Hematology 425 Myeloproliferative Disorders

1. Hematology 425 Myeloproliferative Disorders Russ Morrison December 1, 2006

2. Myeloproliferative Disorders • MPDs are clonal hematopoietic stem cell diseases that result in expansion and excessive production /overaccumulation of erythrocytes, granulocytes and platelets in some combination in the BM, PB and body tissues • They are considered together because they express common clinical features, laboratory changes and pathogenic similarities

3. Myeloproliferative Disorders • MPDs are classified according to predicted length of the disease as chronic, subacute or acute • The subacute group is termed myelodysplastic processes • The acute diseases are one of the variants in the acute myelogenous leukemia classification group

4. Myeloproliferative Disorders • Chronic MPDs include the chronic myelogenous leukemia, CML, polycythemia vera, PV, essential primary thrombocytopenia, ET, and agnostic myeloid metaplasia, AMM • MPD patients present in a clinically stable phase that may transform to an aggressive cellular growth phase such as acute leukemia • MPD may also manifest a depleted cellular phase such as bone marrow hypoplasia ORR exhibit clinical symptoms and morphology resembling a more aggressive expression of chronic MPD

5. Myeloproliferative Disorders • During the transition to acute leukemia, some patients may show progressive clinical symptoms and morphology similar to subacute MPD processes • MPDs may show familial inheritance where two or more members of a family have similar or different MPD syndromes • Childhood MPDs express as juvenile CML and pediatric myelodysplastic syndrome and are associated with monosomy or deletions of the long arm of C7

6. MPD - CML • CML is a MPD arising as a clonal process in a pluripotential hematopoietic stem cell and manifesting with a chronic clinical phase which in 3-4 years terminates as an accelerated acute phase resembling acute leukemias • CML was discussed in Chapter 34 and is included here to show grouping with the MPDs

7. MPD – Polycythemia Vera, PV • PV is a neoplastic clonal MPD that expresses with panmyelosis in the bone marrow and increases in RBCs, granulocytes and platelets in the PB • Splenomegaly is common • In PV, the clonal stem cells are extremely sensitive to EPO for cell growth • Splenomegaly and hepatomegaly as well as generalized vascular engorgement and circulatory disturbances often increase a patient’s risk for the complications of hemorrhage, tissue infarction or thrombosis

8. MPD – PV • Clinical diagnosis of PV includes • an increased RBC mass • Arterial oxygen saturation of 92% or greater • Splenomegaly • Dx may also be made if one of the above is absent and • Thrombocytosis > 400 x 109/L • WBC > 12 x 109/L without fever or infection or increases in LAP, serum vitamin B12 or unbound vitamin B12 binding capacity

9. MPD – PV – Therapy & Prognosis • Treatments include 32P or alkylating agents • The chemotherapy treatments put the patient at risk for progression to acute leukemia, and are usually avoided • Symptoms may be reduced by blood letting (therapeutic phlebotomy) • Low dose aspirin is often prescribed to reduce the risk of thrombotic complications • There is no cure

10. MPD– Essential Thrombocythemia • Essential thrombocythemia, ET, represents a clonal MPD involving increased megakaryopoiesis with thrombocytosis greater than 600 x 109/L and commonly above 1000 x109/L • The striking feature of the PB is increased platelets, it is also the main change seen in the BM

11. MPD - ET • Patients with ET experience relatively long survival rates provided they remain free from serious thromboembolic or hemorrhagic complications • Clinical symptoms are those seen in vaso-occlusive events including burning sensations in the hands and feet • Other thrombotic symptoms include mottled red areas of the skin, transient ischemic attacks, seizures, and cerebral or myocardial infarction

12. MPD - ET • Other symptoms include headache, dizziness, visual disturbances and dyaesthesias (decreased sensations) • Hemorrhagic complications include bleeding from oral and nasal mucous membrane or GI mucosa and apperiance of cutaneous ecchymoses • Treatment involves prevention or early intervention in hemorrhagic or vaso-occlusive complications which tend to appear as the platelet count rises

13. MPD - ET • Chemotherapy is the same as in PV, but the risks are also the same, progression to acute leukemia, so avoided as last resort • Apheresis may be used to reduce platelet counts • Median survival rates of greater than 10 years is common • Adverse prognosis occurs in patients whose cells manifest chromosomal abnormalities

14. MPD – Agnogenic Myeloid Metaplasia - AMM • AMM expresses with ineffective hematopoiesis, marrow hypercellularity (especially increased megakaryocytes), bone marrow fibrosis, splenomegaly and hepatosplenomegaly • PB exhibits immature granulocytes and nRBCs, teardrop cells are common • Platelets may be normal, increased or decreased with abnormal morphology and micromega-karyocytes • Immune responses are altered in half of patients

15. MPD - AMM • AMM occurs in older patients and presents with symptoms of fatigue, weakness, SOB, palpitations, weight loss, and pain in the LUQ associated with splenomegaly • Average survival is 5 years • Mortality is associated with infection, severe hemorrhage, postsplenectomy complications and transformation to acute leukemia

16. MPD - AMM • AMM is also called myelofibrosis • Is typified by extramedullary hematopoiesis and accumulation of clonal stem cells in the liver, sspleen, adrenals, kidney, lymph node, bowel, breast, lungs, mediastinum, mesentery, skin, synovium, thymus and lower urinary tract as well as in body cavities • Treatment is to alleviate symptoms or modify clinical problems • Splenectomy is performed to end severe pain, reduce the need for transfusion or thrombocytopenia and to correct portal hypertension

17. Lymphoproliferative Disorders • Lymphoproliferative disorder refers to a large group of neoplastic lesions of the lymphoid system including • Hodgkin lymphoma • Non-Hodgkin lymphoma • Plasma cell dyscrasias • Chronic lymphocytic leukemias (CLLs) • Other lymphoid proliferations that behave in an aggressive fashion

18. Lymphoproliferative Disorders • The LPDs are broadly divided into Hodgkin and non-Hodgkin lymphomas • Hodgkin lymphoma is a malignant lymphoproliferative disorder associated with fevers, night sweats and cervical adenopathy • Diagnosis is characterized by the Reed-Sternberg cell

19. Hodgkin Lymphoma • Historically survival rates have been extremely low • Combined chemotherapy and irradiation regimens now result in overall survival and cure rates of at least 80% • Clinical course varies with age and state of disease as well as histologic subtype • Patients are at risk for developing secondary malignancies including solid tumors (breast, lung, bone and soft tissue) as well as acute leukemia, sometimes several years after a “cure”

20. Non-Hodgkin Lymphoma • Non-Hodgkin lymphomas include a varied group of disorders that differ in microscopic appearance, immunologic origin and biologic behavior • Subtypes of malignant lymphoma are are broadly divided into B-cell and T-cell neoplasms

21. Malignant Lymphoma • B-Cell Neoplasms include • Small-Cell Lymphocytic Lymphoma and CLL • Lymphoplasmacytoid Lymphoma or Waldenstrom Macroglobulinemia • Mantle Cell Lymphoma • Follicle Center Lymphoma • Marginal Zone B-Cell Lymphoma • Multiple Myeloma/Plasmacytoma/Monoclonal Gammopathy of Uncertain Significance • Diffuse Large B-Cell Lymphoma • Burkitt Lymphoma

22. Malignant Lymphoma • T-Cell Neoplasms include • Precursor T-Cell Lymphoblastic Leukemia/Lymphoma • Mycosis Fungoides/Sezary Syndrome • Peripheral T-Cell Lymphoma • Anaplastic Large-Cell Lymphoma • Other malignant lymphomas are Histiocytic Lymphoma, Composite Lymphoma and Malignant Lymphoma in the Immunocompromised Patient

23. Malignant Lymphoma • Individuals with AIDS are at risk for lymphoproliferative disorders, especially the high-grade malignant lymphomas • Transplant patients may also develop a wide array of post-transplant lymphoproliferative disorders as a complication of immunosuppression

24. Lymphoproliferative Disorders • The LPDs include a large group of benign and malignant lesions involving the lymphoid system • Malignant processes are frequently derived from a single clone of cells and demonstrate immunologic or molecular features of a clonal proliferation • Appropriate recognition and classification involves integration of clinical and morphologic findings along with immunophenotyping, cytogenetics and molecular diagnostics

25. Myelodysplastic Syndromes • MDS are a group of acquired clonal hematologic disorders characterized by progressive cytopenias in the PB • They reflect defects in erythroid, myeloid, and/or megakarocytic maturation • Occur most frequently in people over age 50 • Seem to be increasing, but it could just be related to the changing demographic and increase in the population of the over 60 age group

26. MDS - Etiology • 3 types of MDS • Primary • Therapy-related • Hereditary • All of the MDS are the result of proliferation of abnormal stem cells • The theory is that the abnormal stem cell is the result of cumulative effects of environmental exposure in susceptible individuals • There seems to be an association with smoking

27. MDS - Etiology • The abnormal stem cell may result from chemical exposure, radiation or viral infection • MDS have a multitude of expressionns, but 2 morphologic findings are common to all types • Presence of progressive cytopenias despite cellular BM • Dyspoiesis in one or more cell lines

28. MDS - Etiology • TR-MDS occurs in patients who have been treated with chemotherapy and/or radiotherapy • Onset of TR-MDS is usually 2-5 years after the therapy was initiated • TR-MDS is often more aggressive and may quickly evolve into AML

29. MDS • Dyserythropoiesis, dysmyelopoiesis and/or dysmegakaryopoiesis may occur in MDS • Cells produced not only have abnormal appearance but also abnormal function • FAB Classification of MDS according to morphologic criteria is listed in table 37-1 • Cell surface markers and gene rearrangement studies available through molecular diagnostics are becoming an integral part of the diagnosis of MDS

30. MDS • Prognosis depends on several factors • Classification • % BM blasts • Cytopenias • Karyotypic abnormalities • Treatment depends on prognosis and often is limited to supportive therapy

31. MDS • Other treatments that have been attempted include chemotherapy and biologic response modifiers • The only cure, currently, for MDS is bone marrow transplantation • Research is currently underway to refine and trial an apoptosis-controlling drug

32. Treatment of Leukocyte Neoplasia • Treatments of blood cancers are diverse and constantly changing • They are the subject of intense research and clinical trials • Criteria used to decide a course of treatment include • Age • Physical condition • Patient’s preference • Expense • Availability of donors (transplants) • Progression or stage of disease • Experimental drugs/trials available

33. Treatment of Leukocyte Neoplasia • Optimization of treatment requires • Accurate diagnosis (type and subtype) • Respect for the patient as an individual (feelings, emotions, finances, family support) • Consideration of all of the alternatives in discussion with the patient and family • If a cure is attainable, it is usually the goal of therapy

34. Treatment of Leukocyte Neoplasia • Cure is a realistic goal in • Early stage Hodgkin and non-Hodgkin lymphoma • Children with ALL • BM transplant is given consideration in CML, AML, ALL and other malignancies where BM transplantation has shown success • CML has had higher success with treatment since the introduction of Gleevec in 2001

35. Treatment of Leukocyte Neoplasia • Unfortunately, for many patients with leukocyte neoplasms, remission is the realistic goal of therapy • Treatment is rigorous and supportive care will make an essential difference in survival and quality of life during treatment • When side effects of therapy cause more morbidity than the neoplasm, it may be more humane to omit therapy in favor of supportive care (transfusions, pain killers, fulfilling end of life wishes)

36. Treatment of Leukocyte Neoplasia • Treatment should be started immediately after diagnosis, but the future of a patient’s life wrapped in treatment decisions cannot be overemphasized • Quality of life must always be considered and the treatment should never be worse than the disease • If treatment is not likely to offer any short- or long-term benefits, the best course may be no treatment at all

37. Treatment of Leukocyte Neoplasia • There are 4 major methods of treating leukocyte neoplasia • Chemotherapy • Radiotherapy • Biologic response modifiers • Bone marrow/peripheral blood stem cell transplantation

38. Chemotherapy • Chemotherapy can be defined as the treatment of cancer with the use of compounds with antitumor properties • Drugs are administered orally of parenterally • Methods of action vary considerably, but can be classified in two ways • By their effect on the cell cycle • By their biochemical mechanism of action

39. Chemotherapy • Phase specific drugs affect specific phases of the cell cycle • Phase nonspecific drugs act without regard to the cell cycle and affect any phase of the cell cycle • Phase nonspecific agents usually have a linear dose-response curve (the higher the dose, the more cells are killed

40. Chemotherapy • 2 subgroups of phase nonspecific agents • Cycle-specific, kill cells that are moving through the cell cycle (alkylating agents, cisplatin) • Cycle-nonspecific agents, wich kill non-dividing cells or cells in the resting state (steroids, antitumor antibiotics) • Chemotherapeutics affect normal and neoplastic cells and are harder on rapidly dividing cells of the mucosa of the GI tract and bone marrow which is a limiting factor in dosage

41. Chemotherapy • Chemotherapy agents are categorized into 5 main groups • Alkylating agents • Ionize within cells forming highly reactive free radicals that damage DNA • Act on any phase of the cell cycle • Include nitrogen mustard, cyclophosphamide, chlorambucil, busulfan, melphalan

42. Chemotherapy • Plant alkaloids • Plant alkaloids (stathmokinetic agents), affect microtubules and interrupt the process of mitotic spindle formation during the metaphase of mitosis • Examples include vincristine and vinblastine

43. Chemotherapy • Antitumor Antibiotics • Compounds derived from living microorganisms • Inhibit RNA or DNA synthesis and interfere with the G2 phase of the cell cycle • Include daunorubicin and doxorubicin

44. Chemotherapy • Antimetabolites • Interfere with the normal functions of various essential metabolites • Examples include methotrexate, folate antagonists, and the purine analogues such as 6-mercaptopurine and 6-thioguanine

45. Chemotherapy • Glucocorticoids • Synthetic or natural steroids include compounds such as hydrocortisone, prednisone, dexamethasone and prednisolone • Have a lympholytic effect and affect nonproliferating cells as well as those in cycle • Protein synthesis and mitosis may also be inhibited • Table 38-1 depicts the chemotherapeutic agents, uses and toxic side effects

46. Radiotherapy • Radiation kills cells by producing unstable ions that damage DNA and cause instant or delayed death of the cell • Used in treatment of Hodgkin and non-Hodgkin lymphoma soon after discovery of X-rays • The hematopoietic system, GI tract and skin are most often affected during radiotherapy • Toxic effects are reversible when radiation is stopped

47. Radiotherapy • Radiation is used most commonly in the treatment of localized malignancies • Chemotherapy is the treatment of choice for diffuse malignancies

48. Biologic Response Modifiers • These are substances produced naturally in the human body that are used to help treat cancer, BRMs • CSF is used to support chemotherapy patients by stimulating rapid production and maturation of WBC lines • CSFs are also used to increase the effectiveness of chemotherapy

49. BRMs • Another important BRM is interferon-α • Interferon-α has been used to induce remissions in hairy cell leukemia, B-cell leukemia and lymphoma, and CML • Interleukin-2 is a cytokine that activates cytotoxic T-cells and is effective in treating thymoma and renal cell carcinoma

50. BRMs • Should be the most desirable of cancer treatments as they are selective without impacting normal cell lines • They should minimize side efffects as they are derived from human and animal sources • So far, BRMs have not been toxic enough to kill the tumor off and the tumor later returns • Research continues with much promise for BRMs