Central Morphology Review of Childhood Bone Marrow Failure in Japan

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1604-1604 ◽  
Author(s):  
Asahito Hama ◽  
Manabe Atsushi ◽  
Daisuke Hasegawa ◽  
Kazue Nozawa ◽  
Yusuke Okuno ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Who Classification ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Failure ◽  
Severe Disease ◽  
Refractory Anemia ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Female Ratio ◽  
Cell Lineages

Abstract In the diagnosis of childhood bone marrow failure (BMF), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. In addition, inherited BMF (IBMF) should be excluded from acquired BMF. The 2008 WHO classification has proposed a provisional entitiy, “refractory cytopenia of childhood (RCC)”. The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) in adults. Currently, it is recommended that children who meet the criteria for RCMD should be considered as RCC in the WHO classification until the number of lineages involved have been fully evaluated with regard to their relative importance as prognostic factors in childhood MDS. To enable diagnosis based on the WHO classification, the Japanese Society of Pediatric Hematology and Oncology in February 2009 established a central review system of BM morphology, including peripheral blood (PB) and BM smears and specimens from trephine biopsies in childhood BMF. PB and BM smears were reviewed by two pediatric hematologists, and the specimens from BM trephine biopsies were reviewed by a pathologist. In addition, the telomere length of lymphocytes and paroxysmal nocturnal hemoglobinuria (PNH) clones in PB were measured by flowcytometry for patients with BMF. RCC is defined as persistent cytopenia with <2% and <5% blasts in PB and BM, respectively. BM aspirate smears show dysplastic changes in >2 cell lineages or >10% within one cell lineage. On the other hand, the criteria of RCMD in adult MDS is defined as persistent cytopenia with <1% and <5% blasts in PB and BM, respectively. BM smears show >10% dysplastic changes in >2 cell lineages. We introduced the RCMD criteria in this central review. From February 2009 to October 2013, 1,000 cases including 536 males and 464 females were prospectively reviewed. The median age was six years (range, 0–39 years). Of the 1,000 cases, 575 were classified as BMF, and of them, 137 were classified as AA, 236 as RCC, 103 as RCMD, 38 as hepatitis-related BMF, 3 as PNH and 58 as IBMF. Of the 58 cases with IBMF, 21 were diagnosed as Fanconi anemia, 12 as Shwachman–Diamond syndrome, and 8 as dyskeratosis congenita. Seventeen patients suspected of IBMF were undiagnosed. In 97 advanced cases of MDS, 24 were classified as refractory anemia with excess blasts (RAEB), 6 as secondary MDS, and 21 as therapy-related MDS. To determine the clinical differences among AA, RCC, and RCMD, we compared laboratory and clinical data for 476 patients classified as AA, RCC, and RCMD. Median ages in the AA, RCC, and RCMD groups were 9, 8, and 7 years, respectively (p = 0.007). The male/female ratio in AA, RCC, and RCMD groups was 1.1, 1.2, and 3.6, respectively (p = 0.034). When patients were classified according to the disease severity criteria for AA, 78% of the patients with AA had very severe or severe disease, whereas only 38% of the patients with RCC and 28% of the patients with RCMD had very severe or severe disease (p < 0.001). Chromosomal abnormalities were detected in two patients (1%) with AA (trisomy 8), 10 patients (4%) with RCC (monosomy 7, n = 2; trisomy 8, n = 6; other, n = 2), and 12 patients (12%) with RCMD (monosomy 7, n = 5; trisomy 8, n = 2; other, n = 5) (p = 0.001). Out of the 476 patients, 67 (AA, n = 32; RCC, n = 32; RCMD, n = 3) were administered IST with rabbit antithymocyte globulin (ATG) and cyclosporine. After 6 months, the response rate to IST was not significantly different among the three groups; AA, 41%; RCC, 47%; RCMD, 100% (p = 0.142). In conclusion, the entity of RCMD should be applied to childhood MDS because patients with RCMD exhibited a significantly high frequency of chromosomal abnormalities at the time of diagnosis. To definitively determine whether these three diseases are different entities, it would be necessary to prospectively compare the clinical outcomes and biological findings in a larger number of patients with AA, RCC, and RCMD. Disclosures No relevant conflicts of interest to declare.

Risk Factors For Clonal Evolution Of Acquired Bone Marrow Failure After Immunosuppressive Therapy In Children

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2473-2473
Author(s):  
Asahito Hama ◽  
Hideki Muramatsu ◽  
Masafumi Ito ◽  
Yoshiyuki Kosaka ◽  
Masahiro Tsuchida ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Severe Disease ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Cell Lineages ◽  
A Prospective Study

Abstract Long-term survivors of acquired aplastic anemia (AA) have an increased risk of developing clonal evolution after immunosuppressive therapy (IST). We previously reported that the duration of granulocyte colony-stimulating factor (G-CSF) treatment and non-response to IST at 6 months were risk factors for clonal evolution. In 2008, the revised World Health Organization (WHO) classification proposed a new entity, “refractory cytopenia of childhood” (RCC), which is often difficult to differentiate from aplastic anemia (AA). The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) with mild dysplasia to those with normocellular BM with distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) in adults. Few studies have investigated the correlation between morphological classifications of bone marrow failure (BMF) and clonal evolution. Before introducing the criteria of RCC, we conducted a prospective study with antithymocyte globulin (ATG) and cyclosporine for patients with acquired BMF (AA 97 study), which provided a unique opportunity both to compare the long-term outcome of patients with RCC and AA and to analyze risk factors for clonal evolution. We retrospectively reviewed BM morphology in 186 children (median age, 8 years;range, 1–16 years) who were enrolled in the AA 97 study between July 1999 and November 2008. The median follow-up period was 87 months (range, 1–146 months). Fifty patients had non-severe, 54 had severe, and 82 had very severe disease. RCC criteria were defined as persistent cytopenia with <2% blasts in the peripheral blood (PB) and <5% blasts in the BM. BM aspirate smears showed dysplastic changes in >2 cell lineages or >10% within 1 cell lineage. RCMD criteria were defined as persistent cytopenia with <1% blasts in the PB and <5% blasts in the BM. BM smears showed >10% dysplastic changes in >2 cell lineages. Morphologically, 62 patients (33%) were classified as AA, 94 (49%) as RCC, and 34 (18%) as RCMD. Disease severity differed among the three groups as follows: 76% of the AA patients had very severe disease, while 41% of the RCMD patients had non-severe disease (p<0.001). AA patients received G-CSF more frequently and for a longer duration than other patients (p=0.002). After 6 months, the response rates to IST were not significantly different among the three groups (AA, 52%; RCC, 59%; RCMD, 56%). Predictors of IST response were investigated by multivariate analysis. Morphological classification was not associated with IST response (p=0.519). Acquisition of clonal chromosomal abnormalities was observed in five patients in the AA group (monosomy 7, n=4; monosomy X, n=1), four patients in the RCC group (monosomy 7, n=1; trisomy 8, n=1; other, n=2), and three patients in the RCMD group (trisomy 8, n=3). Although the cumulative incidence (CI) of total clonal evolution at 10 years was not significantly different among the three groups, the CI of monosomy 7 was significantly higher in the AA group than in the other groups (p=0.02). Multivariate analysis revealed that morphology was not related to clonal evolution (p=0.23), and that only duration of G-CSF administration for >40 days was a significant risk factor for the development of monosomy 7 (p=0.016). Death, relapse, development of myelodysplastic syndrome or acute myeloid leukemia (AML), or disease progression requiring clinical intervention was considered to represent treatment failure. A second therapeutic intervention was required in some children. A second IST was therefore performed in 20 children, including five with AA, 11 with RCC, and four with RCMD. Hematopoietic stem cell transplantation was performed in 64 children, including 25 with AA, 29 with RCC, and 10 with RCMD. The rate of failure-free survival at 10 years was not significantly different among the three groups. On the other hand, the rate of overall survival at 10 years was significantly lower in the AA group (85±5.1%) than in the RCC (97±1.9%) and RCMD (100%) groups (p=0.01). Two patients died due to AML, and five patients died due to transplantation-related complications in the AA group. To confirm these results, we are currently conducting a prospective study involving IST in patients with acquired BMF classified according to WHO classification before treatment. Disclosures: No relevant conflicts of interest to declare.

Comparison of Clinical Outcomes Between Pediatric Aplastic Anemia and Refractory Cytopenia of Childhood

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1498-1498
Author(s):  
Asahito Hama ◽  
Atsushi Manabe ◽  
Daisuke Hasegawa ◽  
Kazue Nozawa ◽  
Atsushi Narita ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Clinical Outcomes ◽  
Who Classification ◽  
Chromosomal Abnormalities ◽  
Response Rates ◽  
World Health ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Cell Lineages

Abstract In the diagnosis of childhood bone marrow failures (BMFs), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. The 2008 World Health Organization (WHO) classification has proposed a provisional entity, "refractory cytopenia of childhood (RCC)". The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) defined for adults with MDS. Currently, it is recommended that children who meet the criteria for RCMD should be classified as RCC in the WHO classification until the number of lineages involved has been fully evaluated with regard to their relative importance as prognostic factors. Until now, few studies have addressed the question whether the current WHO classification reflects clinical outcomes of childhood BMFs. To determine the clinical differences among AA, RCC, and RCMD, we compared clinical outcomes for patients with AA, RCC, and RCMD in Japan. From February 2009 to December 2013, 252 patients were registered to the central morphology review system of the Japanese Society of Hematology and Oncology and were diagnosed with BMFs. Peripheral blood (PB) and BM smears were reviewed by two pediatric hematologists, and BM trephine biopsies were reviewed by a hematopathologist. RCC is defined as persistent cytopenia with <2% and <5% blasts in PB and BM, respectively. BM aspirate smears show dysplastic changes in >2 cell lineages or >10% within one cell lineage. On the other hand, the criteria of RCMD is defined as persistent cytopenia with <1% and <5% blasts in PB and BM, respectively. BM smears show >10% dysplastic changes in >2 cell lineages. Patients with inherited BMFs were excluded by family history and physical examination. Further, Fanconi anemia was excluded by chromosome fragility test　and Dyskeratosis congenita was screened by measuring the telomere length of the peripheral lymphocytes by flowcytometry. Out of 252 patients, 63 were classified as AA, 131 as RCC, and 58 as RCMD. Median ages in AA, RCC, and RCMD groups were 10, 8, and 7 years, respectively (p=0.07). The median of leukocyte, neutrophil, reticulocyte, and platelet count, and mean corpuscular volume were significantly lower in AA than in RCC and RCMD groups (p<0.01). Chromosomal abnormalities were detected in 1 patient with AA (trisomy 8), 3 patients with RCC (trisomy 8, n=2; other, n=1), and 9 patients with RCMD (trisomy 8, n=5; monosomy 7, n=1; other, n=3) at the time of diagnosis (p<0.01). Out of 252 patients, 82 (AA, n=3; RCC, n=46; RCMD, n=33) were observed without any treatments (watch and wait, WW). 5-year overall survival (OS)/failure free survival (FFS) rates in WW group were 67%/67% in AA, 98%/54% in RCC, and 100%/69% in RCMD patients (p<0.01/p=0.97). Immunosuppressive therapy (IST) with rabbit antithymocyte globulin and cyclosporine was performed in 110 (AA, n=39; RCC, n=57; RCMD, n=14) patients. Six months after the IST, the response rates to the IST were not significantly different among AA (40%), RCC (63%), and RCMD (64%) (p=0.08). The development of additional chromosomal aberrations was found in 2 patients with RCC, and 1 with RCMD. The 5-year OS/FFS rates in IST group were 89%/36% in AA, 94%/38% in RCC, and 93%/23% in RCMD patients (p=0.64/p=0.86). Stem cell transplantation (SCT) as a first line therapy was performed in 19 patients with AA, 10 with RCC, and 5 with RCMD. The rejection was found in 2 patients with RCC and 3 with RCMD. Although 5-year OS rates in patients who underwent SCT were not different among 3 groups (p=0.26), FFS rate (30%) in patients with RCMD was significantly lower than in those with AA (100%) and RCC (78%) (p<0.01). In conclusion, we could not find any clinical relevance of separating RCC from AA because response rates to IST and the development of clonal evolution did not significantly differ between AA and RCC. The entity of RCMD should be adopted to childhood MDS classification because children with RCMD exhibited a distinct characteristic of morphology and a frequent chromosomal aberration at the time of diagnosis. The optimal treatment strategy including preconditioning regimen of SCT should be established for children with acquired BMFs based on the BM cellularity and morphological classification. Disclosures Kojima: SANOFI: Honoraria, Research Funding.

Comparison of Clinical and Laboratory Features Between Pediatric Aplastic Anemia and Refractory Cytopenia of Childhood

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1213-1213
Author(s):  
Asahito Hama ◽  
Atsushi Manabe ◽  
Daisuke Hasegawa ◽  
Hideki Muramatsu ◽  
Yoshiyuki Takahashi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Clinical Outcomes ◽  
Who Classification ◽  
Response Rate ◽  
World Health ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Female Ratio ◽  
Cell Lineages

Abstract In the diagnosis of childhood bone marrow failure (BMF), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. The 2008 World Health Organization (WHO) classification has proposed a provisional entity, "refractory cytopenia of childhood (RCC)". The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria of refractory cytopenia with multilineage dysplasia (RCMD) defined for adults with MDS. Currently, it is recommended that children who meet the criteria for RCMD should be classified as RCC in the WHO classification until the number of lineages involved has been fully evaluated with regard to their relative importance as prognostic factors. Until now, no studies have addressed the question whether the current WHO classification reflects clinical outcomes of childhood BMF. The Japanese Society of Pediatric Hematology and Oncology has established a central review system of morphology. Peripheral blood (PB) and BM smears were reviewed by two pediatric hematologists, and BM trephine biopsies were reviewed by a hematopathologist. In addition, the telomere length of lymphocytes and paroxysmal nocturnal hemoglobinuria (PNH) clones in PB were measured by flowcytometry. RCC is defined as persistent cytopenia with <2% and <5% blasts in PB and BM, respectively. BM aspirate smears show dysplastic changes in >2 cell lineages or >10% within one cell lineage. On the other hand, the criteria of RCMD is defined as persistent cytopenia with <1% and <5% blasts in PB and BM, respectively. BM smears show >10% dysplastic changes in >2 cell lineages. We classified childhood BMF into AA, RCC, and RCMD in our central review. From February 2009 to February 2015, 1,300 cases were prospectively reviewed. Of the 1,300 cases, 582 were classified as BMF. Among them, 99 were classified as AA, 230 as RCC, 128 as RCMD, 50 as hepatitis-related BMF, 4 as PNH, and 71 as inherited BMF. Of the 71 cases with inherited BMF, 35 were diagnosed as Fanconi anemia, 14 as Shwachman-Diamond syndrome, and 12 as dyskeratosis congenita. To determine the clinical differences among AA, RCC, and RCMD, we compared laboratory and clinical findings for 457 patients classified with AA, RCC, and RCMD. Median ages in the AA, RCC, and RCMD groups were 10, 9, and 7 years, respectively (p<0.01). The male/female ratio in AA, RCC, and RCMD groups was 1.3, 1.4, and 1.1. The median of leukocyte, neutrophil, reticulocyte, and platelet count, and mean corpuscular volume were significantly lower in AA than in RCC and RCMD groups (p<0.01). Chromosomal abnormalities were detected in 1 patient with AA (trisomy 8), 6 patients with RCC (trisomy 8, n=4; monosomy 7, n=1; other, n=1), and 18 patients with RCMD (trisomy 8, n=5; monosomy 7, n=4; other, n=9) (p<0.01). Out of the 457 patients, 69 (AA, n=29; RCC, n=34; RCMD, n=6) were treated with immunosuppressive therapy (IST) with rabbit antithymocyte globulin and cyclosporine. Six months after the IST, the response rate to the IST was not significantly different between AA (38%) and RCC (47%) (p=0.47). Although the number of patients was limited, the response rate to the IST was 100% in patients with RCMD. One patient with RCC developed PNH at 26 months after the IST. Stem cell transplantation was performed in 15 patients with AA, 16 with RCC, and 3 with RCMD. Two patients with AA and 1 patient with RCC died of transplant-related toxicities. In conclusion, the entity of RCMD should be adopted to childhood MDS classification because children with RCMD exhibited a distinct characteristic of morphology and laboratory findings. Further efforts to clarify molecular events and clinical outcomes are necessary to establish the classification system for childhood BMF. Disclosures No relevant conflicts of interest to declare.

Classification of Childhood Bone Marrow Failure Syndrome Based On Revised WHO Classification.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4212-4212
Author(s):  
Asahito Hama ◽  
Ayami Yoshimi ◽  
Shinsuke Hirabayashi ◽  
Hideki Muramatsu ◽  
Nobuhiro Nishio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Who Classification ◽  
Chromosomal Abnormalities ◽  
Response Rates ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Cell Lineages ◽  
Increased Risk

Abstract Abstract 4212 The WHO classification revised in 2008 proposes the term, “refractory cytopenia of childhood (RCC)” for children with myelodysplastic syndrome (MDS) and a low blast count. This condition is characterized by persistent cytopenia with < 5% blasts in the bone marrow and < 2% blasts in the peripheral blood. Dysplastic changes must be recognized in more than two cell lineages, or exceed 10% in a single cell line on bone marrow aspirate smears. To differentiate between RCC and aplastic anemia (AA) is challenging, especially when the bone marrow is hypoplastic and chromosomal abnormalities are undetectable. Aplastic anemia can progress to MDS and some patients with RCC respond to immunosuppressive therapy, suggesting that the two conditions have an overlapping pathophysiology. The spectrum of RCC ranges from mild cytopenia to cytogenetic abnormalities of monosomy 7, which carries an increased risk for disease progression. However, few studies have attempted to differentiate the two diseases. To compare the clinical and biological features of AA and RCC, we retrospectively reviewed bone marrow smears from 140 patients registered for the childhood AA-97 study. The smears were classified as AA (no morphologically dysplastic changes in any hematopoietic cell lineages), AA-RCC borderline (< 10% dysplastic changes only in erythroid lineage) and RCC groups. Disease severity was classified as non-severe (n = 32), severe (n = 43) and very severe (n = 65). Aplastic anemia was idiopathic in 116 patients and associated with hepatitis in 24. Two patients had chromosomal abnormalities at presentation. The AA, AA-RCC borderline and RCC groups comprised 96 (67%), 20 (16%) and 24 (17%) patients, respectively. Bone marrow smears in the RCC group frequently presented megaloblastoid changes in cells of erythroid lineage and the pseudo-Pelger-Huet anomaly in those of myeloid lineage. Dysplastic changes in the megakaryocytic lineage were rare. The median ages were 9, 9 and 11 years in the AA, AA-RCC borderline and RCC groups, respectively. The AA group included most of the patients with hepatitis-associated AA and those with very severe AA. On the other hand, 6 (9%), 7 (16%) and 11 (35%) patients in the RCC group had very severe, severe and with non-severe disease, respectively. Four patients in the AA group developed new chromosomal abnormalities: trisomy 8 (n = 2) and monosomy 7 (n = 2). Two patients with monosomy 7 progressed to acute myeloid leukemia (AML). Three patients in the RCC group developed new chromosome abnormalities; 2 had trisomy 8 and 1 had ? X. None of the patients in the RCC group developed MDS or AML. The response rates for immunosuppressive therapy with cyclosporine and antithymocyte globulin were 55%, 50% and 67% in the AA, AA-RCC borderline and RCC groups, respectively. To determine whether the two diseases are truly different entities, response rates to immunosuppressive therapy, the frequency of clonal evolution and the genetic background should be prospectively compared between AA and RCC in a larger patient cohort. Disclosures: No relevant conflicts of interest to declare.

Suppression of Cyclin D 1 (CD1) by on 01910.Na Is Associated with Decreased Survival or Trisomy 8 Myelodysplastic Bone Marrow: A Potential Targetted Therapy for Trisomy 8 MDS.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1651-1651
Author(s):  
Aarthi Shenoy ◽  
Loretta Pfannes ◽  
Francois Wilhelm ◽  
Manoj Maniar ◽  
Neal Young ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cyclin D1 ◽  
Cultured Cells ◽  
Bone Marrow Failure ◽  
Refractory Anemia ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Diploid Cells

Abstract CD34 positive cells from patients with trisomy 8 myelodysplastic syndrome (MDS) have pronounced expression of early apoptotic markers compared to normal hematopoietic cells. However, trisomy 8 clones persist in patients with bone marrow failure and expand following immunosuppression (Sloand EM et al; Blood2005; 106(3):841). We have demonstrated up-regulation of c-myc, survivin, and CD1 in CD34 cells of patients with trisomy 8 (Sloand et al; Blood2007; 109(6):2399). Employing siRNA mediated knockdown of the anti-apoptotic protein survivin, we demonstrated a decrease in trisomy 8 cell growth and postulated that increased Cyclin D1 caused the upregulation of survivin resulting in resistance of these cells to apoptosis. Using fluorescent in situ hybridization (FISH) we showed that the novel styryl sulfone, ON 01910.Na (Vedula MS et al; European Journal of Medicinal Chemistry2003;38:811), inhibits cyclin D1 accumulation and is selectively toxic to trisomy 8 cells while promoting maturation of diploid cells. Flow cytometry of cultured cells demonstrated increased proportions of mature CD15 positive myeloid cells and decreased number of immature CD33+ cells or CD34+ blasts (Sloand EM et al; Blood2007;110:822). These encouraging in vitro data led to a phase I/II trial of ON 01910.Na in MDS patients with refractory anemia with excess blasts who had IPSS =/&gt; int-2. This study was designed to assess the safety, and activity of escalating doses of ON 01910.Na (800 mg/m2/day × 3 days, 800 mg/m2/day × 5 days, 1500 mg/m2/day × 5 days, 1800 mg/m2/day × 5 days every 2 weeks) in MDS patients. To date five MDS patients have been treated with ON 01910.Na for 4 to 16 weeks in the first two dose cohorts. Two patients had isolated trisomy 8, two had complex cytogenetic abnormalities including trisomy 8 in all aneuploid cells, and one had monosomy 7. Three and five day infusions were well tolerated. Pharmakokinetic analysis showed that the half life of the drug is 1.3 ± 0.5 hours without signs of drug accumulation. Four of five patients demonstrated a rapid and significant decrease in the number of peripheral blasts and aneuploid cells after 4 weeks of therapy (see below), concomitantly with increases in neutrophil and/or platelet counts in four patients. All four patients exhibiting a biological effect of drug treatment had trisomy 8 in their aneuploid clone prior to therapy. One monosomy 7 patient, previously refractory to EPO became responsive to Darbopoietin and another trisomy 8 patient became platelet-transfusion independent. In this early safety trial, ON 01910.Na demonstrates efficacy at early timepoints with respect to improved cytopenias and decreased blast counts. Continued enrollment and long term follow-up will further detail clinical efficacy and impact on the long term prognosis of high risk MDS patients treat with this drug. Figure Figure

Clinical Features and Prognosis of Patients with Myelodysplastic/Myeloproliferative Syndrome-Unclassified (MDS/MPD-U): Refractory Anemia with Ringed Sideroblasts with Thrombocytosis (RARS-T) Is a Favorable Prognostic Subgroup.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2612-2612
Author(s):  
Ehab Atallah ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Sherry Pierce ◽  
Elihu Estey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Median Survival ◽  
Who Classification ◽  
Marrow Transplant ◽  
The Other ◽  
Biological Behavior ◽  
Refractory Anemia ◽  
Trisomy 8 ◽  
Female Ratio

Abstract MDS/MPD-U is a newly defined clinical entity in the WHO classification. It includes patients (pts) with features of both myelodysplasia and myeloproliferation that cannot be classified under any other WHO category. In addition it includes the provisional entity RARS-T. Recent reports found an increased incidence of JAK-2 mutation in pts with RARS-T, suggesting possibly a different biological behavior. The clinical outcome of MDS/MPD-U, and in particular RARS-T, pts have not been well described. We reviewed 142 patients in the MD Anderson Leukemia Department patient database with the diagnosis of MDS/MPD or MPD-U seen from September 1987 to July 2006, and identified 32 pts that fulfilled MDS/MPD-U criteria according to WHO classification. The median age was 64 years (range 21–82), with a male: female ratio of 3:1. Six pts had RARS-T (19%). Six pts had a previous malignancy (19%), of which 3 received radiation therapy; no chemotherapy was given. Twenty-five pts (73%) were symptomatic at presentation, including fatigue in 17 (53%), weight loss in 13 (41%), fever in 2 (6%), and night sweats in 7 (22%) pts. Fifteen (45%) pts were transfusion dependent. The median hemoglobin was 9.6 g/dl (range 4.8–15.3), white blood cell count 9x109/L (range 0.6–141), platelets 234x109/L (range 7–1687), and percentage of bone marrow blasts 3% (range 0–16). Fifteen pts (45%) had more than one lineage dysplasia and 22 pts (69%) had increased reticulin in the bone marrow. Cytogenetic analysis revealed diploid cytogenetics in 13, trisomy 8 (either alone or with other abnormalities) in 8, complex cytogenetics in 3, and others in 8 pts. Twenty-two pts were treated with multiple different therapies, including hypomethylating agent in 8, with no sustained responses to any therapy. Six pts received supportive care only and 4 are unknown. Two pts underwent bone marrow transplant; one is in remission for >4 years and the other died from acute graft versus host disease. Median follow up time for alive pts was 10.6 months (range 0.3–147). Median survival of the whole group was 19 months (95% CI; range 8–29). Of the 6 pts with RARS-T, 5 had diploid cytogenetics, two had prior malignancy and 5 were transfusion dependent at the time of diagnosis. Patients with RARS-T had a significantly better survival than the other pts (median survival not reached vs. 12 months; p=0.019; Figure 1). In conclusion, pts with MDS/MPD-U have a poor prognosis with a median survival of one year. However, RARS-T represents a subgroup of pts with better prognosis and long overall survival justifying their separate categorization. Overall Survival Overall Survival

Comparison of Clinical Outcome Between Children with Aplastic Anemia and Refractory Cytopenia of Childhood Who Received Immunosuppressive Therapy with Antithymocyte Globulin and Cyclosporine

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 53-53 ◽  
Author(s):  
Asahito Hama ◽  
Hideki Muramatsu ◽  
Masafumi Ito ◽  
Masahiro Tsuchida ◽  
Hirotoshi Sakaguchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Antithymocyte Globulin ◽  
Clonal Evolution ◽  
Severe Disease ◽  
Cell Lineage ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Cell Lineages

Abstract Abstract 53 The revised 2008 WHO classification contains the newly proposed term, “refractory cytopenia of childhood (RCC)”. This term applies to children with myelodysplastic syndrome (MDS), which is characterized by a low blast count. RCC is defined as persistent cytopenia with <5% blasts in the bone marrow and <2% blasts in the peripheral blood. In addition, bone marrow aspirate smears need to show dysplastic changes in >2 cell lineages or >10% within 1 cell lineage. The distinction between RCC and aplastic anemia (AA) is normally difficult to make, especially when the bone marrow is hypoplastic and no chromosomal abnormalities can be detected. The spectrum of patients defined as having RCC is quite wide. Cases range from patients with severe hypocellular marrow and mild dysplasia in hematopoietic cells to patients with normocellular marrow and severe dysplasia that meets the criteria of refractory cytopenia with multilineage dysplasia (RCMD) in adult MDS. However, there are few studies that have focused on the difference between these two diseases. Therefore, in order to determine the specific clinical differences between AA and RCC, we retrospectively reviewed bone marrow samples of 117 bone marrow failure syndrome children (males: 69, females: 48) who were administered the same immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine. These patients were classified into AA, RCC and RCMD groups. AA patients exhibited no morphologically dysplastic changes in any of their hematopoietic cell lineages, while RCC patients had <10% dysplastic changes in >2 cell lineages, or >10% in 1 cell lineage. Patients classified as RCMD exhibited >10% of the dysplastic changes in >2 cell lineages. In accordance with the internationally defined criteria for AA, patients were further subdivided on the basis of severity, with 26 classified as non-severe, 35 as severe and 56 as very severe. At the time of initial presentation, 16 patients had a history of acute hepatitis, while one patient had the chromosomal abnormality 49,XY,+8,+16,+18. Out of the 117 patients enrolled, 58 (50%) were classified as AA, 47 (40%) as RCC and 12 (10%) as RCMD. AA and RCC patients tended to exhibit severe hypoplastic bone marrow cellularity, while the RCMD patients were normal or only exhibited mild hypoplastic marrow. The median ages in the AA, RCC, and RCMD groups were 9, 8 and 10 years, respectively. While most of the patients in the AA group (73%) had very severe disease, more than half of the RCMD patients (58%) only had non-severe disease (p<0.001). New chromosome abnormalities were detected in six patients in the AA group (monosomy 7: 4 cases, trisomy 8: 1 case, and 45,X,-X: 1 case), in one patient in the RCC group (46,XX,add(1)(q32),del(13)(q?),del(15)(q?)), and in four patients in the RCMD group (trisomy 8: 3 cases, monosomy 7: 1 case). Cumulative incidence (CI) of clonal evolution at 8 years was 10.9±4.2% in AA, 2.2±2.2% in RCC and 35.7±14.6% in RCMD (p=0.003) (Figure 1). At 6 months after IST, the response rates were 65% in AA, 70% in RCC and 58% in the RCMD group. Failure free survival (FFS) and overall survival (OS) rates at 5 years were 64.1±6.5/94.8±2.9% in AA, 60.4±7.3/97.9±2.1% in RCC and 56.3±14.8/100% in the RCMD group, respectively. A second therapeutic intervention was required in some children, with a second IST performed in eight children (3 in AA and 5 in the RCC group) and hematopoietic stem cell transplantations performed in 25 children (14 in AA, 9 in RCC and 2 in the RCMD group). Since the RCMD group exhibited a significantly high CI for clonal evolution, this suggests that the RCMD criteria should be applied to childhood MDS. However, the FFS and OS rates did not differ among these three groups. Thus, in order to definitively determine whether these three diseases are different entities, it will be necessary to use newly developed methods, such as whole exome analysis, to prospectively compare the clinical outcomes and biological findings in a larger number of the AA, RCC and RCMD patients. Disclosures: No relevant conflicts of interest to declare.

Clonality in Granulocytes Detected by an Improved HUMARA Assay: A Good Prognostic Marker in Bone Marrow Failure Patients Exhibiting Chromosomal Abnormalities of Indefinite Significance.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3702-3702
Author(s):  
Ken Ishiyama ◽  
Chiharu Sugimori ◽  
Hirohito Yamazaki ◽  
Akiyoshi Takami ◽  
Shinji Nakao
Keyword(s):  
Bone Marrow ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Failure ◽  
Bone Marrow Examination ◽  
Refractory Anemia ◽  
Clonal Population ◽  
Dividing Cells ◽  
Humara Assay

Abstract Some patients with aplastic anemia (AA) and approximately 40% of patients with refractory anemia (RA) of myelodysplastic syndrome exhibit karyotypic abnormalities in bone marrow dividing cells. Although some of the patients undergo evolution to acute myeloid leukemia (AML), others follow a clinical course similar to AA patients without chromosomal abnormalities. Except for several abnormalities such as −7 and 5q-, the clinical significance of such chromosomal abnormalities in bone marrow failure patients remains unclear. We recently developed a reliable HUMARA assay capable of detecting a clonal population in granulocytes which constitutes 30% or more of total granulocytes (Blood. 2003;102:1211–1216). Studying correlation between chromosomal abnormalities and the presence of clonality may help in understanding the pathogenetic role of chromosomal abnormalities in AA and RA. We thus analyzed 50 acquired AA and 28 RA female patients who were heterozygous for the HUMARA gene. Chromosomal abnormalities such as add(5)(q13), 9q–9q+ and del(7)(q14q22) were found in 8% of AA and 21% of RA patients. Clonality was detected in 38% of AA patients and 39% of RA patients. Incidence of chromosomal abnormalities in patients with clonality (27%) was higher than that in patients without clonality (4%, p<0.01). In two AA patients who respectively exhibited add(5)(q13) in 10% and +8 in 38% dividing cells, clonality was not detected and these abnormal clones became undetectable at the time of subsequent bone marrow examination. Clonality was detected in the other 2 AA patients respectively exhibiting 9q–9q+ in 40% and del(7)(q14q22) in 25% dividing cells, and in all 5 RA patients respectively exhibiting +8 in 10%, del(5)(q13q31), dup(1)(q32q12) in 90%, del(5)(q13), add(11)(q23), inv(9) in 65% and X,-X in 100% of dividing cells. None of the 50 AA patients including 2 patients with clonality and chromosomal abnormalities underwent evolution to AML during 2-year follow up while one of 28 RA patients who exhibited del(5)(q13q31) progressed to AML. The proportion of clonal granulocytes in total granulocytes estimated by the HUMARA assay remained unchanged in most patients with clonality except for the transformed one. These data indicate that the chromosomal abnormality in bone marrow dividing cells is not necessarily associated with presence of clonal granulocyte population in peripheral blood and that detection of clonality in granulcytes in bone marrow failure patients with chromosomal abnormalities of indefinite significance is useful in predicting prognosis of these patients.

Clinically Silent Carriers in Families with Myelodysplastic Syndrome Due to GATA2 Mutations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1264-1264
Author(s):  
Blanche P Alter ◽  
Neelam Giri ◽  
Katherine R Calvo ◽  
Irina Maric ◽  
Diane C Arthur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Family Members ◽  
Lymphoid Cells ◽  
Refractory Anemia ◽  
Cell Transplant ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Variable Expression ◽  
Increased Risk

Abstract Abstract 1264 Patients with familial myelodysplastic syndrome (MDS) associated with mutations in GATA2 are at increased risk of MDS and acute myeloid leukemia (AML). Specific clinical syndromes recently found to be due to mutations in GATA2 include MonoMAC (monocytopenia and mycobacterial infection), Emberger (MDS with severe lymphedema), and DCML (defects in dendritic cells, monocytes, and B and NK lymphoid cells). Features shared by many patients with these GATA2-associated syndromes include monocytopenia, markedly decreased B and NK cells, and clinical immunodeficiency manifested as warts and mycobacteria and fungal infections. MDS and/or AML occur with multilineage dyspoieses, particularly prominent in the megakaryocyte lineage (micromegakaryocytes, small mononuclear megakaryocytes, and large megakaryocytes with multiple separated nuclei). Several reports mention family members who are “asymptomatic,” without further details. We identified mutations in GATA2 in two of three families with familial MDS. In both families, one apparently healthy parent was found to have a GATA2 mutation; only in-depth laboratory examinations uncovered subtle findings consistent with familial GATA2 mutation in these clinically silent carriers. Family 1: The proband presented at age 15 with pancytopenia, and was found to have MDS and monosomy 7; he died from post-BMT complications including aspergillosis. His brother was found to have leukopenia, neutropenia and macrocytosis at age 13 during an infection with H1N1 influenza; the leukopenia and macrocytosis persisted. Six months later, repeat bone marrow showed early refractory anemia; the next year his marrow had myeloid dyspoiesis and dysplastic megakaryocytes; FISH showed −7 in 2.3% of cells, leading to classification as MDS-RCC. In retrospect, both boys had absolute monocytopenia (<100/uL). GATA2 sequencing of samples from the surviving brother and his 51 y.o. mother identified a deleterious mutation (c.1116_1130del15, p.C373del5). The mother had breast cancer at age 50, but otherwise was asymptomatic. Closer clinical examination revealed lower limb lymphedema, while laboratory studies revealed lymphopenia (360/uL), monocytopenia (110/uL), low lymphocyte subsets, especially CD19 (3/uL) and MCV = 100fL. Her marrow did not show overt dyspoiesis in myeloid or erythroid lineages; among mostly normal megakaryocytes there were occasional atypical forms, including some with hypolobulated or separated lobes; G-banded karyotyping and interphase FISH for −7/7q- were normal. She would not have been suspected to have GATA2-related MDS based on her clinical status, and is thus a silent carrier. Family 2: Three children in this family were diagnosed with MDS. The oldest had a history of warts and pancytopenia at age 18; his marrow showed MDS with trisomy 8. His brother was a compatible transplant donor, but he had mild pancytopenia and monocytopenia; his marrow had MDS and trisomy 8. Their sister was diagnosed at age 14 with MDS and trisomy 8; she, too, had monocytopenia. All 3 were transplanted. Subsequently, a mutation - c.1187G>A, p.R396Q - was found in GATA2, in all 3 brothers and their healthy father. He had normal blood counts (monocytes 500/uL) and immunoglobulins, but low B-cells in peripheral blood (CD20 23/uL) and bone marrow. His normocellular marrow had occasional atypical megakaryocytes with separated lobes, hypolobulation, and mononuclear and micromegakaryocytes. He, too, would not have been suspected to have GATA2-related MDS, and is also a clinically silent carrier. These two families indicate that familial GATA2-related MDS is a dominantly-inherited syndrome. In our two families, dominant inheritance was not initially considered, in part because the genetically affected parent was clinically asymptomatic. It is unclear whether GATA2 MDS shows “anticipation,” in which the younger generation is more severely affected than the parental generation. It is important that GATA2 be evaluated in families with apparently inherited childhood MDS, since the variable expression might lead inadvertently to selecting an asymptomatic GATA2 mutation carrier as a stem cell transplant donor. Genetic counseling needs to be provided with regard to risk to other family members. In addition, only long-term follow-up and surveillance of the clinically silent carriers will determine whether they remain unaffected. Disclosures: No relevant conflicts of interest to declare.

Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4427-4432 ◽  
Author(s):  
Elaine M. Sloand ◽  
Sonnie Kim ◽  
Monika Fuhrer ◽  
Antonio M. Risitano ◽  
Ryotaro Nakamura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fas Ligand ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Active Role ◽  
Trisomy 8 ◽  
Normal Cells ◽  
Monosomy 7 ◽  
Fresh Bone ◽  
Fas L

Increased apoptosis of hematopoietic progenitor cells has been implicated in the pathophysiology of cytopenias associated with myelodysplastic syndromes (MDSs), and inhibition by immunosuppression may account for the success of this treatment in some patients. We examined bone marrow and peripheral blood of 25 patients with chromosomal abnormalities associated with MDS (monosomy 7, trisomy 8, and 5q−) for evidence of apoptosis. When fresh bone marrow was examined, the number of apoptotic and Fas-expressing CD34 cells was increased in patients with trisomy 8, but decreased in monosomy 7, as compared with healthy control donor marrow. Fas expression was increased in the trisomy 8 cells and decreased in the monosomy 7 cells when compared with normal cells from the same patient. Trisomy 8 cells were more likely to express activated caspase-3 than were normal cells. For bone marrow cells cultured with Fas agonist or Fas antagonist, the percentage of cells with trisomy 8 was significantly decreased in most cases after Fas receptor triggering and increased by Fas ligand (Fas-L) antagonist (P < 0.01), suggesting increased Fas susceptibility of cells with trisomy 8. No such changes were seen in cultures of cells with 5q− or monosomy 7. Fas antagonist facilitated the expansion of cells with trisomy 8 only. Cells with trisomy 8 appear to be more susceptible to Fas-mediated apoptosis. Clinical data demonstrating the responsiveness of some patients with trisomy 8 to anti–thymocyte globulin (ATG) and cyclosporine (CsA) would favor an active role of the immune system in this syndrome.

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