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PubMed2026

Splenic extramedullary hematopoiesis in myelofibrosis is shaped by transcriptomic and epigenetic dysregulation.

Myelofibrosis (MF) is a chronic, progressive myeloproliferative neoplasm characterized by bone marrow fibrosis, ineffective blood cell production, and neoplastic extramedullary hematopoiesis (EMH) occurring primarily within the spleen. To explore the molecular mechanisms underlying splenic EMH, we performed single-cell transcriptional and chromatin profiling of cells from MF spleens that had been surgically removed. We demonstrate significant expansion of hematopoietic stem and progenitor cells, coupled with aberrant differentiation toward the erythroid and megakaryocytic lineages, associated with a significant enrichment of inflammatory pathways with enhanced NF-κB signaling and IFN responses, as well as dysregulation of the inferred function of differentiation-defining transcription factors. Finally, we report a significant remodeling of the immune microenvironment in MF spleens, characterized by emergence of dysfunctional T cell subsets and inflammatory memory B cells, suggesting the concomitant establishment of a pro-inflammatory and immune-tolerant tumor microenvironment within the spleen that influences hematopoietic cell differentiation and impairs tumor immune surveillance.

Primary Myelofibrosis↗
PubMed2026

Efficacy and safety of Ruxolitinib-based combination therapy in the patients with Myelofibrosis (MF): a systematic review and meta-analysis.

BACKGROUND: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm. Although Ruxolitinib, a JAK1/2 inhibitor, remains the cornerstone of MF treatment, it does not reverse disease progression, and resistance frequently emerges. These limitations have prompted investigation into combination therapies targeting pathways beyond the JAK-STAT axis. This meta-analysis aims to evaluate the efficacy and safety of Ruxolitinib-based combination therapies in patients with MF. METHODS: We conducted a systematic search of databases for studies published through August 1, 2025. Thirteen distinct Ruxolitinib-based combination regimens were included. Primary efficacy endpoints were ≥35% spleen volume reduction at 24 weeks (SVR35) and ≥50% reduction in total symptom score (TSS50). Safety endpoints focused on the incidence of grade 3/4 thrombocytopenia and anemia. Subgroup analyses were performed based on prior JAK inhibitor exposure and therapeutic mechanism of action. RESULTS: A total of 19 studies comprising 1,088 patients were included in the meta-analysis. Among JAK inhibitor-naïve patients, the combination of Ruxolitinib with Selinexor demonstrated the highest efficacy (SVR35: 92%; TSS50: 78%), followed by Ruxolitinib plus BMS-986158 (SVR35: 90%). For patients with prior JAK inhibitor exposure, Ruxolitinib plus Siremadlin (SVR35: 45%) showed notable activity. CONCLUSION: For JAK inhibitor-naïve patients, Ruxolitinib-based combination regimens demonstrated satisfactory clinical responses and the potential for meaningful disease control. For patients with prior JAK inhibitor exposure, the addition of combination therapy drugs may further enhance the efficacy. Personalized treatment selection remains essential, as therapeutic efficacy is significantly influenced by prior JAK inhibitor exposure.

Humans↗
PubMed1980

Spinal cord compression with paraplegia in myelofibrosis.

Paraplegia developed in a 70-year-old man with a 15-year history of polycythemia rubra vera and a two-year history of myelofibrosis, due to extensive epidural involvement by extramedullary hematopoiesis. Early diagnosis and aggressive therapy is essential if permanent paralysis is to be avoided.

Adolescent↗
PubMed1996

Acute myelofibrosis terminating in acute lymphoblastic leukemia: case report and review of the literature.

Acute myelofibrosis (AMF), as defined by an acute panmyelopathy associated with marked megakaryocytic hyperplasia and marrow fibrosis, appears to be a stem cell disorder. Even though it is most difficult to distinguish from various myeloproliferative and myelodysplastic disorders as well as acute myelogenous leukemia, it has rarely been reported to terminate as acute lymphoblastic leukemia (ALL). Only five cases have been reported in the literature; two from the pediatric literature and only three from the adult literature. Of the three adult cases, two were defined by light microscopy alone. Among the cases with follow-up (3/5), all died within 2 weeks to 2 months of diagnosis. We report an additional case in an adult; the ALL was defined by morphology, flow cytometric immunophenotyping, and cytogenetic analysis. The interval from diagnosis of AMF to ALL was 3 months. Our patient was treated with standard therapy for ALL, was in complete remission at last follow-up (3 months off maintenance therapy), and represents the only reported case who attained a complete remission. There are too few cases to determine the prognostic significance of termination of AMF in an acute leukemia of lymphoid origin vs. myeloid origin.

Adult↗
PubMed1996

Leukemogenic risk of hydroxyurea therapy in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.

In polycythemia vera (PV), treatment with chlorambucil and radioactive phosphorus (p32) increases the risk of leukemic transformation from 1% to 13-14%. This risk has been estimated to be 1-5.9% with hydroxyurea (HU) therapy. When compared with historical controls, the risk with use of HU does not appear to be statistically significant. The leukemogenic risk of HU therapy in essential thrombocytosis (ET) and in myelofibrosis with myeloid metaplasia (MMM) is unknown. HU remains the main myelotoxic agent in the treatment of PV, ET, and MMM. We studied 64 patients with these three disorders, seen at our institution during 1993-1995. The patients were studied for their clinical characteristics at diagnosis, therapies received, and development of myelodysplasia or acute leukemia (MDS/AL). Forty-two had PV, 15 ET, and 6 MMM, and 1 had an unclassified myeloproliferative disorder. Of the 42 patients with PV, 18 were treated with phlebotomy alone, 16 with HU alone, 2 with p32, 2 with multiple myelotoxic agents, and 2 with interferon-alpha (IFN-alpha). Two patients from the phlebotomy-treated group, one from the HU-treated group, and 1 from the multiple myelotoxic agent-treated group developed MDS/AL. In the larger group, 11 received no treatment or aspirin alone, 18 were treated with phlebotomy alone, 25 with HU, 5 with multiple myelotoxic agents, 2 with p32, 2 with IFN-alpha, and 1 with melphalan. Study of the entire group of 64 patients showed that only one additional patient (total of 5 out of 64) developed MDS/AL. This patient had been treated with HU alone. Statistical analysis did not show any association between clinical characteristics at diagnosis, or HU therapy, and development of MDS/AL (P=0.5). Thus, our data provide no evidence suggestive of increased risk of transformation to MDS/AL with HU therapy in PV, ET, and MMM. Larger, prospective studies are needed to study this issue further.

Acute Disease↗
PubMed1998

Familial idiopathic myelofibrosis and multiple hemangiomas.

Idiopathic myelofibrosis (MF) is a rare disease in childhood. The clinical spectrum is very variable. Familial idiopathic MF has been recorded exceptionally. In previous reports idiopathic MF in childhood has been described in association with congenital anomalies and with chromosome abnormalities, although neither of these features have been reported in a familial context. We report two sisters with idiopathic MF and multiple eruptive hemangiomas. Details of their clinical signs, laboratory findings, and histologic features are described.

Adolescent↗
PubMed1979

Malignant myelosclerosis (acute myelofibrosis): report of two cases following cytotoxic chemotherapy.

Malignant myelosclerosis or acute myelofibrosis is a rare acute myeloproliferative disorder characterized by pancytopenia, myeloblastosis and marrow fibrosis. We describe two patients who developed malignant myelosclerosis after receiving cytotoxic chemotherapy, one for Hodgkin's disease, and the other for membranous nephritis. In view of the known leukemogenic effect of cytotoxic drugs, we presume that chemotherapy played a role in the pathogenesis of malignant myelosclerosis in these two patients.

Acute Disease↗
PubMed1986

Splenic irradiation in the treatment of patients with chronic myelogenous leukemia or myelofibrosis with myeloid metaplasia. Results of daily and intermittent fractionation with and without concomitant hydroxyurea.

Seventeen patients with either chronic myelogenous leukemia (CML) or myelofibrosis with myeloid metaplasia (MMM) received 24 courses of splenic irradiation at this institution from 1973 to 1982. Eleven of the 17 patients had received prior chemotherapy. Patients were treated with 60Co gamma rays or 6 MV photons. The fraction size ranged from 15 to 100 rad and the total dose per treatment course from 15 to 650 rad, with the exception of one patient who received 1650 rad. Fourteen of 19 courses (71%) given for splenic pain yielded significant subjective relief while 17 of 26 courses given for splenomegaly obtained at least 50% regression of splenic size. Blood counts were carefully monitored before each treatment to limit hematologic toxicity. From this experience, the authors conclude that splenic irradiation effectively palliates splenic pain and reverses splenomegaly in the majority of patients with CML and MMM. Intermittent fractionation (twice or thrice weekly) is more convenient for the patient, appears to be as effective as daily treatment, and may be associated with less hematologic toxicity. Preliminary results of concurrent treatment with splenic irradiation and oral hydroxyurea show promise and warrant further study.

Adult↗
PubMed1989

Hodgkin's disease presenting as myelofibrosis.

Four patients with Hodgkin's disease and bone marrow fibrosis are presented in whom the clinical presentation was dominated by cytopenias; this was associated with a delayed diagnosis for an average of 20 months. Despite marrow involvement, chemotherapy resulted in complete remissions and two patients appear to have been cured. Marrow fibrosis resolved at least partially after chemotherapy. The medical literature relevant to bone marrow involvement by Hodgkin's disease is reviewed. Hodgkin's disease should be considered in the differential diagnosis of idiopathic myelofibrosis.

Adult↗
PubMed2005

Long-term follow-up of a patient with idiopathic myelofibrosis associated with chromosome 11 and 13 abnormalities.

A case of a leukemic transformation following a 27-year history of idiopathic myelofibrosis (IMF) is presented. The patient had two chromosomal abnormalities: a deletion of chromosome 13, del 13(q12q14), and a deletion of chromosome 11, del 11(q14q23). This patient's final diagnosis was acute micromegakaryocytic leukemia, and she died 1 month after leukemic transformation with an additional chromosomal abnormality, trisomy 8. IMF with myeloid metaplasia associated with deletion of the long arms of chromosomes 11 and 13 has not been previously reported. We speculate that the leukemic transformation in this patient was associated with chromosomal abnormalities del 11 and trisomy 8.

Bone Marrow↗
PubMed2005

Interphase FISH screening for the LCR-mediated common rearrangement of isochromosome 17q in primary myelofibrosis.

Non-allelic homologous recombination (NAHR) between low-copy repeats (LCRs) has been implicated recently in somatic rearrangements including isochromosome i(17q), which is associated with hematologic malignancies as well as solid tumors. In hematological malignancies, the most common i(17q) breakpoint results from LCR-mediated NAHR, which creates a dicentric chromosome, idic(17)(p11.2). We report an elderly patient who presented with primary myelofibrosis (MF) with myeloid metaplasia (MMM), associated with idic(17)(p11.2) as the sole chromosomal abnormality, making this the first idic(17)(p11.2) myeloproliferative case reported in which the breakpoints are mapped to the breakpoint cluster region in proximal 17p. The rearrangement breakpoint maps to the previously defined LCR cluster, further suggesting that the genomic architecture of proximal 17p may be responsible for the formation of the majority of i(17q) cases. We describe our development of a rapid screening test using interphase FISH to detect idic(17)(p11.2), discuss the potential prognostic value of this molecular diagnostic test, and examine the relevance of LCR-mediated NAHR to common rearrangements in neoplasms.

Aged↗
PubMed2006

Dyspnea secondary to pulmonary hematopoiesis as presenting symptom of myelofibrosis with myeloid metaplasia.

We report a case of a patient with myelofibrosis with myeloid metaplasia (MMM) who presented with progressive dyspnea of unexplained origin. Splenomegaly, blood smear, and bone marrow findings allowed diagnosis of MMM. High-resolution CT chest scan revealed diffuse septal thickening, while echocardiography and electrocardiogram showed no indirect evidence of pulmonary hypertension. Finally, lung biopsy revealed irregularly distributed interstitial fibrosis with islands of erythroblasts, immature granulocytic elements, and dysplastic megakaryocytes, allowing diagnosis of pulmonary extramedullary hematopoiesis (EMH). The patient received hydroxyurea as cytoreductive agent, obtaining a good hematologic response and an improvement of dyspnea. Note that, in this patient, dyspnea was the first clinical symptom of MMM; the dyspnea was not associated with pulmonary hypertension and improved following cytoreductive treatment. This case points to the importance of suspecting pulmonary EMH when unexplained progressive dyspnea occurs in a patient with MMM. Early recognition of pulmonary EMH may prevent PH and favor a better response to therapy.

Biopsy↗
PubMed1978

Increased granulocytic, erythrocytic, and megakaryocytic progenitors in myelofibrosis with myeloid metaplasia.

Nucleated cells obtained from blood and/or bone marrow of patients with myelofibrosis with myeloid metaplasia (MMM) were cultured in diffusion chambers (DC) implanted into the peritoneal cavities of irradiated mice. A total of five blood studies and two bone marrow studies were performed using cells obtained from five patients. The DC were harvested at intervals from the host mice and the total and differential cellularity of DC contents were evaluated. The results obtained from MMM cultures were compared with those from similar cultures of blood cells and marrow cells of four and six normal individuals respectively. The proliferation and maturation of the granulocytic, erythrocytic, and megakaryocytic lines in MMM cultures occurred in an orderly fashion as they occur in vivo. The patterns of proliferation and maturation of the three cell lines in cultures after day 7 suggest that they primarily originate from progenitor cells. The numbers of granulocytes in the multiplicative pool, recognizable red cell precursors, and megakaryocytes recovered were significantly greater from the MMM cultures than those from the normal blood or marrow cultures. These results suggest that the blood and marrow cells of MMM patients have increased numbers of progenitors for granulocytes, erythrocytes, and megakaryocytes.

Adult↗
PubMed1978

Myelofibrosis with complex chromosome abnormality in a patient with erythrocytosis due to hemoglobin Rainier and treated with 32P.

A patient with familial erythrocytosis associated with Hemoglobin Rainier, and previously treated with 32P, developed myelofibrosis with a hyperdiploid chromosome clone in the myeloid cells (51,XX,+1,2q-(q33),+6,+9,+11,-19,+20q+,+mar 1.) This transformation from a benign disorder of differentiated erythrocytes to a malignant disorder may have been secondary to radiophosphorus therapy.

Chromosome Aberrations↗
PubMed1980

Lymphoblastic leukemic transformation (lymphoblastic crisis) in myelofibrosis and myeloid metaplasia.

Acute lymphoblastic leukemia (ALL) developing in myelofibrosis (MF) and myeloid metaplasia (MM) is reported in two patients. In both cases, the clinical course of the "blastic crisis" was rapidly progressive with little response to chemotherapy. The circulating cells were readily identified as lymphoblasts on the basis of cytology, cytochemistry, immunologic studies, and ultrastructure. In one of the cases, 40% of cells had T-cell markers and all cells contained paranuclear acid phosphatase. In the second case, cells had a "Burkitt-like appearance, contained multiple cytoplasmic vacuoles positive for oil red O, and one-third of them had B-cell markers. The development of lymphoblastic crisis in MF and MM occurs rarely, is analogous to blastic transformation in chronic granulocytic leukemia, and supports the hypothesis that myeloproliferative disorders originate from pluripotent hematopoietic stem cells.

Cell Transformation, Neoplastic↗
PubMed1981

Extramedullary blast transformation in the central nervous system in idiopathic myelofibrosis.

Idiopathic myelofibrosis (IM) is a myeloproliferative syndrome characterized by anemia, fibrosis of the bone marrow, variable proliferation of megakaryocytes, myelocytic and erythrocytic precursors, and splenomegaly. Extramedullary hematopoiesis can develop in diverse areas. Unlike in chronic granulocytic leukemia, transformation to acute leukemia is uncommon in IM. Transformation to acute leukemia is usually accompanied by the findings of progressive increase in blasts in peripheral blood or bone marrow [1]. We have recently treated a patient with an unusual transition from IM to acute leukemia in whom leukemic transformation began in the central nervous system.

Central Nervous System Diseases↗
PubMed1985

Diagnostic value of bone marrow imaging with 111indium-transferrin and 99m technetium-colloids in myelofibrosis.

111Indium--transferrin (111In) and 99mTechnetium-colloids (99mTc) bone marrow imaging of 55 myelofibrosis (MF) cases has been compared with clinical, histological, and iron-kinetics data. The best correlations are seen between the splenic uptake of 111In with the spleen/sacrum ratio of 59Fe at the first hour (r = 0.69, P less than 0.001) and also with the splenic erythropoiesis histologically assessed in ten splenectomized patients (r = 0.75, P less than 0.01). Moreover, sacrum uptake of 111In, when compared with sacrum uptake of 59Fe (r = 0.51, P less than 0.001) and with hematopoietic cellularity of the bone marrow (r = 0.57, P less than 0.001) reflects faithfully the hematopoietic cell content of the marrow. Thus, 111In bone marrow imaging provides a noninvasive and useful tool for the diagnosis of myeloid metaplasia in MF. Ferrokinetic studies still appreciate with better insight the amount of ineffective erythropoiesis or hemolysis and remains therefore of great value when splenectomy is discussed.

Adult↗