14.          Non-Leukemic Chronic Myeloproliferative Disorders

14.1        General considerations

The non-leukemic chronic myeloproliferative disorders (CMPD) are a group of pre-leukemic disorders characterized by proliferation of one or more lineages of the myelo-erythroid series. The WHO classification of the CMPD recognizes seven entities, including four non-leukemic ones.

• From Vardiman et al

Literature: for review e.g.

      BENCH et al, Best Pract. Res. Clin. Haematol. 14 (2001): 531-551

      CERVANTES, Pathol. Biol. 49 (2001): 148 – 152

• VADIRMAN et al, Blood 100 (2002): 2292 – 2302 (WHO classification of the  myeloid neoplasms)

14.2        Chronic idiopathic myelofibrosis (myelofibrosis with metaplasia, MMM)

General considerations

Myelofibrosis with myeloid metaplasia (MMM) is the designation of a myeloproliferative disorder in which fibrosis of normal bone marrow compartment (occurring in response to an abnormal stem cell clone of megakaryocytic or monocytic origin) is accompanied by extramedullary hematopoiesis in the enlarged spleen, liver and other atypical sites. Massive splenomegaly can also lead to a significant sequestration of erythrocytes and platelets, which exacerbates the underlying cytopenias caused by marrow hypofunction.

Current conventional therapy of MMM has its focus on palliation but has no impact on survival. It includes red blood cell transfusions and treatment of anemia with androgens (nandrolone, oxymetholne, fluoxymesterolone, methandrostenolone, testosterone ethenate). Corticosteroids or erythropoietin. Peripheral signs of hyperproliferation can be treated with hydroxyurea (recommended initial dose 30 mg/kg twice weekly, maintainance dose 500 mg/d ) or interferon alpha (e.g. 5 x 10⁶ IU s.c. 3-5 times weekly, especially for patients < 45 years).

Splenectomy is another palliative procedure in selected patients with progressive transfusion-dependent anemia, painful splenomegaly or hypercatabolic symptoms associated with cytopenia.

Achieving a complete histohematological remission as a prerequisite for a cure is only possible with an allogeneic stem cell transplantation. More recently, preliminary results support the feasibility of reduced- intensity fludarabine- based conditioning prior to allogeneic transplant for older patients.

            Literature: for review e.g.

                        BAROSI, J. Clin. Oncol. 17 (1999): 2954 – 2970 (review)

                        CERVANTES, Pathol. Biol. 49 (2001): 148 – 152  (review)

CERVANTES et al, Br. J. Haematol. 102 (1998): 684 – 690 (allogeneic stem cell transplantation )

DEVINE et al, Blood 99 (2002): 2255-2258 (reduced-intensity conditioning prior to allogeneic stem cell transplantation)

                        GUARDIOLA et al, Blood 93 (1999): 2831 – 2838 (allogeneic stem cell transplantation)

HESSLING et al. Br. J. Haematol. 119 (2002): 769- 772 (reduced- intensity conditioning prior to allogeneic stem cell transplantation)

                        MESA and TEFFERI, Leuk, Lymphoma 42 (2001): 901 – 911 (splenectomy)

                        L1 and DEEG, Leukemia 15 (2001): 465 – 467 (splenectomy)

14.3        Essential thrombocythemia (ET)

14.3.1.                       General considerations

The defining characteristic of essential thrombocythemia (ET) is a sustained elevation of the platelet count above 600000/µl in the untreated patient. Clinically ET is characterized by vasomotor symptoms , thrombohemorrhagic complications, recurrent fetal loss, and tranformation into either chronic idiopathic mylofibrosis (myelofibrosis with myeloid metaplasia ) or acute myeloid leukemia.

About one third of patients are asymptomatic at diagnosis and, untreated, may often remain without complications for years. Present treatment of those patients requiring intervention is a compromise between prevention of ET-related thrombotic and bleeding complications on one hand and avoidance of long-term toxicity on the other hand .

Cytoreduction with hydroxyurea has emerged as the treatment of choice for patients with a a high risk of thrombosis . Because of some concern regarding its potential role in enhancing the risk of leukemic transformation. Hydroxyurea is no longer recommended in young patients at low risk for thrombosis . The more recent availability of nonmutagenic drugs like interferon alpha and anagrelide and the recognition of the role of antiaggregating agents like aspirin in the treatment of microvascular ischemic events has broadened the therapeutic options. Preliminary data indicate that high-dose chemotherapy with hematopoietic stem cell transplantation might be curative for selected patients with advanced disease.

Literature: for review e.g.

            BRIERE and GUILMIN, Pathol. Biol. 49 (2001): 178-183

            GRIESSHAMMER et al, Exp. Opin. Pharmacother. 2 (2001): 385 – 393

            PLATZBECKER et al, Leuk, Lymphoma 43 (2002): 1409 – 1414

            (hematopoietic stem cell transplantation)

            SOLBERG, Semin. Oncol. 29 (Suppl 10 ) (2002): 10 – 15

            TEFFERI, Leuk Res. 25 (2001): 369 – 377

            TEFFERI and MURPHY, Blood Rev. 15 (2001): 121 – 131

14.3.2.                       Hydroxyurea

Literature :

                        FINAZZI and BARBUI, Pathol. Biol. 49 (2001): 167 – 169

                        FINAZZI et al, Br. J. Haematol. 110 (2000): 577 – 583

14.3.3.                       Anagrelide

            Literature:

                        BROOKS et al, Ann, Pharmacother, 33 (1999): 1116 – 1118 , 1121

                        OERTEL, Am. J. Health , Syst. Pharm. 55 (1998): 1979 – 1986

                        SILVERSTEIN and TEFFERI, Semin, Hematol. 36 (Suppl 2) (1999):23 – 25

                        STOREN and TEFFERI, Blood 97 (2001): 863 – 866

14.3.4 Interferon alpha

Literature:

            LENGFELDER et al, Leuk. Lymphoma 22 (Suppl) (1996): 1135 – 1142

14.4.      Polycythemia vera

14.4.1 General considerations

Polycythemia vera (PV) involves a multipotent hematopoietic stem cell and is characterized by an increase in red blood cells, granulocytes and platelets. Erythrocytosis is by far the most prominent clinical manifestation and the cause of its most serious complications like increased risk of thrombosis and abnormal bleeding. Phlebotomy to a hematocrit < 45 %  is the mainstay of treatment for erythrocythemia. The use of a platelet- lowering agent in conjunction with phlebotomy may also be indicated. Cytoreduction with radioactive phosphorus (P32) or alkylating agents is now restricted to patients not younger than 70 years, because of their mutagenicity and leukemogenicity. Newer cytoreductive agents (hydroxyurea, interferon alpha, anagrelide) are increasingly being used but without any clear evidence of superiority. The role of low-dose aspirin as an antithrombotic drug is also under investigation.

Transformation of PV into either myelofibrosis with myeloid metaplasia or acute leukemia remains a major problem that may not be influenced by current palliative therapy. Preliminary data provide some evidence, however, that myeloablative therapy with allogeneic hematopoietic stem cell transplantation can be curative in selected patients with advanced PV.

Literature:

            BERLIN, Expert Rev. Anticancer Ther, 2 (2002): 330 – 336 (review)

            GILBERT, Semin. Hematol, 38 (Suppl 2): (2001): 25 – 28 (review)

PLATZBECKER et al, Leuk. Lymphoma 43 (2002): 1409 – 1414 (curative therapy with hematopoietic stem cell transplantation)

SPIVAK, Blood 100 (2002): 4272 – 4290 and Br. J. Haematol. 116 (2002): 243 – 254 (review)

            TEFFERI, Leuk. Lymphoma 43 (2002): 1- 7 (review)

14.4.2 Hydroxyurea

            Literature :

                        NAJEAN and RAIN, Blood 89 (1997) : 2319 – 2327 and Blood 90 (1997): 3370 –3377

14.4.3 Interferon alpha

Literature:

            FOA et al, Eur. J. Haematol. 60 (1998): 273-277

            LENGFELDER et al, Ann, Hematol. 79 (2000): 103 – 109

            STASI et al, J. Intern. Med. 242 (1997): 143 – 147

14.4.4 Anagrelide

For the reduction of strongly elevated platelet counts. Combination with additional measures to

Control erythropoiesis and granulopoiesis.

Literature:

            PETITT et al, Semin. Hematol. 34 (1997): 51 – 54