Prognostic significance of bone marrow fibrosis in diffuse large B-cell lymphoma.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas. The aim of this study is to determine the relationship between the increase in the degree of fibrosis in the bone marrow and prognosis and mortality in newly diagnosed DLBCL. METHODS: Bone marrow biopsy of 153 newly diagnosed DLBCL patients was determined by staining with reticulin, Masson's trichrome histochemical stain, and the degree of fibrosis was determined. RESULTS: In the bone marrow biopsy performed at the time of diagnosis, bone marrow fibrosis (BMF) was observed in 70 patients. While BMF-1 was detected in 42 patients (60%), BMF-2 was detected in 25 patients (35%) and BMF-3 was detected in 3 patients (4%). As the degree of BMF increased, the median overall survival and median progression-free survival times were significantly shorter (p: 0.008), (p < 0.001). In patients with an increased degree of BMF, a significant decrease in leukocyte and neutrophil counts was observed after chemotherapy (p: 0.004). According to the results of the multivariate Cox regression model, it was determined that high NCCN-IPI risk (HR: 8.25; %95 CI: 1.09-62.52; p = 0.041) and being BMF ≥ 2 (HR: 3.75; %95 CI: 1.65-8.51; p = 0.002), increased the risk of death (p = 0.002, -2 loglikelihood = 392,553). CONCLUSION: When the literature was reviewed, it was seen that this study was the first to define that bone marrow fibrosis grade 2 and above in DLBCL is a prognostic marker associated with worse survival. In the bone marrow pathology, which is examined to detect advanced disease in DLBCL, besides lymphomatous involvement, the detection of fibrosis grade is very important.

Changes in bone marrow fibrosis during momelotinib or ruxolitinib therapy do not correlate with efficacy outcomes in patients with myelofibrosis.

Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor-naive patients from SIMPLIFY-1 (NCT01969838), a double-blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, p = .350; ruxolitinib, p = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, p = .126; ruxolitinib, p = .407)/symptom (momelotinib, p = .617; ruxolitinib, p = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1-grade BMF improvement (momelotinib, p = .395; ruxolitinib, p = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors.

Incorporating mutations and bone marrow fibrosis into the revised international prognostic scoring system in myelodysplastic syndromes.

The independent prognostic significance of bone marrow fibrosis (BMF) in myelodysplastic syndromes (MDS) is challenged under currently molecular prognostic models. In this study, the clinical and genetic data from 438 MDS patients were analyzed retrospectively. The patients were randomly divided into training (n = 306) and validation (n = 132) cohorts. The independent significant prognostic factors included age, IPSS-R, BMF, TP53 and U2AF1. Using their weighted coefficients, we developed a simplified prognostic system. Four risk groups were produced: low, intermediate, high and very high. The new model yielded more clearly separated survival curves than the IPSS-R. In addition, our model achieved higher C-indexes (0.61 in the training cohort and 0.63 in the validation cohort) than the IPSS-RM model (0.59 and 0.58) and IPSS-R (0.57 and 0.56). In conclusion, BMF was an independent significant prognostic factor for MDS, and adding BMF into the IPSS-R improved its predictive capability.

Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.

Malignant peripheral nerve sheath tumor with hemophilic syndrome and bone marrow fibrosis: A rare case report.

BACKGROUND: Malignant schwannoma is a rare tumor in the peripheral nervous system, accounting for approximately 5% to 10% of systemic soft tissue sarcomas. Especially, malignant schwannoma occurring in the broad ligament of the uterus with hemophilic syndrome and bone marrow fibrosis is extremely rare in clinical practice. Here, we report the first case of an patient diagnosed with malignant peripheral nerve sheath tumor (MPNST) of the broad ligament of the uterus with hemophilic syndrome and bone marrow fibrosis, and share our reference clinical diagnosis and treatment experience. CASE SUMMARY: A patient was diagnosed with MPNST of the uterus harboring hemophilic syndrome and bone marrow fibrosis. She received combination, and repeated imaging revealed further encountered rare complications (hemophilia syndrome and bone marrow fibrosis) after two cycles of chemotherapy. Thereafter, combined treatment with pazopanib, gemcitabine, and dacarbazine was initiated. Unfortunately, the patient succumbed to death at hospital after two weeks. CONCLUSION: This report firstly provided reference clinical practice for a patient with MPNST of the uterus harboring hemophilic syndrome and bone marrow fibrosis. Our case raises a reminder about the tolerance and safety of combination therapy, especially in young women.

La relación entre los parámetros inmunohistoquímicos, la fibrosis de la médula ósea y la captación de 18F-FDG en la médula ósea en pacientes con mieloma múltiple sometidos a examen PET/TC / The relationship between immunohistochemical parameters and bone marrow fibrosis and bone marrow 18F-FDG uptake in multiple myeloma patients undergoing PET/CT examination

Objetivo El objetivo de este estudio fue determinar la potencia del valor de SUVmáx obtenido en la PET/TC con [18F]FDG en pacientes con mieloma múltiple para poder predecir las características del inmunofenotipo (expresión de los antígenos CD20, CD44, CD56, CD117, CD138), fibrosis de la médula ósea, oncogén ciclina D1 y subtipos de proteína M que tienen un papel en el diagnóstico, tratamiento y pronóstico de la enfermedad. Material y método Se incluyeron en el estudio 54 pacientes con mieloma múltiple a los que se les realizó PET/TC para su estadificación inicial, así como biopsia de médula ósea. En estos pacientes se examinó la relación entre el valor de SUVmáx medido en la región del hueso ilíaco y los datos inmunohistoquímicos y de fibrosis de la médula ósea a partir de la biopsia obtenida del hueso ilíaco. Se utilizó la prueba U de Mann Whitney en las comparaciones de grupos apareados dependientes y la prueba H de Kruskal Wallis en las comparaciones entre 3 grupos o más. Resultados El valor medio de SUVmáx fue de 4,5 (1,9-15,6) en pacientes con antígeno CD117 positivo, que fue estadísticamente significativamente superior al valor de los pacientes con CD117 negativo (p=0,031). Cuando la agrupación de pacientes se hizo según el nivel de reticulina, encontramos que la mediana del valor de SUVmáx fue de 4,9 (3,0-14,8) en el grupo con mayor fibrosis y de 3,6 (1,6-15,6) en el grupo con poca fibrosis. La mediana del SUVmáx fue significativamente mayor desde el punto de vista estadístico en el grupo con mayor fibrosis en comparación con el grupo con baja fibrosis (p=0,004). No se determinó diferencia estadísticamente significativa en las comparaciones de los valores de SUVmáx cuando los pacientes se agruparon según las características de cadenas pesada y ligera de la inmunoglobulina, CD20, CD44, CD56 y ciclina D1 (p>0,05) (AU)

Aim The aim of this study was to determine the power of the SUVmax value obtained from 18F-FDG PET/CT in multiple myeloma patients to be able to predict immunophenotype characteristics (CD20, CD44, CD56, CD117, and CD138 antigen expressions), bone marrow fibrosis, cyclin D1 oncogene, and M-protein subtypes which play a role in diagnosis-treatment and prognosis of the disease. Material and method The study included 54 patients with multiple myeloma who underwent PET/CT for initial staging and bone marrow biopsy. The relationship was examined in these patients between the SUVmax value measured from the iliac bone region and the immunohistochemical and bone marrow fibrosis data of the biopsy taken from the iliac bone. The Mann–Whitney U-test was used in the comparisons of dependent paired groups, and the Kruskal–Wallis H test in the comparisons of three or more groups. Results The median SUVmax value was 4.5 (1.9-15.6) in patients with CD117 antigen positivity, which was statistically significantly higher than the value in the patients with CD117 negativity (P=0.031). When patient grouping was made according to the reticulin level: We found that the median SUVmax value was 4.9 (3.0-14.8) in the group with increased fibrosis and 3.6 (1.6-15.6) in the group with low fibrosis. The median SUVmax was statistically significantly higher in the group with increased fibrosis compared to the group with low fibrosis (P=0.004). No statistically significant difference was determined in the comparisons of the SUVmax values when the patients were grouped according to the immunoglobulin heavy chain and light chain, CD20, CD44, CD56, and cyclin D1 characteristics (P>0.05) (AU)

Aggressive chronic lymphocytic leukemia masked by extensive marrow fibrosis.

Chronic lymphocytic leukemia (CLL) is one of the most common B-cell leukemias, occurring because of abnormal proliferation of non-functional B-lymphocytes. Progressive disease is commonly complicated by anemia, thrombocytopenia, infections as well as secondary malignancies. Bone marrow fibrosis is infrequently co-occurred along with CLL. Although multiple explanations have been proposed for this association, the etiology remains unclear in most cases. Bone marrow fibrosis occurring as a complication of CLL itself, however, is a rare entity. We present an uncommon case of a patient initially diagnosed with primary myelofibrosis but later revealed to have aggressive CLL leading to bone marrow fibrosis upon re-evaluation. Treatment for CLL resolved the bone marrow fibrosis completely, confirming our suspicion of fibrosis being secondary to CLL. This sheds light on the importance of understanding the etiology of bone marrow fibrosis in patients with CLL owing to its therapeutic implications. The utility of bone marrow biopsy in not only helping understand the etiology of the fibrosis but also providing prognostic information merits reconsideration of performing it in all cases of CLL.

Benefit of Early Ruxolitinib Initiation Regardless of Fibrosis Grade in Patients with Primary Myelofibrosis: A Post Hoc Analysis of the Single-Arm Phase 3b JUMP Study.

Bone marrow fibrosis (BMF) is an adverse prognostic factor for myelofibrosis (MF). The single-arm, open-label, phase 3b JUMP trial (NCT01493414) assessed the safety and efficacy of the JAK1/JAK2 inhibitor ruxolitinib in patients with symptomatic MF. This post hoc analysis investigated the impact of BMF grade on response and outcomes in patients with primary MF (PMF) from the JUMP study. BMF was assessed by biopsy and graded from 0 to 3; grades 0-1 were considered low-grade fibrosis (LGF) and grades 2-3 were considered high-grade fibrosis (HGF). Patients with LGF (n = 268) had lower rates of cytopenias at baseline but showed comparable disease burden vs. patients with HGF (n = 852). The proportion of patients achieving a spleen response was greater in the LGF group vs. the HGF group at Week 24 and at any time during the study, while overall survival estimates were improved in patients with LGF vs. patients with HGF. Early initiation of ruxolitinib therapy (within 2 years of diagnosis) was associated with increased response rates in all patients. These results highlight the efficacy of ruxolitinib in symptomatic patients with PMF, with the greatest clinical improvements observed in patients with LGF and in patients who received early treatment.

The relationship between immunohistochemical parameters, bone marrow fibrosis and bone marrow 18F-FDG uptake in multiple myeloma patients undergoing PET/CT examination.

PURPOSE: The aim of this study was to determine the power of the SUVmax value obtained from 18F-FDG PET/CT in multiple myeloma (MM) patients to be able to predict immunophenotype characteristics (CD20, CD44, CD56, CD117, CD138 antigen expressions), bone marrow fibrosis, cyclin D1 oncogene, and M-protein subtypes which play a role in diagnosis-treatment and prognosis of the disease. MATERIAL AND METHOD: The study included 54 patients with multiple myeloma who underwent PET/CT for initial staging and bone marrow biopsy. The relationship was examined in these patients between the SUVmax value measured from the iliac bone region and the immunohistochemical and bone marrow fibrosis data of the biopsy taken from the iliac bone. The Mann Whitney U test was used in the comparisons of dependent paired groups, and the Kruskal Wallis H test in the comparisons of three or more groups. RESULTS: The median SUVmax value was 4.5 (1.9-15.6) in patients with CD117 antigen positivity, which was statistically significantly higher than the value in the patients with CD117 negativity (p = 0.031). When patient grouping was made according to the reticulin level; we found that the median SUVmax value was 4.9 (3.0-14.8) in the group with increased fibrosis and 3.6 (1.6-15.6) in the group with low fibrosis. The median SUVmax was statistically significantly higher in the group with increased fibrosis compared to the group with low fibrosis (p = 0.004). No statistically significant difference was determined in the comparisons of the SUVmax values when the patients were grouped according to the immunoglobulin heavy chain and light chain, CD20, CD44, CD56, and cyclin D1 characteristics (p > 0.05). CONCLUSION: In MM patients who underwent PET/CT for initial staging, significant relationships were determined between FDG uptake in the bone marrow (SUVmax) and CD117 antigen and bone marrow fibrosis, which is an important prognostic factor. Higher SUVmax values were determined in the bone marrow of patients with increased fibrosis and CD117 positivity.

Improvement in Primary Autoimmune Myelofibrosis Following a Short Course of Steroids and Intravenous Immunoglobulins.

Bone marrow fibrosis (BMF) is a histopathological finding appreciated in a multitude of conditions such as myeloproliferative diseases and malignant neoplasms, along with autoimmune disorders. Autoimmune myelofibrosis (AIMF) is a particularly uncommon etiology of benign BMF. AIMF may be primary with serologic evidence of autoantibodies or secondary to an underlying autoimmune disease. The authors aim to emphasize the importance of distinguishing between primary versus secondary causes owing to significant prognostic and therapeutic discrepancies and in hopes of expediting the diagnostic journey. Research has recommended a treatment strategy of high-dose steroids followed by a steroid taper. However, our patient responded positively to a short course of high-dose steroids and intravenous immunoglobulins (IVIG) as evidenced by an improvement in cytopenias and bone marrow fibrosis grading. This outcome warrants further research on the necessity of steroid tapers in AIMF.

Significance of bone marrow fibrosis in acute myeloid leukemia for survival in the real-world.

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy characterized by the proliferation of myeloid blasts. Bone marrow fibrosis (BMF), characterized by increased deposition of reticulin or collagen fibers, can occur in AML. International authoritative guidelines do not mention AML patients with BMF and the reported studies are inconsistent. Therefore, we retrospectively analyzed the clinical data of newly diagnosed AML patients in our hospital and compared the clinical characteristics, gene mutations and prognosis of AML patients with or without BMF. We found AML patients with BMF tended to be older, were more prone to hepatosplenomegaly, their level of ß2-MG was higher and they often had karyotypes associated with a poor prognosis. The proportion of AML patients without BMF was high in the intermediate-risk group and low in the high-risk group. The mutation rates of ASXL1 and TET2 genes were higher and that of CEBPA was lower in the BMF group. Multivariate analysis showed BMF had independent prognostic significance. AML patients without BMF had higher CR/CRi rate, and the time of hematopoietic recovery in patients achieving CR/CRi was longer in BMF group. The degree of BMF, prognostic level and blasts in peripheral blood were independent risk factors for CR/CRi in newly diagnosed AML. AML patients in the BMF group, especially those with BMF ≥ 2, had a lower OS rate. In age<60 years old group, the higher the degree of BMF was, the shorter the median survival time and the lower the OS rate. In age ≥ 60 years old group, the median survival time in the BMF-1 and the BMF-2/3 groups was shorter. For AML with low, intermediate and high risk, there was always a lower OS rate in patients with BMF. The median survival of AML patients decreased with an increasing degree of BMF in different risk stratifications. BMF had no effect on OS of AML patients with HSCT. In conclusion, AML patients with BMF have a poor prognosis, and BMF was an independent prognostic factor for OS. The assessment of BMF was of great significance for the treatment efficacy and prognosis of newly diagnosed AML.

Tracking fibrosis in myeloproliferative neoplasms by CCR2 expression on CD34+ cells.

In myeloproliferative neoplasm (MPNs), bone marrow fibrosis - mainly driven by the neoplastic megakaryocytic clone - dictates a more severe disease stage with dismal prognosis and higher risk of leukemic evolution. Therefore, accurate patient allocation into different disease categories and timely identification of fibrotic transformation are mandatory for adequate treatment planning. Diagnostic strategy still mainly relies on clinical/laboratory assessment and bone marrow histopathology, which, however, requires an invasive procedure and frequently poses challenges also to expert hemopathologists. Here we tested the diagnostic accuracy of the detection, by flow cytometry, of CCR2+CD34+ cells to discriminate among MPN subtypes with different degrees of bone marrow fibrosis. We found that the detection of CCR2 on MPN CD34+ cells has a very good diagnostic accuracy for the differential diagnosis between "true" ET and prePMF (AUC 0.892, P<0.0001), and a good diagnostic accuracy for the differential diagnosis between prePMF and overtPMF (AUC 0.817, P=0.0089). Remarkably, in MPN population, the percentage of CCR2-expressing cells parallels the degree of bone marrow fibrosis. In ET/PV patients with a clinical picture suggestive for transition into spent phase, we demonstrated that only patients with confirmed secondary MF showed significantly higher levels of CCR2+CD34+ cells. Overall, flow cytometric CCR2+CD34+ cell detection can be envisioned in support of conventional bone marrow histopathology in compelling clinical scenarios, with the great advantage of being extremely rapid. For patients in follow-up, its role can be conceived as an initial patient screening for subsequent bone marrow biopsy when disease evolution is suspected.

"Ideal" parathyroid hormone in erythropoietin-stimulating agents-resistant anemia.

Erythropoietin-stimulating agents (ESAs) have revolutionized anemia treatment in end-stage renal disease (ESRD), but ESA resistance is increasingly identified. Secondary hyperparathyroidism (SHP) is one cause of ESA resistance. We describe a patient with ESA-resistant, transfusion-dependent anemia and mild SHP with remodeling and reticulin fibrosis on bone marrow biopsy, all of which resolved with stricter SHP management. We identified 64 patients with anemia, ESRD, and bone marrow biopsy. The parathyroid hormone (PTH) range for bony remodeling was 183-16,161.9 pg/ml versus 90.8-3283 pg/ml. The PTH range for fibrotic changes was 183-2487 pg/ml versus 90.8-16,161.9 pg/ml. We found no clear PTH range predictive for bone marrow changes.

Eltrombopag may induce bone marrow fibrosis in allogeneic hematopoietic stem cell transplant recipients with prolonged thrombocytopenia.

Poor graft function (PGF) and secondary failure of platelet recovery (SFPR) are significant causes of transplant related morbidity and mortality. Although thrombopoietin receptor agonists (TPO-RA), particularly Eltrombopag (EPAG), have been reported to be efficacious in the treatment of prolonged thrombocytopenia, potential long term adverse effects remain to be elucidated. This retrospective study was performed to determine the efficacy and toxicity profile of TPO-RAs in allogeneic hematopoietic stem cell transplant (alloHCT) recipients. Medical records of 27 patients [median age: 55(21-73) years; male/female: 15/12] who received posttransplant EPAG for SFPR or PGF were analysed. Eltrombopag was started on day 110(33-670) after transplant. Median initial dose was 25(25-50) mg/day which was properly escalated to a maximum dose of 75(50-100) mg/day. Duration of the treatment was median 120(31-377) days. Overall response rate (ORR) was 59.3% in the study population. Time-to-treatment response was 42(3-170) days. Mild-to-moderate bone marrow fibrosis was detected in the posttreatment biopsies of 12/22 patients (54.5%), 9 of whom did not represent any grade of myelofibrosis in their inital biopsies. The grade of posttreatment fibrosis was significantly increased when time-to-treatment response was longer (p = 0.008). Long term use of TPO-RAs may be considered as a potential cause of myelofibrosis in alloHCT recipients.

Bone Marrow Fibrosis at Diagnosis and during the Course of Disease Is Associated with TP53 Mutations and Adverse Prognosis in Primary Myelodysplastic Syndrome.

The prognostic significance of bone marrow fibrosis (MF) grade in patients with myelodysplastic syndrome (MDS) is still debated and the molecular changes remain unclear. In our large cohort, a normal reticulum was found in 211 (25.9%) patients, whereas MF1, MF2 and MF3 were detected in 478 (58.7%), 90 (11.1%) and 35 (4.3%) patients at initial diagnosis, respectively. Patients with MF often correlated with some poor prognostic characteristics, including older age, anemia, unfavorable karyotype, higher BM blast and a higher IPSS-R category. For the entire cohort, the median OS was not reached, 30, 16 and 15 months for patients with MF 0, 1, 2 and 3, respectively. After adjusting for IPSS-R, the hazard ratio for mortality was 1.56 (95% CI, 1.18-2.06) for patients with MF1, 2.29 (95% CI, 1.61-3.27) for patients with MF2 and 2.75 (95% CI, 1.69-4.49) for patients with MF3 compared with those with MF0. The mutational landscape of 370 patients showed that TP53, U2AF1 and KMT2D mutations were more frequent in patients with MF2-3. In addition, of the 408 patients with MF0-1, 62 patients (15.1%) progressed to MF2-3 during the follow-up interval. The clinical features, mutation landscape and prognosis of patients with progressed fibrosis were similar to those of patients with MF2-3 at diagnosis. We concluded that BM fibrosis (MF1, 2 and 3) was an adverse prognosis feature in primary MDS and correlated with TP53 mutations both at the time of initial diagnosis and during the course of the disease. Therefore, BM fibrosis should be included in the revised prognostic scoring system and carefully considered in treatment selection.

Bone marrow fibrosis impact on response to azacitidine in myelodysplastic syndromes.

Bone marrow fibrosis in myelodysplastic syndromes (MDS) has been associated with poor outcome. However, these studies were conducted prior to the widespread use of azacitidine in the management of MDS. Our study aimed to assess whether treatment with azacitidine ameliorates the inferior outcome in MDS with fibrosis. A retrospective study of all patients diagnosed with MDS and treated with azacitidine over 3 years in two institutions was performed. A total of 21 patients were included in this study. Approximately half of these had moderate to severe bone marrow fibrosis at the start of treatment with azacitidine. The median overall survival was 34 months in patients with non-fibrotic bone marrow compared to 14 months in patients with fibrotic marrow (p=0.0007). Median event-free survival was 26 months versus 12 months (p=0.0027) in patients with non-fibrotic and fibrotic marrow, respectively. In multivariate analysis, bone marrow fibrosis was an independent factor in overall survival. Transfusion requirement was not different between the two groups. Despite the small sample size, we observed a worse outcome in azacitidine treated patients with MDS and fibrotic marrow. We suggest a prospective larger study to confirm the above finding.

Defining disease modification in myelofibrosis in the era of targeted therapy.

The development of targeted therapies for the treatment of myelofibrosis highlights a unique issue in a field that has historically relied on symptom relief, rather than survival benefit or modification of disease course, as key response criteria. There is, therefore, a need to understand what constitutes disease modification of myelofibrosis to advance appropriate drug development and therapeutic pathways. Here, the authors discuss recent clinical trial data of agents in development and dissect the potential for novel end points to act as disease modifying parameters. Using the rationale garnered from latest clinical and scientific evidence, the authors propose a definition of disease modification in myelofibrosis. With improved overall survival a critical outcome, alongside the normalization of hematopoiesis and improvement in bone marrow fibrosis, there will be an increasing need for surrogate measures of survival for use in the early stages of trials. As such, the design of future clinical trials will require re-evaluation and updating to incorporate informative parameters and end points with standardized definitions and methodologies.

Novel Usefulness of Krebs von den Lungen 6 (KL-6) with Hemoglobin and Lactate Dehydrogenase for Assessing Bone Marrow Fibrosis.

Bone marrow fibrosis (BMF) is manually assessed by reticulin and trichrome stain of bone marrow (BM) biopsy and graded on a semi-quantitative scale. Krebs von den Lungen 6 (KL-6) and Mac-2 binding protein glycosylation isomer (M2BPGi) are known to be associated with lung and liver fibrosis, respectively. We explored the usefulness of KL-6 and M2BPGi to assess BMF. A total of 250 patients who underwent BM biopsy with hematologic or non-hematologic diseases were included, and 42 patients with lung and liver diseases were excluded. The patients' data, including age, sex, diagnosis, white blood cell, hemoglobin (Hb), platelet, and lactate dehydrogenase (LDH) were collected. Measured KL-6 and M2BPGi levels were compared with reticulin grade (RG) (grade 0-3). KL-6 levels were significantly elevated with an increase in RG, but M2BPGi did not show a significant difference. Hb, LDH, or KL-6 were independent predictors for BMF (odds ratio: 1.96, 2.26, 2.91, respectively), but showed poor predictive ability (area under the curve [AUC] 0.62, 0.61, 0.60, respectively). The combination of Hb, LDH, and KL-6 showed a significantly improved predictive ability for BMF (AUC 0.73; integrated discrimination improvement 0.057; category-free net reclassification improvement 0.625). This is the first study to evaluate the usefulness of KL-6 for assessing BMF. The combination of Hb, LDH, and KL-6 would be an objective and relevant biomarker approach and be applied to risk stratification for BMF.

Myelodysplastic Syndromes with Bone Marrow Fibrosis: An Update.

Myelodysplastic syndrome (MDS) is a diverse hematological malignancy with a wide spectrum of presentations and implications. Treatment strategies for patients with MDS heavily rely on prognostic scoring systems, such as the revised international prognostic scoring system (IPSS-R). Bone marrow fibrosis (BMF) has been identified as an independent risk factor for poor survival in patients with MDS, irrespective of the IPSS-R risk category. However, BMF is not widely included in scoring systems and is not always considered by clinicians when making treatment decisions for patients. In this review, we discuss the available literature about the presentation and prognosis of patients with MDS and concurrent BMF. The prognostic impact of BMF should be factored in when deciding on transplant candidacy, especially for intermediate-risk patients.

Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.

Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.