Bone Marrow Morphology In Patients Research Articles

Day-21 bone marrow morphology in patients with FLT3-mutated AML incorrectly designates persistent leukaemia

Background: In the registration trial for midostaurin (RATIFY) in intensively-treated FLT3-mutated acute myeloid leukaemia (FLT3-AML), day-21 bone marrow biopsy (D21-BMB) was protocolled. Those with persistent leukaemia (PL), as defined by a morphologic blast count ≥ 5% in a cellular (> 20%) marrow received a second induction (∼25% of participants).1 However, a similar D14-BMB early response assessment strategy is known to poorly predict overall induction outcomes.2 Our study aimed to assess the predictive value of D21-BMB on induction outcomes of our local FLT3-AML population treated intensively plus midostaurin.

A predictive model for bone marrow disease in cytopenia based on noninvasive procedures

AbstractBone marrow specimens are the core of the diagnostic workup of patients with cytopenia. To explore whether next-generation sequencing (NGS) could be used to rule out malignancy without bone marrow specimens, we incorporated NGS in a model to predict presence of disease in the bone marrow of patients with unexplained cytopenia. We analyzed the occurrence of mutations in 508 patients with cytopenia, referred for primary workup of a suspected hematologic malignancy from 2015 to 2020. We divided patients into a discovery (n = 340) and validation (n = 168) cohort. Targeted sequencing, bone marrow biopsy, and complete blood count were performed in all patients. Mutations were identified in 267 (53%) and abnormal bone marrow morphology in 188 (37%) patients. Patients with isolated neutropenia had the lowest frequency of both mutations (21%) and abnormal bone marrow morphology (5%). The median number of mutations per patient was 2 in patients with abnormal bone marrow morphology compared with 0 in patients with a nondiagnostic bone marrow morphology (P < .001). In a multivariable logistic regression, mutations in TET2, SF3B1, U2AF1, TP53, and RUNX1 were significantly associated with abnormal bone marrow morphology. In the validation cohort, a model combining mutational status and clinical data identified 34 patients (20%) without abnormal bone marrow morphology with a sensitivity of 100% (95% confidence interval: 93%-100%). Overall, we show that NGS combined with clinical data can predict the presence of abnormal bone marrow morphology in patients with unexplained cytopenia and thus can be used to assess the need of a bone marrow biopsy.

A comprehensive analysis of cytopenias and bone marrow morphology in patients with a history of bariatric and metabolic surgery.

Following bariatric and metabolic surgery (BMS), patients may develop persistent cytopenia(s) despite adequate micronutrient levels. A comprehensive analysis of laboratory and hematopathologic findings in BMS patients with unexplained cytopenia(s) has not been previously described. We reviewed the clinical and laboratory data, bone marrow histology, and used ancillary testing to characterize patients with a history of BMS who had subsequent bone marrow biopsies due to unexplained cytopenia(s). All patients had anemia and 59% (23/39) had additional cytopenias. Myelodysplastic syndrome (MDS) and clonal cytopenia of unknown significance (CCUS) were diagnosed in 8% (3/39) and 10% (4/39), respectively. Remaining cases were classified as idiopathic cytopenia of unknown significance (ICUS) with anemia alone (ICUS-A) in 47% (15/32) or multiple cytopenias (ICUS-PAN) in 53% (17/32). Time since surgery, age, or amount of weight loss was not associated with a specific diagnosis. No patient was vitamin B12 or folate deficient. However, vitamin B6 and zinc were decreased in 47% (5/11) and 29% (9/29), respectively. Examination of bone marrow aspirates revealed slight erythroid dyspoiesis affecting <10% of precursors in 60% (9/15) ICUS-A and 59% (10/17) ICUS-PAN. Bone marrow findings in patients with unexplained cytopenia(s) after BMS are not specific in the majority of cases, and caution is advised when interpreting dyserythropoiesis. Levels of micronutrients and vitamins other than iron, folate and vitamin B12 are frequently disturbed in this patient cohort and warrant correction and close clinical follow-up.

Heterogeneity of Bone Marrow Morphology in Patients with Polycythemia Vera Resistant to First and Second Line Therapies - Impact of Hydroxyurea Dosage on MDS-like Progression

Background: First-line therapy in polycythemia vera (PV) generally consists of low-dose aspirin, phlebotomy, cytoreductive agents, and interferon. Hydroxyurea (HU) is the most frequently used cytoreductive agent, however, about 15-20% of patients (pts) become therapy resistant or intolerant. Resistance to HU is frequently associated with an aggressive disease course by increasing the risk of progression to post-PV myelofibrosis (PPMF). The clinical phenotype at this disease stage is very heterogeneous and often triggers a switch to second-line treatment options like JAK-inhibitor therapy.Design: A series of more than 500 consecutively collected cases with PV was screened in this observational study and analyzed with regard to inadequately controlled disease and resistance, intolerance or both to first-line cytoreductive agents. Only pts with available bone marrow (BM) trephine biopsies at this disease stage were finally selected. PPMF was defined according to the WHO 2016 criteria and HU resistance was assessed according to the European LeukaemiaNet (ELN). BM trephines were evaluated for grade of BM fibrosis (reticulin/collagen), cellularity, amount of CD34+ progenitors and morphology of megakaryocytes including the occurrence of myelodysplastic features associated with disease progression. Hematological and clinical data were collected at corresponding time points.Results: A total of 56 cases (31 males, 25 females, median age 67.5 years) with a representative BM trephine and uncontrolled disease or resistance to first-line cytoreductive agents was analyzed. Median time after diagnosis was 96.5 months (range 4 - 381 months), median treatment time with first-line cytoreductive agents (HU in 87.5%) was 48 months (range 12 - 240 months). Only 62.5% (35/56) of cases presented at this time point with a BM fibrosis grade ≥ 2 and thus fulfilled the WHO criteria for classical PPMF. 14 cases (25.0%) revealed a BM fibrosis grade of 1, whereas an uncontrolled myeloproliferation defined by increased platelet and/or leukocyte counts was found in 7 cases (12.5%). In 2 patients (3.5%) a blast phase was diagnosed at the time of treatment failure which was not associated with progressive fibrosis. In classical PPMF BM cellularity was heterogeneous but generally increased. Cases with grade 1 fibrosis or uncontrolled myeloproliferation had higher hemoglobin levels, lower leukocytes count, and higher platelet counts at time of treatment failure as compared to the PPMF group. On the other site, classical post-PV MF more often was presenting with relevant cytopenia and erythrocyte transfusion dependency. There was no difference in the amount of CD34+ progenitors between classical PPMF and cases presenting with either grade 1 fibrosis or uncontrolled myeloproliferation. MDS-like progression characterized by highly atypical megakaryocytes was observed in 12 pts (21.4%), all pts presented with classical PPMF. For all pts. treated with HU the total cumulative dosage, the average dosage per years, as well as the highest used dosage to control disease was calculated. Pts presenting with MDS-like BM features received a significantly higher total HU dosage (6,230 vs 721 gram, p=0.011) and showed a longer median treatment time with HU (72 vs 48 months), whereas the average annual dosage showed no significant difference.Conclusions: Progression of inadequately controlled PV represents a biological spectrum and is not restricted by degree of BM fibrosis as in classical WHO defined PPMF, but can also be defined by resistance to cytoreductive agents like HU. In clinical practice it is important to recognize that high dosages of HU and long treatment duration are more often seen in the important subgroup presenting with MDS-like features. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

102 Patients with Primary Autoimmune Neutropenia : An Analysis of the European Severe Chronic Neutropenia International Registry (SCNIR)

Background: Primary Autoimmune Neutropenia (AIN) is the most frequent type of neutropenia in children with a prevalence of 1/100,000 between infancy and 10 years of age. Primary AIN is caused by anti-neutrophil antibodies binding to neutrophil-specific antigens, resulting in a decrease of circulating neutrophils in the blood, but normal numbers of mature neutrophils in the bone marrow. Typically, primary AIN is present from infancy on until spontaneous remission in early childhood, when anti-neutrophil antibodies disappear. Patients with primary AIN show severe to moderate neutropenia but only rarely suffer from serious infections. Patients remain in the registry for follow up after normalization of blood counts to evaluate late secondary events. Aims: Here we describe the cohort of AIN pts with positive anti-neutrophil antibody testing documented by the European Branch of the SCNIR. We analyzed the course of neutropenia, the frequency of G-CSF treatment for AIN, the incidence of severe bacterial infections and administration of AB prophylaxis. Methods: We identified 102 primary AIN patients within the neutropenia cohort documented by the European Branch of the SCNIR since 1994. We classified primary AIN by positive anti-neutrophil antibody testing (95 pts) or severe neutropenia in peripheral blood with normal bone marrow morphology in patients with age under 5 years (7 pts). Results: Primary AIN has been identified in 102 (61 female; 41 male) pts. The median age of the cohort is 5.18 years (range 1.37-22.71 years), with 630.28 pt years under observation. Median age at diagnosis was 12.07 months (range 0.9-70 months). All pts are currently alive, 40 patients already resolved from primary AIN at a median age of 3.02 years (range 0.83-9.08 years). Median follow-up time after neutropenia had resolved was 2.25 years (range 0-9.27 years). Sixteen of 102 pts (15.7%) received intermittent G-CSF treatment with a median dose of 4.5 µg/kg/day compared to 4.77 µg/kg/day for the congenital neutropenia cohort of the SCNIR Europe. Analysis of infections (tab.1) showed less minor and severe infections comparing to congenital neutropenia (CN) pts. Life-threatening infections like liver abscesses were not seen in primary AIN patients but in 1.8% of CN pts. Twelve AIN pts (11.7%) have received antibiotic prophylaxis for prevention of infection, 6 pts intermittent and 6 pts continuously. However, antibiotic prophylaxis was usually stopped before termination of AIN. Due to the milder course of infections most AIN pts were able to go to Kindergarten and to live a normal life. In 3 pts additional auto-immune related diseases were identified (autoimmune thrombocytopenia, allergic colitis and Kawasaki syndrome) during AIN. Sixteen of 102 AIN patients received genetic analysis, with no mutation being detected. In addition to the 102 AIN pts we identified another 31 CN pts who have initially been classified as AIN due to positive anti-neutrophil antibodies, but who were later genetically confirmed as CN (15 ELANE+, 8 HAX1+, 2 SBDS+, 2 CXCR4+, 2 CSF3R+, 1 G6PC3+). This proportion of pts showed more and more severe infections compared to primary AIN. Genetic testing has been performed in these pts due to ongoing infections and prolonged neutropenia until school age. Conclusions: Pts suffering from primary AIN present with severe to moderate neutropenia. A minority of pts might require G-CSF treatment on demand/interventionally due to antibiotic resistant infections, but long-term G-CSF treatment is regularly not indicated. Primary AIN is a self-limiting condition and in most pts neutropenia resolves until early childhood. Accumulation of secondary diagnoses like autoimmune related diseases, though postulated, has not been confirmed for AIN pts by our data. In AIN pts with severe infections, or prolonged neutropenia CN should be ruled out by genetic analysis and/or bone marrow morphology. Registries are needed to document long-term data on primary AIN pts to analyse potential additional features of primary AIN, possibly other accompanying autoimmune diseases. Disclosures No relevant conflicts of interest to declare.

A study of hematological indices and bone marrow morphology in patients presenting with anemia

Introduction: The initial workup of anemia includes assessment of hematological indices and examination of the peripheral blood smears. Laboratory evaluation without marrow examination is usually not confirmatory. The objective of this study is to find the underlying etiopathology of anemia and correlate hematological indices, bone marrow study with clinical examination findings in differentiating causes of anemia. Materials and Methods: The present observational study was carried out on 138 patients with anemia, in which bone marrow study (BM aspiration and biopsy) was done for evaluation. Pediatrics population below 15 years and pregnant female and patients who did not give consent for bone marrow aspiration or biopsy were excluded from the study. Results: Dimorphic anemia was the most common non-malignant hematological cause followed by megaloblastic anemia. In hematological malignancies acute myeloid leukemia (4.34%) was most common. Discussion: A comprehensive clinical and hematological study of patients with anemia of various hematological disorders will usually help in identification of underlying cause. However, in view of wide array of etiologies, finding of underlying etiopathology continues to be a challenge for pathologist and hematologists. Keywords: Anemia, Hematological indices, Bone marrow study.

Long-Term Effects of Ruxolitinib on Bone Marrow Morphology in Patients With Myelofibrosis and Comparison to Best Available Therapy

Context: Ruxolitinib is a JAK1/JAK2 inhibitor that reduced splenomegaly and symptoms and was associated with improved survival in patients with myelofibrosis relative to placebo or best available therapy (BAT) in phase 3 studies. Objective: To evaluate the effects of long-term ruxolitinib treatment on bone marrow (BM) morphology in patients with myelofibrosis. Design and Patients: Trephine biopsies were obtained at baseline, 24 (68 patients), and 48 (18 patients) months from ruxolitinib-treated patients enrolled in a phase I/II trial (NCT00509899; Verstovsek, NEJM 2010). Two of the authors (JT, HMK) independently quantified BM fibrosis and a third (CB-R) reviewed the findings. Reviewers were blinded to patient characteristics and outcomes. BM fibrosis grading was determined in prospectively collected specimens from 139 patients (160 biopsies) treated for 24 (97 patients) and 48 (63 patients) months receiving BAT from an independent, multicenter, observational database. BAT included hydroxyurea (47%), interferon-alpha (7%), assorted sequential therapies (25%), or supportive-only therapy (21%). Outcome Measure: BM fibrosiswasgraded per the World Health Organization (WHO) criteria (scale: 0-3). Changes in BM fibrosis grade versus baseline were categorized as improvement, stabilization, or worsening. Results: At baseline, 21% of ruxolitinib-treated patients had grade 1, 53% grade 2, and 26% grade3BM fibrosis;approximately50%ofpatientshadosteosclerosis at baseline (grade 1: 33%; grade 2: 9%; grade 3: 9%). Collagen accumulation was observed in 32 cases (47%): 30% grade 1, 18% grade 2/3. There were no differences in the distribution of baseline BM fibrosis grades between ruxolitinib and BAT (p¼0.441; CochraneManteleHaenszel test). A greater percentage of ruxolitinib-treated versus BAT-treated patients showed stabilization (24 months: 57% versus 54%; 48 months: 56% versus 46%) or improvement (24 months: 15% versus 6%; 48 months: 22% versus 2%) in BM fibrosis. Worsening (excluding patients with baseline grade 3 BM fibrosis) was more prevalent with BAT (24 months: 37% versus62%;OR[95%CI]:0.40[0.18,0.87],48months:25%versus 75%; OR [95% CI]: 0.11[0.03, 0.43]). Conclusions: Long-term ruxolitinib therapy may meaningfully delay BM fibrosis progression. A comparable effect was not seen with long-term BAT, which supports earlier observations with hydroxyurea (Kvasnicka ASCO

Bone Marrow Examination for Unexplained Cytopenias Reveals Nonspecific Findings in Patients With Collagen Vascular Disease

Collagen vascular diseases are frequently included in the differential diagnosis for unexplained cytopenias and often prompt a bone marrow biopsy in this patient population to exclude malignancy. Few large-scale studies have characterized the bone marrow morphology in patients with collagen vascular disease, and most are limited to systemic lupus erythematosus or rheumatoid arthritis. To identify morphologic and immunohistochemical abnormalities specific to each of a wide range of collagen vascular disease cases. We examined 102 cases of collagen vascular disease and 38 controls and evaluated the complete blood count, peripheral blood morphology, bone marrow morphology, as well as immunohistochemical staining, for numerous cell lineages. Bone marrow findings, including abnormalities such as lymphoid aggregates, lipogranulomas, or abnormal localization of immature precursors, were not significantly different as compared to the control group. Bone marrow examination in patients with collagen vascular disease with cytopenias seldom provides new information. Caution should be exercised in interpreting morphologic findings suggestive of myelodysplasia since these are of a reactive nature in up to 27% of patients with collagen vascular disease. In a cost-effective diagnostic strategy, successful utilization may favor postponing a bone marrow biopsy while a more standardized autoimmune diagnostic panel is being performed.

Exploratory analysis of the effect of ruxolitinib on bone marrow morphology in patients with myelofibrosis.

7030 Background: Myelofibrosis(MF) is characterized by splenomegaly, burdensome symptoms, progressive bone marrow (BM) fibrosis, and shortened survival. Ruxolitinib (Rux), an oral, FDA-approved JAK1/JAK2 inhibitor, has demonstrated improvements in spleen volume, symptoms, and survival in patients (pts) with MF. This study was conducted to explore possible effects of long-term Rux treatment on BM morphology in MF. Methods: Trephine biopsies were obtained at baseline, 24 (67 pts), and 48 (17 pts) months (mo) from the cohort of MF patients treated at MD Anderson Cancer Center who participated in a phase I/II trial of Rux (NCT00509899). The clinical outcomes from this trial have been published previously [Verstovsek, NEJM 2010]. Two of the authors (JT and HMK) independently evaluated the World Health Organization (WHO)-defined BM fibrosis grade (0-3). Reviewers were blinded to pts characteristics and outcomes and consensus decided discordant scores. For demonstrative purposes, WHO BM fibrosis grading was also determined for a control cohort of pts treated with hydroxyurea (HU) for 24 (31 pts) and 48 (20 pts) mo. Changes in BM fibrosis grade vs. baseline were calculated for 24 and 48 mo, and categorized as improvement, stabilization, and worsening for each patient. Results: A higher percentage of Rux-treated pts showed stabilization or improvement of BM fibrosis at both 24 and 48 mo than the HU-treated pts. Worsening was greater in the HU-treated cohort at both time points. Conclusions: This exploratory analysis of long-term exposure to Rux in MF provides the first indication that JAK inhibitor therapy may be able to meaningfully retard advancement of BM fibrosis. A comparable effect was not seen with long-term HU therapy. Additional research is needed to further elucidate these findings. Clinical trial information: NCT00509899. [Table: see text]

Correlation of PCR-detected clonal gene rearrangements with bone marrow morphology in patients with B-lineage lymphomas.

Bone marrow biopsy is the conventional staging and posttherapy evaluation method for assessing marrow involvement by lymphoma. Polymerase chain reactions (PCR) for antigen receptor rearrangements have the potential to increase the detection of minimal degrees of marrow involvement. The present study is a concurrent morphologic and PCR evaluation of 225 staging or posttherapy marrow biopsies from 127 patients with B-lineage non-Hodgkin's lymphoma. The biopsies were morphologically categorized into four groups: group 1 (positive for lymphoma), 60 biopsies (27%); group 2 (suspicious for lymphoma), 20 biopsies (9%); group 3 (lymphocytic lesions of indeterminate biology), 22 biopsies (10%); and group 4 (negative for lymphoma), 123 biopsies (54%). Molecular studies were performed on concurrently obtained aspirates and used consensus immunoglobulin-heavy-chain (IgH) and IgH/bcl-2 gene PCR primers. A molecular clone was detected in 53 of the 225 aspirates (24%): group 1, 34 aspirates (57%); group 2, five aspirates (25%); group 3, one aspirate (5%); and group 4, 13 aspirates (11%). A PCR-positive aspirate was present in 47% of follicular lymphomas, 58% of diffuse large cell lymphomas, and 72% of the other lymphomas in the group I specimens. Morphology or PCR was positive in 79 of the 225 cases (35%). The molecular detection of clonality in the aspirate DNA from cases with positive morphologic findings was lower than anticipated. The discordance between morphology and PCR results may be related to sample variation between the trephine biopsy and aspirate, a failure to aspirate sufficient lymphoma cells, or insufficient primer homology for amplification. DNA extracted from trephine sections may provide results more concordant with morphology, because PCR detected a clone in 10 of 11 DNA specimens extracted from trephine biopsies with positive morphologic findings and PCR negative aspirates.

Bone Marrow Morphology in Patients with Neutropenia Due to Chronic Exposure to Organic Solvents (Benzene): Early Lesions

The authors present the histological and cytological features of bone marrow (BM) in 152 employees from the steel plant of Cubatão (S. Paulo-Brazil) who presented with neutropenia, due to chronic exposure to benzene and its homologues. All patients were male. Mean age was 35 years. At the time of this study, all patients were removed from risk areas because of the hematological abnormality. BM morphology was characterized by a hypocellular hemopoiesis (82%). Decrease of the granulocytic precursors (86%) was the most outstanding feature. Erythroid and megakaryocytic series were diminished in 40% and 57% of the cases, respectively. Eosinophilia in BM was observed in 71% of the cases. Cell atypias and stromal changes (necrosis, increase in reticulin fibres) were frequent.

Bone marrow morphology in patients in long-term treatment with azathioprine.

The bone marrow was morphologically analysed in 25 patients receiving long-term azathioprine therapy for chronic renal diseases or after a renal transplantation. There were no significant changes within the granulopoietic or lymphopoietic part of bone marrow even after 10 years of treatment. However, there was a significant "shift to the left" within erythropoiesis as well as greater frequencies of megaloblasts and sideroblasts. A significant increase of "erythroblastic islands" may indicate an increased death rate of defective erythroblasts. The changes within erythropoiesis in some of the patients were so pronounced that the possibility of a preleukaemic condition cannot be excluded.

The Influence of Vitamin B6 Supplementation on the Bone Marrow Morphology in Patients on Regular Haemodialysis Treatment

Bone marrow smears from 20 patients with chronic renal failure and on regular haemodialysis treatment (RDT) were morphologically analysed. A double-blind study of treatment with high doses of vitamin B6 showed that the patients receiving pyridoxine got raising frequencies of lymphocytes and monocytes in the bone marrow and there were morphologic signs of a normalization within the granulopoiesis. It is suggested that this is a sign of an enhancement of the immune response. The vitamin supplementation had no significant effects on the pronounced anemia of the patients.

Bone Marrow Morphology in Patients on Regular Haemodialysis Treatment

Bone marrow smears from 57 patients with chronic renal failure were morphologically analysed. In 55 patients on regular haemodialysis there was a slight 'shift to the left' and a significant eosinophilia within the granulopoiesis concurrently with slight megaloblastic changes of the erythroblasts. It is suggested that these abnormalities are caused by the dialysis procedure and not by the uraemia per se.