eMedicine Specialties > Hematology > Stem Cells and Disorders
Myeloproliferative Disease: Treatment & Medication
Updated: Feb 13, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
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Treatment
Medical Care
- Treatment of chronic myelogenous leukemia (CML):
- Hematopoietic stem cell transplantation can be considered in young patients with chronic myelogenous leukemia in chronic phase if a human leukocyte antigen (HLA)-matched donor is available.
- Imatinib mesylate (Gleevec), a bcr-abl –specific tyrosine kinase inhibitor, is approved for use in Philadelphia chromosome–positive chronic myelogenous leukemia patients in chronic phase. In one study at 18 months, the complete response rate was 76.2% and the major cytogenetic response rate was 87.1%. Imatinib is also indicated for chronic myelogenous leukemia in blast crisis, accelerated phase, or in chronic phase after interferon alfa therapy failure. This is the treatment of choice for most patients.6
- Interferon alfa, usually administered as a subcutaneous daily injection in a dose of 5 million U, produces hematologic and molecular remissions in some patients with chronic myelogenous leukemia. In these patients, evidence shows that it prolongs survival. Several patients who achieved molecular remissions have survived for more than 10 years.
- Addition of low-dose cytosine arabinoside to interferon alfa has been reported to achieve higher remission rates.
- Patients with chronic myelogenous leukemia who are intolerant of interferon alfa therapy can be treated with hydroxyurea.
- Dasatinib (Sprycel) is indicated for the treatment of adults patients with chronic myeloid leukemia in chronic, accelerated, or myeloid or lymphoid blast phase who are resistant or intolerant to prior therapy including imatinib.
- Nilotinib (Tasigna) is a kinase inhibitor indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia in adult patients resistant to or intolerant to prior therapy including imatinib.
- When the disease progresses to the blast phase, it is treated as acute leukemia, though the outcome is usually grave.
- Treatment of polycythemia vera (PV): Treatment is palliative. Young (<40 y), asymptomatic patients with polycythemia vera can be considered for therapeutic phlebotomies alone to maintain hematocrit level at less than 45%.
- High-risk patients with systemic symptoms, history of thrombosis or bleeding, or high rate of phlebotomies or patients older than 69 years are best treated with myelosuppressive therapy in the form of hydroxyurea.7
- An alternative therapy in older patients is radioactive phosphorous (32P), but this is unsuitable for younger patients because of the potential for causing secondary leukemia.
- Treatment of essential thrombocythemia (ET): Treatment of essential thrombocythemia is meant to relieve symptoms and to prevent complications because no curative modality is available at present. The aim of treatment is to maintain the platelet count within the reference range. This usually can be achieved by hydroxyurea or anagrelide.
- Treatment of myelofibrosis (MF): No curative treatment is available at the present time.
- Asymptomatic patients can be monitored clinically until symptomatic. Hydroxyurea is useful to suppress the number of circulating cells.
- Patients with painful, massively enlarged spleens refractory to myelosuppressive therapy are occasionally treated with radiation therapy, but they may ultimately require splenectomy.
- A few recent reports have shown that allogeneic bone marrow transplantation may be effective in some cases.
- Two case reports suggest that oral bisphosphonates may be beneficial in decreasing bone marrow fibrosis associated with this illness.
Surgical Care
Splenectomy is occasionally required in myelofibrosis for symptomatic relief of pain associated with the massive splenomegaly refractory to medical management.
Consultations
- Surgical consultation for permanent central venous access device placement may be required for patients in whom repeated blood draws, blood transfusions, and/or chemotherapy is anticipated.
- A radiation oncologist may need to be involved in selected cases, when splenic radiation is considered appropriate.
Diet
Massive splenomegaly is usually associated with epigastric and left upper quadrant discomfort and early satiety. Patients with these symptoms are encouraged to eat frequent, small meals rather than 3 large meals.
Activity
Individuals with myeloproliferative diseases are not encouraged to restrict their daily activities, but they are encouraged to refrain from physical activities that might expose them to abdominal trauma because massively enlarged spleens are likely to rupture, sometimes in response to minimal trauma.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Interferons
Interferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha-, beta-, and gamma-interferons may be given topically, systemically, and intralesionally.
Interferon alfa-2a and interferon alfa-2b (Roferon-A, Intron A)
Naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha-, beta-, and gamma-interferons may be administered topically, systemically, and intralesionally. Interferon alfa is recommended for the initial management of low-risk CML. In low-risk CML, significant numbers of patients achieve hematological and molecular remissions. These patients have prolonged survival.
Adult
5 million U SC qd
Pediatric
Not established
Corticosteroids diminish effectiveness; theophylline may increase interferon alfa toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity of interferon alfa
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Perform CBC count and serum chemistry prior to and during therapy; caution in brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or compromised CNS
Antimetabolites
Antimetabolites inhibit cell growth and proliferation.
Hydroxyurea (Hydrea)
Antineoplastic agent provides effective palliative treatment that primarily controls symptoms associated with leukocytosis, thrombocytosis, or hepatosplenomegaly due to MPD. Inhibitor of deoxynucleotide synthesis and DOC for inducing hematologic remission in CML. Less leukemogenic than alkylating agents such as busulfan, melphalan, or chlorambucil. Myelosuppressive effects last a few days to a week and are easier to control than alkylating agents. Busulfan has prolonged marrow suppression and can cause pulmonary fibrosis as well. Can be administered at higher doses in patients with extremely high WBC counts (>300,000) and adjusted accordingly as counts fall and platelet counts drop. Dose can be administered as a single daily dose or divided into 2 or 3 doses at higher dose ranges.
Adult
500-3000 mg PO qd (20-30 mg/kg/d); titrate dose
Discontinue if WBC <2500/µL or platelet count <100,000/µL; recheck in 3 d and resume when values significantly rise toward reference ranges
Pediatric
Not established
Coadministration with fluorouracil can increase neurotoxicity
Documented hypersensitivity, severe anemia or bone marrow suppression, WBC <2500/µL, platelet count <100,000/µL
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal impairment; closely supervise therapy; complete examination of blood, bone marrow, kidneys, and liver prior to and during therapy; perform weekly determination of hemoglobin level and total leukocyte and platelet counts; discontinue if leg ulcers develop
Anagrelide (Agrylin)
Reduces elevated platelet count in patients with essential thrombocythemia and polycythemia vera.
Adult
0.5 mg PO qid (1 mg PO bid)
Pediatric
Not established
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Initially monitor platelet count twice weekly; perform periodic hepatic and renal function tests; vasodilation, tachycardia, palpitations, and CHF may develop
Tyrosine kinase inhibitors
These agents inhibit the activity of bcr-abl tyrosine kinase, resulting in decreased proliferation and increased apoptosis in Ph-positive cell lines.
Imatinib mesylate (Gleevec)
Specifically designed to inhibit tyrosine kinase activity of the bcr-abl kinase in Ph+ leukemic CML cell lines. Used to treat newly diagnosed adult patients with CML or those in blast crisis, accelerated phase, or in chronic phase after failure to interferon alfa therapy. Also indicated to treat pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplant or who have demonstrated interferon alfa resistance. Well absorbed after oral administration, with maximum concentrations achieved within 2-4 hours. Elimination is primarily in feces in form of metabolites.
Adult
Chronic phase: 400 mg/d PO with food and large glass of water; may increase to 600 mg/d if no severe adverse effects or severe non–leukemia-related neutropenia or thrombocytopenia, disease continues to progress (any time), hematologic response is not satisfactory (after at least 3 mo treatment), or a loss of previously achieved hematologic response occurs
Accelerated phase or blast crisis: 600 mg/d PO with food and large glass of water; may increase to 800 mg/d (400 mg bid) if no severe adverse effects or severe non–leukemia-related neutropenia or thrombocytopenia, disease continues to progress (any time), hematologic response is not satisfactory (after at least 3 mo treatment), or a loss of previously achieved hematologic response occurs
Pediatric
260 mg/m2/d PO with food; may increase to 340 mg/m2/d with disease progression in absence of adverse effects
CYP3A4 inhibitors (ketoconazole increases distribution of imatinib); CYP3A4 substrates (simvastatin increases maximum concentration of imatinib by a 2-3.5–fold factor); CYP3A4 inducers (phenytoin decreases AUC by approximately one fifth of typical AUC); likely to increase blood levels of drugs that are substrates of CYP2C9, CYP2D6, and CYP3A4/5
Documented hypersensitivity
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Dose must be reduced or interrupted if edema or anemia occur, transaminases or bilirubin become elevated, or grade 3-4 neutropenia or thrombocytopenia develops; pediatric patients commonly experience musculoskeletal pain
Dasatinib (Sprycel)
Multiple tyrosine kinase inhibitor. Inhibits growth of cell lines overexpressing BCR/ABL. Orphan drug indicated for chronic myeloid leukemia (CML) in individuals resistant to or intolerant of prior therapy (eg, imatinib [Gleevec]). Has been able to overcome imatinib resistance resulting from BCR/ABL kinase domain mutations.
Adult
70 mg PO bid; continue until disease progression or no longer tolerated
Chronic-phase CML: Escalate dose to 90 mg PO bid
Advanced-phase CML: May increase to 100 mg PO bid
Coadministration with CYP3A4 inhibitors: 20-40 mg PO qd
Coadministration with CYP3A4 inducers: May need to increase dose
If clinically viable, an alternate medication with no or minimal enzyme inhibition or induction is recommended
Pediatric
Not established
CYP450 3A4 substrate and inhibitor; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) may increase serum concentrations; CYP3A4 inducers (eg, dexamethasone, phenytoin, rifampin, phenobarbital, carbamazepine, St. John's wort) may decrease serum concentrations coadministration with antacids or other drugs that decrease gastric pH (eg, H2 blockers [famotidine], proton pump inhibitors [omeprazole]) may decrease AUC and Cmax; may increase plasma levels of CYP3A4 substrates (eg, alfentanil, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, ergot alkaloids, simvastatin)
None known
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Adverse effects include fluid retention (including pleural effusion), bleeding, diarrhea, rash, pyrexia, infections, headache, fatigue, and nausea; frequently causes anemia, neutropenia, or thrombocytopenia; because of extensive liver metabolism, caution in patients with hepatic impairment (may need to decrease dose); swallow tab whole, do not crush or cut
Nilotinib (Tasigna)
Inhibits BCR/ABL kinase. In vitro, inhibits BCR/ABL –mediated proliferation of murine leukemic cell lines and human cell lines derived from Philadelphia chromosome–positive chronic myeloid leukemia. Under the conditions of the assays, was able to overcome imatinib resistance resulting from BCR/ABL kinase mutations in 32 of 33 mutations tested. In vivo, shown to reduce tumor size in a murine BCR/ABL xenograft model. Indicated for Philadelphia chromosome–positive chronic myeloid leukemia in adults whose disease has progressed or who cannot tolerate other therapies that include imatinib.
Adult
400 mg PO bid 1 h ac or 2 h pc with water only; administer about 12 h apart; swallow whole (do not chew or crush)
Pediatric
Not established
CYP3A4, CYP2C8, CYP2C9, and CYP2D6 inhibitor; CYP2B6, CYP2C8, and CYP2C9 inducer; coadministration with other drugs known to prolong QT interval (eg, class III antiarrhythmics [amiodarone, dofetilide, sotalol], tricyclic antidepressants, verapamil, erythromycin, moxifloxacin, thioridazine) increases risk of life-threatening arrhythmias and sudden death; avoid coadministration with strong CYP3A4 inhibitors (eg, grapefruit, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), which may increase serum levels, thereby increasing QT interval; avoid coadministration with strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's wort)
Documented hypersensitivity; long QT syndrome; uncorrected hypokalemia or hypomagnesemia
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
May prolong QT interval, leading to life-threatening arrhythmias and possible sudden death; this risk is lowered by taking without food, avoiding grapefruit products, and confirming that potassium and magnesium levels are within normal limits; if QTc >480 milliseconds, withhold and analyze concurrent medications, serum potassium levels, and magnesium levels (reduce dose according to prescribing information); food increases bioavailability, thus administer on empty stomach to avoid elevated serum levels and toxicity; common adverse effects include myelosuppression (obtain CBC count q2wk for 2 mo, then monthly), rash, headache, nausea, and itching; may cause hepatic toxicity, edema, and pancreatitis; females of childbearing potential should use effective contraception; caution in liver impairment; withhold drug with ANC <1 X 109/L, platelet count <50 X 109/L, or serum lipase, amylase, bilirubin, or hepatic transaminase levels >grade 3
More on Myeloproliferative Disease |
| Overview: Myeloproliferative Disease |
| Differential Diagnoses & Workup: Myeloproliferative Disease |
 Treatment & Medication: Myeloproliferative Disease |
| Follow-up: Myeloproliferative Disease |
| Multimedia: Myeloproliferative Disease |
| References |
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References
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Further Reading
Keywords
MPD, polycythemia vera, PV, polycythemia rubra vera, primary thrombocythemia, PT, agnogenic myeloid metaplasia, AMM, chronic myelogenous leukemia, chronic myeloid leukemia, CML, myelofibrosis, MF, acute leukemia, myelodysplastic syndrome, essential thrombocythemia, ET, Budd-Chiari syndrome, chronic idiopathic myelofibrosis, CIM, chronic neutrophilic leukemia, CNL, chronic eosinophilic leukemia, CEL, hypereosinophilic syndrome, HES
