Fewer than 40 cases of primary myelofibrosis have been reported in children; hematopoietic stem cell transplantation is the only available curative therapy for this disease. Here, we describe the case of a female infant diagnosed with primary myelofibrosis at the age of 6 months; she underwent successful matched unrelated bone marrow transplantation with complete resolution of disease. We discuss some unique characteristics of primary myelofibrosis in children and review outcome data for children with this disease

de Oliveira, Satiro

Mitton, Bryan B

Moore, Theodore B

Pullarkat, Sheeja T

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UCLAUCLA Previously Published WorksTitleStem cell transplantation in primary myelofibrosis of childhood.Permalinkhttps://escholarship.org/uc/item/5tn158jcJournalJournal of pediatric hematology/oncology, 35(3)ISSN1536-3678AuthorsMitton, Bryan Bde Oliveira, SatiroPullarkat, Sheeja Tet al.Publication Date2013-04-15 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaStem Cell Transplantation in Primary Myelofibrosis ofChildhoodBryan Mitton, MD, PhD,* Satiro de Oliveira, MD,* Sheeja T. Pullarkat, MD,wand Theodore B. Moore, MD*Summary: Fewer than 40 cases of primary myelofibrosis have beenreported in children; hematopoietic stem cell transplantation is theonly available curative therapy for this disease. Here, we describethe case of a female infant diagnosed with primary myelofibrosis atthe age of 6 months; she underwent successful matched unrelatedbone marrow transplantation with complete resolution of disease.We discuss some unique characteristics of primary myelofibrosis inchildren and review outcome data for children with this disease.Key Words: bone marrow transplant, myelofibrosis, pediatrics(J Pediatr Hematol Oncol 2013;35:e120–e122)CASE DESCRIPTIONThe patient is a 6-month-old white girl who presented to herprimary physician with lethargy and pallor. The patient was a full-term infant born without complications and had no significantmedical issues leading up to presentation. There was no pertinenthematologic or oncologic family medical history, there was noconsanguinity, and she had received all of her vaccinations asscheduled. On examination, she was noted to have pallor andsplenomegaly, but had normal growth parameters. A completeblood count was carried out, which revealed a white blood cellcount of 18,200/mL with the presence of 11% blasts on differential.The hemoglobin was 5 g/dL, and platelets were 34.4109/L.For the initial concern of leukemia, a bone marrow biopsyand aspiration was performed. Histologically, the bone marrowbiopsy showed >90% cellularity and marked fibrosis. The normalhematopoietic elements were difficult to ascertain because of theextensive fibrosis; however, there were scattered foci with a myeloidpreponderance and left-shifted maturation. The erythroid serieswas markedly decreased. Megakaryocytes were not readily identi-fied, and those present were small, hypolobated with hyper-chromatic nuclei with scattered micromegakaryocytes by lightmicroscopy. Increased eosinophils were also present (Figs. 1A, B).A reticulin stain was positive for marked fibrosis (Fig. 1C). Blastswere not increased as shown by CD34 and CD117 immunostains,although with this degree of fibrosis, immunostaining and mor-phologic examinations are typically limited in definitively rulingout the presence of blasts. Staining with Masson-Trichrome stainwas also performed, which showed only scattered, coarse collagenfibers; thus, on a semiquantitative grading of marrow fibrosis, herbiopsy was given a score of MF-2 on a scale of 0 to 3. Flowcytometry also demonstrated no increased blasts. Cytogeneticstudies performed showed a normal female karyotype with noclonal abnormalities. The patient was reevaluated with 2 sub-sequent marrow biopsies in the preceding months, both of whichshowed significant fibrosis on reticulin staining. Analysis per-formed for the BCR-ABL, MPL and JAK2 gene mutations werenegative. There was no evidence of JMML on GM-CFU assay.The patient was managed conservatively over the course ofthe next 5 months. However, her splenomegaly increased to a spanof 7 cm, palpable below the costal margin, and she became trans-fusion dependent for both red blood cells and platelets. After dis-cussion with her family, the decision was made to proceed withhematopoietic stem cell transplantation. Genotyping revealed noHLA-matched individuals in her immediate family, and so anunrelated female bone marrow donor matching at 10 of 10 loci(HLA-A, HLA-B, HLA-C, HLA-DR and HLA-DQ) was selectedfor transplantation. The recipient blood type was O+, the donorwas A+ . The patient was conditioned with 16 doses of busulfan(1mg/kg/dose every 6 h), followed by 4 doses of cytoxan (50mg/kg/dose once per d). After 2 days of rest, the patient received the donorcells at a cell dose of 6.4108 total nucleated cells/kg. The pro-phylaxis selected for graft versus host disease was solumedrol(1mg/kg divided every 12 h) for 1 week, which was tapered untilcessation in the following 2 weeks, and cyclosporine. Cyclosporinewas continued until recovery of the immune cell count and func-tionality. White cell engraftment was successful, with an absoluteneutrophil count stable over 1000 achieved on day 26 posttrans-plant. Platelet transfusions were given to keep the platelet countabove 20109/L during conditioning and through this patient’stransplant course; the transfusions were needed approximatelytwice per week. Platelet transfusions were required until day 35, atwhich point endogenous production yielded platelet counts above20109/L. Platelet counts remained stable above 50109/L by day49. By this point, her spleen was palpable to 4 cm below the costalmargin.This patient’s posttransplant course was benign, with no signsof acute skin, gut, or liver graft versus host disease; there was mildelevation of liver transaminases (alanine transaminase and aspar-tate aminotransferase) that was felt to be more consistent with liverfatty change, which was followed carefully by ultrasonography.Her spleen decreased in size to a palpable span of 1.5 cm below thecostal margin 2 months after transplantation. Ten months aftertransplantation, a mitogen proliferation assay showed normallymphocyte function, with normal T-cell and B-cell counts.Cyclosporine was discontinued. A bone marrow biopsy performed1 year after transplantation showed a normocellular marrow with95% cellularity and normal multilineage hematopoiesis (Figs. 1D,E). There was no evidence of increased fibrosis as confirmed byreticulin staining (Fig. 1F).DISCUSSIONPrimary myelofibrosis is a clonal hematopoietic stemcell neoplasm characterized by clonal myeloproliferationand resultant cytopenias, reactive bone marrow fibrosis,and extramedullary hematopoiesis. It is classified as amyeloproliferative neoplasm according to the 2008 WorldHealth Organization classification system, along with poly-cythemia vera, essential thrombocytosis and a variety ofchronic leukemias.1 In adults, this disease has an incidenceReceived for publication April 19, 2012; accepted January 15, 2013.From the *Department of Pediatrics, Division of Hematology-Oncology,Mattel Children’s Hospital at UCLA; and wDepartment ofPathology, UCLA David Geffen School of Medicine, Los Angeles,CA.The authors declare no conflict of interest.Reprints: Theodore B. Moore, MD, UCLA Pediatric Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, MattelChildren’s Hospital at UCLA, UCLA David Geffen School ofMedicine, 10833 Le Conte Avenue, Los Angeles, CA 90095 (e-mail:tmoore@mednet.ucla.edu).Copyright r 2013 by Lippincott Williams & WilkinsCLINICAL AND LABORATORY OBSERVATIONSe120 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 35, Number 3, April 2013of approximately 1 case per 100,000, and is even rarer inchildren, with <40 cases reported.2 This disease is char-acterized by somatic mutations in JAK2, a member of theJanus Kinase tyrosine protein kinase family, present inapproximately 50% of adults diagnosed with primarymyelofibrosis.3–4 The full effector function of the mutatedJAK2 kinase (JAK2-V617F) remains unclear, although it isproposed that this mutant remains constitutively active andelicits activation of the thrombopoietin, erythropoietin, andgranulocyte colony-stimulating factor receptors in theabsence of their respective ligands.5–6 Although the JAK2mutation is the commonest mutation detected in adults,mutations have been described in a diverse array of proteinsthat play important roles in DNA methylation, apoptosis,protein ubiquitinization, and transcriptional regulation.7Notably, in none of the pediatric cases of primarymyelofibrosis reported to date has a previously describedmutation such as JAK2-V617F been identified, includingthe current case.8–18 There are a number of clues in theliterature, however, that suggest that primary myelofibrosisin children may be a heritable disease, passed down in anautosomal recessive manner; this concept stands in contrastto adults diagnosed with this disease, in whom it appears tobe a disease acquired by somatic mutation. Mallouh andSa’di (1992) first raised this possibility on the basis of theobservation of disease in 3 siblings in one family and 4siblings in another.9,16 In the largest case series published todate, consanguinity was noted in 3 families of affectedchildren, again suggesting that homozygosity is an impor-tant factor in the development of this disease.14 Otherphenotypic differences appear to exist in children diagnosedwith primary myelofibrosis compared with adults, such asthe frequent presence of marrow eosinophilia as seen in thecurrent case, a reduced degree of marrow collagen fibrosis,and the absence of significant osteosclerosis. Moreover, asis evident in the current case, the megakaryocytic dysplasiaseen in pediatric cases include hypolobated megakaryocyteswith hyperchromatic nuclei and micromegakaryocytesunlike the hyperchromatic, smudgy, bulbous “cloud-like”nuclei typically described in adults.14The International Prognostic Scoring System wasdeveloped in 2009; this enables patient risk stratificationand thus guides therapy.19 The independent predictors ofpoor prognosis at the time of presentation include ageabove 65 years, hemoglobin <10 g/dL, white blood cellcount >25,000, circulating blasts >1%, and the presenceof constitutional symptoms. These guidelines were devel-oped in a study that included children in the risk strat-ification analysis, making their application appropriate tothis case. Our patient presented with 3 criteria, placing herin the “high risk” category; the associated median survivalfor this category is 2.3 years according to the InternationalPrognostic Scoring System. Owing to the progressing clin-ical disease and this patient’s poor prognosis, the decisionwas made to proceed with hematopoietic stem cell trans-plantation. To date, reports are available for 17 childrenwho have undergone hematopoietic stem cell trans-plantation.12–18 In these cases, all but 3 children underwentmyeloablative conditioning, and only another 3 wereselected for umbilical cord stem cell transplantations. Fivedeaths have been reported in these children, all secondaryto infectious complications of transplantation, except forFIGURE 1. A composite of bone marrow biopsy histology and stains before (A–C) and after (D–F) matched unrelated bone marrowtransplant. A, Bone marrow biopsy section (100) depicts increased eosinophils and left-shifted myeloid maturation. B, A 400 viewreveals extensive fibrosis with normal hematopoietic elements difficult to assess. C, A reticulin stain showing dense fibrous infiltrationthroughout the biopsy. D, Posttransplant bone marrow biopsy section (100) showing 95% cellularity with normal multilineagehematopoiesis. E, A 400 view details normal trilineage hematopoiesis, normal progressive maturation in the myeloid and erythroidseries, and megakaryocytes with normal morphology. F, A reticulin stain (400) depicts no fibrosis.J Pediatr Hematol Oncol  Volume 35, Number 3, April 2013 HSCT for Myelofibrosisr 2013 Lippincott Williams & Wilkins www.jpho-online.com | e1211 child who died from complications of venoocclusive dis-ease and pulmonary hypertension. All other childrendemonstrated resolution of disease after transplantation. Inthe present case, we demonstrate complete resolution ofprimary myelofibrosis after matched unrelated bone mar-row transplantation. The histology demonstrates resolutionof fibrosis, and immune system counts remain normal andstable. This patient has done quite well, and aside from amild elevation of transaminases and radiologic changesconsistent with fatty liver, she has experienced no trans-plant-related adverse effects.The rarity of this disease in children renders thecharacterization of the pathologic processes that lead to orpredispose to this disorder difficult. The hypothesis thatprimary myelofibrosis may stem from a heritable allele isintriguing; perhaps a previously unrecognized poly-morphism in the JAK2 gene or in a specific set of genescauses this disease. The phenotype and etiology of thisdisease suggest a difference in pathophysiology in childrencompared with that in adults. Regardless, transplantationremains the only available curative therapy. Futureresearch may investigate the underlying signaling aberra-tions that lead to this myeloproliferative neoplasm in chil-dren; these inquiries may also shed light on adult diseaseand on other myeloproliferative neoplasms such as essentialthrombocytosis and polycythemia vera.REFERENCES1. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revisionof the World Health Organization (WHO) classification ofmyeloid neoplasms and acute leukemia: rationale and impor-tant changes. Blood. 2009;114:937–951.2. Mesa R, Silverstein M, Jacobson SJ, et al. Population-basedincidence and survival figures in essential thrombocythemiaand agnogenic myeloid metaplasia: an Olmsted County Study,1976-1995. Am J Hematol. 1999;61:10–5.3. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-functionmutation of JAK2 in myeloproliferative disorders. N Engl JMed. 2005;352:1779–1790.4. Levine RL, Wadleigh M, Cools J, et al. Activating mutation inthe tyrosine kinase JAK2 in polycythemia vera, essentialthrombocythemia, and myeloid metaplasia with myelofibrosis.Cancer Cell. 2005;7:387–397.5. Lindauer K, Loerting T, Liedl KR, et al. Prediction of thestructure of human Janus kinase 2 (JAK2) comprising the twocarboxyterminal domains reveals a mechanism for autoregu-lation. Protein Eng. 2001;14:27–37.6. Luo H, Rose P, Barber D, et al. Mutation in the Jak kinaseJH2 domain hyperactivates Drosophila and mammalian Jak-Stat pathways. Mol Cell Biol. 1997;17:1562–1571.7. Tefferi A. Primary myelofibrosis: 2012 update on diagnosis,risk stratification, and management. Am J Hematol. 2011;86:1017–1026.8. Boxer LA, Camitta BM, Berenberg W, et al. Myelofibrosis-myeloid metaplasia in childhood. Pediatrics. 1975;55:861–865.9. Mallouh AA, Sa’di AR. Agnogenic myeloid metaplasia inchildren. Am J Dis Child. 1992;146:965–967.10. Altura RA, Head DR, Wang WC. Long-term survival ofinfants with idiopathic myelofibrosis. Br J Haematol. 2000;109:459–462.11. Walia MR, Mehta R, Paul P. Idiopathic myelofibrosis withgeneralized periostitis in a 4-year-old girl. J Pediatr HematolOncol. 2005;27:278–282.12. Sekhar M, Prentice HG, Popat U, et al. Idiopathic myelofib-rosis in children. Br J Haematol. 1996;93:394–397.13. Domm J, Calder C, Manes B, et al. Unrelated stem celltransplant for infantile idiopathic myelofibrosis. Pediatr BloodCancer. 2009;52:893–895.14. DeLario MR, Sheehan AM, Ataya R, et al. Clinical,histopathologic, and genetic features of pediatric primarymyelofibrosis - an entity different from adults. Am J Hematol.2012;87:461–464.15. Shaikh F, Naithani R, Kirby-Allen M, et al. Allogeneic cordhematopoietic stem cell transplantation in an infant withprimary myelofibrosis. J Pediatr Hematol Oncol. 2012;34:e199–e201.16. Rossbach HC. Familial infantile myelofibrosis as an autosomalrecessive disorder: preponderance among children from SaudiArabia. Pediatr Hematol Oncol. 2006;23:453–454.17. Cahn JY, Plouvier E, Flesch M, et al. T cell-depletedallogeneic bone marrow transplantation in a case of childhoodidiopathic myelofibrosis. Bone Marrow Transplant. 1987;2:209–211.18. Shankar S, Choi JK, Dermody TS, et al. Pulmonary hyper-tension complicating bone marrow transplantation for idio-pathic myelofibrosis. J Pediatr Hematol Oncol. 2004;26:393–397.19. Cervantes F, Dupriez B, Pereira A, et al. New prognosticscoring system for primary myelofibrosis based on a study ofthe International Working Group for Myelofibrosis Researchand Treatment. Blood. 2009;113:2895–2901.Mitton et al J Pediatr Hematol Oncol  Volume 35, Number 3, April 2013e122 | www.jpho-online.com r 2013 Lippincott Williams & Wilkins

Stem cell transplantation in primary myelofibrosis of childhood.

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