Early and Sustained Response to Azacytidine in High-Risk MDS Patients with Monosomy 7 Correlates with Increased Apoptosis and Not CDKN2B Demethylation.

Abstract Disease progression in MDS is associated with CDKN2B (encodes p15INK4b) promoter methylation and an inhibition of apoptosis. We therefore studied predominantly high-risk MDS patients treated with azacitidine in order to determine whether clinical responses correlated with changes in CDKN2B promoter methylation and bone marrow apoptosis. In all, 24 patients (19 male) with a median age of 66.7 years were treated with azacitidine (75mg/m2/day x 7 days, every 28 days). Patients were FAB RA (n=2), RAEB (n=7), RAEB-T (n=13) and AML (n=2) with 18/24 having an IPSS risk of Int-2 or High. Cytogenetic abnormalities were present in 17 patients (4 patients with monosomy 7; 1 with der(7) as the sole cytogenetic abnormality and 1 as part of a complex karyotype; 4 with trisomy 8; 1 with 11q abnormalities; 1 with 5q-, 1 with 20q, 1 with iso 17p; and the remaining -y or misc). A median of 5 courses of azacitidine was administered (range: 1–13). Complete remission was achieved in 6 patients: 2 with trisomy 8, 3 with monosomy 7, and 1 with der(7). Haematological Improvement (HI) in Platelets occurred in 6 patients, HI-E in 2 patients, and HI-N in 3 patients. Five patients had a reduction in blast percentage. Importantly, even in complete cytogenetic remission bone marrow dysplasia persisted. All patients with monosomy 7/der(7) are in complete remission (median follow up of 10 months) whereas those with trisomy 8 relapsed their response at 2 and 5 months. CDKN2B promoter methylation in patients pre-treatment and at hematological remission was studied by bisulfite genomic sequencing (region: −263 to +243). There was no difference in CDKN2B methylation in CD34+ or CD33+ cells of responders and non-responders (both had low level, heterogeneous methylation patterns). However, CDKN2B was unmethylated in lymphocytes of responders and methylated in non-responders. Demethylation was not evident following treatment. Baseline bone marrow mononuclear cell apoptosis of 16 patients (12 RAEB, 2 RAEB T, 2 AML) analysed by PI/Annexin V staining (6% mean, 4.06% median); was not significantly different from normal controls (2%: mean, 0.77%; median, n=3) (2 sample T-test 0.103). From 12 treated patients, 8 patients responding to azacitidine (6 CR; 2 blast reduction with HI-E major and HI-N major, regardless of cytogenetic subtype), the mean apoptosis at the time of remission (11.61% mean; 9% median) was significantly higher than the mean apoptosis of 1.82% (median, 1.095%) in 4 non- responders (2 sample t-test p = 0.006). Azacitidine treatment induced sustained responses in all patients with monosomy 7, in whom the CDKN2B promoter is unmethylated. We propose that increased bone marrow apoptosis disrupts the leukaemic clone and leads to disease regression to an earlier stage.

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ON 01910.Na Suppresses Cyclin D1 Accumulation in trisomy 8 Myelodysplastic Syndromes Patients While Decreasing Bone Marrow CD34+ Blast Counts and Aneuploid Clone Size.

Blood ◽

10.1182/blood.v114.22.120.120 ◽

2009 ◽

Vol 114 (22) ◽

pp. 120-120

Author(s):

Elaine M Sloand ◽

Matthew J. Olnes ◽

Naomi Galili ◽

Aarthi Shenoy ◽

Loretta Pfannes ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Cyclin D1 ◽

Research Funding ◽

Treatment Options ◽

Cell Cycle Control ◽

Trisomy 8 ◽

Clone Size ◽

Monosomy 7

Abstract Abstract 120 Patients with high risk MDS can be successfully treated with 5-azacytidine, or with lenalidomide but non-responding patients have few treatment options. Chemotherapy produces significant morbidity and very short remissions and most patients are too old for bone marrow transplantation. We previously demonstrated up-regulation of c-myc, survivin, and cyclin D1 in CD34+ cells in patients with trisomy 8 (and selected patients with monosomy 7). siRNA-mediated knockdown of survivin or c-myc decreased trisomy 8 cell growth in vitro (Sloand et al, Blood 2007, 110: 822). We postulated that increased cyclin D1 causes upregulation of survivin, resulting in resistance of these cells to apoptosis. The styryl sulfone, ON 01910.Na, decreases cyclin D1 accumulation in cultured bone marrow from patients with high risk trisomy 8 MDS and in some monosomy 7 patients (who also show upregulation of cyclin D1), while selectively decreasing blasts and aneuploidy with this cytogenetic abnormality (ASH Abstracts Nov 2008; 112: 1651). Here we examine the clinical response to ON1910 in an ongoing phase I/II clinical trial in which 13 evaluable patients with intermediate-1(int-1) to high risk MDS and treatment-refractory trisomy 8 AML were enrolled. Patients were treated with escalating doses of ON 01910.Na at 800 mg/m2 × 2 days every 3/4 weeks, 800 mg/m2 × 3 days every 2 weeks, 800 mg/m2 × 5 days every 2 weeks, and 1500 mg/m2 × 2 days every 3/4 weeks at two institutions. No significant toxicity could be ascribed to the drug. Patients with trisomy 8 and monosomy 7 demonstrated significant declines in aneuploidy measured by florescence in situ hybridization (FISH) (mean aneuploidy; 50% before and 24% after 1 cycle of treatment; p=0.02 :Fig below). Rather than becoming cytopenic, many patients showed substantial improvements of blood counts and one patient (01-02; graphic shown below) became red cell transfusion-independent and maintains his remission 14 months after stopping therapy. Cyclin D1 measurement by flow cytometry showed decreases of this protein in both CD34 and CD33 cells during infusion of ON 1910 infusion (example shown in Fig below). Results from individual evaluable patients are shown in table 1. These results indicate that modulation of cell cycle control by cyclin D1 may represent a novel targeted approach for trisomy 8 and monosomy 7 MDS. Disclosures: Sloand: Onconova: Research Funding. Olnes:Onconova: Research Funding. Galili:Onconova: Research Funding. Wilhelm:Onconova: Employment. Groopman:Onconova: Membership on an entity's Board of Directors or advisory committees. Raza:Onconova: Research Funding.

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Secondary CNS Relapse in DLBCL in the Rituximab Era - an Analysis of Prospective Studies

Blood ◽

10.1182/blood.v124.21.1644.1644 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1644-1644 ◽

Cited By ~ 1

Author(s):

Abhimanyu Ghose ◽

Harold Kunal Elias ◽

Gunjan Guha ◽

Mahender Yellu ◽

Ria Kundu ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Prospective Studies ◽

T Test ◽

Population Characteristics ◽

Cns Prophylaxis ◽

Cns Relapse ◽

Study Population ◽

The Mean ◽

One Way Anova

Abstract INTRODUCTION CNS relapse in DLBCL carries poor prognosis. Some studies have suggested decreased incidence with rituximab, but there are several others reporting otherwise. We analyzed prospective studies in literature to understand the role of rituximab and CNS prophylaxis in DLBCL, in comparison to CHOP based therapy. METHOD Extensive searches using PUBMED, EMBASE, CENTRAL and major hematology conferences were conducted for prospective studies. The keywords CNS, diffuse large B-cell lymphoma, relapse, prophylaxis, rituximab, CHOP were used. Inclusion: (i) prospective or randomized trials (ii) Entire study population or a significant majority of patients were newly diagnosed DLBCL, (iii) no evidence of CNS involvement at baseline, (iv) use of rituximab-chemotherapy or CHOP-based chemotherapy, (v) have data relevant to our study. Exclusion: (i) retrospective studies, review article or case reports, (ii) exclusively testicular, mediastinal or double hit lymphoma, (iii) HIV positive patients. Data is presented as mean ± standard error of mean. Significant differences (at P<0.05) between groups and couplets were determined by one-way ANOVA and by two-tailed unpaired t-test respectively. Significance of the Kaplan-Meier survival curves was determined using Log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests. RESULTS The study population characteristics are shown in Table. The mean incidence of CNS relapse with rituximab-chemotherapy (R-CHOP/R-CHOEP) was found to be 5.52% (3.21%-7.73%), while that with CHOP-based chemotherapy alone was 4.43% (3.53% -5.33%). No significant difference was observed by two-tailed unpaired t test (P = 0.94). The median time from diagnosis to CNS relapse was 6.5-7 months. The mean incidence of leptomeningeal, parenchymal and both relapses in the rituximab-chemotherapy group were 38.62(±1.93)%, 57.32(±3.06)%, 5.36(±1.79)% compared to 16.17(±0.44)%, 66.17(±0.44)%, 22.06(±0.41)% with chemotherapy alone. One-way ANOVA also showed that use of rituximab resulted in statistically significant (P<0.0001) differences between the patterns of CNS relapse. About 74.1% of CNS relapses among patients receiving rituximab-chemotherapy were isolated CNS relapse, compared to 69.2% for those receiving CHOP chemotherapy. The mean incidence of CNS relapse with the use of any prophylactic CNS directed therapy was observed to be a significantly (P = 0.044) lower [2.97% (2.32%-3.62%)] compared to that without [6.12% (5.91%-6.335]. Median survival following CNS relapse of 365 days following rituximab based chemotherapy and 75 days after CHOP were significantly different (HR for CHOP use 4.867±0.77 at P<0.05). CONCLUSION Rituximab hasn't significantly decreased overall incidence, but causes less parenchymal CNS relapse. CNS prophylaxis has a definite role in high risk population. There is significantly better survival after CNS relapse in the rituximab era. Abstract 1644. TABLE STUDY Age (yr) Sex (M:F) No. Stage 3/4 IPI int-high/ high (>=3 IPI or >=2 aa IPI) Extranodal (>=2) high LDH Follow up (m) Criteria for CNS prophylaxis Patients receiving CNS prophylaxis (IT=intrathecal, S=systemic) Chemo Tilly 2003 61-69 ACVBP vs CHOP : M 182 vs 177 F 141 vs 135 635 (501 DLBCL) 267 vs 253 210 vs 207 (aa IPI) 155 VS 156 231 VS 241 68 None for CHOP VS ACVBP (IV methotrexate, etop + IT mtx) 323 (ACVBP) 323 ACVBP vs 312 CHOP Feugier 2004 69 M 92 (CHOP-R) vs 107 (CHOP) 202 vs 197 161 vs 157 121 vs 120 61 vs 51 131 vs 132 24 NA no prophylaxis 202 R-CHOP Vs 197 CHOP Bernstein 2009 97/ 225 for CHOP were >60 yrs NR 899 aggressive lymphoma 191/ 225 CHOP 95/ 225 CHOP 81/225 CHOP 146/ 225 CHOP 20 years none for CHOP 121 IT MTX or radiation (24 Gy) 225 CHOP vs ProMACE-CytaBOM vs mBACOD vs MACOP-B Boehme 2009 68 648 vs 569 1217 (944 DLBCL) 687 507 212 602 24 bone marrow, testes, sinuses, orbits, oral cavity, tongue, salivary glands. 475/1217 (IT-MTX) 608 RCHOP Vs 609 CHOP Kim 2012 59.5 NR 564 276 192 193 NR 10.5 ≥1 risk factor 59 IT RCHOP Kumar 2012 56 (prophylaxis) VS 58 (no prophylaxis) male: 74 vs 476 female: 43 vs 396 989 85 vs 454 55 vs 240 66 vs 220 57 vs 372 30 High risk site involvement : orbit, testis, peripheral blood, vertebra, bone marrow, nasal/paranasal sinuses 117/989 IT- 84/117 (AraC/MTX) S--33/117 (MTX) R-CHOP Holte 2013 54 97 vs 59 156 (145 DLBCL) 150 156 41 151 36 everyone 156/156 (S- Ara-c+ MTX) 1 dose of IT-MTX RCHOEP Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Bone marrow mononuclear cell telomere length in acute myeloid leukaemia and high‐risk myelodysplastic syndrome

European Journal Of Haematology ◽

10.1111/ejh.13196 ◽

2019 ◽

Vol 102 (3) ◽

pp. 218-226

Author(s):

Marie Warny ◽

Jens Helby ◽

Henrik Sengeløv ◽

Børge G. Nordestgaard ◽

Henrik Birgens ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Acute Myeloid Leukaemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukaemia ◽

Telomere Length ◽

Mononuclear Cell ◽

Bone Marrow Mononuclear Cell ◽

Acute Myeloid

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Partially matched bone marrow transplantation in patients with myelodysplastic syndromes.

Journal of Clinical Oncology ◽

10.1200/jco.1988.6.12.1851 ◽

1988 ◽

Vol 6 (12) ◽

pp. 1851-1855 ◽

Cited By ~ 30

Author(s):

N J Bunin ◽

J T Casper ◽

C Chitambar ◽

J Hunter ◽

R Truitt ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Rabbit Serum ◽

Normal Rabbit Serum ◽

Trisomy 8 ◽

Monosomy 7 ◽

Patients Âgés ◽

Curative Therapy ◽

Unrelated Donors

Six patients with a myelodysplastic syndrome (MDS) were treated with bone marrow transplantation (BMT) using partially-matched related (3) or unrelated (3) donors. Patients' ages ranged from 7 to 31 years (median, 10 years). Bone marrow karyotype abnormalities were present in five patients included four with monosomy 7 and one with trisomy 8. One patient was in complete remission before transplant; the remaining five had excess of blasts or were undergoing leukemic transformation. Donor, and recipient were mismatched at the DR locus (2), A locus (2), B locus (1), or A and B loci (1). Conditioning included busulfan, cytarabine, cyclophosphamide, methylprednisolone, and total body irradiation. Cyclosporine was started on day -1. Marrows were T-cell depleted using a monoclonal antibody (MoAb) (CD3) and normal rabbit serum. Four patients engrafted routinely. One patient died of aspergillosis before engraftment (day 12) and one patient failed to engraft on first attempt, but engrafted following additional preparation. Median time to neutrophils greater than 500/microL and platelets greater than 25,000/microL were 16 and 19 days, respectively. Acute graft-v-host disease (GVHD) was less than or equal to grade II in all patients. One patient died with recurrent disease (day 257). One patient died at day 515 of pancreatitis and respiratory failure. Three patients are alive and disease-free at 240, 395, and 560 days post-BMT including two patients with unrelated donors. Partially matched T-depleted bone marrow from related or unrelated donors may be effective, and possibly curative therapy for patients with MDS who lack a histocompatibility locus antigen (HLA)-identical sibling donor.

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Allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: impact of conditioning regimen without total-body irradiation--a report from the Société Française de Greffe de Moelle.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.6.1217 ◽

1994 ◽

Vol 12 (6) ◽

pp. 1217-1222 ◽

Cited By ~ 67

Author(s):

G Michel ◽

E Gluckman ◽

H Esperou-Bourdeau ◽

J Reiffers ◽

J L Pico ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

Bone Marrow Transplantation ◽

High Risk ◽

Complete Remission ◽

Total Body Irradiation ◽

Conditioning Regimen ◽

Total Body ◽

First Complete Remission ◽

Risk Of Relapse

PURPOSE To analyze the French experience of chemotherapeutic preparation before human leukocyte antigen (HLA)-identical bone marrow transplantation (BMT) in children with acute myeloblastic leukemia (AML) in first complete remission (CR). PATIENTS AND METHODS The data base used for this study was a French BMT registry for childhood AML. Twenty-three children were conditioned with busulfan and 120 mg/kg cyclophosphamide (Bu-Cy 120 group). Nineteen received busulfan and 200 mg/kg cyclophosphamide (Bu-Cy200 group). During the same time period, 32 patients were prepared with total-body irradiation (TBI group) most often in combination with 120 mg/kg of cyclophosphamide. RESULTS The probability of relapse was 54%, 13%, and 10% for the Bu-Cy120, Bu-Cy200, and TBI groups, respectively (P < .05 in the univariate analysis, log-rank test, 2 df). In the multivariate analysis, a conditioning regimen with Bu-Cy120 was significantly associated with a higher risk of relapse (P = .02; relative risk, 3.62). The probability of transplant-related mortality (TRM) was 0% for Bu-Cy120, 5% for Bu-Cy200, and 10% for TBI. Kaplan-Meier estimations of event-free survival (EFS) were 46% +/- 24%, 82% +/- 18%, and 80% +/- 14%, respectively, for the three groups, with median follow-up durations of 28 months (range, 3 to 78), 31 months (4 to 68), and 48 months (2 to 73). In the multivariate analysis, two factors adversely affected EFS: a conditioning regimen with Bu-Cy120 (P = .07) and a long interval from diagnosis to BMT (> or = 120 days, P = .08). CONCLUSION Bu-Cy120 is a well-tolerated preparation, but results in a high risk of relapse for children with AML in first CR. This high risk of relapse is not observed when the dose of cyclophosphamide is increased to 200 mg/kg.

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Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia

Blood ◽

10.1182/blood-2002-11-3419 ◽

2003 ◽

Vol 102 (4) ◽

pp. 1202-1210 ◽

Cited By ~ 57

Author(s):

Eric Solary ◽

Bernard Drenou ◽

Lydia Campos ◽

Patricia de Crémoux ◽

Francine Mugneret ◽

...

Keyword(s):

Bone Marrow ◽

Multidrug Resistance ◽

Complete Remission ◽

Significant Influence ◽

Acute Myelogenous Leukemia ◽

De Novo ◽

Myelogenous Leukemia ◽

P Glycoprotein ◽

Acute Myelogenous ◽

The Mean

Abstract Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein–mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These patients randomly received (n = 213) or did not receive (n = 212) a 30 mg/kg/day continuous intravenous infusion of quinine in combination with induction chemotherapy combining idarubicine and cytarabine and, depending on bone marrow examination at day 20, an additional course of cytarabine and mitoxantrone. The mean steady-state quinine concentration was 7.8 mg/L and the mean multidrug resistance reversing activity of serum was 1.96. Complete remission (CR) was obtained in 344 patients (80.9%) without significant influence of quinine. Of the patients in complete remission, 82 were assigned to receive HLA-matched bone marrow transplants, whereas 262 were assigned to 2 courses of intensive consolidation chemotherapy, with or without quinine, depending on initial randomization. The 4-year actuarial overall survival (OS) of the 425 eligible patients was 42.0% ± 2.5%, without significant influence of quinine. Of 160 patients who could be studied, 54 demonstrated rhodamine 123 efflux. In these patients, quinine significantly improved the CR rate from 12 of 25 (48.0%) to 24 of 29 (82.8%) (P = .01). However, there was no significant difference in OS. Neither mdr1 gene nor P-glycoprotein expression influenced the outcome. We conclude that quinine does not improve the survival of adult patients with de novo AML, even though it improves CR rate in a small subgroup of patients defined by rhodamine 123 efflux.

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Autologous Transplantation of Non-Cryopreserved Bone Marrow for the Treatment of High-Risk Adult Acute Lymphoblastic Leukemia in First Complete Remission.

Blood ◽

10.1182/blood.v106.11.5492.5492 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5492-5492

Author(s):

Jerzy Holowiecki ◽

Sebastian Giebel ◽

Malgorzata Krawczyk-Kulis ◽

Maria Sadus-Wojciechowska ◽

Lucja Kachel ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Complete Remission ◽

Hospital Stay ◽

Lymphoblastic Leukemia ◽

Autologous Transplantation ◽

Hematopoietic Stem ◽

Long Term Outcome ◽

First Complete Remission

Abstract Autologous hematopoietic stem cell transplantation (HSCT) is a recognised option of post-consolidation therapy for adults with high-risk acute lymphoblastic leukemia (ALL) not having a donor. G-CSF-stimulated peripheral blood SCT results in faster recovery compared to cryopreserved bone marrow transplantation (BMT) and is currentlly used by the majority of centres. In the current study we analyze the feasibility of a new technique of autologous BMT, which does not require cryopreservation. 115 adult patients (median age 24.5 (16–53) years) with high-risk ALL in first complete remission (CR) were treated with autologous BMT between 1991–2004 in a single center using uniform standard operating procedures. Immune phenotype was as follows: proB 17%, preB 9%, common 44%, mature B 1%, preT 9%, mature T 19%. Initial WBC was >30 G/l in 30% of patients. 8% of patients were bcr/abl(+), 38% required >1 course of induction to achieve CR. Bone marrow was collected in general anaesthesia and further stored for 72 hours in 4degC without any processing and reinfused 24 hours after completion of myeloablative therapy. Conditioning regimen (CAV) consisted of cytarabine 2x1000 mg/m2 d. −3, −2, −1, etoposide 800 mg/m2 d. −3, −2, cyclophosphamide 60 mg/kg d. −3, −2. Median NC dose was 2.0 (0.9–10.8)x10e8, CD34+cell dose − 1.6 (0.4–15)x10e6/kg. Median recovery of ANC>0.5 G/l equaled 16(11–45) days, PLT>50 G/l – 16(10–53) days (11% patients received cytokines to stimulate NC recovery). Median duration of hospital stay since the date of BMT was 19(13–51) days. The OS rate at 10 years (median follow-up 6.5 years) equaled 57% (+/−5%), LFS rate − 47% (+/−5%). Three patients died within 100 days after ABMT of septic infections (non-relapse mortality rate − 2.6%). None of the analysed factors (age, WBC at diagnosis, immonophenotype, time to achieve CR) was found to influence the long-term outcome. We conclude that autologous transplantation of non-cryopreserved bone marrow after CAV conditioning is feasible for adults with high-risk ALL. The method is characterized by fast recovery, short hospital stay and low non-relapse mortality, and may constitute good alternative to autologous PBSCT.

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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 ◽

10.1182/blood.v112.11.1651.1651 ◽

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 =/> 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

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Clinical Features of Shwachman-Diamond Syndrome Patients Lacking Biallelic SBDS Mutation

Blood ◽

10.1182/blood.v118.21.4367.4367 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4367-4367

Author(s):

Akiko Shimamura ◽

Audrey Anna Bolyard ◽

Satabdi Chakrabarti ◽

Jordan M. Bond ◽

Theresa Cole ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplant ◽

Marrow Transplant ◽

Trisomy 8 ◽

Monosomy 7 ◽

The North ◽

Pancreatic Dysfunction ◽

Shwachman Diamond Syndrome ◽

Biallelic Mutations ◽

Clonal Abnormalities

Abstract Abstract 4367 Shwachman-Diamond syndrome (SDS) is an autosomal recessively inherited disorder defined clinically by marrow failure and exocrine pancreatic dysfunction. Previous research estimates that 90% of patients harbor biallelic mutations in the SBDS gene. The clinical course of patients lacking SBDS mutations has not been examined previously. To address this question, we examined 102 patients referred to the North American Shwachman-Diamond syndrome registry (SDSR) or the Severe Chronic Neutropenia International Registry (SCNIR). Seventy-nine subjects were <18 years of age (median age 8.8, range 2.8–17.6), with a male:female ratio of 1:1.7. Twenty-three subjects were >18 years of age (median 23.6, range 18.2–61.9), with a male:female ratio of 1.6:1. SBDS genetic analyses were available for 75 patients; 48 of 75 have biallelic SBDS mutations. Twenty-seven patients were phenotypically consistent with SDS, as demonstrated by exocrine pancreatic dysfunction and marrow failure, but either lacked SBDS mutations (24 patients) or harbored only one mutant SBDS allele (3 patients). The remaining 27 subjects were indeterminate for SDS or lacked sufficient data. In this study, we compared the hematologic complications of the 75 SDS patients presenting with or without SBDS mutations. Fifty-two subjects had complete hematological data. Of the 28 patients with SBDS mutations, neutropenia was noted in 21 (6 severe with ANC <500/mm3), thrombocytopenia in 14 (2 severe with platelets <20,000/mm3), macrocytosis in 5, and anemia in 20 (1 transfusion-dependent). Of the 24 subjects lacking biallelic SBDS mutations, 20 had neutropenia (11 severe) and 8 had thrombocytopenia (6 severe), 1 had macrocytosis and 15 had anemia. Bone marrow reports were available for 47 patients. Of the 21 patients with SBDS mutations, 17 had marrow hypoplasia, 5 had marrow dysplasia. Nine showed clonal abnormalities including del(20q), iso(7q), monosomy 7, trisomy 8, and trisomy 7q21. Of the 26 patients without biallelic mutations, 16 had marrow hypoplasia, 3 had marrow dysplasia and 8 showed clonal abnormalities including del(20q), monosomy 7, del(3q), del (21q), del (7q), and iso(7q). Three subjects (2 with biallelic SBDS mutations, 1 lacking SBDS mutations) developed MDS. One patient without SBDS mutations developed AML. Three deaths have been reported. All deaths involved patients with clinical SDS lacking SBDS mutations. Causes of death were AML, failure to engraft during bone marrow transplant, and sepsis. Eight patients (4 with biallelic SBDS mutations and 4 lacking SBDS mutations) underwent bone marrow transplant. These data suggest that patients without mutations in SBDS may be more common than previous estimates. The hematological complications for patients with and without SBDS mutations appear to be similar. These Registries offer important opportunities to study the genetic and pathophysiological mechanisms for SDS. Disclosures: Boxer: Amgen: Equity Ownership. Dale:Amgen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Prognostic and therapeutic impact of cytogenetic abnormalities in patients with myelodysplastic/myeloproliferative neoplasms, unclassifiable.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.7058 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 7058-7058

Author(s):

Abhishek Avinash Mangaonkar ◽

Hassan Alkhateeb ◽

Aref Al-Kali ◽

Naseema Gangat ◽

Kebede Begna ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Treatment Guidelines ◽

Myeloproliferative Neoplasms ◽

Univariate Analysis ◽

Prognostic Impact ◽

Trisomy 8 ◽

Abnormal Karyotype ◽

Immature Myeloid Cells

7058 Background: The 2016 WHO classification includes myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U), as an MDS/MPN overlap syndrome not meeting criteria for well-defined entities such as CMML. No standard prognostication or treatment guidelines exist for such patients. Methods: We retrospectively identified MDS/MPN-U cases from 1990-2016 through our myeloid malignancies database. All bone marrow reports were reviewed to ensure compliance with 2016 WHO criteria. Clinical & cytogenetic parameters at diagnosis were assessed & compared with treatment outcomes. Results: Eighty nine patients met study criteria, with a median age of 69 years (range: 37-93); 58 (65%) males. Median follow-up was 22.2 months (range: 0-172), with 41 (46%) deaths & 13 (15%) leukemic transformations. Median OS was 24.8 months (range: 0-172). 43 (53%) patients had an abnormal karyotype, with common abnormalities being trisomy 8 (12%), complex karyotype (9%) & del (20q) (6%). Given the fewer types of abnormalities identified, the IPSS cytogenetic stratification was more effective than IPSS-R, with risk categorization including; 45 good (55%), 20 intermediate (25%) & 16 high risk (20%) respectively (8 unavailable). On univariate analysis, increased age (p = 0.05), decreased hemoglobin (p = 0.02), higher ANC (p = 0.03), circulating immature myeloid cells (p = 0.02), higher LDH (p = 0.009), absence of bone marrow ring sideroblasts (p = 0.001) & higher risk (intermediate & high) IPSS cytogenetic categories (p = 0.01) adversely impacted OS. In a multivariate model that included the aforementioned variables, higher risk IPSS cytogenetics retained a negative prognostic impact (p = 0.04). 28 patients received a median of 6 cycles (range: 1-21) of hypomethylating agent therapy (HMA), with an overall response rate of 18% (CR-3, PR-2). All responders had an abnormal karyotype (p = 0.01). However, HMA did not affect either OS or LFS. Conclusions: Intermediate & high risk IPSS cytogenetic categories independently & adversely impact survival in WHO defined MDS/MPN-U patients. HMA use did not impact OS; however, patients with abnormal karyotypes were more likely to respond.

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