Long-term survival of infants with idiopathic myelofibrosis


Dr Rachel A. Altura, Assistant Professor of Hematology/Oncology, Columbus Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA. E-mail: alturar@paediatrics.ohio-state.edu


Idiopathic myelofibrosis can develop in children as well as adults. However, the disease appears to be much more aggressive in adults, being characterized by poor survival rates and a high frequency of malignant transformation. Here, we describe three cases of idiopathic myelofibrosis in infants, two of whom were followed for 16 and 22 years after diagnosis. Neither of these patients required more than minimal supportive care, and both have had spontaneous erythropoietic recovery as early as 2–3 years after diagnosis. There have been no indications of malignant transformation or clinical deterioration. Thus, idiopathic myelofibrosis may have a different pathogenesis and clinical course in infants from adults, requiring a more conservative approach to management.

Idiopathic myelofibrosis (IMF), or agnogenic myeloid metaplasia, is a chronic myeloproliferative disorder with features that include bone marrow fibrosis with prominent progressive reticulin and/or dense collagen deposition, extramedullary haematopoiesis, hepatosplenomegaly, anaemia and a leucoerythroblastic peripheral blood picture ( Ward & Block, 1971). The disorder has an overall poor prognosis in adults despite multimodal therapy ( Anger et al, 1990 ; Visani et al, 1990; Dupriez et al, 1997 ; Reilly et al, 1997 ). Recently, two subgroups of the adult form of disease have been identified and confirmed through clinical studies, showing different life expectancies based on the presence or absence of several clinical features. The ‘short-lived group’ had an average survival time of 2 years whereas the ‘long-lived group’ carried a mean survival time of 10 years ( Cervantes et al, 1997 ; Manoharan, 1998). Interestingly, younger patients (< 64 years) were included in the favourable survival group ( Cervantes et al, 1997 ; Manoharan, 1998). In children, the outcome appears to be even more favourable ( Reid et al, 1988 ; Cetingul et al, 1994 ; Sekhar et al, 1996 ). Here, we describe the clinical characteristics of IMF in three infants, two of whom are long-term survivors. Both of the long-term survivors have required only transient supportive care with blood transfusions and have shown spontaneous partial recovery of haematopoiesis over time with non-progressive fibrosis, whereas the third appears to be following a similar course with a shorter follow-up.

Case reports

The clinical and laboratory features and bone marrow characteristics of the patients are summarized in Table I.

Patient 1

Patient 1, a 17-year-old white woman, was diagnosed as having IMF at 10 months of age. She originally presented at 3 weeks old with an absolute neutrophil count (ANC) of 0·46 × 109/l, which was associated with a presumed osteomyelitis of her right hand. She was treated for 3 weeks with intravenous antibiotics including ampicillin, gentamicin and methicillin, followed by 3 weeks of an oral cephalosporin. She subsequently had persistent neutropenia (average ANC < 1 × 109/l; range 0·80–2·6 × 109/l). At 10 months of age, she was referred to St. Jude Children's Research Hospital (SJCRH) because of a slow decline in haemoglobin (Hb) concentration from 11 to 5 g/dl over 4 months. A peripheral blood smear showed normal red blood cell, white blood cell and platelet morphologies with no basophilia. A bone marrow biopsy revealed hypercellularity with increased granulopoiesis and an increased reticulin content without dysplasia. The karyotype was normal. At 14 months of age, she developed splenomegaly without hepatomegaly. She initially required monthly blood transfusions and had frequent admissions for fever and neutropenia without serious bacterial infections. At 3 years old, she showed spontaneous improvement in erythropoiesis, resulting in haemoglobin levels of 8–10 g/dl. Despite persistent neutropenia, she required few admissions for antibiotic treatment over the next 13 years (average 1 hospitalization per year for i.v. antibiotics for skin infections). At 9 years of age, she developed right femoral head necrosis (Legg–Calvé–Perthes disease) , which resolved after 6 months of treatment with non-steroidal anti-inflammatory agents and immobilization with a leg brace. Annual bone marrow biopsies disclosed hypercellularity (95–100%) and moderate accumulations of reticulin, with a mild increase in megakaryocyte numbers with large size, a tendency to clustering and mild nuclear dysplasia (excess nuclear material with hypersegmentation). Her most recent blood count, at 16 years after presentation, included a WBC of 1·7 × 109/l (ANC 0·24 × 109/l), haemoglobin concentration of 11·4 g/dl and platelet count of 114 × 109/l.

Patient 2

Patient 2, a 22-year-old white man, was diagnosed at 9 months of age with IMF. He presented with anaemia, thrombocytopenia and splenomegaly. His blood count included a haemoglobin concentration of 5·2 g/dl, platelet count of 23 × 109/l and WBC of 7·8 × 109/l with 30% neutrophils and 64% lymphocytes. A review of his peripheral blood smear showed normal red blood cell, white blood cell and platelet morphologies and no basophilia. Bone marrow biopsy specimens showed increased cellularity with increased myeloid progenitors, a lack of dysplasia and an increased reticulin content. The karyotype was normal. Clinically, the patient had frequent nosebleeds and required multiple transfusions of erythrocytes and platelets for the first 3 years of life. At 9 years of age, he was successfully treated with platelet transfusions for lower gastrointestinal tract bleeding. At age 12 years, he had a spontaneous recovery of erythropoiesis, maintaining a haemoglobin concentration of 9·5–13 g/dl since that time. Remarkably, his mucosal bleeding also considerably improved, coincident with erythropoietic recovery. Annual bone marrow biopsies revealed persistent hypercellularity, a mild increase in megakaryocyte numbers, with large size and mild nuclear dysplasia (high N/C) and modest osteosclerosis. At 22 years of age, his WBC was 4·5 × 109/l with 60% neutrophils and 36% lymphocytes, haemoglobin 10·4 g/dl and platelet count 9 × 109/l. He became asymptomatic despite chronic thrombocytopenia and has not required platelet transfusions for more than 10 years.

Patient 3

Patient 3, a 36-month-old white boy, was diagnosed as having IMF at 12 months of age. He was placed on iron therapy for anaemia, without improvement. At 14 months of age, he was hospitalized after an increase in his abdominal girth. At that time, the WBC was 21·7 × 109/l with 24% neutrophils and 43% lymphocytes, haemoglobin concentration 8·3 g/dl and platelet count 40 × 109/l. A bone marrow biopsy revealed granulocytic hyperplasia, megakaryocytic hyperplasia and mild reticulin fibrosis. An abdominal computerized tomography (CT) scan showed hepatosplenomegaly with mesenteric and periportal adenopathy. He then underwent laparotomy with lymph node and liver biopsies. The results showed follicular hyperplasia without fibrosis and portal inflammation of the liver with a small amount of collagen deposition. Serological tests were negative for hepatitis A, B, C, Epstein-Barr virus and cytomegalovirus. Over the following year, anaemia and thrombocytopenia persisted. When referred to SJCRH at 27 months of age, he had significant hepatosplenomegaly (liver 7 cm and spleen 9 cm below the costal margin) without adenopathy. The WBC was 9·7 × 109/l with 25% neutrophils and 51% lymphocytes, haemoglobin concentration 10 g/dl and platelet count, 64 × 109/l. Review of his peripheral blood smear at this time showed normal red blood cell, white blood cell and platelet morphologies with no basophilia. A corresponding bone marrow biopsy specimen showed a hypercellular marrow with an increased reticulin content but no dysplasia. He is asymptomatic despite persistent hepatosplenomegaly; the most recent blood count at age 33 months included a WBC of 12·6 × 109/l with 40% neutrophils and 41% lymphocytes, a haemoglobin concentration of 11·3 g/dl and a platelet count of 155 × 109/l. A corresponding bone marrow biopsy showed mildly increased blasts (5%) with morphologies consistent with myeloblasts and stem cells, a mild clustering of megakaryocytes and normal cytogenetics. He has not required transfusions for anaemia or thrombocytopenia.


Idiopathic myelofibrosis occurs predominantly in older adults at an average age of 65 years of age ( Cervantes et al, 1997 ; Dupriez et al, 1997 ; Reilly et al, 1997 ). It is characterized by anaemia, teardrop red blood cells on peripheral smears, extramedullary haematopoiesis and bone marrow fibrosis in the absence of other pre-existing conditions such as chronic infection, primary marrow malignancy and secondary metastatic disease ( Ward & Block, 1971; McCarthy, 1985). The adult form appears to be a clonal neoplastic disorder, as demonstrated through DNA analysis of all haematopoietic lineages. Abnormalities of growth factor production and immune complex formation have been hypothesized to play an active role in the progression of the disease, including the fibroblast component. Cytogenetic abnormalities, observed in a high frequency of cases (30–75%) at diagnosis with a progressive increase in aberrancies reported at the time of malignant transformation (up to 90% of cases), lend support to a multistep mutagenesis model of the adult disease. In this model, a series of critical mutagenic events occur over time, culminating in the observed leukaemic phenotype.

Given the high rate of leukaemic transformation observed (15%) and the poor overall survival of individuals with this disorder, there has been a concerted effort to identify risk factors in the adult form of this disease. Prognosis has been correlated with increased age ( Barosi et al, 1988 ; Cervantes et al, 1997 ; Dupriez et al, 1997 ; Reilly et al, 1997 ), severity of anaemia ( Barosi et al, 1988 ; Visani et al, 1990; Cervantes et al, 1997 ; Dupriez et al, 1997 ; Reilly et al, 1997 ), thrombocytopenia and the extent of the increase in leucocyte count ( Dupriez et al, 1997 ; Reilly et al, 1997 ). Most recently, karyotypic abnormalities have been reported to be associated with a poor prognosis ( Demory et al, 1988 ; Dupriez et al, 1997 ; Reilly et al, 1997 ). The most common cytogenetic abnormalities reported by one study, occurring in over one-third of patients over 68 years of age, were deleted regions within the long arms of chromosomes 13 and 20 ( Reilly et al, 1997 ).

Fewer than 25 cases of paediatric IMF, none of which had the extent of long-term follow-up detailed here, have been reported ( Lau et al, 1981 ; Cetingul et al, 1994 ; Sekhar et al, 1996; Domingues et al, 1998 ). Furthermore, among a large series of childhood myelodysplastic syndrome–myeloproliferative syndrome cases, IMF was not identified ( Luna-Fineman et al, 1999 ). Most of the early reports of myelofibrosis in childhood involved underlying or associated disorders such as infections, vitamin D-dependent rickets, collagen vascular disease, renal failure, trisomy 21 and preleukaemic syndromes. Although the presenting ages of children with true idiopathic myelofibrosis varied widely, most of the patients had some manifestation of the disease during infancy, suggesting a congenital pathogenesis beginning in utero. Many of the children reported were of Indian or Asian descent, suggesting possible environmental vs. genetic influences. Clinical features of the childhood form of the disease include anaemia (Hb 5–9 g/dl), normal to mildly elevated leucocyte counts (5–35 × 109/l), variable platelet counts (10–1970 × 109/l), extramedullary haematopoiesis with or without splenomegaly and/or hepatomegaly at diagnosis, teardrop poikilocytosis, hypercellular bone marrow with excess reticulin and abnormal megakaryocytes, the absence of marrow dysplasia and a normal bone marrow karyotype. Review of the therapy for paediatric IMF is complicated by the inclusion of cases of pre-existing disorders with associated myelofibrosis. High-dose steroids, interferon α (IFN-α) and bone marrow transplantation (BMT) have been successfully utilized in individual cases with reversal of bone marrow fibrosis documented after IFN and BMT ( Ozsoylu & Ruacan, 1986; Sekhar et al, 1996; Domingues et al, 1998 ). The majority of children diagnosed with the idiopathic form of the disease reported within the last decade, however, have had stable clinical courses, requiring minimal intervention aside from supportive care with blood and platelet transfusions or iron therapy. Additionally, there is one prior report of spontaneous resolution of bone marrow fibrosis and haematological abnormalities after 4 months of observation ( Lau et al, 1981 ). Therefore, the clinical course of IMF in children appears generally less aggressive than in adults with less potential of progression to acute leukaemia, indicating the need for a different therapeutic strategy.

Of the two patients we describe here, one has been followed for 16 years and the other for 22 years from diagnosis. Their courses have been relatively benign, requiring only supportive care in the form of blood transfusions. Both patients had partial haematological recovery, particularly of erythropoiesis, after 2–11 years. The third patient has had a shorter follow-up, but appears to be following a similar course. There was no evidence of teardrop erythrocytes, evolution of dysplastic marrow features, malignant transformation or progressive fibrosis in any of our three cases, nor did any of the patients have associated cytogenetic abnormalities. These observations contrast sharply with the usual ominous course of IMF in adults. Taken together, our clinical and laboratory findings suggest that IMF presenting in infancy may represent a distinct clinical entity compared with the disease in adults. The early appearance of clinical manifestations in these patients is consistent with onset of the disease process in utero, possibly because of genetic damage of a pluripotent haematopoietic stem cell by an unknown mutagen or, alternatively, because of an inherited defect of haematopoietic progenitors. The relatively benign course of IMF in young children may reflect the lack of continuing mutagenic exposures ex utero or could reflect the limited effects of an inherited genetic defect.

Given the relatively benign course of paediatric IMF presenting in infancy, we recommend a conservative approach to clinical management, with more aggressive therapeutic intervention such as allogeneic bone marrow transplant being reserved for children with intractable symptomatic cytopenias or a rising blast count.


We thank Martha Reiman, FNP, for her invaluable assistance in the care of these patients. This study was supported in part by the American Lebanese Associated Charities (ALSAC), St. Jude Children's Research Hospital.