Initial Clinical Presentation and Predictors of Thrombotic Thrombocytopenic Purpura in Quebec

Abstract Thrombotic microangiopathies (TMA) constitute a group of life-threatening diseases of different aetiologies characterized by similar symptoms. The compilation of comprehensive data related to the initial clinical presentation of TMA is challenging due to their rare occurrence. The objective of this study was to assess and determine the predictive value of the clinical presentation of patients with a suspected TMA episode, subsequently confirmed as thrombotic thrombocytopenic purpura (TTP), compared with non-TTP TMA by taking advantage of the centralized ADAMTS-13 testing in Quebec. All ADAMTS-13 activity and antibody titration were performed at CHU Saint-Justine (CHUSJ). Measurements and patient demographics (from April 2012 to December 2019) were extracted from the Laboratory Information System of the CHUSJ. Patients with presumed TMA were classified into TTP when ADAMTS-13 activity was ≤10%, or suspicion of TMA other than TTP (non-TTP TMA) when ADAMTS-13 activity was >10%. Clinical presentation was obtained through a survey form received with each plasma sample and containing information related to prior episodes of TMA, underlying conditions (pregnancy, cancer, infection, transplant, medication, other), clinical symptoms (fever, neurological signs, abdominal signs), and biological parameters (hemolytic anemia, thrombocytopenia). Statistical analyses were performed with IBM SPSS 26.0. The study was approved by the Research Ethics Committee of CHUSJ. A total of 2081 requests for ADAMTS13 testing were received during the study period, in 846 different individuals with suspected TMA: 147 patients (17%) had a confirmed TTP and 699 had a suspected non-TTP TMA. Clinical and biological characteristics associated with TMA suspicion were available for 105 TTP and 470 non-TTP TMA patients (68% of subjects). More than half of patients with TTP (55%; 48/87) had neurological signs at presentation compared to one third of patients (33%; 124/375) with non-TTP TMA (p=0.0001). There were no significant differences regarding fever and abdominal signs between the 2 groups (p=0.383 and p=0.355 respectively). Anemia and thrombocytopenia were reported in 92% (80/87) and 93% (86/92) of TTP patients compared to 74% (291/396) and 83% (352/426) of non-TTP TMA patients (p=0.0002 and p=0.009, respectively). Underlying conditions were reported in 62% (287/460) of non TTP-TMA patients compared to 35% (34/97) of TTP patients (p<0.0001). Kidney involvement was documented in 20% (91/460) of non-TTP TMA and 7% (7/98) of TTP (p=0.003). Transplantation tended to be more often reported in non-TTP TMA (11%;58/560 versus 4%;4/98 in TTP; p=0.079). Pregnancy or postpartum was found in 11% (29/267) of females with non-TTP TMA and 5% (3/57) of females with TTP (p=0.232). Infections were present in 15% (68/462) of non-TTP TMA and 14% (14/98) of TTP (p=0.912). Drug associated TMA was reported in 15% (70/461) of non-TTP TMA and 9 % (9/98) of TTP (p=0.123). Cancers were documented in 16% (74/462) of non-TTP TMA and 9% (9/98) of TTP (p=0.084). When addressing the odds of TPP according to the clinical presentation, patients with neurological signs were at higher risk to be diagnosed with TTP compared to those who did not have neurological signs (odds ratio, 2.52; IC95%, 1.51 to 4.20; p<0.001). Thirty percent of patients presenting with neurological signs had TTP compared to 14% presenting without neurological signs. Conversely, the risk to be diagnosed with TTP was lower in the setting of transplantation (odds ratio, 0.32; IC95%, 0.11 to 0.92; p=0.015). Indeed, among patients who have had a transplantation 7% were diagnosed with TTP, while 93% had non-TTP TMA. Finally, the risk of TPP was also lower in patients with TMA and concomitant kidney-related issue (OR=0.31; IC95%: 0.14 to 0.69; p=0.004) as among patients presenting with renal disorders, 93% were not subsequently diagnosed with TTP. In conclusion, the centralization of ADAMTS-13 activity testing in one reference center has enabled to determine the predictive value of clinical characteristics associated with TPP in comparison to other types of TMA for the entire province of Quebec, Canada. This study provides useful insight for caregivers and paves the way to the establishment of a provincial registry of TMA patients. Figure 1 Figure 1. Disclosures Lapeyraque: Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rivard: Bayer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees. Bonnefoy: Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Genzyme Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Single-Nucleotide Variations Defining Previously Unreported ADAMTS13 Haplotypes Are Associated With Differential Expression and Activity Of The VWF-Cleaving Protease In a Salvadoran Congenital Thrombotic Thrombocytopenic Purpura Family

Blood ◽

10.1182/blood.v122.21.2319.2319 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2319-2319

Author(s):

Benjamin Kim ◽

Zachary A. Hing ◽

Andrew Wu ◽

Tal Schiller ◽

Evi B. Struble ◽

...

Keyword(s):

Steady State ◽

Board Of Directors ◽

Thrombotic Thrombocytopenic Purpura ◽

Research Funding ◽

Rt Pcr ◽

Advisory Committees ◽

Single Nucleotide ◽

Thrombocytopenic Purpura ◽

Congenital Thrombotic Thrombocytopenic Purpura ◽

Single Nucleotide Variations

Abstract Background Although autosomal recessive hematologic disorders are individually rare and difficult to ascertain, studies involving one or more homozygous affected children and their unaffected heterozygous parents have led to expanded understanding of known and discovery of previously unknown processes. The son and daughter of two Salvadoran parents were diagnosed with congenital thrombotic thrombocytopenic purpura (cTTP) at 6 and 2 years of age, respectively, after presenting with fever, respiratory symptoms, hemolytic anemia, and thrombocytopenia and being found to have ADAMTS13 activities <1% without neutralizing IgG antibodies. They remain without long-term neurologic or renal sequelae following prophylactic infusions of fresh plasma (10 mL/kg every 2.5-weeks). The purpose of this study was to characterize and correlate single-nucleotide variations (SNVs) in each parent's, non-mutant ADAMTS13 allele with its mRNA and protein expression, activity, and enzyme kinetics. Methods Prior to a plasma infusion, blood samples were collected from the children and parents. Genomic DNA was isolated for polymerase chain reaction (PCR), and direct Sanger sequencing of all ADAMTS13 exons and flanking intronic segments was performed; all variants identified were confirmed by bidirectional sequencing of a second, independently generated amplicon. Total RNA was isolated and the steady-state level of ADAMTS13 mRNA was measured using a quantitative real-time PCR (q-RT-PCR)-based assay. ADAMTS13 was characterized enzymatically using the fluorogenic FRETS-VWF73 substrate and antigenically by ELISA. Results Both children were found to be homozygous and parents to be heterozygous for the previously described, cTTP-causing ADAMTS13 single-base-substitution mutation 20506C>T, a missense mutation that encodes cDNA-nucleotide 2518 (c.2518C>T) and ADAMTS13 residue 692 (692Arg>Cys [692R>C]) (Fig. A). As expected, the children's ADAMTS13 antigen and activity levels were undetectable, although notably, steady-state levels of the ADAMTS13 mRNA were >2.5-fold higher in the daughter than in the son. The re-sequenced regions of the ADAMTS13 loci segregating within this family contained 26 additional SNVs, seven of which were nonsynonymous (ns) including two previously unreported ns-SNVs: 27852C>T (c.3362C>T; 972Arg>Trp) and 33325G>A (c.3733G>A; 1096Arg>His) (Fig. A, left panel). The parents' genotypes differed at nine positions, including three ns-SNVs, creating two distinct, non-mutant haplotypes (designated I and III) at the gene, mRNA and protein levels. The q-RT-PCR assay revealed >4-fold higher steady-state mRNA levels in the father compared to the mother (p<0.001; Fig. B). Plasma ADAMTS13 activity and antigen levels were ∼2-fold greater in the father than in the mother (p=0.00164 and p=0.0633, respectively), but the specific activities of these structurally distinct ADAMTS13 proteins were notably almost identical (253.5 vs. 256.2 U/μg). Moreover, initial velocity kinetic analysis using the Michelis-Menten equation demonstrated that the Vmax of the father's ADAMTS13 was twice that of the mother's (1.4 vs. 0.7; p < 0.0001) while its affinity for substrate was one-third that of her ADAMTS13 (Km = 0.3 vs. 0.1; p = 0.0585). Discussion We capitalized on the fortuitous finding of children with complete homozygosity across ancestrally-related ADAMTS13 alleles harboring a null-type, loss-of-function mutation, as this enabled the substantially different levels of gene expression and function observed in the parents to be attributed to their two previously unreported, SNV-based, ADAMTS13 haplotypes. Additional investigation at the molecular, biochemical, cellular, and organismal levels will be necessary to determine which of the myriad potential individual SNV- and/or haplotype-based mechanisms are responsible for the observed parental differences in circulating ADAMTS13 antigen and activity. Disclosures: Kim: Haplomics, Inc.: Membership on an entity’s Board of Directors or advisory committees; Baxter: Honoraria. Marder:Baxter: Research Funding. Howard:Haplomics, Inc.: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Baxter: Research Funding.

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Use of Preemptive Treatment for Immune Thrombotic Thrombocytopenic Purpura: A Matched Survival Analysis

Blood ◽

10.1182/blood-2021-149984 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2084-2084

Author(s):

Aaron Boothby ◽

Michael Evans ◽

Radhika Gangaraju ◽

Camila Masias ◽

Aric D. Parnes ◽

...

Keyword(s):

African American ◽

Board Of Directors ◽

Thrombotic Thrombocytopenic Purpura ◽

Research Funding ◽

The United States ◽

Treatment Center ◽

Clinical Relapse ◽

Advisory Committees ◽

Thrombocytopenic Purpura ◽

Preemptive Treatment

Abstract Background: Immune Thrombotic thrombocytopenic purpura (iTTP) is a relapsing disorder, resulting from depletion of ADAMTS13. With the goal of preventing clinical relapse there has been considerable interest in ADAMTS13 monitoring and preemptive treatment. Indeed, preemptive treatment with rituximab has shown significant promise and is now included in the 2020 International Society on Thrombosis and Haemostasis (ISTH) treatment guidelines. Evaluation of long-term outcomes of ADAMTS13 based preemptive treatment have generally relied on limited numbers of historical controls which did not incorporate matching for known risk factors for relapse such as race, number of prior episodes, and immunosuppression. Our study aims to leverage the data in the United States Thrombotic Microangiopathy (USTMA) iTTP registry to compare the clinical relapse-free survival (RFS) intervals between iTTP patients treated preemptively based on ADAMTS13 level and those treated only for clinical relapse base on clinical and laboratory manifestations of iTTP. Methods: We carried out a retrospective study utilizing the multi-center cohort of patients with iTTP from the USTMA Consortium (spanning 1985-2019 and containing 780 participant records). We selected for patients with relapsing disease treated either preemptively based on ADAMTS13 level or for clinical relapse. Each preemptively treated episode was matched to up to five clinically relapsed episodes using covariate balancing propensity score nearest-neighbor matching by age, gender, race, prior relapse status, acute treatment, treatment center, and calendar year, with exact matching required for treatment center and prior relapse status. Time from prior episode to relapse was compared between preemptively treated episodes and matched controls using a Cox proportional hazards model weighted by the matching weights, including subclasses as a cluster, and using cluster-robust standard errors. Results: We identified 1068 episodes of iTTP. Of these. Thirteen participants accounting for a total of seventeen preemptive treatment episodes were included in the data set however, we included only the thirteen first uses of preemptive treatment to avoid selection bias. These were matched with 59 episodes treated for clinical relapse. Over 70% of the included participants in both groups were identified as black/African American. Distribution of immunosuppressive medications used in clinically relapsed cases were not significantly different than those used in preemptive treatment, and corticosteroids were the most frequently used. Demographic and treatment data before and after matching are included in Table 1. There was no significant difference in RFS between the groups, hazard ratio 0.63 (95% confidence interval 0.26-1.54), p=0.31. Conclusion: To our knowledge this is the first study to use matching controls to obtain a causal estimate of the effect of ADAMTS13 monitoring based preemptive treatment on RFS in iTTP. In contrast to previous work, we did not observe a significant increase in RFS in the preemptively treated group. It is possible that the limited number of preemptively treated episodes herein did not provide sufficient power to detect a difference. However, given the significant effect size that has been proposed, based on prior work, we suspect other factors may have also influenced this finding. Previous analysis of the USTMA iTTP registry has shown a higher incidence of relapse in African American participants. While the precise reason for this finding is not yet clear, it is worth considering that there may also be differential response to preemptive treatment. Our study highlights the importance of continued efforts to determine the generalizability and efficacy of ADAMTS13 monitoring based preemptive treatment in iTTP. Figure 1 Figure 1. Disclosures Gangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy. Masias: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. Parnes: Sigilon: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; I-mAb: Consultancy; Sunovion: Consultancy; Genentech/Hoffman LaRoche: Research Funding; UniQure: Membership on an entity's Board of Directors or advisory committees; Aspa: Consultancy. Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. OffLabel Disclosure: Rituximab, an anti CD20 monoclonal antibody will be discussed in relation to treatment of thrombotic thrombocytopenic purpura.

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Deficient ADAMTS13 Activity in Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura (TTP) in Populations From Japan in 2012: Validation of Findings Initially Reported in the United States in 1998 and 2000.

Blood ◽

10.1182/blood.v120.21.2203.2203 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2203-2203

Author(s):

Charles Bennett ◽

Masanori Matsumoto ◽

Peter Georgantopoulos ◽

Sony Jacob ◽

Brianne L Dunn ◽

...

Keyword(s):

United States ◽

Board Of Directors ◽

Thrombotic Thrombocytopenic Purpura ◽

Research Funding ◽

The United States ◽

Advisory Committees ◽

Laboratory Findings ◽

Thrombocytopenic Purpura ◽

Causal Pathway ◽

Adamts13 Deficiency

Abstract Abstract 2203 Background: Thrombotic thrombocytopenic purpura (TTP) is frequently characterized by severe ADAMTS13 deficiency, the cause of which is unknown. An important exception is ticlopidine-associated TTP (tc-TTP), the most common drug-induced TTP syndrome. In 1998, a possible association of TTP with ticlopidine was reported. In 1999, two additional series reported this association. In 2000, a fourth study reported severe A DAMTS13 deficiency among six of seven tc-TTP persons- suggesting a causal pathway. All of these reports were from the United States. Recently, we reported characteristics of 186 acquired idiopathic (ai)- TTP patients in Japan with severe ADAMTS13 deficiency, noting that clinical and laboratory findings for ai-TTP patients in Japan differed from those for cohorts of ai-TTP patients in Europe and North America- raising concern that TTP findings vary by region of the world. (PLOS One 2011) We now on report clinical and laboratory characteristics of a cohort of TTP patients from Japan with tc-TTP, and compare these findings to three cohorts of tc-TTP in the United States and one cohort of ai-TTP patients from Japan. Methods: We queried a database of thrombotic microangiopathy patients identified from a national TTP referral laboratory in Japan of cases identified between 1998 and 2008. Severe ADAMTS13 deficiency was characterized by activity levels < 5%. All tc-TTP patients and 186 of 911 ai-TTP patients in the database had severe ADAMTS13 deficiency and first onset of TTP. Comparisons were made to tc-TTP patients reported previously from the United States. Results: Characteristics of ai- TTP with severe ADAMTS13 deficiency in Japan and tc-TTP in Japan and US Conclusions: These data from Japan validate insights about tc-TTP initially proposed in 1998, 1999, and 2000 in the United States. Ticlopidine is a likely cause of TTP, the mechanism is via a cross-reactive antibody to ADAMTS13:AC resulting in formation of an ADAMTS13:INH, and therapeutic plasma exchange is necessary for treatment. Disclosures: Ortel: Eisai: Research Funding; Glaxo SmithKline: Research Funding; Pfizer: Research Funding; Instrumentation Laboratory, Inc: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.

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Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

Blood ◽

10.1182/blood-2020-141890 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Maël Heiblig ◽

Hélène Labussière ◽

Marie Virginie Larcher ◽

Gaelle Fossard ◽

Marie Balsat ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Predictive Value ◽

Scoring System ◽

Research Funding ◽

Risk Group ◽

Advisory Committees ◽

Post Induction ◽

Mutational Status ◽

Elderly Aml

Minimal residual disease is now a powerfull surrogate marker to assess response to chemotherapy in acute myeloid leukemia (AML). In younger adults, NPM1 MRD has recently demonstrated to be a favorable predictive marker for EFS and OS independently of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) status. However, there is very few datas regarding predictive value of NPM1 MRD in elderly patients treated with intensive chemotherapy. Moreover, numerous studies have suggested the negative impact of DNMT3a mutation in NPM1 AML patients, especially in those with concurrent FLT3-ITD mutation. In this study, we aimed to investigate the impact of DNMT3a status on post induction NPM1 MRD1 predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1 mutated AML in two French institutions (Lyon, Lille) were analyzed retrospectively. Median age of the entire cohort was 66.1 years old (range 60-78.2). An FLT3-ITD mutation was evidenced in 52 of 138 patients (37.6%) with a median FLT3-ITD AR of 0.53 (range, 0.05-3). With a median follow-up of 19.61 months (0.07-128.4), the overall CR rate was 89.9% with no influence of DNMT3a or FLT3 mutational status on the probability of CR. In this elderly cohort of NPM1mut patients, a 4log reduction of NPM1 bone marrow (BM) MRD1 was associated with better outcome (median OS: NR vs 13.4 months, HR=0.35, p<0.01)(Figure A). Overall, DNMT3 status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. However, only 9/44 (20.4%) FLT3-ITD patients reached ≥ 4log MRD1 reduction whereas 38/80 FLT3wt (47.5%) were good molecular responders (p<0.001). FLT3-ITD mutated patients who achieved a 4log reduction had a superior outcome compared to those who did not (HR=0.34; 95% CI, 0.16 to 0.70; P <0.001). Similarly, NPM1mut FLT3wt patients with a 4log reduction in NPM1 BM-MRD1 had a longer OS (3-year OS, 68.1%; 95% CI, 48.8 to 82.9) than those without good molecular response (3-year OS, 46.5%; 95% CI, 30.2 to 61.7)(Figure B). DNMT3a negative patients who achieved a 4log reduction had a superior outcome to those who did not reached at least a 4log reduction (HR=0.23; 95% CI, 0.07 to 0.72; P <0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and leukemia free survival (LFS) in DNMT3amut patients. DNMT3amut patients has a very poor LFS which was even worst in poor NPM1 MRD1 responders compared to those who reached at least 4log reduction (median LFS: 8.3 months vs 17.4 months, HR = 0.48, 95% CI, 0.25-0.91, p=0.023)(Figure C). In multivariate analysis, only DNMT3a mutational status and a 4-log reduction in NPM1 BM-MRD were significantly associated with survival. Based on these results, we identified among NPM1 positive patients 3 groups with distinct prognosis, based on FLT3-ITD, DNMT3a status and NPM1 BM-MRD post induction response (NPM1 scoring system)(Figure D). When compared to ELN 2017 intermediate risk group (AUC=0.695), NPM1 scoring system (NPM1 SS) was more accurate for OS prediction in patients within intermediate (AUC=0.833) and unfavorable (AUC=0.863) NPM1 SS risk group. However, there was no significant difference in AUC between NPM1 SS favorable and ELN 2017 favorable risk group. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3a also identify a subgroup of patients at very high risk of relapase, despite good molecular responses. As hematopoietic stem cell transplantation (HSCT) might improve OS in elderly patients, DNMT3a positive AML elderly patients should be considered for HSCT or post induction maintenance strategies, even within the favorable ELN risk group. Figure Disclosures Sujobert: Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding.

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Splenectomy for Primary Immune Thrombocytopenia Revisited at the Era of Thrombopoietin Receptor Agonists: New Insights for an Old Treatment

Blood ◽

10.1182/blood-2021-147450 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 17-17

Author(s):

Arthur Mageau ◽

Louis Terriou ◽

Mikael Ebbo ◽

Odile Souchaud-Debouverie ◽

Corentin Orvain ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Sustained Response ◽

White Pulp ◽

Advisory Committees ◽

Thrombocytopenic Purpura ◽

Thrombopoietin Receptor ◽

Primary Immune Thrombocytopenia

Abstract Introduction Although splenectomy is still considered as the most effective curative treatment for primary immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the emergence of thrombopoietin receptor agonist (TPO-RAs) and anti-CD20 monoclonal antibodies 1-3. The main objective of our study was to evaluate if splenectomy was still as effective in the modern era, particularly for patients who failed to respond to TPO-RAs and rituximab. One of the secondary objectives was to assess, among patients who did not respond to or relapse after splenectomy, the pattern of response to subsequent intervention with treatments used before splenectomy and particularly TPO-RAs. Methods This multicentre retrospective observational study involved adults who underwent surgical splenectomy for primary ITP in France from 2011 (authorization of TPO-RAs in France) to 2020. To be included in the study, patients had to fulfil the following criteria : age ³18 years, primary ITP diagnosis defined according to the usual international criteria 2. Patients with abnormal spleen histology (other than reactional lymphoid hyperplasia, white-pulp hypoplasia or red pulp hyperplasia) or yet definite secondary ITP were excluded. Response was defined according to international criteria 4. Sustained response was defined as the absence of ITP relapse at last visit. We performed univariable and multivariable logistic regression procedures to calculates the odds ratio associated with a sustained response. Results In total,185 patients, 98 (53 %) women, with median age at splenectomy of 43.3 [interquartile range 27.6-64.3] years, were included in 18 French university and general hospitals from the French reference center network. Most of the patients were splenectomised at the chronic phase of ITP (n=150, 81.1%) and only two patients had undergone surgery within 3 months after ITP onset. Of note, 100 (54.1%) and 135 (73.0%) patients received TPO-RAs and/or rituximab prior to the splenectomy, respectively. The median time of follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) of patients had an initial response and 23 patients (12.4%) relapsed during follow-up leading to an overall rate of sustained response of 65.4%, similar to the one observed in the pre-TPO-RA's era 1. Characteristics of patients according to the period during which occurred the splenectomy is available in Table 1. Among the 14 patients who failed to respond to both eltrombopag and romiplostim prior to splenectomy a sustained response after splenectomy was observed in 7 (50%). Among the 13 patients who had failed after both TPO-RAs and rituximab, we observed a sustained response in 6 (46%). In the multivariate analysis, an older age (60-75 years: OR 0,39 [0,17-0,86], p=0.02; >75 years: OR 0,28 [0,10-0,75], p=0.013) and a history of more than 4 treatment lines for ITP before splenectomy (OR 0.25 [0.08-0.66], p=0.010) were significantly associated with a lack of sustained response after splenectomy. TPO-RAs were used for 57/64 (89.1%) patients who failed to respond to splenectomy. Among them, 21 were treated with one TPO-RA (i.e. eltrombopag or romiplostim) which was previously used before splenectomy without any efficacy and a response was observed in 13 (62%) of them. Conclusions In conclusion, splenectomy seems to be still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients who fail to respond or relapse after splenectomy should be re-challenged with TPO-RAs. 1. Kojouri, K., Vesely, S. K., Terrell, D. R. & George, J. N. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term 2. Provan, D. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 3.Neunert, C. et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 3, 3829-3866 (2019). 4. Rodeghiero, F. et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113, 2386-2393 (2009). Figure 1 Figure 1. Disclosures Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ebbo: Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Attendance Grant; Sobi: Other: Attendance Grant. Viallard: Novartis: Consultancy; Amgen: Consultancy; Grifols: Consultancy; LFB: Consultancy. Jeandel: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Support for congress; Sobi: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Support for congress; GSK: Other: Support for congress; Pharming: Other: support for congress. Michel: Amgen: Consultancy; Novartis: Consultancy; Rigel: Honoraria; UCB: Honoraria; Alexion: Honoraria; Argenx: Honoraria. Godeau: Grifols: Consultancy; Sobi: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Comont: Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

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External Validation and Revision of Thrombosis Lymphoma /Throly/ Score

Blood ◽

10.1182/blood-2018-99-115568 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 140-140 ◽

Cited By ~ 1

Author(s):

Darko Antic ◽

Natasa Milic ◽

Biljana Mihaljevic ◽

Bruce Cheson ◽

Mayur Narkhede ◽

...

Keyword(s):

At Risk ◽

Board Of Directors ◽

Predictive Value ◽

Research Funding ◽

Validation Cohort ◽

External Validation ◽

Advisory Committees ◽

Final Model ◽

Risk Patients ◽

Reduced Mobility

Abstract Introduction Lymphoma patients are at increased risk of thromboembolic events (TE), however, thromboprophylaxis in these patients is largely under utilized. Actual guidelines recommend different models for thromboembolic risk estimation in cancer patients. Proposed models are of limited use in lymphoma patients as their development is not based on specific characteristics for this patient population. Previously, we developed and internally validated a simple model, based on individual clinical and laboratory patient characteristics that would classify lymphoma patients at risk for a TE. The variables independently associated with the risk for thromboembolism were: previous venous and/or arterial events, mediastinal involvement, BMI>30 kg/m2, reduced mobility, extranodal localization, development of neutropenia and hemoglobin level < 100g/L. For patients classified at risk in derivation cohort (n=1236), the model revealed positive predictive value of 25.1%, negative predictive value of 98.5%, sensitivity of 75.4%, and specificity of 87.5%. The diagnostic performance measures retained similar values in the internal validation cohort (n=584). The aim of this study was to perform external validation of the previously developed thrombosis lymphoma (Throly) score. Methods The study population included patients with a confirmed diagnosis of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) from 8 lymphoma centers from USA, France, Spain, Croatia, Austria, Switzerland, Macedonia, and Jordan. During 2015 to 2016, data were prospectively collected for venous TE events from time of diagnosis to 3 months after the last cycle of therapy for newly diagnosed and relapsed patients who had completed a minimum of one chemotherapy cycle. The score development and validation were done according to TRIPOD suggested guidelines. Sensitivity analyses were carried out to test the model robustness to possible different settings, according to in/out patient settings and according to different countries included. Results External validation cohort included 1723 patients, similar to the developed group and consisted of 467 indolent NHL, 647 aggressive NHL, 235 CLL/SLL and 366 HL patients, out of which 121 (7%) patients developed venous thromboembolic events. For patients classified at risk in external validation cohort, the model resulted in positive and negative predictive values of 17% and 93%, respectively. Based on new available information from this large prospective cohort study this model was revised to include the following variables: diagnosis/clinical stage, previous VTE, reduced mobility, hemoglobin level < 100g/L and presence of vascular devices. In the new score we divided patients in two groups: low risk patients, score value ≤ 2; and high risk patients, score value > 2. For patients classified at risk by the revised model, the model produced positive predictive value of 22%, negative predictive value of 96%, sensitivity of 51%, and specificity of 72%. In sensitivity analysis, the final model proved its robustness in different settings of major importance for lymphoma patients. The final model presented good discrimination and calibration performance. Concordance C statistics was 0.794 (95% CI 0.750-0.837). Conclusions Revised Thrombosis Lymphoma - ThroLy score is more specific for lymphoma patients than any other available score targeting thrombosis risk in solid cancer patients. We included biological characteristic of lymphoma, indolent vs aggressive, as well as data about dissemination of disease, localized vs advanced stage, reflecting specificity of lymphomas comparing to other types of cancer. Also, we pointed out significance of central vascular devices as risk factor having considered the role of vascular damage during insertion as a potential trigger for activation of the clotting cascade. This score is user friendly for daily clinical practice and provides a very good predictive power to identify patients who are candidates for pharmacological thromboprophylaxis. Disclosures Cheson: AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jaeger:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees.

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Results of Bone Marrow Examinations in Patients with Chronic Immune Thrombocytopenic Purpura Treated with Eltrombopag.

Blood ◽

10.1182/blood.v114.22.1326.1326 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1326-1326 ◽

Cited By ~ 4

Author(s):

Mansoor N. Saleh ◽

James B. Bussel ◽

Oliver Meyer ◽

Henrik Frederiksen ◽

Diane Johnni ◽

...

Keyword(s):

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Blood Smear ◽

Peripheral Blood Smear ◽

Advisory Committees ◽

Thrombocytopenic Purpura ◽

Chronic Itp ◽

Reticulin Fibers ◽

Equity Ownership

Abstract Abstract 1326 Poster Board I-348 BACKGROUND Bone marrow (BM) reticulin fibers can be increased in conditions such as neoplasms and autoimmune diseases (Frisch Haematol [Budap] 1982; Aharon Lupus 1997) and can lead to a clinical situation similar to osteomyelofibrosis. In healthy individuals, grade 1 and 2 reticulin have been reported in 27–70% and 4–20% of BM biopsies, respectively (Hultdin Med Onc 2007; Beckman Arch Path Int Med 1990; Bauermeister Am J Clin Path 1971). The presence of grade 1/2 reticulin was reported in the BM of up to 67% of patients with immune thrombocytopenic purpura (ITP) (Mufti J Supp Onc 2007). Theoretically, prolonged stimulation of megakaryocytes with TPO-R agonists might increase the risk of myelofibrosis (MF). Increased reticulin and peripheral nucleated RBCs have been reported in chronic ITP patients treated with romiplostim (Bussel Blood 2009). Eltrombopag, an oral, small molecule, TPO-R agonist, is approved in the United States for the treatment of chronic ITP. OBJECTIVE To determine whether eltrombopag treatment is associated with an increase in BM reticulin. METHODS Reports of BM biopsies performed prior to eltrombopag treatment were reviewed. In eltrombopag studies, complete blood counts (CBC) including white blood cell (WBC) differentials were performed at each visit. If a WBC differential indicated the presence of immature or dysplastic cells in the RAISE, REPEAT, and EXTEND studies, then a peripheral blood smear was performed. If the presence of immature or dysplastic cells on the blood smear was not consistent with the chronic ITP diagnosis, then a BM biopsy was performed. Additionally, a BM biopsy could be performed at any time at the investigator's discretion. In EXTEND, a BM biopsy was required after 1 year on treatment. Reticulin was quantified using the modified MF scale (Thiele Haematologica 2005). RESULTS Prestudy BM biopsies were available for 64/446 patients subsequently exposed to eltrombopag; 51 reports did not mention reticulin or fibrosis. Of the 13 remaining prestudy reports, 4 (31%) had increased reticulin. Ninety-one patients (5 patients RAISE; 86 patients EXTEND) had a BM biopsy following treatment initiation; none of the BM biopsies were prompted by an abnormal peripheral blood smear. In a 6-month placebo-controlled study (RAISE), 1 placebo-treated patient had an on-treatment BM examination that showed myelodysplastic syndrome, and 4 eltrombopag-treated patients (2 on-treatment and 2 posttreatment) had BM examinations. One patient treated with eltrombopag for 41 days had a posttreatment marrow examination that showed grade 2 (Bauermeister) reticulin. None of the 4 showed hematologically relevant BM alterations. In an open-label extension study (EXTEND), 86 patients treated for a median of 12 months (range: 1–18 months) at the time of the procedure had BM biopsies; 83 had mention of reticulin fibers in the report and were evaluable for this analysis. Five patients had MF grade 2 reticulin with no clinical signs or symptoms of BM dysfunction (eg, abnormal WBC differential or peripheral blood smear); 2 reported collagen. One patient had a biopsy 2 years prior to EXTEND (grade 1/3). After 15 months on study, a biopsy showed grade 2/3; this patient was withdrawn. Of note, while on treatment the patient was not considered a responder (platelets <50,000/μL) but did have decreased bleeding. The second patient was 81 years old with a history of 3 cancers. A similar degree of reticulin was observed when comparing the biopsy taken 6 years prior to EXTEND and after 14 months on study, but collagen was noted on the second BM. A patient with MF grade 1 reticulin reported collagen, but did not experience any adverse event or significant change in CBC and is continuing on study with good platelet response. CONCLUSION There was no evidence of clinically relevant BM abnormalities or clinical findings typically associated with MF in patients treated for up to 18 months with eltrombopag. Systematic longitudinal evaluation of BMs in EXTEND will provide meaningful data regarding incidence of fibrosis during long-term treatment. Disclosures Saleh: GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau. Bussel:Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Research Funding; Sysmex: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Meyer:GlaxoSmithKline: Consultancy, Honoraria. Frederiksen:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Johnni:GlaxoSmithKline: Employment. Aivado:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.

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Thromboembolic Events Observed in Eltrombopag Clinical Trials in Chronic Immune Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v114.22.2423.2423 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2423-2423 ◽

Cited By ~ 8

Author(s):

James B. Bussel ◽

Gregory Cheng ◽

Mansoor N. Saleh ◽

Sandra Vasey ◽

Manuel Aivado ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Thromboembolic Events ◽

Study Medication ◽

Normal Range ◽

Advisory Committees ◽

Thrombocytopenic Purpura ◽

Platelet Counts ◽

Equity Ownership

Abstract Abstract 2423 Poster Board II-400 BACKGROUND: Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA), an oral, small molecule, thrombopoietin receptor agonist, was recently approved in the United States for the treatment of patients with chronic immune thrombocytopenic purpura (ITP). Limited published data indicate that patients with chronic ITP experience thromboembolic events (TEEs) with a frequency of 3% to 6%. (Aledort, Am J Hematol, 2004; Bennett, Haematologica, 2008). OBJECTIVE: To evaluate the incidence of TEEs in patients with chronic ITP treated with eltrombopag and to determine if the occurrence of TEEs was associated with elevated platelet counts. METHODS: Data from 446 patients from 3 placebo-controlled eltrombopag studies (TRA100773A, TRA100773B, and RAISE) and 2 open-label studies (REPEAT and EXTEND) were analyzed. The frequency of TEEs or suspected TEEs before and after the first dose of study medication (placebo or eltrombopag) was examined across the program. Potential risk factors, including platelet counts proximal to the event, were evaluated in patients experiencing a TEE. RESULTS: Prior to the initiation of study medication (placebo or eltrombopag), 16/493 (3.2%) of the patients entering the program had a history of TEEs (one of these patients experienced 2 additional TEEs [TIA, MI] while on treatment with eltrombopag). Across the ITP clinical program, 17/446 patients treated with eltrombopag (3.8%) experienced 22 TEEs. No patient treated with placebo experienced a TEE. The patient-years (PYs) of exposure to study medication was approximately 14 times greater for patients treated with eltrombopag compared to placebo (eltrombopag 377 PYs; placebo 26 PYs). Most patients (13/17) experienced 1 TEE; 3 patients experienced 2, and 1 patient experienced 3 (2 TEEs were 6 months off-therapy). The most common TEEs were deep vein thrombosis (n=8) and pulmonary embolism (n=6). A total of 18/22 events were resolved or resolving at the time of this analysis; all patients experiencing a TEE had at least 1 risk factor for these events other than ITP (eg, use of IVIg [n=3], hospitalization with no prophylactic anticoagulation [n=4], oral corticosteroids [n=6]). The platelet counts proximal to the event ranged from 14,000/μL to 420,000/μL. The majority of patients had platelet counts below 150,000/μL (9; 53%) or between 150,000/μL and 400,000/μL (5; 29%); 2 had platelet counts above 400,000/μL and the platelet count in 1 was unknown. All 446 patients were categorized by the maximum platelet count achieved during treatment with eltrombopag (above normal [>400,000/μL], normal range [150–400,000/μL], below normal range [<150,000/μ]; Table 1). The majority of patients (14; 82%) experienced the TEEs at a platelet count lower than their maximum platelet count, while 3 patients (18%) experienced a TEE proximal to their maximum platelet count. CONCLUSION: TEEs occurred with eltrombopag. None occurred with placebo; however, the PYs of exposure was considerably less with placebo than with eltrombopag. The frequency of TEEs observed during eltrombopag treatment (3.8%) is similar to that reported in the literature and prior to enrollment in the eltrombopag program (3.2%). No discernible correlation has been observed between platelet count increases and TEEs, and these events do not appear to be associated with maximum platelet counts during treatment with eltrombopag. Disclosures: Bussel: Sysmex: Research Funding; Eisai, Inc: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Cheng:GlaxoSmithKline: Research Funding. Saleh:GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau. Vasey:GlaxoSmithKline: Employment. Aivado:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.

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Baseline PET-Derived Metabolic Tumor Volume Metrics Predict Progression-Free and Overall Survival in DLBCL after First-Line Treatment: Results from the Phase 3 GOYA Study

Blood ◽

10.1182/blood.v130.suppl_1.824.824 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 824-824 ◽

Cited By ~ 2

Author(s):

Lale Kostakoglu ◽

Maurizio Martelli ◽

Laurie H. Sehn ◽

David Belada ◽

Angelo-Michele Carella ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Predictive Value ◽

Research Funding ◽

Metabolic Tumor Volume ◽

First Line ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomography assessment using total metabolic tumor volume (TMTV) and tumor lesion glycolysis (TLG) measurements has been found promising as an objective method to predict survival in diffuse large B-cell lymphoma (DLBCL) patients (pts). However, the methodology for PET-derived metrics is still evolving, and their predictive value is yet to be proven in large-scale, prospective, multicenter studies. We investigated the prognostic value of baseline maximum standardized uptake value (SUVmax), TMTV and TLG for progression-free survival (PFS) in a large pt cohort treated with obinutuzumab (GA101; G) or rituximab (R) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the Phase 3 GOYA study (NCT01287741; Vitolo et al. J Clin Oncol 2017). Methods: Pts aged ≥18 years, with previously untreated, CD20-positive DLBCL and an International Prognostic Index (IPI) score ≥2 and low-risk pts with IPI scores of 1 (not due to age alone) or 0 (with bulky disease) were randomized 1:1 to receive 8 x 21-day cycles of G (1000mg intravenous [IV] on Days [D] 1, 8, and 15 of Cycle [C] 1 and D1, C2-8) or R (375mg/m2 IV on D1, C1-8) plus 6 or 8 cycles of CHOP. All pts had a baseline and end of treatment (EOT) PET. PET images were segmented using an automated workflow program in MIM software, applying thresholds of 1.5 x liver background and a minimum volume of 1mL to the whole body PET images. The data were analyzed for the overall population and according to germinal center B-cell-like (GCB), unclassified, and activated B-cell-like (ABC) subtypes of DLBCL. TMTV, TLG, and SUVmax were split into 4 categories/levels according to the following quartiles: Q1, <25%; Q2, 25-50%; Q3, 50-75%; and Q4, 75-100%, which were obtained based on their distribution in the available population. The reported hazard ratios (HRs) refer to stratified log-rank tests comparing Q2, Q3, and Q4 to Q1, adjusted for stratification factors of the study: IPI score (low [0-2], intermediate [3], and high [4-5]) and number of planned CHOP cycles (6 or 8). Results: Of 1418 enrolled pts, 1346 had a baseline PET scan and 1334 had detectable lesions. There was no statistical difference in PFS between the treatment arms (G vs R), thus the entire cohort was analyzed as a whole. Results of the predictive value of baseline TMTV for PFS are presented in quartiles in Figure 1, and results of the predictive value of TLG for PFS are presented in quartiles in Figure 2, for the overall PET intent-to-treat population. After a median follow-up of 29 months TMTV and TLG were highly predictive of PFS when comparing Q4 vs Q1: HR=2.21, 95% CI 1.48-3.29, p<0.0001, and HR=1.91, 95% CI 1.28-2.85, p=0.0005, respectively. TMTV was also predictive of overall survival (OS): HR=2.63, 95% CI 1.55-4.46; p<0.0001. However, SUVmax-based prediction of PFS was not statistically significant (HR=0.84, 95% CI 0.57-1.23, p=0.3782). Three-year PFS for pts in TMTV Q1, 2, 3 and 4 was 86% (95% CI 81-89%), 84% (95% CI 78-88%), 78% (95% CI 72-83%) and 66% (95% CI 59-71%), respectively. TMTV also showed a trend for a better prediction of PFS (Figure 3) and OS in pts with the unclassified and ABC DLBCL subtypes when compared with those with the GCB subtype. Conclusions: This large prospective study confirms baseline TMTV and TLG as predictors of PFS and OS in DLBCL after first-line immunochemotherapy, while SUVmax may not be a predictor. Furthermore, TMTV and TLG appear to be better predictors of survival for pts with the unclassified and ABC subtypes of DLBCL than for those pts with the GCB subtype. Further analyses are underway comparing these results with the predictive value of percentage change from baseline to EOT PET, Deauville score-based analysis of EOT PET, and the various molecular DLBCL subtypes. Figure 1 Figure 1. Disclosures Kostakoglu: Roche: Consultancy, Other: GOYA is sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Lale Kostakoglu and Denis Sahin, was provided by Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Sehn: Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria. Chua: Lundbeck: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Merck: Honoraria. Gonzalez-Barca: Gilead: Consultancy; Sandot: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Pinto: Millenium Takeda: Research Funding; Gilead: Honoraria; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Merck Sharp Dome: Honoraria; Celgene: Honoraria; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Knapp: Roche: Employment. Mattiello: Roche: Employment. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam: Roche: Employment. Sahin: Roche: Employment, Equity Ownership. Vitolo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Mundipharma: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Trněný: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

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Targeted Sequencing of 7 Genes Can Help Reduce Pathologic Misclassification of MDS

Blood ◽

10.1182/blood-2020-140317 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Johannes B Goll ◽

Travis L Jensen ◽

R. Coleman Lindsley ◽

Rafael Bejar ◽

Jason Walker ◽

...

Keyword(s):

Logistic Regression ◽

Board Of Directors ◽

Predictive Value ◽

Research Funding ◽

Targeted Sequencing ◽

Advisory Committees ◽

Test Set ◽

Oncology Research ◽

Central Pathology ◽

Pathology Review

Introduction: The NHLBI National MDS Study (NCT02775383) is a prospective cohort study conducted at 92 community hospitals and 29 academic centers. It enrolls patients undergoing work up for suspected MDS to understand the genetic, epigenetic, and biological factors associated with the initiation and progression of the disease. Previously untreated, cytopenic participants undergo both local and centralized pathology review and are assigned a diagnosis, including MDS, MDS/MPN, AML with blasts < 30%, and "Other". Emerging data suggests that Next Generation Sequencing (NGS), along with cytogenetics and clinical variables, may improve MDS diagnostic precision. Given that our study relies on central review (with additional tertiary pathology review used to adjudicate disagreements), we examined whether targeted gene sequencing data could be used to increase the agreement between local and central pathologic diagnosis of MDS vs. Other. Methods: Peripheral blood and bone marrow (BM) biopsy specimens from cytopenic patients, along with clinical history, CBC, and other results including karyotyping, FISH and pathology reports from local pathologists were reviewed by central pathologists. The updated 2016 WHO classifications were used to diagnose MDS. Targeted exon sequencing of 96 genes was performed using BM specimens. A subset of 648 individuals that were classified as MDS (n=212) or Other (n=436, including 90 CCUS and 89 individuals with other cancers) by pathology assessments were selected. A mean coverage of 1,317X was achieved and variants had a minimum variant allele frequency (VAF) of 2% (except FLT3). Variants for 596 subjects were manually reviewed to retain likely disease-causing variants to build a binary classifier (MDS vs. Other) using the maximum VAF per gene as input (Figure 1). Subjects diagnosed with MDS or Other by both central and local pathology were used for training, validation, and testing, and were considered "gold standard" (GS) cases (n=546). These subjects were split into 4 random groups with equal proportions of MDS cases. 75% of the GS cases were used to train and validate lasso-regularized logistic regression models using 3-fold cross validation. ROC curve analysis was carried out using the remaining 25% of GS cases (Test Set 1) on the best model to identify an optimal probability cut off point for classifying subjects as MDS. Model performance was then tested on 50 subjects for which the central and local pathology diagnosis disagreed (Test Set 2), as well as on 52 additional subjects irrespective of agreement (Test Set 3). Results : The best performing logistic regression model retained 7 genes as most informative in a discriminating diagnosis of MDS from Other based on their VAFs, in order of impact: TP53, SF3B1, U2AF1, ASXL1, TET2,STAG2, and SRSF2. We used this model to assign probabilities for each of the subjects in Test Set 1 and to estimate the performance using ROC analysis (Figure 1), resulting in a high area under the curve (AUC) of 0.89. We chose a probability cut-off of ≥0.17, being associated with a high percentage of correct classification of MDS with a sensitivity and specificity of 0.90 and 0.81, respectively. Among the cohort of 50 subjects with a discordant local and central pathology diagnosis (Test Set 2), the classifier accurately reassigned 37 subjects (accuracy = 74%) from the local to the central pathology. The blinded tertiary pathology reviewer agreed with central in all Test Set 2 cases. This included 24/34 MDS cases that had been labeled as Other by local pathology (positive predictive value [PPV]=0.89). 3/16 final pathology-classified Other cases were mis-classified as MDS by the local pathologist (negative predictive value [NPV] = 0.57). Next, we assessed the ability of the model to predict MDS vs. Other for 52 additional independent subjects using the third pathologist's diagnosis to break any ties (Test Set 3). The classifier correctly predicted 15/21 MDS cases (PPV=0.83) and misclassified 6/31 Others as MDS (NPV=0.82). The overall accuracy was 83%. Conclusions: We identified that VAFs for 7 genes can correctly re-classify subjects as either MDS or Other in 74% of cases that were misclassified between local and central pathology review. Further assessment on an independent cohort showed an accuracy of 83% of the model. Taken together, these data suggest that complementing pathology reviews with targeted sequencing of 7 genes could improve MDS diagnosis. Disclosures Lindsley: MedImmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy; Takeda Pharmaceuticals: Consultancy. Bejar:Aptose Biosciences: Current Employment; AbbVie/Genentech: Honoraria; Astex/Otsuka: Honoraria; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Forty-Seven/Gilead: Honoraria; Genoptix/NeoGenomics: Honoraria. DeZern:MEI: Consultancy; Astex: Research Funding; Abbvie: Consultancy; Celgene: Consultancy, Honoraria. Foran:H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Revolution Medicine: Consultancy; Xencor: Research Funding; Agios: Honoraria, Research Funding; Aprea: Research Funding; Actinium: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Komrokji:Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Geron: Honoraria; Novartis: Honoraria. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Padron:Novartis: Honoraria; BMS: Research Funding; Incyte: Research Funding; Kura: Research Funding. Starczynowski:Captor Therapeutics: Consultancy; Tolero Therapeutics: Research Funding; Kurome Therapeutics: Consultancy, Current equity holder in private company, Research Funding. Sekeres:BMS: Consultancy; Takeda/Millenium: Consultancy; Pfizer: Consultancy.

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