Pediatric Myelofibrosis Treatment & Management
- Author: J Martin Johnston, MD; Chief Editor: Robert J Arceci, MD, PhD more...
Approach Considerations
Treatment should be directed at the underlying process when childhood myelofibrosis is identified. Therapeutic options include transfusion support, corticosteroids, intravenous (IV) immunoglobulin, interferon alfa, vitamin D, conventional antileukemic chemotherapy (eg, hydroxyurea), and allogeneic bone marrow transplantation (BMT). In addition, splenectomy may be palliative in selected patients.
Treatment with imatinib mesylate (Gleevec) is occasionally effective. Patients who do respond to imatinib sometimes exhibit increased platelet or WBC counts, which in turn require treatment with hydroxyurea or interferon.
Other promising new agents in adult myelofibrosis include thalidomide (alone or in combination with prednisone), lenalidomide, and decitabine.[39]
Vitamin D
Myelofibrosis is observed in some patients with severe vitamin D deficiency. In addition, cases of myelofibrosis associated with essential thrombocythemia or myelomonocytic leukemia, as well as acute (idiopathic) myelofibrosis (IMF), have responded to vitamin D administration.[40, 41]
IV immunoglobulin
An 8-month-old girl with myelofibrosis and dysgranulopoiesis responded to IV immunoglobulin (added to previous corticosteroid therapy).[42] Her disease was unusual and was characterized by a positive Coombs test result and antineutrophil antibodies, suggesting an autoimmune etiology.
Corticosteroids
Corticosteroids have been used to treat many cases of pediatric myelofibrosis, with occasional, apparent successes.[43] However, one concern is that the literature does not always allow for a clear distinction between primary and secondary cases of myelofibrosis. Patients with systemic lupus erythematosus, or even ANLL, might show a response to steroid therapy, although this would be only a temporary effect with the latter diagnosis.[29]
In particular, treatment with high-dose methylprednisolone has been touted as an effective therapy; however, this recommendation is based on a published series of only 5 older pediatric patients (aged 9-14 y), at least one of whom had a positive PPD finding and was also treated with isoniazid.[44]
Thalidomide
For palliation of anemia and thrombocytopenia in adult patients with agnogenic myeloid metaplasia with myelofibrosis (AMMM), the combination of prednisone and thalidomide appears to be reasonably effective.[45]
Among 36 patients with symptomatic AMMM who enrolled in either a trial of single-agent thalidomide (n = 15) or a trial of low-dose thalidomide (50 mg/day) combined with prednisone (n = 21), 20 (56%) showed some improvement.[46] Responses included improvements in anemia (15 of 36 [42%]), thrombocytopenia (10 of 13 [77%]) and splenomegaly (5 of 30 [17%]). The combination of low-dose thalidomide and prednisone was better tolerated and more efficacious than thalidomide alone. After a median follow-up of 25 months, 10 of 36 patients (28%) showed a persistent response, including 8 patients whose protocol treatment had been discontinued for a median of 21 months.
Lenalidomide
Another inhibitor of angiogenesis, this agent has also shown efficacy in adults with myelofibrosis or agnogenic myeloid metaplasia with myelofibrosis (AMMM).[47] Protocol treatment consisted of oral lenalidomide 10 mg daily for 3-24 months, depending on response. Among 68 patients, overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed "impressive" in 8 patients.
Additional observed effects included resolution of leukoerythroblastosis (4 patients), a decrease in medullary fibrosis and angiogenesis (2 patients), and del(5)(q13q33) cytogenetic remission accompanied by a reduction in JAK2(V617F) mutation burden (1 patient). A follow-up report suggested that responses are more likely in patients exhibiting del(5q).[48]
Interferon alfa
Interferon alfa has been used to treat at least 2 adults with acute myelofibrosis and one 14-year-old boy with indolent myelofibrosis. The adolescent patient showed resolution of fibrosis and restoration of blood counts after 6 months of therapy with interferon alfa 3 million IU, 3 times per week.[49] He continued to do well for at least 2 years on a maintenance dose of 2 million IU twice a week.
Two adult males (aged 63 and 71 y) with acute myelofibrosis (and excess blasts) were treated with subcutaneous interferon alfa-2a at doses of 1-6 million IU daily. Both showed resolution of fibrosis. The first patient was maintained on interferon for 12 weeks, but his disease progressed shortly after it was discontinued. After 4 weeks of interferon, the second patient stayed in an unmaintained remission for 4 months before dysplastic hematopoiesis recurred.
Chemotherapy
Conventional chemotherapy, as would otherwise be used to treat acute myeloid/megakaryocytic leukemia, has been used to treat patients with acute myelofibrosis of childhood (C-AMF), under the assumption that C-AMF is a preleukemic condition.
Decitabine, an S-phase specific inhibitor of deoxyribonucleic acid (DNA) methyltransferase, has shown promise in adult patients with myelofibrosis.[50] Pediatric dosing for this drug has not been established, and no literature regarding its use in children with myelofibrosis has been published.
Bone Marrow Transplantation
Allogeneic BMT has been used successfully to treat patients with myelofibrosis.[51] Thirteen adult patients with myelofibrosis (8 primary and 5 associated with either polycythemia vera or essential thrombocytosis) received allogeneic BMTs at the Fred Hutchinson Cancer Research Center.[52] Preparative regimens and donors varied. Four patients died of transplant-related complications. Nine patients were apparent long-term survivors, 2 of whom experienced a relapse and entered a chronic myeloproliferative state.
Published experience from Sweden and Germany demonstrated that reduced-intensity preparative regimens are often effective for treating myelofibrosis and clearly have less treatment-related mortality than do myeloablative regimens.[53, 54]
In a 2009 report from Tennessee, 2 children with infantile myelofibrosis were successfully treated with unrelated hematopoietic stem cell transplantation.[55]
Imatinib
In a published report, 3 of 11 adult patients with idiopathic myelofibrosis (IMF) or postpolycythemic myelofibrosis (PPMF) benefited from treatment with imatinib at a dose of 400 mg/day.[56] Nine patients in the study were in an advanced disease phase. At the time of publication, the patients had been followed for a median of 2 months. Leukocytosis and thrombocytosis were seen in most patients with myelofibrosis during treatment with imatinib. Other reports have been less encouraging.[57]
Combination therapy with hydroxyurea or interferon seems safe and well tolerated and is followed by a decrease in disease activity.
Splenectomy
Some adult patients with agnogenic myeloid metaplasia with myelofibrosis (AMMM) are candidates for splenectomy, but patient selection for this procedure is controversial.[58] Transfusion-dependent anemia, portal hypertension, and/or symptoms of hypercatabolism are potential indications for splenectomy, but the surgery-related mortality rate may be as high as 9%.[59] Similar statistics are not available for pediatric patients.
Splenomegaly alone is not an indication for splenectomy. In adults with symptomatic splenomegaly, irradiation of the spleen is sometimes performed as an alternative to splenectomy.
Placement of a central venous access device may facilitate care in patients requiring complex therapies or frequent transfusions.
Supportive Care and Monitoring
Supportive care of myelofibrosis with transfusions (red blood cells [RBCs], platelets) is crucial to short-term management. Blood products should be leukodepleted (to decrease the likelihood of human leukocyte antigen [HLA] sensitization) and, ideally, cytomegalovirus (CMV) negative.
Prophylaxis against opportunistic infections (eg, fluconazole) may be indicated for some patients with neutropenia.
The Mayo Clinic described a patient-reported outcomes (PRO) instrument designed specifically to assess quality of life in (adult) patients with myelofibrosis.[60]
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