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  • 1
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    Accelerated Telomere Shortening Precedes Development of Therapy-Related Myelodysplasia or Acute Myelogenous Leukemia After Autologous Transplantation for Lymphoma
    American Society of Clinical Oncology (ASCO) ; 2009
    In:  Journal of Clinical Oncology Vol. 27, No. 5 ( 2009-02-10), p. 791-798
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 27, No. 5 ( 2009-02-10), p. 791-798
    Abstract: Therapy-related myelodysplasia or acute myelogenous leukemia (t-MDS/AML) is a lethal complication of autologous hematopoietic stem-cell transplantation (aHCT) for Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). Here, we investigated the hypothesis that accelerated telomere shortening after aHCT could contribute to the development of t-MDS/AML. Patients and Methods A prospective longitudinal cohort was constructed to investigate the sequence of cellular and molecular abnormalities leading to development of t-MDS/AML after aHCT for HL/NHL. This cohort formed the sampling frame for a nested case-control study to compare changes in telomere length in serial blood samples from patients who developed t-MDS/AML with matched controls who did not develop t-MDS/AML. Results An initial increase in telomere length at day 100 after aHCT was followed by an accelerated telomere shortening in t-MDS/AML patients when compared with controls. These telomere alterations preceded the onset of t-MDS and were independent of other known risk factors associated with development of t-MDS/AML on multivariate analysis. Additionally, we observed reduced generation of committed progenitors in patients who developed t-MDS/AML, indicating that these telomere alterations were associated with reduced regenerative capacity of hematopoietic stem cells. Conclusion The development of t-MDS/AML after aHCT is associated with and preceded by markedly altered telomere dynamics in hematopoietic cells. Accelerated telomere loss in patients developing t-MDS/AML may reflect increased clonal proliferation and/or altered telomere regulation in premalignant cells. Genetic instability associated with shortened telomeres may contribute to leukemic transformation in t-MDS/AML.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2008.17.1033
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2009
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Do Changes in Transplant Practice Influence Risk of Therapy-Related Myelodysplasia/ Acute Myeloid Leukemia after Autologous Hematopoietic Cell Transplantation (aHCT) for Non-Hodgkin Lymphoma (NHL)?
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 430-430
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 430-430
    Abstract: Background: t-MDS/AML is the leading cause of non-relapse mortality after aHCT for NHL. Older age at aHCT, exposure to total body irradiation (TBI), and low number of CD34+ cells infused are associated with an increased risk of developing t-MDS/AML. However, over the past decade, aHCT has been increasingly used for older patient populations (potential for increase in t-MDS/AML risk). On the other hand, use of TBI has declined and number of CD34+ cells infused has increased (potential for decrease in t-MDS/AML risk). The impact of these changes in aHCT clinical practice on t-MDS/AML risk has not been assessed, and is addressed here. Methods: Information regarding t-MDS/AML diagnosis was procured from medical records and California Cancer Registry to ensure near-complete capture of events. Competing risk analysis was used to describe the cumulative incidence of t-MDS/AML, and to evaluate the role of host and aHCT-related factors in the development of t-MDS/AML. In order to understand the impact of changing clinical practices, patients were classified into those transplanted in the early era (1986-2002) vs. recent era (2003-2009). Results: A total of 1,261 consecutive patients received aHCT for NHL between 1986 and 2009 at City of Hope, and were followed for development of t-MDS/AML until 12/31/2011. Median age at aHCT was 50y (range, 5-78). Compared with patients transplanted in early era, those transplanted in recent era were more likely to be ≥50y at aHCT (recent era: 65% vs early era: 44%, p 〈 0.001); less likely to be conditioned with TBI (recent era: 17% vs. early era: 67%, p 〈 0.001); but more likely to receive a larger CD34+ cell dose ( 〉 3x10(6)/Kg: recent era 18% vs. early era: 12%, p 〈 0.0001). After a median follow-up of 4.8y (range, 0.02-24.6),78 patients developed t-MDS/AML, yielding a 15y cumulative incidence of 7.5%. The cumulative incidence of t-MDS/AML was higher among those ≥50y (10.0% vs. 5.3%, p=0.002), and among those exposed to TBI (8.8% vs. 5.2%, p=0.07). Taken together, older patients exposed to TBI had a significantly higher cumulative incidence of t-MDS/AML (10.9%), as compared with younger patients not exposed to TBI (2.3%, p 〈 0.001, Figure). Furthermore, the cumulative incidence of t-MDS/AML was higher among those with a low CD34+ cell dose ( 〈 3x10(6)/Kg) (14.2%) vs. those with a high CD34+ cell dose (≥3x10(6)/Kg) infusion (4.3%, p 〈 0.0001). Multivariable competing risk analysis (adjusted for era) demonstrated the independent and significant impact of older age (≥50y: HR=2.4, 95%CI, 1.5-3.9, p=0.0004 [ref grp: 〈 50y]), exposure to TBI (HR=1.8, 95%CI, 1.1-3.1, p=0.02 [ref grp: no TBI] ), and low CD34+ cell count ( 〈 3x10(6)/Kg, HR=3.3, 95%CI, 1.9-5.8, p 〈 0.0001 [ref grp: ≥3x10(6)/Kg]) in increasing the risk of t-MDS/AML. The impact these findings in light of changing practices with time is detailed in Table and summarized here. Multivariable analysis (taking age at aHCT into account) demonstrated that the risk of t-MDS/AML was reduced by 50% among those transplanted in the recent era (HR=0.5, 95%CI, 0.3-0.9, p=0.03 [ref grp: early era] ) (Model 1). However, inclusion of TBI and CD34+ cell count in the model abrogated the reduction in the risk of t-MDS/AML during the recent era (HR=0.97, 95%CI, 0.5-1.9, p=0.9, referent grp: early era) (Model 2). Conclusions: This large study spanning over 25y confirms the independent role of age at aHCT, TBI, and CD34+ cell count in t-MDS/AML risk. More importantly, the study delineates the risk of t-MDS/AML in the context of changes in clinical practice of aHCT for NHL, demonstrating a reduction in the incidence of t-MDS/AML (despite an increase in age limit for aHCT) that is likely due to the declining practice of using TBI and the ability to use a higher number of CD34+ cells for aHCT. Table Model 1 Model 2 Model 3 HR (95% CI), p-value HR (95% CI), p-value HR (95% CI), p-value Era of aHCT 1986-2002 1.0 1.0 1.0 2003-2009 0.54 (0.3-0.9), p=0.03 0.71 (0.4-1.3), p=0.3 0.97 (0.5-1.9) p=0.9 Age at aHCT 〈 50y 1.0 1.0 1.0 ≥50y 2.09 (1.3-3.4), p=0.002 2.25 (1.4-3.6), p=0.0007 2.41 (1.5-3.9) p=0.0004 Conditioning with TBI No TBI 1.0 1.0 Yes TBI 1.80 (1.1-3.0), p=0.02 1.8 (1.1-3.1) p=0.02 CD 34 counts 〉 3 1.0 ≤3 3.32 (1.9-5.8) p 〈 0.001 missing 2.36 (1.2-4.5) p=0.01 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.430.430
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 3
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    Altered Hematopoietic Cell Gene Expression Identifies Patients at Risk for Development of Therapy-Related Leukemia (t-MDS/AML)
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 234-234
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 234-234
    Abstract: Abstract 234 Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a lethal complication of cancer treatment. Study of t-MDS/AML offers a unique opportunity to understand leukemogenesis since known genotoxic exposures can be temporally and causally related to genetic changes associated with development of leukemia. Although development of t-MDS/AML is associated with known genotoxic exposures, its pathogenesis is not well understood, and methods to predict risk of development of t-MDS/AML in individual cancer survivors are not available. To better understand the pathogenetic mechanisms underlying development of t-MDS/AML we performed microarray analysis of gene expression in patients who developed t-MDS/AML after autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) and controls that did not develop t-MDS/AML after aHCT. Peripheral blood stem cell (PBSC) samples obtained pre-aHCT from patients who subsequently developed t-MDS post-aHCT (cases) and controls matched for primary diagnosis, age, race/ethnicity, and time since aHCT were studied. In a training set of 18 t-MDS/AML cases and 37 controls, CD34+ cells were selected from PBSC samples using flow cytometry, and gene expression evaluated using Affymetrix HG U133 plus 2.0 Arrays. Differences in gene expression in CD34+ cells from cases and controls were analyzed using conditional logistic model. Significant differences in gene expression were seen in PBSC obtained pre-aHCT from patients who later developed t-MDS/AML compared to controls.(Blood, 2009; 114: 677) PBSC obtained pre-aHCT from patients who subsequently t-MDS/AML after aHCT showed significant downregulation of gene sets related to mitochondria and oxidative phosphorylation, ribosomes, aminoacyl-tRNA biosynthesis, amino acid metabolism, cell cycle regulation, and hematopoietic differentiation. G-protein coupled receptors, hematopoietic regulation, and cell adhesion related genes were upregulated in PBSC from cases. There was reduced expression of genes with binding motifs for the transcription factor NRF2, which regulates oxidative stress and drug detoxification. We then sought to identify a smaller PBSC gene signature that would identify NHL and HL patients at the pre-aHCT timepoint at high risk for developing t- MDS/AML after aHCT (Figure 1). A cross-validated 38-gene classifier was derived from the training set using prediction analysis of microarray (PAM). This gene classifier was applied to an independent test set of PBSC obtained pre-HCT from 16 patients who developed t-MDS/AML after aHCT for NHL or HL, and 20 matched controls that did not develop t-MDS/AML. Application of the 38-gene signature to the test set correctly classified 19 of the 20 subjects (95%) who did not subsequently develop t-MDS/AML, and 14 of the 16 subjects (87.5%) who did develop t-MDS/AML, with significant correlation between predicted and true disease status (P 〈 0.001). These results indicate that the gene expression profile of hematopoietic cells pre-aHCT can identify patients at high risk for t-MDS/AML post-aHCT. GSEA analysis revealed extensive overlap of up and down-regulated gene sets in t-MDS/AML cases in the training and test sets (Figure 2). Gene expression changes related to mitochondria, metabolism, cell cycle regulation and hematopoietic progenitors that were observed in the training set were validated in the test set. These results indicate that genetic programs associated with t-MDS/AML are perturbed long before disease onset, and that PBSC gene signatures can accurately identify patients at high risk of developing this complication. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.234.234
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 4
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    Genetic Susceptibility to Therapy-Related Leukemia (t-MDS/AML) After Hodgkin Lymphoma (HL) or Non-Hodgkin Lymphoma (NHL).
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 199-199
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 199-199
    Abstract: Abstract 199 Therapy-induced t-MDS/AML is the leading cause of non-relapse mortality after HL or NHL. However, there exists a wide variation in t-MDS/AML susceptibility – potentially explained by individual variability in drug metabolism, DNA repair and apoptosis, or in genetic profiles shared with de novo AML. Using a matched case-control study design, we examined the association between t-MDS/AML and candidate genes (n=29) in relevant biological pathways, including hematopoietic regulation (RUNX1, HLX1); apoptosis (TP53, MDM2); drug metabolism (CYP3A4, CYP1A1, GSTM1, GSTP1, GSTT1, NQO1); DNA repair (MGMT, MUTYH, MLH1, MSH2, MTHFR, RAD51, RAD51C, RAD52, XRCC1, XRCC2, XRCC3, XRCC4, XPD); and genes associated withde novoAML (LAMC2/NMNAT2, SGCE/PEG10, FRAP1, and PTPRT). The study cohort consisted of 46 cases with t-MDS/AML after HL/NHL and 46 controls with HL/NHL, but without t-MDS/AML (matching criteria: primary diagnosis, age and year of primary diagnosis, length of follow-up and genetic ancestry [see Table]). Sequenom MassArray and PCR were used to analyze 55 SNPs and 2 deletions in these genes. After correction for multiple testing, we could not identify significant association between any single SNP and t-MDS/AML. However, we did confirm enrichment of risk genotypes in t-MDS/AML for 2 of 4 loci previously implicated in de novo AML by a genome wide association study in Caucasians: LAMC2/NMNAT2 (minor allele carrier [MAC] odds ratio [OR]=4.0, p=0.1) and PTPRT (MAC OR=4.5, p=0.06). Next, we tested the hypothesis that TP53 plays a role in mediating apoptotic response to DNA damage following genotoxic exposures. We modeled interactions between a common coding SNP of TP53 causing a Pro 72 to Arg variant (P72R: Pro allele is associated with ∼15-fold decreased apoptotic capacity compared to Arg) and other candidate SNPs. We identified significant interaction between TP53 and several SNPs in MTHFR (Min. likelihood ratio pinteraction=0.0003 and 0.04 adjusted after 10000 permutations). Although the homozygous T allele of rs7538516 (associated with lower MTHFR expression) was not associated with t-MDS/AML by itself, it increased the risk 11-fold (OR=11.4, p=0.005) when combined with a Pro/Arg or Pro/Pro genotype of P72R compared to its combination with Arg/Arg. This observation suggests that reduced MTHFR activity (associated with increased risk of chromosomal aberrations during DNA repair), in combination with reduced apoptotic capacity (Pro/Arg or Pro/Pro variant of TP53), increases the risk of t-MDS/AML. Next, we examined expression levels of these 29 genes (79 probe sets in Affymetrix U133 Plus 2.0 microarrays) in a subset of 13 cases matched with 28 controls. Using a general linear model adjusted for age, gender, race, and exposure to alkylating agents, topoisomerase inhibitors and radiation, we detected 11 of the 29 (38%) genes to be differentially expressed between cases and controls (p 〈 0.05). Strong signals (p 〈 0.05 after Holm-Bonferroni adjustment) were observed for TP53 (apoptosis), genes involved in drug metabolism (CYP3A4 [activation] , GSTM1, GSTP1, and GSTT1 [detoxification]), in DNA repair (MSH2), and genes associated with de novo MDS/AML (NMNAT2, PEG10). Taken together, these observations provide evidence supporting the following: i) a significant association between individual capacity of apoptosis, drug metabolism, DNA repair, and t-MDS/AML; and ii) shared genetic susceptibility between t-MDS/AML and de novo AML. These observations not only further our understanding of the pathogenesis of t-MDS/AML, but also help identify those at the highest risk, setting the stage for targeted surveillance or pharmacological interventions. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.199.199
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 5
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    Genetic Susceptibility to Therapy-Related Leukemia – Role of Expression Quantitative Trait Loci (eQTL)
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2438-2438
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    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2438-2438
    Abstract: Abstract 2438 Therapy-related leukemia (t-MDS/AML) is a leading cause of non-relapse mortality in patients treated for cancers, such as Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). Although the association between therapeutic exposures (alkylators, topoisomerase II inhibitors) and t-MDS/AML is clearly defined, inter-individual variability does exist, suggesting the role for genetic factors. Understanding the full spectrum of genetic susceptibility to t-MDS/AML should help identify those at highest risk, setting the stage for targeted surveillance and/or pharmacological intervention. Using a matched case-control design (clinical characteristics – Table 1), we previously identified an association between t-MDS/AML and GSTM1 deletion, demonstrated as differences in both genotype frequency and gene expression level, suggesting that drug-metabolizing enzymes contribute to individual susceptibility. In general, genotyping study analyzes germ line variant alleles that potentially affect function or production level of genes; while expression analysis investigates differences in transcription level resulting from germ line or somatic variations caused by genetic or epigenetic changes, or treatment exposures. In the previous study, after adjusting for treatment exposures, we had detected association of t-MDS/AML with GSTM1 deletion (P = 0.057), and significantly lower expression of GSTM1 (measured by 2 probesets on Affymetrix HG U133 Plus 2 Array) in cases compared with controls (p = 0.0058). Interestingly, several cases with at least one intact allele of GSTM1 expressed low levels of GSTM1; levels that were comparable to individuals who were homozygous for the null allele. Therefore we hypothesized that additional loci control expression levels of this gene and may also predict susceptibility to t-MDS/AML. These expression quantitative trait loci (eQTL) represent genomic regions for the control of quantitative variation in gene expression, typically through modulation of activity of cis-regulatory elements. To test this hypothesis, we identified one SNP, rs11101992, as a genetic marker to a cis-acting eQTL for GSTM1 in lymphoid cell lines (p = 1.6 × 10−10) based on data from a previous study (Dixon et al. Nat Genet 39, 1202–1207) and confirmed its effect in CD34+ peripheral blood stem cells from 32 subjects of Caucasian ancestry (p = 0.078). We then genotyped this SNP in the 49 pairs of matched cases/controls and identified a much stronger association of t-MDS/AML with this SNP (P = 0.0026). The association persisted after adjusting for GSTM1 deletion (P = 0.0076). This SNP was also correlated with expression level of other GSTM gene family members located within the same chromosomal region in lymphoid cell lines (p = 3.4 × 10−10 with GSTM2, p = 3.8 × 10−7 with GSTM3, and p = 4.1 × 10−7 with GSTM4), possibly due to cross hybridization among probe sets or co-expression control of these homologous genes. Our results suggest that additional germ line variation other than GSTM1 deletion regulates expression level of this or other members of the GSTM family and contributes to the risk of t-MDS/AML. We are currently evaluating genetic effect of individual GSTM genes to t-MDS/AML. To our knowledge, this is the first report of the role played by eQTL in defining the genetic susceptibility of t-MDS/AML and provides a novel strategy to uncover new risk loci for this lethal complication resulting from cancer treatment.Table 1:Clinical CharacteristicsCharacteristicsGenotyping StudyExpressionStudyCases (n=49)Controls (n=49)Cases (n=12)Controls (n=22)Primary Diagnosis (%)    HL292400    NHL 7176100100Age at Primary Diagnosis (Median, Range)49.1 (13–73)47.9 (26–75)48.9 (26–67)48.2 (26–64)Race/ethnicity (%)    Caucasians77.681.658.386.4    Hispanics18.414.333.39.1    African-Americans2.02.08.34.6    Asians/others2.02.00.00.0Gender (%)    Male71595077    Female29415023Type of Treatment (%)    Autologous HCT7145100100    Conventional295500Latency or follow-up from Primary Diagnosis (Year, Median, Range)4.9 (0.6–29)8.1 (2.4–30)3.6 (1.2–9.2)8.2 (4.8–21)Latency or Follow-up from aHCT (Year, Median, Range)3.1 (0.4–17)3.9 (0.6–10)2.8 (0.5–3.7)7.2 (0.5–8.4)Cytogenetic Abnormality (%)    5q- or 7q-5733    11q236.5NA25NA    Others3025    Normal6.517Treatment Exposure    Radiation (%)69658368    Alkylating Agent Score3 (1–6)3 (0–6)2 (1–4)3 (1–5)    Topoisomerase II Inhibitor Score3 (0–4)3 (0–4)3 (2–4)3 (2–4) Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2438.2438
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 6
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    Long-Term Morbidity and Mortality Experienced By Chronic Myeloid Leukemia (CML) Patients after Allogeneic Hematopoietic Cell Transplantation (HCT) - a Report from BMTSS-2
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 823-823
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    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 823-823
    Abstract: Background: Tyrosine kinase inhibitors have become the treatment of choice for CML. However, the high cost and need for life-long treatment contribute to non-adherence and represent a major challenge in their use. Allogeneic HCT is potentially curative, but the very long-term health of the survivors is not known. It is also not clear whether a subgroup of CML patients carries a relatively low risk of long-term morbidity. Methods: We addressed these gaps by studying long-term outcomes in 637 CML patients treated with allogeneic HCT between 1981 and 2010 at City of Hope or Univ MN, and surviving for at least 2y after HCT (median follow-up: 16.7y from HCT); 80% of the cohort was 〈 45y at HCT; 68% received HCT in 1st chronic phase (CP); 63% received matched related [MRD], 34% matched unrelated donor (MUD) and 3% non-myeloablative HCTs; 79% received TBI; 65.8% developed chronic GvHD. Vital status information was collected as of May, 2016, using medical records, National Death Index and Lexis Nexis. US mortality rates were obtained from CDC's National Center for Health Statistics. Thirty percent (n=192) died after having survived at least 2 years after HCT; median time between HCT and death was 8.3y. Of the 445 patients alive at study, 288 (65%) completed the BMTSS health questionnaire used to examine the risk of CTCAE grade 3 (severe) or 4 (life-threatening) chronic health conditions. A sibling comparison group (n=404) also completed the BMTSS questionnaire. Results: Late Mortality: Overall survival was 72.1% at 20y and 69.9% at 30y from HCT. The 20y cumulative incidence of relapse-related mortality was 3.9% (95% CI, 2.6-5.8%) and of non-relapse-related mortality was 18.2% (95% CI, 19.8-28.1%) (Figure 1). 20y cumulative incidence of mortality by cause of death was as follows: infection (7%), chronic GvHD (6%), subsequent malignant neoplasms (SMNs: 3%). HCT recipients were at 4.4-fold increased risk of death (95% CI, 3.8-5.1, p 〈 0.0001) than age-, race-, and sex-adjusted normal populations. For patients transplanted in 1st CP and surviving 15y, mortality rates became comparable with the general population (SMR, 1.5, 95% CI, 0.9-2.3, p=0.1). Among CML patients receiving HCT at 〈 45y with Bu/Cy (n=70), overall survival was 81.5% at 20y from HCT; the 20y cumulative incidence of relapse-related mortality was 2.9% and of non-relapse-related mortality was 14%. This cohort was at 3.3-fold higher risk of death when compared with the general population (95% CI=1.7-5.7, p 〈 0.0001). Late Morbidity: The 20y cumulative incidence of a severe/life-threatening chronic health condition among HCT survivors was 47.2% (95% CI, 39.0-54.9%); the incidence was higher (p=0.0006) for MUD vs. MRD recipients (Figure 2). After adjusting for age, sex, race and SES, HCT survivors were at 2.7-fold higher risk for severe/life-threatening chronic health conditions as compared with siblings (95% CI, 1.8-3.9, p 〈 0.0001). The 20y cumulative incidence of specific conditions experienced by survivors and siblings were: SMNs (10.1% vs. 1.7%, p 〈 0.001); diabetes (11.1% vs. 1.5%, p 〈 0.001) and coronary artery disease (6.9% vs. 3.2%, p 〈 0.001). CML patients receiving MRD HCT at 〈 45y with Bu/Cy were not at increased risk of severe/life-threatening chronic health conditions when compared with the sibling comparison group (HR=0.81, 95% CI, 0.26-2.54, p=0.7). Conclusions: Conditional on surviving the first 2y after HCT, the overall survival exceeds 70% at 20y and remains stable at 70% at 30y after HCT. Non-relapse related mortality (infections, chronic GvHD, SMNs) is by far the major contributor to the late mortality. Conditional on surviving the first 15y, mortality rates are similar to those observed in the general population. HCT survivors are at a 2.7-fold higher risk of severe/life-threatening morbidity when compared with siblings. The more common morbidities include SMNs, diabetes and coronary artery disease. However, CML patients receiving HCT at 〈 45y with Bu/Cy conditioning enjoy survival rates exceeding 81% at 20y from HCT, and their burden of long-term morbidity is comparable to that experienced by siblings. These findings could help inform decisions regarding therapeutic options for management of CML. Disclosures Snyder: BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.823.823
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 7
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    Secondary breast cancer (s-BC) after hematopoietic cell transplantation (HCT) for leukemia: Role of total body irradiation (TBI).
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 1592-1592
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 1592-1592
    Abstract: 1592 Background: s-BC after conventional chest radiation for histologically distinct cancer is well-recognized, and has resulted in radiologic screening recommendations by American Cancer Society. However, risk of s-BC after TBI is not well-defined. Methods: We determined the risk of s-BC in 648 consecutive females transplanted for leukemia (ALL [19%], AML/MDS [57%] , CML [24%]) between 1976 and 2008 with a post-HCT survival of ≥2 years. The study was restricted to leukemia to understand the role of TBI without the influence of pre-HCT chest radiation. Near-complete ascertainment of s-BC was assured by combining institutional follow-up with California Cancer Registry data. Results: Median age at HCT was 38 years (range, 0-71); 14% had received autologous HCT, 64% related and 22% unrelated donor HCT; 70% had received TBI for myeloablative conditioning. After 5,675 person-years of observation, 16 patients developed s-BC (14 after TBI). Median latency from HCT to s-BC was 16y (2-27). Median age at s-BC was 50y (29-66). Cumulative incidence of s-BC was 6% at 20y after HCT, contributed to largely by TBI (s-BC incidence after TBI: 5.7%). Among TBI-exposed, 8.6% were projected to develop s-BC by age 65y (1.6% among non-TBI-exposed, p=0.03). TBI-exposed patients were 2.4 times more likely to develop s-BC compared with general population (p=0.001); non-TBI exposed were not at increased risk (SIR=0.9, p=0.9). Multivariate analysis (adjusted for age at HCT, follow-up and primary diagnosis) revealed a 4.7-fold (p=0.068) increased risk of s-BC among TBI-exposed.  Conclusions:   Risk of s-BC after TBI as the sole source of radiation to breast is increased. Nearly 9% of those exposed to TBI will develop s-BC by age 65y. Identification of vulnerable sub-populations among the TBI-exposed patients is underway to create target ed screening strategies for early detection of s-BC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.1592
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Cytopenias in the Early Post-Autologous Hematopoietic Cell Transplantation (aHCT) Period Predict for Subsequent Development of Therapy-Related Myelodysplasia/ Acute Myeloid Leukemia (t-MDS/AML) Among Patients with Lymphoma
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2507-2507
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2507-2507
    Abstract: t-MDS/AML is the most common cause of non-relapse mortality in patients undergoing autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). Cytopenias are a common occurrence in the early post-aHCT period. To better understand the significance of cytopenias with respect to the risk of t-MDS/AML, we conducted a prospective, longitudinal study in patients undergoing aHCT for HL or NHL between 1999 and 2009 at City of Hope, with serial collection of peripheral blood samples from pre-aHCT to 10y. Patients with post-aHCT persistent disease (n=55) or solid second malignancies (n=9) or refusal to participate (n=18) were excluded from the analysis, leaving 292 study participants (HL: n=81; NHL: n=211). The median length of follow-up was 4.5y from aHCT. The cumulative incidence of t-MDS/AML approached 9% at 7y (Figure). Older age at aHCT (50+y: RR=3.6, 95%CI, 1.3-9.8, p=0.01) and exposure to total body irradiation (TBI: RR=2.5, 95%CI, 1.0-5.9, p=0.04) were associated with an increased risk of t-MDS/AML. Serial evaluation of peripheral blood parameters (hematocrit [Hct], mean corpuscular volume [MCV] , red blood cell [RBC] count, hemoglobin [Hgb] , red cell distribution width [RDW], white blood cell [WBC] count, and platelet [Plt] count) were abstracted from medical records at pre-aHCT, and after aHCT at d100, 6m, 1y, and annually thereafter for up to 10y (a total of 1,919 time points). This report focuses on alterations in peripheral blood parameters from pre-aHCT to several years post-aHCT among patients who developed t-MDS/AML (n=21; cases) and those who did not (n=271; controls). Values of peripheral blood parameters associated with post-aHCT relapse or development of t-MDS/AML were censored at 3m prior to the development of these events. As shown in the Figure, comparison of the peripheral blood parameters between cases and controls revealed that Hct, Hgb, Plt, and RBC values were significantly lower for cases compared to controls at d100, 6m, 1y, and 2y (p 〈 0.001); WBC values for cases were lower than for controls at the pre-aHCT, d100, and 6m time points (p 〈 0.01); RDW and MCV values did not differ between cases and controls. A Cox regression model was fitted to the data to examine the association between t-MDS/AML and specific low peripheral blood parameter values at d100, 6m, and 1y post-aHCT (adjusting for year of aHCT, age at aHCT, primary diagnosis, race/ethnicity, sex and TBI). The following parameters (with their cutpoints) emerged as significantly associated with increased risk of t-MDS/AML: Hgb 〈 12, Plt 〈 100k, and RBC 〈 3. Compared with patients with Hgb, Plt and RBC values above these cutpoints at d100, 6m, or 1y, those with low values for all three blood parameters had a significantly increased risk of developing t-MDS/AML (d100: HR=10.5, 95%CI, 2.1-53.1, p=0.004; 6m: HR=9.9, 95%CI, 1.9-53.1, p=0.007; 1y: HR=10.7, 95%CI, 1.5-74.0, p=0.02). In summary, we consistently observed lower values for specific blood parameters during the post-aHCT period among patients who subsequently developed t-MDS/AML as compared to controls across multiple timepoints post-aHCT. These differences appeared soon after aHCT, persisted, and preceded the development of t-MDS/AML, providing evidence that bone marrow injury long predates the development of t-MDS/AML. Importantly, the combination of low Hgb, Plt, and RBC values at d100, 6m, or 1y predicted future development of t-MDS/AML, and could be used as early indicators of t-MDS/AML risk and the need for close monitoring. Abstract 2507. Table Peripheral blood parameters Day 100 (HR, 95%CI) p-value 6 month (HR, 95%CI) p-value 1 year (HR, 95%CI) p-value All normal Hgb≥12 and Plt ≥100 and RBC ≥3 1.00 0.004 1.00 0.007 1.00 0.02 All low Hgb 〈 12 and Plt 〈 100 and RBC 〈 3 10.5 (2.1-53.1) 9.9 (1.9-53.1) 10.7 (1.5-74.0) Figure Figure. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2507.2507
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
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    Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining
    American Society of Hematology ; 2012
    In:  Blood Vol. 119, No. 26 ( 2012-06-28), p. 6187-6197
    Details
    In: Blood, American Society of Hematology, Vol. 119, No. 26 ( 2012-06-28), p. 6187-6197
    Abstract: Chromosomal aberrations are an important consequence of genotoxic exposure and contribute to pathogenesis and progression of several malignancies. We investigated the susceptibility to chromosomal aberrations in chronic myelogenous leukemia (CML) progenitors after exposure to ionizing radiation. In normal progenitors, ionizing radiation induced both stable and unstable chromosomal lesions, but only stable aberrations persisted after multiple divisions. In contrast, radiation of chronic phase CML progenitors resulted in enhanced generation of unstable lesions that persisted after multiple divisions. CML progenitors demonstrated active cell cycle checkpoints and increased nonhomologous end joining DNA repair, suggesting that persistence of unstable aberrations was the result of continued generation of these lesions. CML progenitors demonstrated enhanced susceptibility to repeated cycles of chromosome damage, repair, and damage through a breakage-fusion-bridge mechanism. Perpetuation of breakage-fusion-bridge cycles in CML progenitors was mediated by classic nonhomologous end joining repair. These studies reveal a previously unrecognized mechanism of chromosomal instability in leukemia progenitors because of continued generation of unstable chromosomal lesions through repeated cycles of breakage and repair of such lesions.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2011-05-352252
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Increased Risk Of Brain Tumors Among First-Degree Relatives Of Patients With Therapy-Related Myelodysplasia and Acute Myeloid Leukemia (t-MDS/AML)
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 5228-5228
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 5228-5228
    Abstract: t-MDS/AML is a leading cause of non-relapse mortality among patients undergoing autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). A combination of therapeutic exposures prior to aHCT, aHCT-related conditioning regimens, peripheral blood stem cell mobilization and post-aHCT hematopoietic regeneration contribute to the development of t-MDS/AML. However, significant inter-individual variability is observed despite similar therapeutic exposures. This inter-individual variability could possibly be explained by low-penetrance, high-prevalence polymorphisms in genes involved in DNA damage and repair. On the other hand, a small but quantifiable fraction of the inter-individual variability observed in the risk of t-MDS/AML (in the context of comparable genotoxic exposures) could be attributable to the familial predisposition to cancer that is associated with rare polymorphisms in high-penetrance genes – an area that has not been explored thus far. Methods This study aimed to describe the excess risk of specific cancers among first-degree relatives of HL/NHL patients with t-MDS/AML after aHCT compared to first-degree relatives of HL/NHL patients without t-MDS/AML. We have constructed a prospective, longitudinal cohort of patients undergoing aHCT for HL and NHL, where patients are followed from pre-aHCT to 10 yrs post-aHCT (period of risk for t-MDS/AML) allowing for complete ascertainment of t-MDS/AML cases. Study participants were invited to complete a family history questionnaire. Probands with at least one sibling, parent or offspring with cancer were defined as having a positive family history of cancer. Person-yrs at risk for the cohort of relatives were determined from birth to the development of cancer, death or date of questionnaire completion (whichever occurred first). Person-yrs at risk were stratified by age, sex and calendar yr and applied to SEER registry data to yield expected numbers of each type of cancer to compute standardized incidence ratios (SIR: observed/expected) with 95% confidence intervals (CI) for cancer incidence in first-degree relatives of probands with and without t-MDS/AML. Results The 446 HL/NHL patients in the cohort reported on 2,664 first-degree relatives, yielding 130,578 person-yrs of follow up. A positive family history of cancer was reported by 103 patients, with 370 incidences of cancer. When stratified by t-MDS/AML status, a positive family history of cancer was identified in 15 of 64 patients with t-MDS/AML (23%) vs. 88 of 382 (23%) patients without t-MDS/AML, yielding an overall SIR of 1.09 (0.82-1.42) for relatives of HL/NHL patients with t-MDS/AML vs. 1.01 (0.89-1.13) for relatives of HL/NHL patients without t-MDS/AML (p=0.60) (Table). However, examination of risk by family history of specific cancer type demonstrated an excess risk of brain tumors among relatives of HL/NHL patients with t-MDS/AML (SIR=5.27, 95% CI, 1.89-11.31) as opposed to relatives of lymphoma patients without t-MDS/AML (SIR=1.55, 95% CI, 0.71-2.89, p=0.03) (Table). This excess risk was contributed to largely by brain tumors among fathers of patients with t-MDS/AML (SIR=5.84, 95% CI, 0.97-18.05) when compared with fathers of patients without t-MDS/AML (SIR=1.05, 95% CI, 0.18-3.27, p=0.09). Conclusions This study demonstrates an excess risk of brain tumors among first-degree relatives (and in particular fathers) of HL/NHL patients with t-MDS/AML after aHCT, as compared to HL/NHL patients without t-MDS/AML. This information may serve as a basis for the discovery of underlying genetic predisposition syndromes as well as specific genes responsible for their development. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.5228.5228
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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