eMedicine Specialties > Pediatrics: General Medicine > Oncology
Myelodysplastic Syndrome: Treatment & Medication
Updated: May 22, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
- Initially, administer supportive care until the diagnosis is established. Many patients present with profound cytopenia and a notable risk for infection. Initial care may include transfusion support, and the administration of broad-spectrum antibiotics to treat life-threatening anemia, thrombocytopenia, and infection may be required until definitive therapy can be started.
- In patients with refractory cytopenia, HSCT from a matched related or unrelated donor early in the course of the disease is the treatment of choice, especially in those with monosomy 7, 7q-, or complex karyotype. In a cohort of 27 children with refractory cytopenia, Yusuf et al reported an estimated survival probability of 0.74 following various high-intensity conditioning regimens.18 In an Italian study involving 49 children, using the busulfan/cyclophosphamide regimen, the 5-year estimate of event-free survival (EFS) rate was 77%, whereas the 5-year cumulative incidence of transplant-related mortality and disease recurrence were 19% and 2%, respectively. These data indicate that transplant-related mortality represents the main cause of treatment failure. Using a reduced intensity conditioning regimen with fludarabine, Strahm et al reported a pilot study involving 19 children with refractory cytopenia. The 3-year overall survival and EFS were 0.84 and 0.74, respectively.19
- Children with refractory cytopenia and a normal karyotype or chromosomal abnormalities other than aberrations of chromosome 7 and absence of transfusion dependency or severe neutropenia may be carefully observed over time. If cytopenia necessitates treatment, then options include HSCT with either myeloablative or reduced intensity preparative therapies. Some patients may respond to immunosuppressive therapy with cyclosporine and antithymocyte globulin. Yoshimi et al reported a pilot study involving 29 children who received therapy with these agents.20 At 6 months, 22 children had a complete or partial response. Six patients were subsequently transplanted for nonresponse, progression, or evolution of monosomy 7. Overall and failure-free survivals were 89% and 55%, respectively.
- In patients with myelodysplastic syndrome (MDS) who have an increased blast count, allogeneic HSCT is the treatment of choice. Toxicity of the procedure and relapse rate contribute equally to the number of adverse events. A recent study reported 5-year EFS rates of 60% and 47% for HSCT using matched sibling donors or compatible unrelated donors, respectively.21 Whether intensive chemotherapy prior to HSCT should be routinely administered is highly controversial. In the United States and United Kingdom, children with refractory anemia with excess blasts (RAEB) and RAEB in transition to acute myeloid leukemia (AML) are generally included in pediatric AML trials. Most AML studies reported significant morbidity and mortality in patients with MDS, and an overall survival of less than 30%.22,23 Zecca et al reported AML-type therapy prior to HSCT did not prolong survival in 101 children with MDS and an increased blast count.
- In contrast to children, using the International Prognostic Scoring System (IPSS), adults with low-risk MDS can often be monitored for extended periods without specific therapy; however, those with intermediate-risk or high-risk MDS benefit from treatment.
- Currently, the US Food and Drug Administration (FDA) has approved 3 agents for treatment of adult MDS in the past 3 years: azacitidine (Vidaza), decitabine (Dacogen) and lenalidomide (Revlimid). None of these compounds have been approved for the pediatric population.
- In adults, lenalidomide is approved for the treatment of transfusion-dependent anemia in patients with MDS and chromosome 5q deletion. In the pivotal trial, 76% of patients had a 50% or greater reduction in transfusions, with 67% achieving transfusion independence.24 Furthermore, the response of transfusion independence strictly correlated with cytogenetic response. In addition, cytogenetic response had the highest predictive value for prolonged survival in a multivariate analysis, as well as a statistically significant decreased risk for AML progression.
- In the early-phase clinical trials, both azacitidine and decitabine demonstrated impressive response rates (20-40%), including some complete remissions. Results from these studies resulted in large, randomized trials for both agents, which ultimately established these agents as part of the standard medications in the treatment of MDS. In a phase III study of azacitidine, Silverman et al reported an overall response rate of 60% in 191 patients, with 7% complete response, 16% partial response, and 37% hematological response.25 In a phase III study using decitabine, Kantarian et al reported an overall response rate of 17% in 170 patients, with 9% complete response, 8% partial response, and 13% hematological response.26
- Because of the rarity of studies that address MDS as a unique disease entity, the Children's Oncology Group (COG) began a phase II study (AAML0121) that is currently closed due to lack of accrual, which reveals the rarity of de novo MDS in children. In addition, investigators in an open phase I study (ADVL0319) are enrolling patients with relapsed or refractory MDS. Details of these studies can be found on the COG Web site.
- Because MDS is a clonal early stem-cell disorder with very limited residual nonclonal stem cells, myeloablative therapy is the only treatment option with a realistic curative potential. Regimens for hematopoietic stem cell rescue result in a 30-50% EFS rate at 3 years. Outcomes improve in children who are relatively young and who receive hematopoietic stem cell rescue soon after diagnosis. Myeloablative therapy with hematopoietic stem cell rescue from a human leukocyte antigen (HLA)–matched sibling is the best therapy for MDS. For children who do not have an eligible sibling donor, seek alternative donors, although outcome is even less favorable than it is with a sibling donor.
- Growth factors may be indicated.
- Hesitation in using growth factors has been based on the known increased response of myelodysplastic clone to GM-CSF and on the reported associated of the use of G-CSF in children with severe aplastic anemia with the later development of MDS or AML.
- The use of erythropoietin is helpful in patients who have low erythropoietin levels. Recent data from a phase III adult trial by the Eastern Cooperative group (ECOG) showed that erythropoietin treatment improved overall survival in patients responding to the erythropoiesis-stimulating agents compared with the best supportive care management.27 This has also been confirmed by the Nordic and French MDS Study Groups.
- G-CSF has also been used, with a transient improvement in neutropenia.
Surgical Care
- A central line is often needed to administer chemotherapy and transfusions.
- Splenectomy may prove helpful in patients with marked splenomegaly or hypersplenia. No significant change in the EFS rate is noted in patients who are undergoing hematopoietic stem cell rescue.
- The biggest risk is infection, as is the case with any patient who is asplenic.
Consultations
- Pediatric hematologist/oncologist
- Clinical geneticist
- A clinical geneticist may provide an invaluable opinion for many children because of the notable association of MSD with other anomalies.
- Family members of children with monosomy 7 cytogenetics should be evaluated for familial monosomy 7.
Diet
- No dietary restrictions are needed.
- Patients should take adequate amounts of folate and vitamin B-12.
- Limitation of iron intake may be necessary in patients who are transfusion dependent.
Activity
- Activity should be undertaken as tolerated.
- Restriction of activity when platelet counts are low is necessary to prevent hemorrhagic complications from minor trauma.
Medication
Children are treated with a wide variety of drugs. The most frequently used chemotherapeutic agents include idarubicin, dexamethasone, cytarabine arabinoside, fludarabine, etoposide, daunorubicin, L-asparaginase, and thioguanine.
Antineoplastic agents
Cancer chemotherapy is based on an understanding of tumor cell growth and of how drugs affect this growth. After cells divide, they enter a period of growth (G1 phase), followed by DNA synthesis (S phase). The next phase is a premitotic phase (G2 phase). Finally, a phase of mitotic cell division (M phase) occurs.
The rate of cell division varies for different tumors. Most common cancers grow slowly compared with normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant cells, and it is in part the rationale for current cyclic dosage schedules.
Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.Cytarabine (Cytosar-U)
Antimetabolite antineoplastic agent. Converted intracellularly to active compound, cytarabine-5'-triphosphate, which inhibits DNA polymerase. Metabolized in liver with half-life of 1-3 h. Widely distributed, including in CNS and tears after IV administration. Not PO active.
Adult
100-200 mg/m2/d IV qd for 5-7 d; not to exceed 3 g/m2 IV infusion q12h
Pediatric
Administer as in adults
Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase toxicity
Documented hypersensitivity; liver failure
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
If bone marrow suppression notably worsens, reduce number of treatment days; patients with hepatic or renal insufficiencies at increased risk for CNS toxicity after high dose (reduce dose)
Pegaspargase (Oncaspar)
Polyethylene glycol-L-asparaginase. Catabolizes asparagine, essential amino acid for lymphoblast growth. Half-life 2-3 wk.
Adult
2500 IU/m2 IM q14d
Pediatric
Administer as in adults
Increase toxicity with vincristine; may displace highly protein-bound drugs (eg, warfarin); increased bleeding with warfarin, heparin, aspirin, NSAIDs, or dipyridamole
Documented hypersensitivity; pancreatitis; previous thrombosis associated with pegaspargase
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in hypofibrinogenemia, confusion, diabetes mellitus, or hepatic impairment
Fludarabine (Fludara)
2-Fluoro, 5-phosphate derivative of vidarabine. Converted to 2-fluoro-ara-A that enters cell; phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. Half-life of active metabolite is 9 h.
Adult
25-30 mg/m2 qd for 5 d q28d
Pediatric
Administer as in adults
Pentostatin increases risk of pulmonary toxicity; cytarabine administered with or before decreases conversion to active drug
Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Frequently monitor peripheral blood cell counts to detect anemia, thrombocytopenia, and neutropenia; monitor for tumor lysis syndrome; adjust dose in renal impairment, severe bone marrow suppression, severe neurologic effects, or life-threatening or fatal autoimmune hemolytic anemia
Idarubicin (Idamycin)
Anthracycline antineoplastic agent. Inhibits cell proliferation by inhibiting DNA and RNA polymerase. Metabolized in liver to active idarubicinol. Half-life 14-35 h (PO) or 12-27 h (IV). Vesicant.
Adult
12 mg/m2 IV qd for 3 d
Breast cancer: 30-45 mg/m2 PO q3wk
AML: 20-25 mg/m2 qd for 3 d
Pediatric
12 mg/m2 IV qd for 3 d
Trastuzumab increases risk of cardiotoxicity
Documented hypersensitivity; severe CHF; cardiomyopathy; arrhythmias; previous treatment with maximal cumulative doses of other anthracyclines
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Extravasation can result in severe tissue necrosis; caution in preexisting cardiac disease, impaired hepatic or renal function, or myelosuppression; cardiac toxicity is most serious complication
Daunorubicin (Cerubidine)
Anthracycline antineoplastic agent. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs. Half-life 14-20 h (23-40 h for active metabolite).
Adult
25-100 mg/m2 IV qd for 3-5 d intermittent or continuous infusion
Pediatric
Administer as in adults
Trastuzumab increases risk of cardiotoxicity
Documented hypersensitivity; severe CHF; cardiomyopathy; arrhythmias; previous treatment with maximal cumulative doses of other anthracyclines
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Extravasation may occur, resulting in severe tissue necrosis; caution in impaired hepatic, renal, or biliary function; monitor for myelosuppression and, if necessary, decrease dose; may discolor urine (red)
Dexamethasone (Decadron)
Long-acting fluorinated corticosteroid. Induces apoptosis of leukemia cells by means of glucocorticoid receptors. 0.75 mg equivalent to 4 mg methylprednisolone, 5 mg prednisolone, 30 mg hydrocortisone, or 25 mg cortisone.
Adult
0.75-9 mg/d PO q2-4d
0.5-9 mg/d IV qd or divided q6h
Pediatric
0.03-0.15 mg/kg/d PO or 1-5 mg/m2/d PO divided q6-12h; not to exceed 25 mg/m2 IV qd
Phenobarbital, phenytoin, ephedrine, and rifampin may enhance clearance of corticosteroids; coadministration with potassium-depleting diuretics increases risk of hypokalemia; may alter response to warfarin anticoagulants (usually inhibitory but unsubstantiated reports of potentiation have been made); decreases effect of salicylates and vaccines for immunization
Documented hypersensitivity; active bacterial or fungal infection
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
Increases risk of several complications, including severe infections; monitor adrenal insufficiency when tapering; abrupt discontinuation of glucocorticoids may cause adrenal crisis; possible complications of glucocorticoid use are hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections
Thioguanine
Purine analog with antineoplastic and antimetabolite properties.
Adult
40-100 mg/m2 PO qd
Pediatric
2 mg/kg PO qd
Increases busulfan toxicity
Documented hypersensitivity; previous resistance to antitumoral effects
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Adjust dose to compensate for myelosuppression, renal disease, or hepatic disease; may cause neurotoxicity, hyperuricemia, or myelosuppression
Etoposide (VePesid, VP-16)
Semisynthetic podophyllotoxin with poor penetration of CSF. Inhibits topoisomerase II and causes DNA strand breakage, which arrests cell proliferation in late S or early G2 portion of cell cycle. Half-life 4-11 h.
Adult
Low dosage: 20-100 mg/m2/d IV for 5 d
High dosage: up to 3 g/m2 IV qd
Pediatric
Low dosage: 20-100 mg/m2/d IV for 5 d
High dosage: up to 3 g/m2 IV qd
May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in cytotoxicity of tumor cells
Documented hypersensitivity; intrathecal administration (may cause death)
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Bleeding and severe myelosuppression may occur; monitor for hypotension during administration
New antineoplastic agents
As noted in the Treatment section, the following drugs are approved for use in adults with myelodysplastic syndrome (MDS): azacytidine, decitabine, and lenalidomide (for those with 5q- MDS).
Azacitidine (Vidaza)
Pyrimidine nucleoside analog of cytidine. Interferes with nucleic acid metabolism. Exerts antineoplastic effects by DNA hypomethylation and direct cytotoxicity on abnormal hematopoietic bone marrow cells. Hypomethylation may restore normal function to genes critical for cell differentiation and proliferation. Nonproliferative cells are largely insensitive to azacitidine. Indicated to treat MDS in adults. FDA approved for all 5 MDS subtypes.
Adult
75 mg/m2 IV/SC qd for 7 days initially, repeat cycle q4wk; may increase to 100 mg/m2 if no beneficial effect after 2 cycles; treat for a minimum of 4 cycles; treatment may be continued as long as response continues and treatment tolerated
Pediatric
Not established
Limited data exist, none reported
Documented hypersensitivity to azacitidine or mannitol; advanced malignant hepatic tumors
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
While receiving azacitidine, males should avoid fathering children; do not use in breastfeeding women; may cause neutropenia and thrombocytopenia (following first cycle, may require dose adjustment or delay based on nadir counts and hematologic response); caution with hepatic or renal impairment; common adverse effects following SC administration include nausea, vomiting (premedicate for nausea and vomiting before administration), diarrhea, constipation, anemia, thrombocytopenia, leukopenia, neutropenia, pyrexia, fatigue, infection site erythema, and ecchymosis; administer IV over 10-40 min in clinic or hospital setting; common adverse effects following IV administration include petechiae, rigors, weakness, and hypokalemia
Decitabine (Dacogen)
Hypomethylating agent believed to exert antineoplastic effects by incorporating into DNA and inhibiting methyltransferase, resulting in hypomethylation. Hypomethylation in neoplastic cells may restore normal function to genes critical for cellular control of differentiation and proliferation. Indicated for treatment of MDSs, including previously treated and untreated, de novo, and secondary MDSs of all FAB subtypes (ie, RA, RARS, RAEB, RAEBT, CMML) and IPSS groups intermediate-1 risk, intermediate-2 risk, and high risk.
Adult
15 mg/m2 IV q8h for 3 d; infuse over 3 h; repeat q6wk for at least 4 cycles and as long as continued benefit observed
Pediatric
Not established
None reported
Documented hypersensitivity
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Common adverse effects include neutropenia (90%), thrombocytopenia (89%), anemia (82%), pyrexia (53%), fatigue (48%), nausea (42%), cough (40%), petechiae (39%), constipation (35%), and diarrhea (34%); males must avoid fathering children while receiving decitabine and for 2 mo following discontinuation; decrease or delay dose if hematologic recovery requires >6 wk
Lenalidomide (Revlimid)
Indicated for transfusion-dependent MDS subtype of 5q- cytogenetic abnormality. Structurally similar to thalidomide. Elicits immunomodulatory and antiangiogenic properties. Inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.
Adult
10 mg PO qd initially; dose adjustment required if renal impairment, thrombocytopenia, or neutropenia occurs
Pediatric
<18 years: Not established
>18 years: Administer as in adults
Data limited; none reported
Documented hypersensitivity; pregnancy
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Available only through RevAssist, a risk management plan to prevent fetal exposure; only pharmacists and prescribers registered with the program may prescribe and dispense (program requires mandatory pregnancy testing and limits prescription to 1-mo supply via mail); male patients, including those with vasectomy, must use latex condom during sexual contact with female of childbearing potential; women must not become pregnant 4 wk before starting lenalidomide and 4 wk after discontinuing lenalidomide; may cause anemia, DVT, pulmonary embolism, thrombocytopenia, neutropenia, diarrhea, pruritus, rash, and fatigue; renal excretion substantial, caution in elderly patients or those with renal impairment (may need to decrease dose); not break, chew, or open cap
More on Myelodysplastic Syndrome |
| Overview: Myelodysplastic Syndrome |
| Differential Diagnoses & Workup: Myelodysplastic Syndrome |
 Treatment & Medication: Myelodysplastic Syndrome |
| Follow-up: Myelodysplastic Syndrome |
| References |
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Further Reading
Keywords
myelodysplastic syndrome, MDS, MDS, chronic myelomonocytic leukemia, CMML, clonal hemopathy, juvenile chronic myeloid leukemia, JCML, juvenile myelomonocytic leukemia, JMML, monosomy 7, oligoblastic leukemia, preleukemia, refractory anemia, RA, smoldering acute leukemia, acute myelogenous leukemia, acute myeloid leukemia, AML, adult-type MDS, a-MDS, refractory anemia with ringed sideroblasts, RARS, refractory anemia with excess blasts, RAEB, refractory anemia with excess blasts in transition to AML, RAEBT
cytopenia, preleukemia, hematopoietic stem cell transplantation, HSCT, 5q- syndrome, 5q deletion syndrome, infantile monosomy 7, myeloproliferative disorders, bone marrow dysfunction, neurofibromatosis type 1, NF1, cytopenia, short stature, obesity, gonadal failure, hypothyroidism, cataracts, bone marrow failure, lymphadenopathy, therapy-related MDS, Down syndrome, myeloid leukemia of Down syndrome, ML-DS, pancreatic insufficiency, Fanconi anemia, Kostmann syndrome, Diamond-Blackfan anemia, dyskeratosis congenita
