gene known as Janus kinase 2 (JAK 2) is found in a large proportion of people with MPDs implying a plausible association. There are several risk factors associated with chronic MPDs. Some of them are [4-7]

Age and Sex

PV is more common in men than in women. The condition is rarely seen in people under the age of 40, but a few cases have been diagnosed among children. CMML is about twice as common in men as in women. The risk of CMML increases with age., with most cases found in people aged 60 and above. The disease is rare in those below 40.

Cancer Treatment

Prior treatment with chemotherapy seems to increase the risk of CMML. The risk of CMML post cancer chemotherapy, however, is not as high as the risk of other blood problems, such as myelodysplastic syndromes and acute myeloid leukemia.

Exposure to petrochemicals

Benzene and Toluene, and ionizing radiation increase the risk of MMM.

Pathophysiology/Molecular basis of MMM

Cytogenetic abnormalities originating on the progenitor cell level are found in MMM, particularly deletions of chromosomes 13q and 20q, trisomy 8 and abnormalities in chromosomes 1, 7 and 9 [8,9]. Several molecular mutations have also been identified.

The JAK2–V617F mutation is present in 50 to 65% of patients with MF [10-12]. Although, JAK2–V617F murine models can summarize a myelofibrotic myeloproliferative disease intricately, experiments done on primary myelofibrosis patient samples suggest that this mutation may not be a disease-initiating event in humans. Other molecular mutations, present to a lesser extent, have been reported in the following genes: myeloproliferative leukemia virus (MPL), LNK, Casitas B-lineage lymphoma (CBL), ten-eleven-translocation 2 (TET2), additional sex-combs-like 1 (ASXL1), isocitrate dehydrogenase (IDH) 1 and 2, IKAROS family zinc finger-1 (IKZF1) and enhancer of zeste homolog 2 (EZH2) [13, 14]. JAK2 and MPL mutations and loss of function of LNK result in the activation of JAK signal transducer activator of transcription (STAT), and induction of MPN-like disease in mice [15, 16]. An activated JAK–STAT pathway promotes the transcription of a plethora of pro-proliferative and antiapoptotic genes [17-19].MMM is also characterized by bone marrow changes induced by cross-communication among clonal stem cells, megakaryocytes, and monocytes with stromal cells, leading to inappropriate cytokine release, myeloproliferation, neoangiogenesis and fibrosis [9]. Excessive releases of cytokines may further result in JAK–STAT activation, resulting in the propagation of the cycle [20].

Immunotherapy in MMM

Kinase Inhibitors

FDA Approved Drug

It is a JAK inhibitor, approved by the FDA. Ruxolitinib specifically binds to and inhibits protein tyrosine kinases JAK 1/2, leading to reduced inflammation and inhibition of cellular proliferation [21].

Indication and Uses

Ruxolitinib is indicated for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-PV myelofibrosis and post-ET myelofibrosis.

PD/PK

Ruxolitinib is rapidly absorbed orally and Cmax is achieved within one to two hours post the dose. The mean volume of distribution at a steady-state is 72 L with an inter-subject variability of 23%, metabolized by CYP3A4, and the mean elimination half-life is approximately three hours.

Contraindication: None

Warning

Thrombocytopenia, anemia and neutropenia, risk of infection, and non-melanoma skin cancer

AE

The most common hematologic adverse reactions are thrombocytopenia and anemia. The most common non-hematologic adverse reactions are bruising, dizziness and headache.

Non-FDA Approved Drug

Momelotinib

It is an orally bioavailable small-molecule inhibitor of JAK1/2 with potential antineoplastic activity. Momelotinib competes with JAK1/2 for ATP binding, inhibits JAK1/2 activation and the JAK–STAT signaling pathway, thereby inducing apoptosis and reducing proliferation of JAK1/2-expressing tumor cells.

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Journal Name:
Clinical Case Reports, Research & Trials

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