Page 1353 - Williams Hematology ( PDFDrive )

1328 Part X: Malignant Myeloid Diseases Chapter 86: Primary Myelofibrosis 1329

patients with primary myelofibrosis with pulmonary hypertension by Staging protocols may be useful in comparing concurrent and sequential
the latter’s high-circulating CD34+ cell count, the presence of clonal clinical trial results (see “Course and Prognosis” below). In an individual
platelets and granulocytes, a high frequency of dacryocytes in the blood patient under the care of a clinician experienced in the disease, follow-
film, and a JAK2 V617F mutation. 346 ing the disease for evidence of progression is a very important additional
Metastatic carcinoma, especially derived from carcinoma of breast factor in determining the timing of treatment, even in patients deemed
or prostate 347–352 or disseminated mycobacterial infection, 353,354 can at higher risk by formulaic techniques, especially before introducing
induce reactive marrow fibrosis and occasionally simulate primary mye- allogeneic stem cell transplantation with its morbidity and potential
lofibrosis. Demonstration of metastatic carcinoma cells or mycobacte- mortality in this age group.
ria in the marrow indicates the etiology. Other disorders reported with
secondary myelofibrosis include mastocytosis, 355–358 angioimmunoblas- RED CELL TRANSFUSION
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tic lymphadenopathy, angiosarcoma, lymphoma, 361–363 multiple
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myeloma, 364–366 renal osteodystrophy, hypertrophic osteoarthropa- Patients with severe anemia or with moderate but symptomatic ane-
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thy, gray platelet syndrome, systemic lupus erythematosus, 251–254 mia may require periodic red cell transfusions (Chap. 138). Alternative
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polyarteritis nodosa, hypereosinophilic syndrome, 370,371 kala azar, mechanisms for raising the blood hemoglobin concentration include
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primary thrombocytopenic purpura, thrombotic thrombocytopenic use of recombinant erythropoietin and androgen therapy.
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purpura, tretinoin administration, neuroblastoma, giant lymph
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node hyperplasia, vitamin D-deficiency rickets, 378–381 Langerhans cell RECOMBINANT HUMAN ERYTHROPOIETIN
histiocytosis, acute promyelocytic leukemia, 383,384 and malignant histi- FOR ANEMIA
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ocytosis. Correction or amelioration of the primary disorder can lead Serum erythropoietin levels usually are appropriate to the severity of
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to disappearance of the marrow fibrosis. anemia in patients with myelofibrosis. Thus, use of erythropoietin for
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Lymphoma, 386,387 chronic lymphocytic leukemia, 388,389 hairy cell anemia is, usually, disappointing. In some studies, patients selected by
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leukemia, 342,390 systemic mastocytosis, macroglobulinemia, amyloi- their inappropriately low serum erythropoietin levels (<125 U/L) for
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dosis, 244,245 myeloma, 393,394 malignant teratoma, and essential mono- the degree of anemia, beneficial effects can result. 408,409
clonal gammopathy can coincide with primary myelofibrosis.
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ANDROGENS AND GLUCOCORTICOIDS
TRANSITIONS TO AND FROM FOR ANEMIA
MYELOFIBROSIS AMONG CLONAL Severe anemia may improve with androgen therapy in some patients.
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HEMOPATHIES Testosterone, oxymetholone, and fluoxymesterone have been used but
have virilizing effects. In addition, they have the potential for hepatic
All clonal hematopoietic diseases (AML, CML, oligoblastic myelog- injury and other side effects. Danazol, 600 to 800 mg/day orally for up
enous leukemia [MDS], lymphomas) may have increased marrow to 6 months, can be used. The drug is tapered to the minimum effec-
reticulin fibers but only infrequently have collagen fibrosis. Acute tive dose or discontinued if no significant response occurs. Improve-
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megakaryoblastic leukemia is accompanied by intense marrow fibro- ment may be limited to a decreased frequency of red cell transfusion.
sis (Chap. 88). Approximately 15 percent of patients with polycythemia Androgens often are used after splenectomy if anemia returns and
vera, whether treated by phlebotomy, alkylating agents, or P, develop requires transfusion of red cells. They are more effective in splenecto-
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a clinical state indistinguishable from primary myelofibrosis during mized patients or those with less splenic enlargement. Patients under-
20 years of observation (Chap. 84). 398–400 Essential thrombocythemia going androgen therapy should have periodic assessment of liver size
may evolve into a myelofibrotic stage, estimated to occur in approxi- by physical examination, measurement of liver function tests, and, if
mately 7 percent of cases (Chap. 85). This estimate is complicated by appropriate, ultrasonographic imaging to detect liver injury (e.g., pelio-
the question of whether some cases of essential thrombocythemia actu- sis) or tumors. Evaluation of male patients for prostatic enlargement
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ally were distinguished as early (prefibrotic) primary myelofibrosis. 340,341 or cancer is prudent before starting androgen therapy. Patients with
Sideroblastic anemia has progressed to primary myelofibrosis. Rarely, significant hemolytic anemia may benefit from glucocorticoid therapy.
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primary myelofibrosis reverts to polycythemia vera, with disappearance Prednisone 25 mg/m per day orally can be tried. If tolerated, the dose
of marrow fibrosis. 402,403 Even more rarely, primary myelofibrosis, carry- can be continued for 1 to 2 months and then tapered gradually. In chil-
ing the JAK2 mutation, has undergone clonal evolution to BCR-ABL– dren, high-dose glucocorticoid therapy can ameliorate marrow fibrosis
positive CML or vice versa. 404,405 and improves hematopoiesis. 412,413
THERAPY DRUG THERAPY FOR MYELOPROLIFERATION,
SPLENOMEGALY, OR CYTOPENIAS
DECISION TO TREAT A variety of drugs have been used for treatment of massive splenomeg-
A proportion of asymptomatic patients remains stable for years and they aly, thrombocytosis, or constitutional symptoms.
do not require specific treatment. Constitutional symptoms, anemia,
thrombocytopenia, and splenomegaly are the principal initial reasons JAK2 V617F Kinase Inhibitors
for therapy. A hemoglobin less than 10 g/dL, 12,14,20 a white count less Because JAK2 mutations and the resulting effects on JAK-STAT sig-
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than 4000/μL (4.0 × 10 /L) or greater than 30,000/μL (30.0 × 10 /L), a naling are thought to be a key factor in the clonal expansion leading
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platelet count under 100,000/μL (100 × 10 /L), and blood blasts above to primary myelofibrosis in at least 50 percent of patients, an effort to
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1 percent of total leukocytes 12,20,406 predict more rapid progression of dis- synthesize and test inhibitors of the mutant JAK2 protein product were
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ease. In addition, patients may have a loss of sense of well-being, fatigue, conducted. Early studies of the JAK2 kinase inhibitor TG101209, an
night sweats, loss of weight, low-grade fever, and loss of functionality oral, bioavailable small molecule, and a potent inhibitor of JAK2 kinase,
as a result of the accompanying elaboration of inflammatory cytokines. showed its ability to inhibit JAK2 V617F -dependent phosphorylation of
Kaushansky_chapter 86_p1319-1340.indd 1328 9/18/15 10:24 AM