scholarly journals Perl's Stain Grade in the Bone Marrow Aspirate Correlates with Overall Survival in Low Risk Myelodysplastic Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5517-5517
Author(s):  
Federica Pilo ◽  
Giovanni Caocci ◽  
Anna Angela DiTucci ◽  
Valentina Serreli ◽  
Emanuele Angelucci ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Bone Marrow Aspirate ◽  
Bone Marrow Aspiration ◽  
Advisory Board ◽  
Low Risk ◽  
Iron Storage ◽  
Bone Marrow Iron ◽  
Grade 3

Abstract Background Myelodysplastic syndromes (MDS) are heterogeneous group of acquired clonal hematopoietic stem cell disorders characterized by atypical stem cells maturation and genetic instability leading to an enhanced risk of progression to acute myeloid leukemia. Low risk MDS patients have a lower probability to evolve in leukemia but are commonly characterized by dyseritropoiesis. These patient are incline to long term accumulation of iron in the organs due mostly to red blood cell transfusion (RBC) but iron overload may also occur in MDS patients who do not receive RBC transfusions due to the ineffective erythropoiesis. It is well known the effect of oxidant-mediated tissue's injury through the formation of free toxic iron species in the liver and heart site, but recent knowledges assumes that this mechanism is effective also in the bone marrow nice, where oxidative stress seems to impaired the haematopoietic stem cells growth. At this moment microscopic examination of the stainable iron in the bone marrow is considered the gold standard for determining the iron stores. The effect of bone marrow's iron overload on overall survival in the low risk MDS has been a matter of unresolved debate. We aimed to investigate the predictive value of bone marrow iron accumulation as demonstrated by Perl's staining on outcome in such patients. Design We retrospectively analyzed all low risk,intermediate-I MDS patients who had diagnosed in our institution in the last 20 years (since 1998). Diagnosis of MDS was made according to WHO criteria. Patients were stratified based on International Prognostic Scoring System (IPSS). Patients had undergone bone marrow aspiration as part of the diagnostic work up for their MDS. Two different experienced hematologist analyzed all samples. Bone marrow aspiration slides with at least seven fragments were considered suitable. Perl's Prussian blue stain was used to stain bone marrow, assessed by modified Gale's grading (Tab. 1) and then correlated with outcome. Patients and methods Marrow staining of one hundred and fourteen consecutive MDS patients were revised and analyzed. Median age was 70 years (range 32-93). Eighty three patients were IPSS low- risk and 30 Intermediate I. All patients were evaluated for bone marrow iron stores with Perl's stain. Twenty-seven patients had grade 1 (+), 31 grade 2 (++) and 56 grade 3 (+++). Patients had never or minimally received RBC . None of these patient had received iron chelation before marrow examination. Probability of overall survival (OS) was estimated by the Kaplan-Meier method and the significance was assessed by the log-rank test. Results 20-year OS was significantly lower in patients with higher Perl's score (median = 80 ±7 months in grade 3; median = 70 ±17 months in grade 2; median = 144 ±18 months in grade 1 , P=0.011); Fig. 1 Conclusions We evaluated retrospectively the bone marrow aspirate from 114 consecutive new MDS low-risk, Intermediate-I IPSS patients with Perl's stain for iron detection. Although Perl's grading is a qualitative method, it is still the gold standard to detect iron storage in the bone marrow. Our results correlate Perl's stain at diagnosis with long term outcome in MDS patients. We show how higher grade of iron storage at diagnosis can impact on outcome in these patients. We conclude that Perl's stain, together with Ferritin and blood transfusional burden could be another marker at diagnosis of iron-related toxicity that predict overall survival. Disclosures Pilo: Novartis Italy: Honoraria. Angelucci:Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC.

Perls Stain Grade in Bone Marrow Aspirate Correlates with Overall Survival in Low-Risk Myelodysplastic Patients

2020 ◽  
pp. 1-5
Author(s):  
Federica Pilo ◽  
Giovanni Caocci ◽  
Giannalisa Mele ◽  
Giorgio La Nasa
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Bone Marrow Aspirate ◽  
Low Risk

scholarly journals Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Paula A. Lengerke Diaz ◽  
Michael Y. Choi ◽  
Eider F. Moreno Cortes ◽  
Jose V. Forero ◽  
Juliana Velez-Lujan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (>5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as <10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

scholarly journals The Necessary for Long-Term Follow-up of Mutated Genes and Clonal Evolutions in Multiple Myeloma Combined with cfDNA Assay

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5515-5515
Author(s):  
Yuko Mishima ◽  
Yuji Mishima ◽  
Masahiro Yokoyama ◽  
Noriko Nishimura ◽  
Yoshiharu Kusano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Genomic Dna ◽  
Research Funding ◽  
Somatic Mutations ◽  
Clinical Course ◽  
Bone Marrow Aspiration ◽  
Long Term Follow Up

Introduction)Somatic mutations in multiple myeloma (MM) are strongly related to the clinical outcome and clonal evolution over the clinical course, and are a major problem. From a clinical viewpoint, although numerous novel drugs have been utilized, achieving long-lasting and complete remission remains difficult. Recent studies have elucidated the mutated genes using next-generation sequencing, and have examined how clonal change can be acquired in myeloma. In this study, we traced the transition of the somatic mutations of bone marrow tumor cells in patients with MM over a long-term follow-up. Furthermore, we compared the somatic mutations found in serum cell-free DNA (cfDNA) and mutated genes obtained from bone marrow myeloma cells. Material and Methods)Patients diagnosed with multiple myeloma who provided written informed consent to participate in the study were enrolled. Patients were treated by immuno-chemotherapy with or without radiation between 2000 and 2017 at our institute. Bone marrow aspiration and biopsy were performed at the time of diagnosis and upon disease progression. Around the time of bone marrow aspiration, serum was obtained from a peripheral blood sample for cfDNA analysis. Myeloma cells were separated from bone marrow samples with MicroBeads of CD138 antibody and genomic DNA was extracted. The peripheral blood samples derived from myeloma patients. The cfDNA was extracted from the serum using a Maxwell RSC cfDNA Plasma kit. Using genomic DNA derived from cfDNA and bone marrow, multiplex polymerase chain reaction (PCR) was performed, and a sequence library was then constructed with an Ion Custom Amplicon panel. The panel for the sequence library was designed using an Ion AmpliSeq DesignerTM. 126 targeted genes were selected. The genomes were sequenced using the Ion ProtonTM System. This protocol was approved by the institutional review board and the Genomic Review Board of the Japanese Foundation for Cancer Research. Result)We followed 7 patients' long term-clinical course and the transition of mutations (8.5 year average). The expression of myeloma driver genes, such as RAS, BRAF, and MYC, were not critical. We did, however, detect a relationship between an increase in the dominant mutated gene, such as TP53, DIS3, FAM46C, KDM6B, and EGR1 and poor prognosis in patients with myeloma. Next, we calculated the cfDNA concentrations from 34 cases. The cfDNA concentrations were significantly higher than 10 control cases (average 62.0 ng/mL (0-200 ng/mL) and 8.18 ng/mL (4.3-14.1 ng/mL), P=0.0046). The 2.5 year-progression free survival (PFS) during the first treatment of MM were tend to be poorer in the group with cfDNA>50 ng/mL (72.9%) than the group with cfDNA<50 ng/mL(25.9%), however there are no statistical significance (P = 0.15).We caluculated concordance rate of derived mutations from bone marrow MM cells and cfDNA in 7 cases. The somatic mutations found in serum cell-free DNA (cfDNA) and bone marrow MM cells were determined the correlation coefficients. However, there are few difference expression pattern in each source. In cfDNA assay, CREEP, EGR1, HDAC4, HDAC6, and JMJD1C were highly expressed as 57.1% (4/7) - 85.7% (6/7), and these results were almost the same as those for bone marrow MM cells. On the other hand, KDM1A (85.7%), PI3KCD (71.4%), and KDM3B (57.1%) were highly detected in cfDNA, although those were not frequently expressed in bone marrow. Discussion)Our data demonstrate the importance of the long-term follow-up of somatic mutations during the clinical course of myeloma. Serum cfDNA is a useful alternative source for detecting somatic mutations in MM patients during long-term follow-up. Disclosures Mishima: Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Yokoyama:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Nishimura:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy; Celgene K.K.: Honoraria. Hatake:Celgene K.K.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Takeda Pharmaceutical Co.,Ltd.: Honoraria. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria.

scholarly journals Efficacy and Safety of Blinatumomab for Relapsed or Refractory Pediatric ALL Patients: A Systematic Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Anam Khan ◽  
Atif Irfan Khan ◽  
Sana Irfan Khan ◽  
Sobia Aamir ◽  
Usman Ali Akbar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Clinical Trials ◽  
T Cells ◽  
Complete Remission ◽  
Adverse Outcomes ◽  
Term Survival ◽  
Paediatric Patients ◽  
Grade 3

Background Most children with Acute Lymphoblastic Leukaemia achieve complete remission and subsequent cure after chemotherapy. But, ALL relapse is the leading cause of treatment failure in paediatric patients, causing long term survival to below. Chemotherapy along with targeted therapies have been explored in relapsed/refractory ALL (R/R ALL) patients. One such targeted therapy is Blinatumomab (Blin), a bi-specific T-cell engagers (BiTEs) antibody, it binds to CD3 receptors on T-cells and CD19 receptors on B-cells thereby re-directing T-cells to exert their cytotoxic effect on malignant as well as non-malignant B-cells. Blin was approved by FDA in March 2018 for the treatment of B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) ≥0.1%. This approval was based on BLAST trial conducted on ≥18-year-old ALL patients. The drug has been studied in children (1-18 years) with five clinical trials exclusively in children of which two have reported their results and three are ongoing. In this systematic review, we evaluated the safety and efficacy of Blin as a monotherapy in paediatric R/R ALL patients. Material/Methods We performed a search on PubMed, Embase, Clinical Trials, Web of Science and Cochrane. We used Mesh Terms "ALL" and "Blinatumomab" without any filters. After screening of 1199 articles, 5 clinical trial, 3 retrospective studies and 1 case series were included. These studies included only paediatric patients (&lt;18yrs) evaluating the role of Blin as monotherapy in R/R ALL. We followed the PRISMA guidelines for literature search and selection of studies RESULTS: A total number of patients who received Blin was 320, all were &lt;18 years. The preceding treatment regimens included multi-agent chemotherapy with or without hematopoietic stem cell transplant (HSCT). Five studies included only those patients with more than ≥5% bone marrow blasts. Though many combination monoclonal antibody therapies are available, we included only patients given Blin as monotherapy. Blin therapy was a 4 weeks continuous infusion at a dosage of 5 or 15μg/m2/day followed by 2 weeks of treatment-free interval as one cycle, in the studies, the number of treatment cycles ranged from 1-18. A median follow up in the studies ranged from 6 months to 5 years. Overall, complete response (CR) was found to be 58% (n=184) ranging between 31% to 100%. Following CR with Blin relapse rate was 40% (n=66). The overall median survival ranged from 4.3 to 22 months amongst 5 of the nine studies, while it was reported to be 80% (n=9) survival at the end of 12 months by Elitzur et al and 33.3% (n=3) at the end of two cycles of blin by Schlegel, P et al, the remaining two studies did not mention the duration of overall survival. The cumulative hematologic adverse outcomes of ≥grade 3 amongst the studies reported were neutropenia 22% (n=70), Anemia 27.7%(n=55), thrombocytopenia as reported in four studies was 21.5% (n=30). Fuster J et al. reported a cumulative non-hematologic adverse outcome of 40%(n=6) while other studies reported ≥ grade 3 non-hematologic adverse outcomes with increased liver enzymes, neurologic problems and fever to be most common. Cumulative cytokine release syndrome was reported as 4.7% (n=14) in 6 out of 9 studies. Elitzur et al. reported no non-hematologic adverse effect. We found total cumulative death reported as 17% of cases (n=34). Conclusion Blinatumomab use for R/R ALL paediatric patients treatment showed promising outcomes with more than half of the patients achieving CR. Overall survival has been good with median patient surviving disease-free between 4 to 22 months at large. Though, low mortality indicated long term survival, a high relapse rate points that Blin with combination therapy may show better outcomes. Fifteen ongoing clinical trials are testing Blin currently, three of which are on paediatric R/R ALL group. One trial is testing a combination of Blin and pembrolizumab. The results of these trials will further provide information on its effectiveness in combination therapy. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

scholarly journals Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up

Blood ◽  
2018 ◽  
Vol 131 (21) ◽  
pp. 2331-2334 ◽  
Author(s):  
Robert J. Kreitman ◽  
Martin S. Tallman ◽  
Tadeusz Robak ◽  
Steven Coutre ◽  
Wyndham H. Wilson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Aspirate ◽  
Phase 1 ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Key Points ◽  
Long Term Follow Up ◽  
Minimal Residual

Key Points Moxetumomab pasudotox eradicated HCL MRD in >50% of CRs, even by the most sensitive measure, bone marrow aspirate flow cytometry. Elimination of MRD was significantly associated with prolonged CR duration.

A study of bone marrow iron storage in hematological disorder

2014 ◽  
Vol 3 (4) ◽  
pp. 221 ◽  
Author(s):  
KrupalM Pujara ◽  
RohitV Bhalara ◽  
GauraviA Dhruva
Keyword(s):  
Bone Marrow ◽  
Iron Storage ◽  
Hematological Disorder ◽  
Bone Marrow Iron

scholarly journals Outcomes Following Treatment of Talar Osteochondral Lesions with a Mixture of Particulate Allogenic Cartilage Extracellular Matrix and Bone Marrow Aspirate Concentrate: A Case Control Series

2019 ◽  
Vol 7 (7_suppl5) ◽  
pp. 2325967119S0032
Author(s):  
Mark C. Drakos ◽  
Taylor Nicole Cabe ◽  
Carolyn Sofka ◽  
Peter D. Fabricant ◽  
Jonathan T. Deland
Keyword(s):  
Bone Marrow ◽  
Extracellular Matrix ◽  
Bone Marrow Aspirate ◽  
Case Control ◽  
Osteochondral Lesions ◽  
Treatment Groups ◽  
Cartilage Extracellular Matrix

Objectives: There continues to be a general lack of consensus regarding the optimal treatment for osteochondral lesions of the talus (OLTs). Microfracture, once considered the gold-standard, has been associated with poor long-term results due to the formation of biomechanically inferior reparative fibrocartilage as opposed to hyaline cartilage. Particulate allogenic cartilage extracellular matrix offers a promising solution as an adjuvant therapy; however, there is currently minimal objective evidence to indicate its effect on post-operative outcomes. This study compares post-operative radiographic and clinical outcomes following treatment of OLTs with an adjuvant mixture of particulate cartilage extracellular matrix and bone marrow aspirate concentrate (BMAC) against outcomes following microfracture with or without BMAC. Methods: Patients diagnosed with an OLT and treated by a fellowship-trained orthopedic surgeon were screened for inclusion. Those whose surgical intervention included microfracture, microfracture augmented with BMAC alone, or microfracture augmented with a mixture of BMAC and particulate allogenic cartilage extracellular matrix were eligible for this case-control study. Lesion size, location, and concurrent injuries were recorded following retrospective chart review. Foot and Ankle Outcome Scores (FAOS) were collected pre-operatively and at a minimum of 1 year post-operatively through the prospective Registry database at the authors’ institution. Modified magnetic resonance observation of cartilage repair tissue (MOCART) scoring evaluated the structural quality of repaired lesions on MRIs collected greater than six months post-operatively. Differences in post-operative MOCART and FAOS scores were evaluated using ANOVA tests. Results: Forty-seven patients treated with microfracture alone, forty-seven treated with microfracture augmented by BMAC, and fifty-two treated with an adjuvant mixture of particulate allogenic cartilage extracellular matrix and BMAC were identified at a minimum of 2 years post-operatively. Average MOCART scores were significantly different between treatment groups (p=0.03). At an average follow-up of 10.86 months, patients who received adjunctive therapy had an average MOCART score of 73.5 ± 11.13. At an average follow-up of 23.06 months and 43.6 months respectively, patients treated with microfracture and BMAC and microfracture alone scored 63.33 ± 22.23 and 55 ± 23.92. There was no detectable statistically significant difference in post-operative FAOS scores between treatment groups. With respect to revision surgery, two patients (3.84%) originally treated with adjuvant particulate cartilage extracellular matrix and BMAC have required a secondary surgery as opposed to nine patients (9.57%) treated with microfracture and BMAC or microfracture alone. Conclusion: Increases in post-operative FAOS scores compared to pre-operative FAOS scores for all treatment groups indicate patients’ function and symptoms improved regardless of intervention received. However, significantly higher MOCART scores for the particulate cartilage extracellular matrix and BMAC treatment group suggest adjuvant treatment may help achieve better post-operative fill and structural integrity. Thus, long-term outcomes and the quality of reparative tissues may be improved through use of adjuvant treatments such as particulate allogenic cartilage extracellular matrix and BMAC.

A Case of Fulminant Myelodysplastic Syndrome Versus Acute Erythroleukemia Variant.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4900-4900
Author(s):  
Fermina M. Mazzella
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Aspirate ◽  
Reticulocyte Count ◽  
Bone Marrow Aspiration ◽  
Chronic Fatigue ◽  
Red Cell ◽  
Significant Past Medical History ◽  
Normal Limits ◽  
Rare Instance

Abstract Case: A 73 year old male with no significant past medical history presented with chronic fatigue. A routine CBC revealed an H/H of 6.8/19, MCV 103, WBC 4,100 and platelet count 92,000. Reticulocyte count was 0.6%. Serum iron, B12 and red cell folate studies were within normal limits. A bone marrow aspiration and biopsy were performed. Bone Marrow Findings: The bone marrow aspirate showed an M:E ratio of 1.8:1, with 33% erythrocytic elements. There was markedly left shifted erythropoiesis, with 57% of erythrocytic precursors being pronormoblasts. 1.2% blasts were present. Moderate erythrocytic dysplasia was present, with mild granulocytic and megakaryocytic changes. Vacuolated pronormoblasts were readily identified. No ringed sideroblasts were present. A diagnosis of MDS, NOS was rendered. No cytogenetics were obtained. Follow-up: The patient was transfused 4 units of packed red cells. Due to the patient’s rapidly deteriorating condition, comfort measures only were provided. The patient died 2.5 weeks after the bone marrow procedure. No autopsy was performed. The cause of death was listed as MDS. Discussion: This case is an extremely rare instance of left shifted erythropoiesis in the absence of the requisite number of erythrocytic elements for consideration of acute erythroleukemia (50%). By current definitions, this is an example of a fulminant MDS. However, this case does beg the question of whether or not pronormoblasts should be included in the assessment of malignant disorders of bone marrow.

Effect Of Treatment With The JAK2-Selective Inhibitor Fedratinib (SAR302503) On Bone Marrow Histology In Patients With Myeloproliferative Neoplasms With Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2823-2823 ◽  
Author(s):  
Catriona HM Jamieson ◽  
Robert P Hasserjian ◽  
Jason Gotlib ◽  
Jorge E. Cortes ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Selective Inhibitor ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.

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