The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P = 0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P = 0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P = 0.08) and del(5q) (P = 0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progressionfree survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P = 0.05). These findings comprise the largest MDS R72P SNP analysis

Validation of the new DSM‐5‐TR criteria for prolonged grief disorder and the PG‐13‐Revised (PG‐13‐R) scale

Although the concept of pathological grief dates back at least as far as Freud’s “Mourning and Melancholia”, there has been opposition to its recognition as a distinct mental disorder. Resistance has been overcome by evidence demonstrating that distinctive symptoms of prolonged grief disorder (PGD) – an attachment disturbance featuring yearning for the deceased, loss of meaning and identity disruption – can endure, prove distressing and disabling, and require targeted treatment. In acknowledgement of this evidence, the American Psychiatric Association Assembly has recently voted to include PGD as a new mental disorder in the DSM-5-TR. We tested the validity of the new DSM criteria for PGD and of an adapted version of our PG-13 scale, the PG-13-Revised (PG-13-R), designed to map onto these criteria, using data from investigations conducted at Yale University (N=270), Utrecht University (N=163) and Oxford University (N=239). Baseline assessments were performed at 12-24 months post-loss; follow-up assessments took place 5.3-12.0 months later. Results indicated that the PG-13-R grief symptoms represent a unidimensional construct, with high degrees of internal consistency (Cronbach's alpha = 0.83, 0.90 and 0.93, for Yale, Utrecht and Oxford, respectively). The DSM PGD diagnosis was distinct from post-traumatic stress disorder (phi=0.12), major depressive disorder (phi=0.25) and generalized anxiety disorder (phi=0.26) at baseline. Temporal stability was remarkable for this diagnosis (r=0.86, p<0.001). Kappa agreement between a PG-13-R threshold symptom summary score of 30 and the DSM symptom criterion for PGD was 0.70-0.89 across the datasets. Both the DSM PGD diagnosis and the PG-13-R symptom summary score at baseline were significantly associated (p<0.05) with symptoms and diagnoses of major depressive disorder, post-traumatic stress disorder and/or generalized anxiety disorder, suicidal ideation, worse quality of life and functional impairments at baseline and at follow-up, in the Yale, Utrecht and Oxford datasets. Overall, the DSM-5-TR criteria for PGD and the PG-13-R both proved reliable and valid measures for the classification of bereaved individuals with maladaptive grief responses

Validation of the new DSM‐5‐TR criteria for prolonged grief disorder and the PG‐13‐Revised (PG‐13‐R) scale

Although the concept of pathological grief dates back at least as far as Freud’s “Mourning and Melancholia”, there has been opposition to its recognition as a distinct mental disorder. Resistance has been overcome by evidence demonstrating that distinctive symptoms of prolonged grief disorder (PGD) – an attachment disturbance featuring yearning for the deceased, loss of meaning and identity disruption – can endure, prove distressing and disabling, and require targeted treatment. In acknowledgement of this evidence, the American Psychiatric Association Assembly has recently voted to include PGD as a new mental disorder in the DSM-5-TR. We tested the validity of the new DSM criteria for PGD and of an adapted version of our PG-13 scale, the PG-13-Revised (PG-13-R), designed to map onto these criteria, using data from investigations conducted at Yale University (N=270), Utrecht University (N=163) and Oxford University (N=239). Baseline assessments were performed at 12-24 months post-loss; follow-up assessments took place 5.3-12.0 months later. Results indicated that the PG-13-R grief symptoms represent a unidimensional construct, with high degrees of internal consistency (Cronbach's alpha = 0.83, 0.90 and 0.93, for Yale, Utrecht and Oxford, respectively). The DSM PGD diagnosis was distinct from post-traumatic stress disorder (phi=0.12), major depressive disorder (phi=0.25) and generalized anxiety disorder (phi=0.26) at baseline. Temporal stability was remarkable for this diagnosis (r=0.86, p<0.001). Kappa agreement between a PG-13-R threshold symptom summary score of 30 and the DSM symptom criterion for PGD was 0.70-0.89 across the datasets. Both the DSM PGD diagnosis and the PG-13-R symptom summary score at baseline were significantly associated (p<0.05) with symptoms and diagnoses of major depressive disorder, post-traumatic stress disorder and/or generalized anxiety disorder, suicidal ideation, worse quality of life and functional impairments at baseline and at follow-up, in the Yale, Utrecht and Oxford datasets. Overall, the DSM-5-TR criteria for PGD and the PG-13-R both proved reliable and valid measures for the classification of bereaved individuals with maladaptive grief responses

TP53 and MDM2 Single Nucleotide Polymorphisms Influence Survival in Non-del(5q) Myelodysplastic Syndromes

P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to −2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome

Phase 2 Multicenter Trial of Rabbit Anti-Thymocyte Serotherapy In Myelodysplastic Syndrome: Rate of Hematological Improvement Associated with Pre-Treatment Disease Duration

Abstract Abstract 602 Introduction: T–cell depleting regimens that contain anti-thymocyte globulin (ATG) have been used for the treatment of myelodysplastic syndrome (MDS) suggesting a link between immune dysregulation and ineffective hematopoiesis in a subset of patients. Pre-treatment clinical features such as younger age, shorter duration of red cell transfusion dependence, and HLADR15 genotype were identified as response co-variates in a single institutional experience with equine ATG (eATG). We report results from the first US multicenter study examining rabbit (rATG) for the treatment of MDS. Methods and Patients: This study was a non-randomized, multicenter Phase II clinical trial of rATG (Thymoglobulin®) designed to examine the response and safety of this agent in MDS patients. The primary endpoint was IWG 2000 response rate with secondary analyses of duration of response, time to response, time to progression and tolerance. rATG 2.5 mg/kg/day was administered IV for 4 doses. The relationship between response and variables such as age, bone marrow cellularity, HLA-DR15, karyotype, blood counts, and disease duration were also investigated. Eligible patients had severe neutropenia (ANC < 1000), severe anemia (untransfused hemoglobin <9 g/dl), anemia requiring transfusion, or thrombocytopenia (platelet count < 50,000/mm3) plus the presence of 10% bone marrow blasts in patients with int-2. Patients with chronic myelomonocytic leukemia (CMML) and lab abnormalities were excluded. Statistical methods include Wilcoxon rank-sum test, Kaplan-Meier survival curve and log-rank test. Results: Between Aug.2004 and May 2010, 39 MDS patients were enrolled: 24 patients were eligible for treatment, and 21 evaluable for response. Drop out occurred due to initiation of therapy off study (n=5), non-compliance (n=1), death prior to treatment (n=2), and failure to meet eligibility criteria (n=7). IPSS risk categories in the evaluable patients included low-risk (n=6, 29%), int-1 (n=12, 57%), and int-2 (n=3, 14%). Infusion-related reactions were the most common adverse event, generally occurring with the first dose of rATG. There were 3 deaths among treated patients related to infection, including 1 patient with neutrophil hematologic improvement (HIN). Nine (43%) of the 21 evaluable patients experienced HI. Twelve (57%) were non-responsive including patients with stable disease (n=7, 33%) and disease progression (n=5, 24%) including 3 with excess blasts (n=2) or prior history of cancer treatment (n=1). The median time to response was 75 days (range 3 days–3.7 months) and median duration of response was 7.2 months (range 2–22+ months) with a median follow up of 20 months. Two patients maintained HI at the time of this analysis and response was extended in two patients by initiating cyclosporine As shown in Fig. 1, progression free survival (PFS) was greater in responders compared to non-responders (median PFS in responders 1 vs 0.23 year), but did not reach statistical significance (p=0.1). The mean age at treatment for evaluable patients was 64 years (median 66, range 44–79), however, age was not a significant co-variate for HI (median age in responders 65 years, non-responders 66, p=0.5). Only 4 patients had the HLADR15 allele, among whom 3 achieved HI (75%). Other factors such as IPSS, cytopenias, LDH, karyotype, age-adjusted bone marrow cellularity, and M:E ratio showed no association with HI in univariant analyses. Responding patients had a shorter time from diagnosis to treatment (responders median 8 months vs non-responders median 41.8 months, (p=0.18). Conclusions: This multicenter study provides evidence that rATG is safe and has significant activity in MDS that warrants further study. Although independent of age, a pretreatment rATG response algorithm inclusive of HLADR15 and duration of disease appears to be similar to prior predictive models of eATG response. These results suggest that T-cell depleting rATG therapy may produce the best clinical outcome when implemented early in the disease process and further suggests that T-cell hematological suppression may contribute to the initiation of MDS pathogenesis. Support: This trial was conducted by the Bone Marrow Failure-Rare Disease Clinical Research Network (BMF-RDCRN 5406) sponsored by the NIH and Genzyme, Corp. This trial was registered at www.clinicaltrials.gov (NCT00466843). Disclosures: Epling-Burnette: Genzyme: Consultancy, Research Funding. Maciejewski:Genzyme Corp: Research Funding

The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P = 0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P = 0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P = 0.08) and del(5q) (P = 0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progressionfree survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P = 0.05). These findings comprise the largest MDS R72P SNP analysis