Presence Of Monosomal Karyotype Research Articles

Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS

Allogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2–4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32–1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28–1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome.

CPX-351 Induces Deep Response and Suppress the Impact of Poor Prognosis Mutations (TP53, ASXL1, RUNX1 and EVI1) Defined By ELN-2017 in t-AML and MRC AML: A Report from a Multicentric French Cohort

CPX-351 Induces Deep Response and Suppress the Impact of Poor Prognosis Mutations (TP53, ASXL1, RUNX1 and EVI1) Defined By ELN-2017 in t-AML and MRC AML: A Report from a Multicentric French Cohort

Frequency and Prognostic Significance of the Presence of Additional Cytogenetic Abnormalitions (ACA) to the Philadelphia (Ph) Chromosome in Young Adults with ACUTE Lymphoblastic Leukemia (ALL) Treated with the ALL Ph08 Trial from the Pethema Group

Background. About 25-35% of adult patients with acute lymphoblastic leukemia (ALL) show the Philadelphia (Ph) chromosome. Their outcome has improved with the combination of tyrosine kinase inhibitors (TKI) and chemotherapy, generally followed by allogeneic hematopoietic stem cell transplantation (alloHSCT). However, few series have evaluated the prognostic value of the additional cytogenetic alterations (ACA) to the Ph chromosome, with contradictory results. The aim of this study was to analyse the frequency, type and prognostic significance of ACA to the Ph chromosome in young adults with Ph+ ALL treated with the ALL Ph-08 trial from the PETHEMA group.Patients and methods.Between 2008 and 2016, 95 patients with Ph+ ALL from 30 Spanish hospitals were included in the ALL Ph08 trial. This trial includes concurrent administration of imatinib (600 mg/d) and standard induction and consolidation chemotherapy, followed by alloHSCT (or autologous HSCT if alloHSCT not feasible) and maintenance chemotherapy with imatinib in cases of MRD persistence of reappearance after alloHSCT (Ribera et al, Br J Haematol 2012; 159: 78-81). The cytogenetic reports were centrally reviewed. Major molecular response (MMR) was defined as BCR-ABL/ABL ratio ²0.1% and complete molecular response (CMR) as BCR-ABL/ABL ratio ²0.01% or undetectable.Results. In 74 out of 95 patients the karyotype was evaluable after review (in the remaining 21 cases the diagnosis was carried out by FISH [n=9] or PCR [n=12]). The median age of the 74 patients was 39 years (limits 19-63) and 44 patients (59%) were males. The median WBC count was 17.6x109/L (limits 0.2-390) and 8 out of 66 evaluable patients had CNS involvement at diagnosis. The CR rate was achieved in 72/74 patients (97%) (1 patient did not achieve CR and 1 died during induction therapy). To date, 57 patients underwent to HSCT, of them 46 were in MMR, at least, at the time of HSCT. With a median follow-up of 1.89 years (limits 0.10-7.38) the probabilities of the CR duration, OS and EFS at 4 years were 69% (95%CI: 54%-84%), 39% (23%-55%) and 38% (23%-53%), respectively. Out of 74 patients, 52 (70%) showed at least one ACA and in the remaining 22 (30%) the t(9;22) was the only cytogenetic alteration. No clinical or biologic differences were observed on comparison of the two groups of patients. Twenty (27%) out of 73 evaluable patients showed trisomies and 19 (26%) monosomies. No differences in CR attainment were observed according the presence and type of ACA. The 4-yr. probability of CR duration in patients with t(9;22) and one or more monosomies (monosomal karyotype) vs. those without monosomies was 23% (95%CI: 0%;49%) vs. 88% (77%;99%) (p<0.001) and the 4-yr. EFS probability was 15% (95%CI: 0%;34%) vs. 48% (30%;66%) (p=0.032). Patients with one or more trisomies showed better CR duration probability at 4-years (86% [95%CI: 60%;100%] vs. 60% [42%-78%], p=0.040).The probability of CR duration was higher in patients who achieved MMR before HSCT (79% [63%-95%] vs. 38% [0%-77%], p=0.021). No other clinical or biologic parameter showed prognostic significance. By multivariate analysis the only variable with prognostic impact for CR duration and EFS was the presence of monosomal karyotype (HR [95%CI] 7.95 [2.04-30.95], p=0.003 and 2.18 [1.05-4.51], p=0.036, respectively).Conclusions. In young patients with Ph+ ALL treated within the ALL Ph08 trial, the frequency of ACA was high, being trisomies and monosomies shown in similar frequency. The monosomal karyotype was the most important unfavourable prognostic factor in this series of patients.Funded in part by grants PI10/01417 (FIS), RD12-0036-0029 from RTICC, Instituto Carlos III and RD14-SGR225(GRE), Generalitat de Catalunya. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation Outcomes in Monosomal Karyotype Myeloid Malignancies.

The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n= 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n= 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n= 3360; MDS, n= 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+ AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P= .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed.

Clinical Impact of Complex Karyotype, Monosomal Karyotype and Acquisition of Chromosomal Abnormalities in Patients with Myelodysplastic Syndromes

ObjectivesDespite azacitidine prolonging the survival of patients (pts) with myelodysplastic syndromes (MDS), the overall survival (OS) of those with complex karyotype (CK) or monosomal karyotype (MK) remains dismal, and optimal treatments for these pts have not been established. Furthermore, the prognostic impact of acquisition of additional cytogenetic abnormalities (ACA) during the follow-up periods is poorly understood. In this retrospective study, we aimed to evaluate the prognostic impact of CK, MK, and ACA in MDS pts, and determine optimal treatments.MethodsWe collected clinical data on consecutive adult MDS pts who first visited Kobe City Medical Center General Hospital or Kyoto University Hospital between January 2004 and April 2014. Patients were divided into groups based on the number of chromosomal abnormalities (abns) and presence or absence of MK. ACA was defined as any gain in the number of chromosomal abns before treatments. Survival analysis was adjusted using the following variables; sex, age, IPSS-R parameters and MK. A Cox regression model was applied to the results. ACA was fit into the model as a time-dependent covariate.ResultsA total of 299 pts with MDS were identified, five of which were excluded from the study due to a lack of chromosomal information. Median follow-up time was 24.5 months (M). Pts’ characteristics, treatments and incidence of ACA are summarized in Table 1. Among 47 CK pts, 34 (72%) carried MK. Survival analysis revealed that presence of 4 or more chromosomal abns was significantly associated with increased mortality. Among pts with 2–3 chromosomal abns, the presence of MK was a poor prognostic factor, although it had no significant impact on survival in pts with 4 or more abns (Figure 1). Median survival times of pts with 2–3-abns without MK, with 2–3-abns together with MK, and 4 or more abns were 39 M, 12 M (HR 6.6, 95% confident interval, [2.6-17], p < 0.001), and 9 M(HR 5.4, [3.1–9.3], p < 0.001) respectively. Regarding ACA, changes from normal karyotype (NK) to 1 abn (N=15) had no effect on mortality, but changes from NK to 2 or more abns (N=10) led to a significant increase in mortality (HR 9.2 [3.7–24], p < 0.001). Further, changes from 0–3 chromosomal abns without MK to either MK or 4 or more abns were associated with higher mortality (HR 2.7 [1.0–7.1], p = 0.045). Among pts with 2–3-chromosomal abns with MK or those with 4 or more abns at diagnosis (N=45) or during follow-up (N=10), 20 (36%) underwent allogeneic stem cell transplantation (allo-SCT) and only six survived beyond 24 M. Five of these received allo-SCT and were alive at the last follow-up. The other was treated with azacitidine and lived for 33 M.ConclusionThis study revealed that MK or 4 or more chromosomal abns is significantly associated with high mortality. Among NK pts, acquisition of 2 or more abns was associated with a poor outcome. Allo-SCT is the only strategy to increase the chance of long-term survival for pts with MK or 4 or more chromosomal abns, although only a few survivors were identified even after allo-SCT. More data are needed to identify the optimal therapeutic options for this subgroup.Table 1Clinical parameters and treatments received by patientsNumber of abnormalities<3 (N=247) (%)3 (N=10) (%)4<= (N=37) (%)p-valueSex (male/female) (N=195/99)170(69)/77(31)4(40)/6(60)21(57)/16(43)0.04Age =<65 (N=158) >65 (N=136)130(53) 117(47)7(70) 3(30)21(57) 16(43)0.89Bone marrow blast% <=2 (N=123) >2-<5 (N=45) >=5-<=10 (N=50) >10 (N=74) Missing (N=2)112(45) 35(14) 39(16) 59(24) 2(0.81)4(40) 3(30) 2(20) 1(10) 07(19) 7(19) 9(24) 14(38) 00.06Hemoglobin (g/dL) >=10 (N=91) >=8-<10 (N=93) <8 (N=106) Missing (N=4)83(34) 72(29) 88(36) 4(1.6)3(30) 5(50) 2(20) 05(14) 16(43) 16(43) 00.076Platelets (103/ƒÊL) >=100 (N=118) >50-<100 (N=82) <50 (N=90) Missing (N=4)100(40) 68(28) 75(30) 4(1.6)6(60) 1(10) 3(30) 0(0)12(32) 13(35) 12(32) 00.50Neutrophils (/ƒÊL) >=800 (N=183) <800 (N=106) Missing (N=5)160(65) 82(33) 5(2.0)5(50) 5(50) 018(49) 19(51) 00.078Monosomal karyotype (N=39)5(2)3(30)31(79)<0.001ACA (N=37)30(12)1(10)6(16)0.7Initial treatments CC (N=92) azacitidine (±CC) (N=63) Chemo-naïve allo-SCT (N=37) Palliative CT/BSC (N=102)78(32) 43(17) 31(13) 95(38)1(10) 3(30) 3(30) 3(30)13(35) 17(46) 3(8) 4(11)<0.001Allo-SCT (total)79(32)7(70)13(35)0.77 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Transplantation for myelodysplastic syndromes 2013

The only current treatment capable of curing patients with myelodysplastic syndromes (MDS) is allogeneic haematopoietic stem cell transplantation (HCT). However, many MDS patients are older, often with substantial comorbid conditions, and the disease is heterogeneous. As a consequence, results of HCT vary considerably, and the practices of HCT for MDS are evolving. The newly published modified International Prognostic Scoring System (IPSS-R), developed for nontransplanted patients, also correlates with post-HCT outcome, with the patient's karyotype having the strongest impact. The presence of monosomal karyotype and various genetic and molecular markers have also been shown to have a prognostic value. The use of hypomethylating agents, before or after HCT, may reduce the post-HCT relapse risk or delay relapse. Low and reduced-intensity conditioning regimens have allowed to transplant growing numbers of older patients with MDS, and the development of novel regimens may lead to improved relapse-free survival even in patients with high-risk cytogenetics. The optimal stem cell source may differ for different patient populations and different disease risk categories. Transplant results for MDS have improved in recent years. Some patients even in the eighth decade of life have been transplanted successfully. Ongoing studies are aimed at further reducing transplant-related toxicity, graft-versus-host disease and post-HCT relapse.

Evaluation of IPSS-Revised (IPSS-R) Cytogenetic Risk Stratification and Prognostic Impact of Monosomal Karyotype in 1,014 Patients with Myelodysplastic Syndromes (MDS)

AbstractAbstract 423 Background:Cytogenetic abnormalities at diagnosis are seen in 20–70% of patients with myelodysplastic syndromes (MDS). The International Prognostic Scoring System -revised (IPSS-R) classifies these cytogenetic abnormalities into five prognostic groups: very good (del(11q), ΠY with overall survival (OS) of 61 months); good (normal, del(20q), del(5q), del(12p) with OS 49 months); intermediate (+8,7q-, i(17q),+19,+21 with OS 26 months); poor (der(3)q21/q26, −7, complex with 3 abnormalities with OS 16 months); and very poor (complex with >3 abnormalities with OS of 6 months) (Schanz J, JCO 2012, Greenberg P, Blood 2012). Monosomal karyotype (MK) is defined as the presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality. We have previously shown that MK identifies a prognostically worse subgroup of MDS patients with a complex karyotype (Patnaik M, Leukemia 2010). Objectives:i.To validate the IPSS-R cytogenetic risk groups in an independent cohort of patients with MDS.ii.Evaluate the prognostic impact of MK to refine the current IPSS-R cytogenetic risk classification. Methods:The Mayo Clinic database for MDS was used to identify patients in whom bone marrow histologic and cytogenetic information was obtained at the time of diagnosis. WHO criteria were used for MDS diagnosis and leukemic transformation. Results:i) Patient characteristics: A total of 1,014 patients met the above-stipulated criteria. Median age of the cohort was 71 years (range: 18–98 years) with 684 (67%) males. 819 patients (81%) had primary MDS with 195 cases (19%) of therapy-related MDS. 759 patients (75%) are dead at a median follow-up of 18 months (range: 0–223 months) with leukemic transformation documented in 125 cases (12%). IPSS-R risk distribution was as follows: very low (n=149, 15%), good (n=261, 26%), intermediate (n=221, 22%), high (n=131, 13%), and very high (n=252, 25%).ii) IPSS-R karyotype (Entire cohort; n=1,014): The five cytogenetic groups by IPSS-R were as follows: very good (n=43, 4%), good (n=577, 57%), intermediate (n=187, 18%), poor (n=83, 8%), and very poor (n=124, 12%). We evaluated the prognostic impact of the above groups by Kaplan Meier and Cox proportional hazards analysis. OS for the five cytogenetic groups was as follows: good (36 months), very good (28 months), intermediate (20 months), poor (13 months), and very poor (6 months) (Figure 1). OS of patients with very good karyotype was significantly better than patients with very poor and poor karyotype (p<0.0001, RR 3.2 and p=0.04, RR 1.6 respectively) but similar to patients with intermediate and good karyotype (p=0.22 and 0.28 respectively).iii) IPSS-R karyotype (Primary MDS; n=819): Cytogenetic risk groups by IPSS-R were as follows: very good (n=38, 5%), good (n=512, 63%), intermediate (n=153, 19%), poor (n=46, 6%), and very poor (n=70, 9%). OS of the five groups was as follows: good (39 months), very good (23 months), intermediate (21.5 months), poor (14.5 months), and very poor (6.5 months). OS of patients with very good karyotype was significantly better than patients with very poor karyotype (p=0.0002, RR 2.5) but similar to patients with poor, intermediate and good karyotype (p=0.23, 0.26 and 0.18 respectively).iv) Monosomal karyotype: MK was identified in 153 (15%) cases of which 4 cases were intermediate, 42 poor, and 107 very poor by IPSS-R. OS of patients with MK was similar to those with very poor karyotype (6 months). In addition, OS of patients with very poor without MK was akin to patients with poor without MK (p=0.21). Furthermore, among primary MDS we identified 83 (8%) cases of MK of which 4 were intermediate, 21 were poor, and 58 very poor by IPSS-R. We confirmed that OS of patients with MK was similar to patients with very poor karyotype (6.5 months). Moreover, survival of patients with very poor without MK was similar to patients with poor without MK (p=0.51). Conclusions:In this independent analysis of 1,014 patients with MDS, IPSS-R cytogenetic risk characterization failed to discriminate between very good, good and intermediate prognostic groups. In addition, patients with very poor without MK have a similar prognosis to patients with poor without MK and should be included in the poor category whereas the presence of MK should warrant inclusion into the very poor risk category. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

CD11b expression correlates with monosomal karyotype and predicts an extremely poor prognosis in cytogenetically unfavorable acute myeloid leukemia

Several cytogenetic features, including monosomal karyotype (MK), have been associated with unfavorable prognosis in acute myeloid leukemia (AML). However, little is known about the prognostic significance of immunophenotypes in AML patients with unfavorable-risk cytogenetics. We evaluated immunophenotypes, cytogenetics, clinical features and survival outcomes in 233 uniformly treated AML patients who harbored unfavorable cytogenetics. CD11b expression was observed in 145 (70%) of 208 patients and emerged as an independent prognostic factor for inferior overall survival in multivariate analysis (p=0.024). MK and age≥60 years were predictors for lower complete remission rate (p=0.017, p<0.0001, respectively) and shorter overall survival (p=0.024, p<0.0001), while complex karyotype (CK) predicted a shorter overall survival (p=0.013). CD11b expression was strongly correlated with MK and identified a subset of patients with MK who had extremely poor overall survival. We proposed a prognostic scoring model using CD11b positivity, age≥60 years, the presence of MK and the presence of CK to classify the patients into distinct risk groups. We identified the poor prognosis of CD11b expression and validated the adverse influence of MK, CK and age≥60 years in cytogenetically unfavorable AML patients. Our proposed scoring model may be adapted in clinical practice to further the stratification of this high-risk population.

Monosomal karyotype in acute myeloid leukemia predicts adverse treatment outcome and associates with high functional multidrug resistance activity

Monosomal karyotype (MK) reflects highly unfavorable prognosis in patients with acute myeloid leukemia (AML). This study aimed to study the association of AML-MK with multidrug resistance (MDR) functional activity. A total of 369 AML patients (excluding APL) between 1995 and 2008 at a single center were included retrospectively. Functional MDR activity was evaluated with rhodamine-123 efflux activity with/without verapamil inhibition. MK was noted in 23 patients, only among whom classified into unfavorable cytogenetic risk group. Unfavorable cytogenetic subgroup with MK showed shorter OS (8.7 ± 5.9% vs. 23.5 ± 7.5% at 3 years, P = 0.030), EFS (8.7 ± 5.9% vs. 19.0 ± 6.9% at 3 years, P = 0.029), and a lower CR rate (34.8% vs. 65.7%, P = 0.031) compared with unfavorable subgroup without MK. Functional MDR activity was significantly higher in the unfavorable cytogenetic group with MK compared to all other cytogenetic risk groups taken as a whole (P = 0.026) and showed a trend toward statistical significance when compared with the unfavorable cytogenetic risk group without MK (P = 0.06). AML patients harboring MK showed a poor outcome in terms of lower CR rate and worse EFS/OS, and the presence of MK appeared to be associated with higher MDR functional activity of leukemic blasts.

Prognostic Impact of Monosomal Karyotype in Patients with Myelodysplastic Syndrome and Abnormal Karyotype. A Report From the Spanish Group of MDS (GESMD)

Abstract 1724Cytogenetic abnormalities (CA) are the most important prognostic factor in patients with myelodysplastic syndromes (MDS). Monosomal karyotype (MK) defined as the presence of at least two autosomal monosomies or one monosomy plus other structural CA, has been associated with poor prognosis in acute myeloid leukemia (AML) but its significance in MDS remains unclear. The aim of our study was to analyze the prognostic impact of MK in adult patients with MDS and CA.Patients from Spanish Registry of MDS diagnosed with MDS by WHO 2008 criteria and with CA detected by conventional cytogenetics have been included in the study. Statistical analysis consisted of Kaplan-Meyer univariate analysis (UA) including all known variables associated with prognosis in MDS and a Cox-regression multivariate analysis (MA) in which we included only those variables with a P<0.1 in UA.There were 1054 patients, 478 (45.3%) women. The median age was 71 (range 16–96) years. Median follow-up for survivors was 24.1 (range 0–210) months. There were 609 (57,8%) refractory anemia (RA) and 445 (42.8%) refractory anemia with excess of blasts (RAEB). The IPSS was low, intermediate-1, intermediate-2 and high in 18.3%, 39.3%, 25%, and 10.6%, respectively (6.7% were unclassifiables). Complex karyotype (CK) and MK was observed in 203 (19.3%) and 172 (16.3%) patients, respectively. Patients with MK showed worse prognostic characteristics than those without MK: More Intermediate-2 and high risk patients (50% vs. 20% and 30% vs. 6.7%; P<0.001); more frequent CK: (87.2% vs. 6%; P<0.001), higher median bone marrow (BM) blast count (7% vs. 3%; P<0.001) and lower hemoglobin (Hb) level (89 vs. 96 g/L; P<0.001).Median OS for the whole group was 32.7 months. In the UA, the variables associated with lower OS were: Male sex, RAEB subtype (vs. RA), higher IPSS, CK, MK, older age, higher peripheral blood (PB) and bone marrow (BM) blast percentage and lower Hb, platelets and neutrophil count. In the MA the variables associated with lower OS were: Age>60 years (HR 1.7; P<0.001), CK (HR 2.19; P<0.001), higher BM blast (HR 1.07; P<0.001), Hb<100 g/L (HR 1.788; P<0.001) and platelet count <100×109/L (HR 1.62; p<0.001). MK did not reach statistical significance in the MA (HR 1.45; P=0.059).In the group of patients with CK the UA showed that the presence of MK was associated with a trend to lower OS (Log rank 2.8, P=0.092) while the presence of ≥4 vs. 3 CA was associated with lower OS (Log rank 7.5; P=0.006). Other variables associated with lower OS in UA in this subset of patients were: RAEB (vs RA), presence of abnormalities of 5 and/or 7 chromosome, higher IPSS group, older age, higher BM blast percentage, and lower Hb and platelet count. In MA the variables associated with lower OS in patients with CK were: age>60 years (HR 1.734, P=0.008), RAEB vs. RA (HR 1.542, P=0.02) Hb <100 g/L (HR 2.1, P<0.001) platelets <100×109/L (HR1.886; P=001) and the presence of abnormalities of both 5 and 7 chromosomes (HR 2.058; P=0.001). The presence of MK did not reach statistical significance in the MA.At last follow-up, 221(21%) patients had shown AML evolution at a median of 9 months (0–125 months) for a 1 and 4 years probability of AML evolution of 14.2% (95% CI 11.8–16.6) and 28.6% (95 CI: 24.8–32.4). The variables associated with higher risk of AML evolution in the UA were: RAEB, higher IPSS, CK, MK, higher PB and BM blast percentage and lower hemoglobin, platelet and neutrophil count. In multivariate analysis the only variables that retained statistical significance were BM blasts (HR 1.13; P<0.001) and CK (HR 3.2; P<0.001).In conclusion, our study shows that the presence of MK is highly associated with CK and other high-risk features of MDS. In our population, the MK was not an independent risk factor for OS while the presence of CK was the main risk factor associated with poorer OS in MDS patients with abnormal karyotype. Disclosures:No relevant conflicts of interest to declare.

Predictors of Greater Than 80% Two-Year Mortality in Primary Myelofibrosis: A Mayo Clinic Study of 884 Karyotypically-Annotated Cases

Abstract▪2806▪This icon denotes a clinically relevant abstract Background:A high degree of prognostic certainty is required to recommend or discourage high risk treatment procedures in primary myelofibrosis (PMF). The Dynamic International Prognostic Scoring System (DIPSS-plus) uses eight risk factors to predict overall survival (OS) in PMF: unfavorable karyotype, peripheral blood (PB) blast count ≥1%, platelet count <100 × 109/L, white blood cell count (WBC) >25 × 109/L, hemoglobin level <10 g/dL, red blood cell transfusion need, constitutional symptoms, and age >65 years (Gangat et al. JCO 2011;29 :392). The presence of four or more of these risk factors defines high-risk disease. purpose:The purpose of the current study was to enhance the prognostic weight of some of the DIPSS-plus risk factors with the intent to identify one or two parameters that can reliably predict death in the first two years of disease. Methods:An updated Mayo Clinic database of 884 karyotypically-annotated patients with PMF was used. Calculations of 2-year mortality rates and variables considered for prognostic value were from time of referral to the Mayo Clinic. Cytogenetic risk categorization per DIPSS-plus was further refined to capture additional prognostic information from monosomal karyotype (MK) (Vaidya et al. Blood 2011;117 :5612) and inv(3)/i(17q) abnormalities (Caramazza et al. Leukemia 2011;25 :82). Receiver operating characteristic (ROC) analysis was employed to define best discriminant levels. Results:To date, 564 (64%) deaths have been documented. Each one of the aforementioned DIPSS-plus risk factors was associated with a 2-year mortality rate that ranged from 42% (PB blast count ≥1%) to 60% (unfavorable karyotype). High-risk disease per DIPSS-plus was associated with 57% two-year mortality. The only risk factors that were associated with >80% two-year mortality were MK (n =19) and inv(3)/i(17q) abnormalities (n =8) and both were associated with significantly worse survival, compared to other unfavorable karyotype (n =102): HR (95% CI) of 5.1 (3.1−8.4) and 3.9 (1.7−8.8), respectively. ROC analysis identified PB blast counts of 2% and 9% (AUC 0.62) and WBC of 43 × 109/L (AUC 0.66) as best discriminant levels for predicting 2-year mortality; OS was significantly worse in the presence of PB blast >9% (HR 4.1, 95% CI 2.8–6.1) vs. 2% to 9% (HR 1.8, 95% CI 1.5–2.2) vs. <2%; the corresponding 2-year mortality rates were 73%, 46% and 25%. OS was also significantly worse in the presence of WBC ≥40 × 109/L (HR 2.8, 95% CI 2.2–3.6) vs. 26–39 × 109/L (HR 1.6, 95% CI, 1.2–2.1) vs. <26 × 109/L; the corresponding 2-year mortality rates were 63%, 42% and 28%. Two-year mortality rates exceeded 80% in the presence of any two of the following: PB blast count >9%, WBC ≥40 × 109/L or unfavorable karyotype other than MK or inv(3)/i(17q). Conclusions:A greater than 80% 2-year mortality in PMF is predicted by the presence of MK, inv(3)/i(17q) abnormalities, or any two of the following: PB blast >9%, WBC ≥40 × 109/L, other unfavorable karyotype. Such patients and those with high DIPSS-plus risk should be referred to allogenic stem cell transplantation earlier than later. Disclosures:No relevant conflicts of interest to declare.

Monosomal Karyotype in Myeloid Malignancies Is Prognostically Worse Even After Allogeneic Hematopoietc Stem Cell Transplantaion; Results From Two Transplant Centers,

Abstract 4154 Background:Monosomal karyotype (MK) has been defined as the presence of two or more autosomal monosomies or of a single monosomy associated with at least one structural abnormality (Breems et al, JCO 2008). The presence of MK has been associated with extremely poor prognosis in patients with not only acute myeloid leukemia (AML) but myelodysplastic syndrome (MDS) (Patnaik et al, Leukemia 2011). Our goal was to investigate the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for myeloid malignancies with MK. Patients and methods:We combined data from two transplant centers, Sapporo Hokuyu Hospital and Hokkaido University Hospital, and analyzed consecutive patients who underwent allogeneic transplantation for AML and MDS between January 2003 and July 2010. Patients were divided according to MK classification scheme into four groups (Oran et al, BBMT 2011), CN; cytogenetically normal, MK; monosomal karyotype, CBF; core binding factor abnormalities, Oth (Others); non-CBF and non-MK abnormalities. Patients with acute promyelocytic leukemia were excluded. Resuts:One-hundred eighty three out of 229 patients were analyzed with a median age of 48 years(15–68). Sixty one (33%) were from HLA-matched related donors, 86 (47%) from unrelated and 36 (20%) were cord blood.Conditioning regimens were myeloablative (MAC, n=102, 56%) or reduced intensity(RIC, n=81, 44%). Seventy patients (38%) were cytogenetically normal, 27 (15%)had CBF abnormalities, 70(38%) had non-CBF and non-MK abnormalities and 16(9%) had monosomal karyotype. There was no statistically difference between four groups in age, donor source and conditioning regimen. In the MK group, the proportion of MDS and non-remission state at stem cell transplantation were significantly higher than other groups (p=0.002, p<0.001). Four-year over all survival in patients with MK was 0%, which was significantly inferior to other groups; 50% for CN, 30.4% for CBF, 29.4% for Oth(p<0.001). Cox regression modeling showed that the disease status at stem cell transplantation (p=0.026) and the existence of MK (p=0.012) had prognostic value.Seven of 16 patients with MK died within the first 50 days after transplantation, and 9 patients died within 120 days. Five patients died of infection and 2 died of complicated organ failure and 2 died of progression disease. Three patients who underwent transplantation at non-remission setting, survived more than 1-year experienced chronic graft-versus-host disease, suggesting the existence of GVL effect to myeloid malignancies with MK. Conclusion:This retrospective analysis revealed the dismal prognosis of myeloid malignancies with MK, even after allogeneic HSCT. Novel therapies and strategies are urgently needed for this very poor prognostic group.TablePatient characteristics based on MK classification schemeKNMKCBFOtherspn70162770Median Age (range)47 (15–66)50 (26–65)46 (17–68)49 (16–65)n.s.Male ratio41 (58%)10 (63%)17 (63%)36 (51%)n.s.Disease0.002AML50 (70%)7 (44%)26 (96%)47 (66%)MDS20 (30%)9 (56%)1 (4%)23 (34%)Status @SCT<0.001CR43 (61%)3 (19%)23 (85%)30 (43%)CR1343723CR290167nonCR27 (39%)12 (75%)4 (15%)41 (57%)Unknown1100Conditioningn.s.MAC44 (63%)7 (44%)14 (52%)36 (51%)RIC27 (39%)9 (56%)13 (48%)34 (49%)Donor sourcen.s.rBM10 (14%)4 (25%)4 (15%)3 (4%)rPBSC16 (23%)2 (13%)3 (11%)19 (27%)uBM30 (43%)6 (38%)14 (52%)35 (50%)CB14 (20%)4 (25%)6 (22%)13 (19%) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Monosomal Karyotype Provides Better Prognostic Prediction after Allogeneic Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia

We studied cytogenetic risk grouping schemes to stratify patients with acute myelogenous leukemia (AML) (n= 212) into prognostically distinct subgroups for relapse incidence (RI), progression-free survival (PFS), and overall survival (OS) after allogeneic hematopoietic stem cell transplantation (HSCT). Patients were divided according to cytogenetic abnormalities based on the Medical Research Council, Southwest Oncology Group, Cancer and Leukemia Group B (CALGB), Dana-Farber, and recently described monosomal karyotype (MK) classification schemes and analyzed separately for first complete remission (CR1; n = 134) and beyond (CR2+; n = 78). Multivariate analysis was performed after adjusting for age, conditioning intensity, donor type, and cytomegalovirus serology status. Although none of the covariates was associated with OS in CR1, the presence of MK (MK(+)) was associated with worse RI and PFS (hazard ratio [HR], 3.3, P = .01 and HR, 2.0, P = .05, respectively). No other classification scheme was predictive of outcomes in CR1. In CR2+, for RI, only MK(+) was predictive of poor outcome (HR, 3.7; P = .03). For PFS, all 5 classification schemes were predictive, and for OS, both the MK(+) and CALGB adverse karyotypes were predictive. In addition to cytogenetics, nonmyeloablative conditioning was associated with decreased PFS and OS in patients in CR2+ in all models. Our results indicate that among all classification schemes, MK classification can identify a subgroup with very poor prognosis in patients with AML after allogeneic HSCT.

Prognostic Value of Monosomal Karyotype in Patients with Primary Acute Myeloid Leukemia On Behalf of Spanish CETLAM Group.

Abstract 1003Poster Board I-25 Introduction:Recently, the cooperative group HOVON-SAKK has refined the prognostic impact of cytogenetic abnormalities in acute myeloid leukemia (AML) by introducing the concept of monosomal karyotype (MK). This consists of ≥ 2 autosomal monosomies or one autosomal monosomy in addition to a structural alteration. In their experience, MK would explain the poor prognosis of AML with a complex karyotype. Objective:To investigate the prognostic impact of MK in patients with primary (de novo) AML enrolled in the Spanish CETLAM group protocols (AML 94/99/03). Also, to determine whether considering MK added predictive value to the cytogenetic classification of the Medical Research Council (MRC). Methods:Retrospective analysis of data from 1149 AML patients. Chromosomal formula was centrally reviewed with karyotypes being classified by the presence of MK and allocated into the MRC risk categories. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were calculated. Results:The karyotype was assessable in 904 (79%) of the 1149 cases. In 145 of the 904 cases (16%), abnormalities involving CBF gene were detected and in 437 (48%) the karyotype was normal (NK). In 253 (28%) additional patients the karyotype was not monosomal; of them, 61 (24%) belonged to the unfavorable MRC with 17 cases harboring a complex karyotype ≥ 5 abnormalities, 7 cases with rearrangements 3q, 13 cases with -7, 9 cases with 5q abnormalities and 16 cases with t(6;9)). The remaining 69 (7.7%) patients had a MK; of them, 59 (85.5%) were from the unfavorable MRC category and included 43 cases with complex karyotype ≥ 5 abnormalities, 6 cases with rearrangements 3q, 5 cases with -7, 5 cases with alterations of 5q). The following table summarizes the results in terms of CR rate, DFS and OS:CBFNKMK- (IP)*MK- (UP)**MK+***pCR92%82%76%68%52%< 0,001DFS (4 years) median (month)58%± 5114.845%± 322.638%± 516.320%± 812.315%± 74.73<0,001OS (8 years) median (month)62%± 4-35%± 321.234%± 416.016%± 612.83%± 36.6<0,001*MK- (IP): Non-monosomal karyotype in the intermediate prognosis MRC cytogenetic group.**MK -(UP): Non-monosomal karyotype in the unfavorable prognosis MRC cytogenetic group.***MK+ : Cases with MK Conclusions:The addition of MK to the MRC cytogenetic classification refines the prognostic prediction. In our series, the dismal outcome of patients with MK is confirmed; these patients had worse prognosis than those with adverse cytogenetics without MK. Alternative treatment strategies are mandatory for MK+ patients.Supported in part by grants: GR1-01075, ECO07/90065, PI080672 and RD06/0020/0101. Disclosures:No relevant conflicts of interest to declare.

Impact of Cytogenetics and New Molecular Markers On the Achievement of Complete Remission in Patients with Primary Acute Myeloid Leukemia. On Behalf of CETLAM Cooperative Group. Spain.

Abstract 4711 AimTo analyze the prognostic impact of cytogenetics and main molecular abnormalities on the achievement of complete remission (CR), in patients with primary (de novo) AML (M3 excluded). Patients and MethodsBetween december-2003 and july-2009, 605 patients up to 70 years-old were included in the CETLAM AML-03 protocol. Induction therapy consisted in one or two courses of idarubicin, intermediate dose ara-C and etoposide, in addition to G-CSF priming from day 0. Cytogenetics classification was as in the MRC studies: Favorable prognosis (FP), intermediate (IP) and adverse (AP). In the IP group, molecular analysis of NPM1 (NPM1+) mutations, CEBPA mutations and internal tandem duplication of FLT3 gene (ITD/FLT3) was performed. In the AP group, the absence (MK-) or presence of monosomal karyotype (MK+) was studied; MK+ was defined as 2 or more autosomal monosomies, or one monosomy and ≥1 structural alteration. ResultsMedian age of the series was 53 years (range, 16-73). In 538 (89%) patients cytogenetic data were available; of them, 64 (10,5%) had FP, 375 (61,8) IP (included 255 with normal cytogenetics) and 99 (16,3%) AP. In the FP group, 33 (5,4%) had the AML1/ETO fusion and 31 (5,1%) the CBF/MYH11. In the IP group, 121 (31%) of 279 patients studied were NPM1+, 100 (26,7%) of 346 were DIT/FLT3+ and 22 (6%) of 235 analyzed were CEBPA+. In patients with AP, 47 were MK- and 33 MK+. Overall, 447 (73,8%) of 588 patients evaluable at the moment of the analysis achieved a CR. CR rates according cytogenetics were: FP 92,2%, IP 76,5% and AP 69,4%, p=0.01. In AML, with AML1-ETO+ and CBF/MYH11+, CR rates were 91% and 93.5%, respectively; of note no chemorefractory cases were observed. In the IP group, CR rates according to mutational status were: NPM1+/FLT3- 91.2%, CEBPA+/FLT3- 94.4%, no mutations 79.1% and DIT/FLT3+ 69.7% (p=0.003). Again, no refractoriness was observed in patients in IP patients belonging to the two groups with favourable molecular profile (p=0.003). In patients with AP, CR rate was 76.1% if MK- and 65.6% if MK+ (p=0.46). The prognostic impact of the herein described cytogenetic and molecular findings was confirmed in multivariate analyses. CommentsGenetic characterization is nowadays mandatory in AML. CR rate is high and refractoriness exceptional in the presence of AML1-ETO or CBF/MYH11 rearrangements, or NPM1 or CEBPA mutations without DIT/FLT3. In contrast, CR probability is lower in AP group patients, mainly in those with MK+. These patients require new strategies within clinical trials.Supported in part by grants: GR1-01075, ECO07/90065, PI080672 and RD06/0020/0101. Disclosures:No relevant conflicts of interest to declare.