Presence Of Hyperdiploidy Research Articles

Presence of hyperdiploidy and history of tobacco use in African American patients with SMM.

8062 Background: Smoldering multiple myeloma (SMM) has a clinically variable course in progression to active myeloma (MM). Accurate risk stratification is essential in identifying which patients may benefit from early therapeutic intervention. Current models do not account for the potential impact of race on risk of progression to SMM. Here, we seek to identify independent risk factors for progression in African American (AA) versus white patients in a real-world single institutional database of SMM patients. Methods: We retrospectively identified 224 patients (pts) with untreated SMM from 2007 to 2021 treated at our institution. Patient demographics and disease characteristics were obtained from our IRB-approved myeloma database. TTP was defined as the time from diagnosis of SMM to diagnosis of active MM, estimated by Kaplan-Meier and compared by log-rank test. Univariate analyses were performed using Cox proportional hazard models for TTP. Results: A total of 224 pts (AA 35%, white 47%, other/unknown 17%) were identified with median age 62y (range 32-82). Median follow-up was 4.3y in Whites and 5y in AA pts. Notable characteristics include M/F 45%/54%, IgG/IgA/FLC 76%/17%/6%, 30% current/past smoker (median 15 pack-years), 12% alcohol use (≥10 drinks/wk), 45% with BMI > 30. Multiple cytogenetic abnormalities were defined as presence of ≥2 of the following: t(4;14), t(14;16), gain(1q21), del(1p), del(13), or del(17p). The median TTP (mTTP) was 6.8 [95% CI (3.7, 8.2)] years in whites and 5.6 [95% CI (4.6, 11.8)] years in AA. On univariate analysis, M-spike > 1.5, involved K/L ratio > 12, and bone marrow PC > 20% were associated with increased risk of progression for both AA and whites (all p < 0.05). As expected, gain of 1q21 was associated with increased risk of progression for both groups, though more pronounced in AA (HR 2.94, p = 0.025) versus whites (HR 2.33, p = 0.013). Hyperdiploidy was associated with shorter mTTP in AA (HR 3.03, p = 0.004) compared to whites (HR 1.39, p = 0.3). Multiple cytogenetic abnormalities was associated with shorter mTTP in whites (HR 2.63, p = 0.004) but was not statistically significant in AA (HR 2.63, p = 0.104). Interestingly, tobacco use was associated with shorter mTTP in Blacks (HR 2.94, p = 0.005) but not in whites (HR 0.96, p = 0.85). Conclusions: Understanding the potential impact of racial background on progression from SMM to MM is critical in the appropriate management of all patients with SMM. In this database, with a large proportion of AA patients, hyperdiploidy and +1q portend high risk of progression in AA patients. Further study is needed to better classify these potential differences to ensure risk stratification models are applicable to all patients.

Clinical Significance of Plasma Cell Tetrasomy in Multiple Myeloma

Background: Cytogenetic abnormalities in multiple myeloma are known to influence the clinical presentation, treatment results, as well as disease outcome. Presence of hyperdiploidy, especially trisomies have a favorable impact on disease outcomes, even among patients with high risk abnormalities. In a proportion of these patients, up to 4 copies of several chromosomes (tetrasomy) can be seen and the prognostic relevance of this finding is unclear. In the current study, we have examined the patients with newly diagnosed MM to determine the prevalence and clinical outcomes in the patients with tetrasomy.Patients and methods: This retrospective study included NDMM patients seen between 5/1/2004 and 12/31/2015, with bone marrow plasma cell FISH performed within 1 year prior to diagnosis or 6 months after diagnosis. FISH was performed on bone marrow aspirates and patients with insufficient plasma cells or no plasma cells seen on the FISH test were excluded from the study. The survival analysis was done using the Kaplan- Meier curves and compared using the log rank test. Cox proportional hazards models were used to evaluate the prognostic relevance of the variables.Results: The median age was 64 years and 60% were male. The median follow-up for the entire cohort was 62.6 months (95% CI; 59, 66) and the median overall survival was 80.4 months (95% CI; 74, 90). Tetrasomies of one or more chromosomes were seen in 14% of patients, trisomies without tetrasomies were seen in 40% of patients and in the remaining 46% of patients, neither trisomies or tetrasomies of any chromosomes were observed. Among the 227 patients with tetrasomies, the most common chromosomes were chr 9 (51%), chr 15 (40%) and chr 11 (30%). High risk FISH abnormalities (t(4;14), t(14;16), t(14;20) or del 17p) were seen in 22% of patients. The median overall survival of patients with one or more tetrasomies was superior at 112 months (95% CI; 97, NR) compared with those with trisomies alone (75 months, 95% CI; 67, 85) and those with neither (77.7 months, 95% CI; 67, 90); p<0.001 (Figure 1a). Among those with tetrasomies, those with tetrasomies of more than 1 chromosome had better OS (NR vs 100 months; p<0.05). The median OS for those with any high-risk abnormality was 49 months (95%CI; 42, 60) compared with 92 months (95% CI; 83, 103), p < 0.0001. Looking at concomitant abnormalities, patients with HR abnormalities with concurrent trisomy or tetrasomy had a better OS compared with those with HR and no overlapping abnormality (58 months vs. 42 months), but both inferior to those with no HR abnormalities (92 months), p<0.001 (Figure 1b).Conclusion: Patients with trisomy/ tetrasomy have a better survival than patients with trisomy alone or other chromosomal abnormalities. Increasing number of chromosomes with tetrasomy appear to improve the survival pointing towards a dose effect. Concomitant trisomy/ tetrasomy and high risk appear to improve the outcomes of those with high risk abnormalities. [Display omitted] DisclosuresKumar:Skyline: Honoraria; Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy. Gertz:Millennium: Consultancy, Honoraria; Celgene, Novartis, Smith-Kline, Prothena, Ionis, Amgen: Honoraria. Dispenzieri:Celgene, Millenium, Pfizer, Janssen: Research Funding. Russell:Vyriad: Equity Ownership; Imanis Life Sciences: Equity Ownership. Kapoor:Takeda, Celgene and Amgen: Research Funding.

Prevalence of Genetic Abnormalities in Patients with Multiple Myeloma and Its Clinical Relevance in a Developing Country like India

Introduction Multiple myeloma (MM) is a malignancy involving terminally differentiated plasma cells. Its incidence in India is about 0.7/1,00,000 population amounting to about 6,800 new cases a year A number of genomic aberrations are associated with MM, most of which confer prognostic significance. Cytogenetic abnormalities are a part of R-ISS score for prognostication which stratifies presence of del(17p), t(4;14) or t(14;16) as stage 3, mSMART is another risk stratification tool which divides MM into high risk and standard risk groups based on genetic aberrations. Hence it is evident that determining the genetic abnormality in MM is important. however, due to limited resources genetic testing is not routinely done and the data in the Indian population is limited. Objective: To estimate the prevalence of molecular cytogenetic abnormalities by Fluorescent in situ hybridization (FISH) analysis in patients with MM and to assess the co-relation with response to induction chemotherapy, relapse and overall survival. Material and Methods: 64 patients were included from January 2016 to December 2019 and followed up till June 2020. Interphase FISH study was performed either at diagnosis or at relapse, on bone marrow aspirate with panel of probes consisting of CKS1B (1q21-22), CDKN2C (1p32.3), D13S319 (13q14.2/13q34), IGH (14q32.33), p53 (17p13.1) and trisomy (5p15/9q22/15q22) (trisomies are considered as hyperdiploidy in this study). Plasma cell purification techniques were not applied prior to FISH analysis. Patients were divided into 2 risk groups; 1) high risk group with presence of del17p, del13q, amplification 1q, del1p and two or more aberrations with either of these and 2) standard risk group with presence of hyperdiploidy or no genetic abnormality. There was no difference in chemotherapy regimen between the 2 groups; 46 (71.8%) received bortezomib-thalidomide-dexamethasone, 10 (15.6%) received bortezomib-cyclophosphamide-dexamethasone, 2(3.1%) received bortezomib-lenalidomide-dexamethasone, 1(1.5%) received daratumumab-bortezomib-dexamethasone and 5(7.8%) received 2 drug chemotherapy. Patients who did not complete minimum follow up of 6 months either due to death or lost to follow up were excluded from the study. Institutional Ethics Committee's approval was taken. Results: Mean age of the population was 60.33 years and male to female ratio was 1.65. 46.87%, 28.13% and 25% of the study population were in the age group of ≤ 60, 61 - 65 and ≥66 years respectively. 12.3%, 43.8% and 43.8% were in R ISS stage 1, 2 and 3 respectively. FISH analysis was done on 61 out of 64 patients (remaining 3 were excluded due to hemodilute bone marrow sample). 22 (36.1%) patients had abnormal genetic aberration on FISH analysis with 10 (16.39%) having two or more abnormalities. The frequency of genetic aberrations was as follows; amplification 1q (13/61, 21.31%), del13q (9/61, 14.75%), hyperdiploidy (7/61, 11.47%), del17p (4/61, 6.55%), IgH rearrangement (3/61, 4.91%), and del1p (1/61, 1.6%). All 3 patients with IgH rearrangement had associated one or more high-risk genetic aberration and hence were included in high risk group. 31.1% of the patients were high risk and 68.9% were standard risk. The response to induction chemotherapy, incidence of relapse, time to 1st relapse and total number of relapses are shown in (table;1) and there was no significant difference between high risk and standard risk group. Overall survival in standard risk group at 2 and 5 years was 89.6% ± 5.8% and 78.6% ± 13.9% and in high risk group was 60.7% ± 13.2% and 29.5% ± 23.1% respectively (p value: 0.762). Overall survival was significantly lower in age group ≥66 years as compared to age group ≤ 60 years and 61 - 65 years (p value 0.001) and it was also significantly lower in R ISS stage 3 as compared to R ISS stage 1 and 2 (p value 0.006). Conclusion: More than one third patients of MM (36.1%) showed genetic abnormality, amplification 1q being the most frequent. Overall survival was significantly lower in older age group and R ISS stage 3 patients. Response to induction chemotherapy and relapse rate were similar in high and standard risk groups. Although overall survival was lower in high risk group, it was statistically not significant. This study highlights the importance of FISH analysis for disease stratification and prognostication which should be routinely practiced. Disclosures No relevant conflicts of interest to declare.

Cytogenetic Characteristics and Outcomes of Patients Receiving CTL019 CAR T Cell Therapy

Background: CTL019 is a therapy derived from autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) that was approved by the FDA in August 2017 (tisagenlecleucel). Complete and durable remissions have been seen in the setting of pediatric and young adult patients with relapsed and refractory B cell acute lymphoblastic leukemia (ALL) (Maude NEJM 2018). Initial case reports suggested that there may be differential outcomes mediated by cytogenetic characteristics of the leukemia at CAR T cell infusion. Here, we report results from a single institution experience of 112 patients. Methods: Patients with relapsed/refractory ALL were identified as having received CTL019 either in the context of a clinical trial (NCT02906371) or commercial product (tisagenlecleucel) at Children's Hospital of Philadelphia from October 2016 to April 2019. Patients who received prior CAR T therapy were excluded. Demographic, cytogenetic, and outcome data were manually abstracted from the medical record or clinical trial datasets. High risk lesions were defined as MLL(KMT2A) rearrangements, Philadelphia-chromosome (Ph+), Ph-like, hypodiploidy, and TCF3/HLF fusion. Favorable cytogenetics were defined as the presence of hyperdiploidy or ETV6/RUNX1fusion and intermediate were defined as iAMP21, IKZF1deletion, or TCF3/PBX1. Patients were classified according to their highest risk cytogenetic characteristic and stratified by cytogenetic risk category present at CAR T cell infusion. Relapse-free survival (RFS) and overall survival (OS) was described for cohorts with more than 10 patients. Results: One hundred and twelve patients were included in the analysis, with a median age of 11 years (range 1-29) at infusion, of which 32% had had a previous allogeneic hematopoietic stem cell transplant (alloHSCT). Disease burden at the time of CTL019 infusion was heterogenous, with 61% having detectable disease in the bone marrow and 21% having more than 25% blasts by flow cytometry. Thirty-six patients (32%) had leukemias with high-risk genetic lesions at infusion, including 12 with MLL rearrangements and 18 with Ph+ or Ph-like lesions (Table 2). Thirty-one patients (28%) had hyperdiploidy or ETV6/RUNX1; 3 additional were in conjunction with high-risk cytogenetics (t(17;19) and 2 with Ph+), and 3 in the setting of intermediate-risk cytogenetics (iAmp21, TCF3/PBX1, IKZF1deletion). Figure 1 demonstrates RFS for those patients in remission at day 28 following infusion, stratified by cytogenetic risk category. Complete remission (CR) rate in the high-risk cytogenetics group was 94%. RFS at 12 months was 69% (0.50-0.82), 69% (0.40-0.86), and 67% (0.48-0.80) for non-informative, favorable, and high-risk cytogenetic groups, respectively. Figure 2 shows OS of patients infused with CTL019, again stratified by cytogenetic categories of interest, with a maximum follow-up time of 30 months. OS at 12 months was 84% (0.68-0.93) and 76% (0.56-0.88) for the non-informative and high-risk cytogenetic groups, respectively. There were no deaths in that time period for the favorable risk category. There was no statistically significant difference in RFS or OS for patients with high-risk cytogenetics. The intermediate-risk cytogenetics group (n&amp;lt;10) was excluded from these analyses. Conclusion: Durable remissions can be achieved with CTL019 across several high-risk cytogenetic subtypes of B-ALL. Stratifying outcomes by cytogenetic risk category in this unadjusted analysis does not show a statistically significant difference in either RFS nor OS. Further investigation is needed to parse out the contribution of individual cytogenetic lesions as well as the effects of other relapse and survival risk factors at play. Figure Disclosures Rheingold: Novartis: Consultancy; Pfizer: Research Funding. Callahan:Novartis: Consultancy. Hunger:Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Equity Ownership; Jazz: Honoraria; Novartis: Consultancy. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Maude:Kite: Consultancy; Novartis: Consultancy.

Hyperdiploidy as a rare event that accompanies poor prognosis markers in CLL.

The objective of this study was to analyse by FISH the frequency and prognostic impact of hyperdiploidy in CLL. A review of 1359 consecutive cases diagnosed with CLL referred for FISH analysis to a unique institution was carried out. Hyperdiploidy was considered when a gain of at least three of the five FISH probes used was observed. Seven cases (0.51%) with hyperdiploidy were found, confirming that it is a rare event in this disease. Although most patients presented with early Binet stages at diagnosis, six of seven (86%) shortly progressed. The median of time to the first therapy (TTFT) and overall survival (OS) for the patients with hyperdiploidy were short (1.4 months and 20 months, respectively). Moreover, comparing them with a control group of patients (non-hyperdiploid) with completed follow-up data, TTFT and OS of the patients with hyperdiploidy were significantly shorter than the control group. The presence of hyperdiploidy is uncommon and probably associated with poor prognostic markers in CLL.

A bright and colorful future for DNA cell cycle analysis.

A bright and colorful future for DNA cell cycle analysis.

Co-Existent Hyperdiploidy Does Not Abrogate The Poor Prognosis Associated With Adverse Cytogenetics In Myeloma

AbstractThe development of the cytogenetic abnormalities hyperdiploidy or a translocation involving the immunoglobulin heavy chain are initiating events in the pathogenesis of myeloma. Previous studies have shown that hyperdiploidy is associated with a more favorable outcome whilst the presence of specific translocations (4;14), (14;16) and (14;20) are associated with poor clinical outcomes especially when they occur in association with other high risk features such as del17p and 1q+. While it has been generally accepted that these events are mutually exclusive, review of a number of clinical datasets shows that they occur together in a significant proportion of cases. This raises the mechanistic issue of which cytogenetic abnormality occurs first as well as the more practical issue of what it means for prognosis. In order to address these important questions we have investigated these cases with interphase FISH (iFISH) as well as determining their outcome in the Myeloma IX study.Myeloma IX is a large study (1960 newly diagnosed myeloma patients) that has been extensively described. iFISH results with a complete data set for hyperdiploidy, adverse IgH translocations, 1q+ and del17p were available for 847 patients with a median follow up of 5.9 years. 58% of patients (499/847) had hyperdiploidy and had a significantly improved survival compared with non-hyperdiploid patients (Median OS 49.7 vs 42.8 months, p=0.016 and PFS 18.8 vs 16.3 months, p=0.028).Hyperdiploid patients were divided into those who had one or more of the adverse lesions t(4;14), t(14;16), t(14;20), del17p and 1q+ (61%, 304/499) and their outcome was compared to those with none (39%, 195/499). The overall and progression free survival was significantly worse for those with hyperdiploidy plus an adverse lesion compared to those with hyperdiploidy alone (Median OS 60.9 vs 35.7 months, p<0.001, median PFS 23 vs 15.4 months, p<0.001). These results remained significant on multivariate analysis. When subdivided into those patients with hyperdiploidy plus: del17p alone, 1q+ alone, an adverse translocation alone or >1 adverse lesion, there remained a significant detrimental effect on survival (OS and PFS) for the del17p, 1q+ and >1 lesion groups and a trend towards worse survival for those with an adverse translocation (numbers too small to prove significance) when compared to those with hyperdiploidy and no adverse lesion. (table 1)Table 1HD = HyperdiploidyNo. of patientsPFS (months)OS (months)HD, no adverse lesions3042360.9HD plus del 17p2019.1 (p=0.019)35.2 (p=0.003)HD plus 1q+14215.4 (p<0.001)38.1 (p<0.001)HD plus adverse translocation915.4 (p=0.272)40.1 (p=0.180)HD plus >1 lesion2412.1 (p<0.001)19.9 (p<0.001)The converse situation was also examined by taking each population with an abnormal lesion and dividing them by the presence or absence of hyperdiploidy. 409/847 (48%) of patients had at least one adverse lesion and they had a significantly worse outcome within the whole data set than those without any adverse lesions (OS 60.6 vs 33.7 months, p<0.001, PFS 23.3 vs 15 months, p<0.001). When the impact of hyperdiploidy within the high-risk population (195/409 hyperdiploid, 214/409 non-hyperdiploid) was examined there was no difference in survival, (OS 35.7 vs 33.6 months p=0.64, PFS 15.4 vs 14.5 months, p=0.58). This remained true across each adverse lesion when individually analysed.A group of patients with hyperdiploidy and a (4;14) translocation were analysed at a single-cell level using iFISH. Within each case the percentage of cells with a translocation was consistently high, whereas the frequency of individual chromosomal trisomies varied. This suggests that the translocation event may occur earlier. Single cell genetic analysis using the Fluidigm technology is ongoing in order to confirm this finding.In conclusion, patients with co-existent hyperdiploidy and adverse cytogenetics have worse outcomes than those with hyperdiploidy alone. The progression of their disease is not different to those patients with adverse cytogenetics alone and our data suggests that the presence of hyperdiploidy is not able to abrogate or even ameliorate this adverse prognostic feature. It is important that this is recognised when designing treatment strategies for this group of patients as they should be treated with more aggressive chemotherapy regimens to maximize their response and control disease. Disclosures:No relevant conflicts of interest to declare.

Correlación de la t(9;22), t(12;21) e hiperdiploidia de ADN, con el inmunofenotipo, y la tasa proliferativa de células B neoplásicas de pacientes pediátricos con leucemia linfoide aguda de precursores B

Introduction. 60-80% of patients with acute B lymphoblastic leukemia show genetic abnormalities that influence the prognosis of the disease and the biology of the tumor. Objective. To analyze different genetic abnormalities in acute B lymphoblastic leukemia in children, its relationship to immunophenotype and proliferative rate compared to normal B cell precursors. Materials and methods. A total of 44 samples were studied by flow cytometry for immunophenotype, DNA content and proliferative rate and RT-PCR for translocations t(9;22), t(12;21), t(4;11) and t(1;19). Using a hierarchical cluster analysis some immunophenotypic patterns were identified and associated to genetic abnormalities when compared to normal B cell precursors. Results. DNA quantification showed that 21% of the cases were hyperdiploid high index and 47.47% hyperdiploid low index. The presence of hyperdiploidy was associated with increased tumor proliferation and aberrant immunophenotypes including abnormal expression of CD10, TdT, CD38 and CD45 and increased size of the lymphoblasts. The presence of t(9;22) and t(12;21) discriminates normal cells of the tumor cells with aberrant immunophenotype in the expression of CD19, CD22, CD13, CD33, CD38, CD34 and CD45. Conclusions. The aberrant immunophenotype profile detected in neoplastic cells in conjunction with abnormalities in proliferative rate was significantly associated with DNA hyperdiploidy and clearly distinguished blasts with t(9;22) and t(12;21) of normal B cell precursors. The identification of these parameters is useful as a tool for classification and monitoring of these patients. doi: http://dx.doi.org/10.7705/biomedica.v33i3.1441

Biologically defined risk groups can be used to define the impact of thalidomide maintenance therapy in newly diagnosed multiple myeloma

Maintenance therapy is an attractive strategy for patients with multiple myeloma. However, the impact of maintenance thalidomide according to the underlying biology of the disease is still a matter of debate, with some studies suggesting that thalidomide is more beneficial in high risk disease, whilst others show the opposite. Biological risk groups defined by interphase fluorescence in situ hybridization (FISH) are powerful predictors of outcome. In this report we investigated the effect of maintenance thalidomide in different biological risk groups defined by different FISH categories. Our data show that maintenance thalidomide improves outcome in patients with biologically low risk disease, defined by the absence of adverse cytogenetic lesion or by the presence of hyperdiploidy alone. Conversely, thalidomide maintenance is detrimental for the overall survival of patients with biological high risk. We conclude that it is important to identify biologically low risk patients who will benefit from a maintenance strategy with thalidomide.

Pre-Transplant Minimal Residual Disease Detected by Multiparameter Flow Cytometric Analysis Predicts for Disease Relapse in Adult Patients with Acute Lymphoblastic Leukemia Post Allogeneic Hematopoietic Stem Cell transplantation

Abstract 3072Allogeneic hematopoietic stem cell transplantation (SCT) is the only effective treatment for high-risk or relapsed acute lymphoblastic leukemia (ALL). However, SCT carries high treatment-related mortality (TRM). There have been continuing efforts to refine criteria for patients who may benefit most from SCT. Minimal residual disease (MRD) at the end of induction or induction/consolidation therapy has emerged as the most significant risk factor for disease relapse in ALL patients, and has become an indicator for SCT or intensified chemotherapy. In addition, MRD prior to SCT is highly predictive for post-transplant relapse in the pediatric population. The significance of pre-SCT MRD in adult patients with ALL remains to be determined. Patients and methods: In this retrospective analysis, we examined the impact of MRD detected within one month prior to SCT on risk of disease progression in adult patients with ALL who were in complete remission, defined by less than 5% blasts in bone marrow by morphologic assessment and normal blood counts at time of SCT. MRD has been uniformly assessed in patients using multiparameter flow cytometry since 2004. Bone marrow aspirates were stained using a comprehensive panel of >=15 markers and 200, 000 cells were analyzed. MRD was scored as positive based on a distinct cluster of >=20 cells, showing a significant difference in the level of expression (>=3-fold) of >=2 antigens, in comparison to the known phenotype of benign immature B-cell precursors. Disease progression (relapse) was defined as leukemic blast count >= 5%. Therefore, limiting our data set to transplants performed during February 2004 through May 2010 at MD Anderson Cancer Center, we identified 98 patients with median age 34 years (range 19–68) treated with a median of 2 lines of chemotherapy (range 1–6) who received a matched sibling (n=51), matched unrelated (n=36), haplo-identical family (n=3), or cord blood donor (n=8) transplant for ALL of B-(n=86) or T-lineage (n=12) in CR1 (n=52), CR2 (n=39) or CR3 (n=7) using a myeloablative non-TBI based (n=62) or TBI-based (n=36) transplant conditioning regimen. GVHD prophylaxis was tacrolimus-based for all patients. Among 88 patients with available cytogenetic data at diagnosis, 59% were considered high risk defined by the presence of the t(9;22), t(4;11), hypodiploid or complex cytogenetics, 2% were classified as good risk by the presence of hyperdiploidy, and the remaining 34% were intermediate risk. Results: Ninety-two patients were evaluable for response and all had sustained CR following transplant; 6 had early death. With a median follow-up of 33 months among survivors (range 5.8–80.7), patients transplanted without detectable MRD at time of SCT had a significantly lower cumulative incidence of relapse than those transplanted with MRD, 30% versus 70%, p=.004 (Figure 1). There was also a trend for better 3-year PFS in the MRD negative group, 38% versus 13%, p=0.1. Additional factors, including disease stage at time of SCT, cytogenetic profile at diagnosis, donor relation, and development of GVHD were evaluated in a univariate analysis for relapse rate, PFS, and overall survival. Only the presence of MRD remained a significant predictor for relapse. Conclusion: This study demonstrates that the presence of MRD prior to SCT in adult ALL patients is a significant predictor for relapse. Improvements in our current therapies are urgently needed to improve the outcomes for MRD positive patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Impact of FISH and Cytogenetics On Overall and Event Free Survival in Myeloma: An IMWG Analysis of 9,897 Patients.

Abstract 743 BackgroundThere has been considerable recent focus upon the molecular classification of myeloma. However, the prognostic impact of molecular changes has mostly been assessed from small and/or incomplete studies from single institutions or groups. There has been no large scale analysis of molecular features linked to ISS stage. MethodsIn order to clarify the overall impact of molecular changes we undertook a collective analysis of 9,897 patients through the International Myeloma Working Group (IMWG). Within this population 2,295 patients had presence of cytogenetic abnormalities (Any CA); 1,713 hypodiploidy; 1,673 hyperdiploidy; 2,309 cytogenetic deletion 13; 3,226 deletion 13 by FISH; 1,573 FISH t(4;14); 1,486 FISH del p17; 1, 683 FISH t(11:14); and 366 FISH t(4;16). Enrolled patients had complete clinical and treatment details available including baseline standard prognostic factors, ISS stage, as well as both progression free survival (PFS) and overall survival (OS) information. Data came from 14 sites: 3 from the US and the remainder from Europe, Asia, and Latin America as for the ISS staging system analyses. Univariate and multivariate analyses were performed. ResultsEach of the known adverse molecular features had a negative impact upon both PFS and OS (p=002 - <0.0001). Among the deleterious FISH abnormalities the t(4;14) abnormality was the most highly correlated with poorer outcomes by PFS: 4 year estimate: 32% vs. 60% (p<0.0001). The t(4;14) abnormality combined with ISS Stage also significantly enhanced predictive capability: ISS Stage I without t(4;14) OS 81% @ 4 years; ISS Stage III with t(4;14) OS 22% @ 4 years (P<0.0001) [Figure 1]. The best outcomes were for ISS Stage I in the presence of t(11;14): OS 89% @ 4 years. Absence of any one adverse feature correlated with 80-81% OS @ 4 years for Stage I. Presence of any one adverse feature had a more variable impact and correlated with 22%-40% OS at 4 years for Stage III.In univariate correlations the most predictive correlations with OS were presence of Any CA, t(4;14), 17p-, hypodiploidy, cytogenetic 13q- with R2 values of 6.9%, 4.5%, 4.1% and 3.8% respectively. In multivariate analyses, ISS stage provided the best predictions: R2 values = 13.3%. The added contributions from molecular features were: t(4;14) 3.8%; cytogenetic 13q- 2.9%; Any CA 2.3%; and 17p- 1.0%. The maximum total R2 for OS was 22%. ConclusionsThis large multicenter analysis confirms the correlations between abnormal molecular findings and outcomes. Combinations with ISS Stage provide the best predictive capability. Presence of Any CA, t(4;14), 17p-, hypodiploidy and cytogenetic 13q- contribute to poorer outcomes by ISS stage. The presence of hyperdiploidy and/or t(11;14) contribute to better outcomes. There is thus validation of prior molecular studies related to prognosis utilizing this large IMWG database. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A607 Clinical Implication of Hyperdiploidy/Non-Hyperdiploidy in MM Patients Treated by Newer Drugs

Multiple myeloma (MM) is a haematological disease characterised by accumulation of changed clone of plasma cells (myeloma cells) in bone marrow. This disorder is currently incurable and therefore there is a need for searching new prognostic factors, which are suitable for treatment optimalization. Among the most significant factors in multiple myeloma diagnosis belong cytogenetic changes. The main aim of this work was investigation of bone marrow samples from 74 MM patients treated by new drugs (Velcade/Thalidomid) for presence of hyperdiploidy / non-hyperdiploidy. Partial aims were focused on both comparison of incidence another prognostic important chromosomal MM abnormalities (translocation t(4;14); deletion 13q14, deletion 17p13 and gain/amplification 1q21) between hyperdiploid and non-hyperdiploid group of patients and comparison of impact of hyperdiploidy / non-hyperdiploidy on disease prognosis using survival analyses of both groups of patients.

Minimal Residual Disease (MRD) Analysis in Non-MRD Based ALL IC-BFM 2002 Protocol for Childhood ALL: Is It Possible To Omit Minimal Residual Disease in Risk Stratification?.

More than 800 children with acute lymphoblastic leukaemia (ALL) are treated every year according to ALL IC-BFM 2002 protocol, which was designed by the International-BFM Group as a parallel to MRD-based ALL/AIEOP BFM 2000 study. The ALL-IC BFM 2002 risk group stratification comprises blast proportion in peripheral blood (PB) after 7 days of prednisone and one IT-MTX (prednisone response) and bone marrow (BM) morphology evaluation at days 15 and 33 of therapy together with age, initial WBC and presence of BCR/ABL and MLL/AF4 fusion. One of the aims of the ALL IC-BFM 2002 study is the comparison of this risk group assessment to the MRD-based criteria used in ALL-BFM 2000. We analyzed a total of 203 patients treated according to the ALL IC-BFM 2002 in the Czech Republic, Israel, Hong Kong and Uruguay for the presence of clonal antigen receptor rearrangements. MRD was evaluated in 175 patients at several time-points of therapy including mandatory points at week 5 and 12, which are used in the ALL/AIEOP BFM 2000 stratification. In total, 654 follow-up BM specimens and 80 PB samples were tested. In the univariate analysis, a good molecular response defined as MRD negativity at both week 5 and 12 was associated with the age of 1–6 years (p=0.0001), WBC<20,000/mm3 (p=0.0002), non-T immunophenotype (p<0.0001), good prednisone response (p=0.0006), presence of TEL/AML1 fusion (p=0.003) and non-M3 morphology (≤25% blasts in BM) at day 15 (p=0.02). There was no significant association of MRD negativity with sex and hyperdiploidy; non-M3 BM morphology at day 8 was significant only when analyzing non-T ALL (p=0.02). Patients with BCP ALL had significantly lower MRD levels at day 15 (p=0.03) and at day 33 (p=0.001) than T-ALL patients; the difference was no more significant at week 12. Patients stratified to standard risk group (SRG) according to the ALL IC-BFM 2002 criteria had a significantly better molecular response defined as MRD negativity at week 5 and 12 than intermediate risk group (IRG) patients (p=0.009). However, in 24 of 69 SRG patients (34.7%), MRD positivity at week 5 and/or at week 12 was observed (ranging from borderline positivity to 1.5x10(-2)), thus identifying patients who would not qualify to MRD-based SRG in ALL/AIEOP BFM 2000. Within ALL IC SRG, patients with slow molecular response did not differ significantly from those with good MRD response in age, sex, WBC, BM morphology at day 15 and presence of hyperdiploidy or TEL/AML1 fusion. The only difference was in a higher proportion of M3 BM at day 8 in MRD slow-responders (p=0.04). Our findings revealed a significant divergence between the stratification results of ALL IC-BFM 2002 and ALL-BFM 2000. A fast morphological response to treatment (M1 or M2 bone marrow at day 15) together with other low-risk features does not necessarily correspond with rapid MRD clearance. Supported by MSM0021620813, Israel Cancer Association and Children's Cancer Foundation Hong Kong.

Genetic studies in NZB mice

The presence of hyperdiploidy was studied in New Zealand black (NZB) mice and the progeny of NZB X DBA/2 crosses and backcrosses. Hyperdiploidy was observed in the spleens of a majority of NZB mice but not in DBA/2 mice at 1 year of age. In crosses of NZB with the DBA/2 strain, hyperploidy was observed only in backcrosses to NZB. Hyperdiploidy appeared to be determined by a recessivley inherited trait and was not related to the presence of other immunological abnormalities, including splenomegaly, hypergammaglobulinemia, and spontaneous antibodies cytotoxic for T cells and reactive with single-stranded DNA. Abnormal cells were not present in Concanavalin A-stimulated 48-h spleen cultures. There was no difference in the in vitro sister chromatid exchange rate between the autoimmune NZB strain and the non-autoimmune DBA/2 strain. Identification of NZB chromosomes by banding analysis showed that chromosomes 15 and 17 were frequently present in more than two copies in hyperdiploid spleen cells. NZB chromsomes also had reduced C-banding in an autosomal pair. These studies indicate that chromosomal abnormalities which occur in NZB mice may be useful as genetic and cytogenetic markers.