Bone Marrow Transplantation (2004) 34, 273–274. doi:10.1038/sj.bmt.1704578 Published online 31 May 2004

Long-term remission of myelofibrosis following nonmyeloablative allogeneic peripheral blood progenitor cell transplantation in older age: the Scripps Clinic experience

N Greyz1, W E Miller1,2, J Andrey1,2 and J Mason1,2

  1. 1Division of Hematology and Oncology, Scripps Clinic, La Jolla, CA, USA
  2. 2Scripps Blood and Marrow Transplant, Scripps Clinic, La Jolla, CA, USA

Myelofibrosis with myeloid metaplasia (MMM) is classified as a chronic myeloproliferative disorder and this term encompasses idiopathic myelofibrosis (IMF) as well as MMM occurring in patients with a prior history of essential thrombocythemia or polycythemia vera.1 IMF has the worst prognosis among all chronic myeloproliferative diseases (MPD) with a median survival not exceeding 5.5 years.1, 2 Studies have proven that the trilineage proliferation in IMF is of clonal hematopoietic stem-cell origin and that standard therapies are palliative in nature and do not change the natural history of the disease.1 Growing data in the literature support the notion that allogeneic transplantation offers the only potentially curative option in myelofibrosis.3, 4, 5, 6, 7 The majority of patients are diagnosed at age above 60 years and paradoxically this is the group that continues to present a therapeutic dilemma owing to increased toxicity of the conventional myeloablative preparative regimens as well as the suggestion of inferior transplant outcomes in advanced age reported in two largest studies on allogeneic stem-cell transplantation for myelofibrosis.3, 4 Nonmyeloablative conditioning thus represents a promising alternative. There are two small studies on this approach in seven patients with IMF aged 44–58 years5, 6 and no data exist to guide the therapy in a more advanced age group. We hereby describe our experience with nonmyeloablative allogeneic peripheral blood progenitor cell transplantation (PBPCT) in an elderly patient with IMF.

A now 71-year-old male patient was first found to have thrombocythemia in 1996 presenting to a hematologist in 1997 with a platelet count of 730 times 109/l. Other comorbid conditions included essential hypertension and atherosclerotic CAD requiring PTCA and later complicated by dilated cardiomyopathy with an ejection fraction of 45%. The patient was followed with no further treatment until September of 1999 when he developed macrocytic anemia with Hb of 9 g/dl prompting bone marrow biopsy that was consistent with early MPD. By early 2001, the patient's MPD progressed with worsening anemia unresponsive to erythropoietin therapy and constitutional symptoms, including fatigue, night sweats and a 20 pounds weight loss. Physical examination confirmed the emergence of splenomegaly and bone marrow biopsy was classified as IMF with the presence of diffuse reticulin and patchy mature collagen fibrosis (Figure 1a). Peripheral blood review demonstrated leukocytosis of 21.6 times 109 with increased circulating myeloid precursors. Cytogenetic analysis demonstrated normal male karyotype. By June 2001, the patient's LDH rose to above 500 IU/l. An HLA-matched sibling (sister, age 64 years) was identified. Nonmyeloablative preparation (cladribine 0.14 mg/kg/day i.v. days -9 to -5, melphalan 60 mg/m2 i.v. days -6 and -5 and ATG 1.5 mg/kg/day i.v. days -4 to -1 with allogeneic PBPCT on day 0) using a research protocol of the Scripps Blood and Marrow Transplant program was proposed. The cladribine was chosen with the intention of preventing host T-cell-mediated rejection of the allograft given the data showing its ability to inhibit T- and B-cell activation.8 ATG also contributes to the host T-cell ablation and has been used successfully in various hematologic diseases9 as well as in solid organ transplantation. GVHD prophylaxis consisted of a single-agent cyclosporine.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Normalization of bone marrow morphology following PBPCT. The bone marrow before (a) and 2 years after (b) transplantation shows diffuse increase in reticulin fibers (reticulin, times 400) and normal pattern, respectively.

Full figure and legend (538K)

This elderly patient tolerated the conditioning very well with no grade 3 or 4 regimen-related toxicities. He had prompt achievement of neutrophil (day 12) and platelet (day 18) engraftment, comparing favorably with other reported reduced-intensity regimens.6, 7 Red blood cell transfusion independence was reached on day 79. Full donor chimerism was present in the bone marrow and peripheral blood on day 30. Day 100 bone marrow biopsy was consistent with resurgence of normal hematopoiesis and a 2-year bone marrow biopsy showed continued morphologic remission with findings of normal cellularity with trilineage hematopoiesis and no histopathologic features of IMF (Figure 1b). The patient's splenomegaly resolved and he remains free of disease over 3 months post transplant with minimal cGVHD involving oral mucosa that is under excellent control on low-dose cyclosporine and budesonide.

Based on the Dupriez criteria,2 our patient had multiple adverse prognosticators for survival, namely, age >60 years, weight loss, male sex and anemia with Hb <10 g/dl. The severity score (considering Hb and leukocyte count) was intermediate corresponding to a category with a median survival of only 26 months.

We conclude that allogeneic PBPCT following non-myeloablative preparation regimen is well tolerated and can induce prolonged complete remission of myelofibrosis in patients of advanced age and its value as a potentially curative approach in this setting needs to be investigated further.



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