Anti-Glycoprotein V Autoantibodies in Patients with Immune Thrombocytopenia: Regularly Detectable and Functionally Relevant

Abstract Immune thrombocytopenia (ITP) results from autoimmunization against platelet antigens. Autoantibodies (aabs) are considered to represent a major mechanism of thrombocytopenia in ITP by inducing platelet clearance from the circulation. Several lines of evidence demonstrate that aabs against glycoproteins (GP) IIb/IIIa and Ib/IX are predominant in ITP patients. Both disease severity and treatment response rates to specific therapeutics have been associated with aabs patterns. GP V is a well characterized immune target in Varicella-associated and drug-induced thrombocytopenia, but has never been studied systematically in ITP. In this study, patients with a suspected diagnosis of primary ITP were included once they met pre-defined clinical inclusion criteria. The presence of GP IIb/IIIa-, GP Ib/IX, and GP V-specific aabs was investigated by monoclonal antibody immobilization of platelet antigens (MAIPA) assay, both on patients' autologous platelets (direct MAIPA) and in serum (indirect MAIPA). In addition, serum IgG fractions were prepared from all patients with a positive direct MAIPA. IgG fractions were tested by surface plasmon resonance (SPR) technology for the presence of anti-GP V aabs. Complete data sets were obtained from 1,140 qualified patients. Platelet-bound aabs were detected in 343/1,140 patients (30.1%). Of these, 222 (64.7%) had platelet-bound anti-GP V aabs, either alone (10/222), or together with other specificities (211/222). Free anti-GP V aabs were detected in 30/222 patients by indirect MAIPA, but in 88/222 by SPR. The avidity of aabs detected by both methods (n=29; R700/R350=0.73±0.14) was significantly higher than the avidity for aabs detected by SPR only (n=59; R700/R350=0.32±0.13, p < 0.001). In order to study the potential biological relevance of anti-GP V, a phagocytosis assay using CD14+ positively-selected macrophages from spleen specimens from splenectomized ITP patients was performed. Anti-GPV aabs induced a modest amount of platelet uptake above the normal human serum-incubated control. No difference was observed between high avidity and low avidity anti-GP V. The effect of anti-GPV on platelet clearance was further studied in a NOD/SCID mouse model. Freshly isolated human platelets were injected into the lateral mouse tail vein; after 30 min, IgG fractions isolated from human sera containing anti-GPV antibodies or control sera from healthy donors were injected into the other lateral tail vein, and the survival of human platelets in the mouse circulation was analyzed by taking murine blood 60, 120, 300 min and 24h after baseline. High avidity and low avidity anti-GP V aabs (n=3 per group) eliminated human platelets with no detectable difference between the groups (mean platelet survival at t=300 min: 40% [range 27-55] versus 35% [range, 16-46]). A comparable, dose-dependent platelet clearance was also obtained with monoclonal antibody SW16 against GP V. In summary, we have demonstrated that anti-GP V autoantibodies are regularly detectable in ITP patients; and that they are able to induce phagocytosis and platelet clearance. Our findings have implications for both, further development of laboratory testing, and guidance for clinical decision making. First, comparison between MAIPA and SPR reveals that free aabs may be more frequent than reported, since aabs appear to escape detection by standard laboratory methods because of low avidity. Better test methods are required. Second, predicting disease severity and/or tailoring ITP therapy can possibly not be restricted to the postulated difference between anti-GP IIb/IIIa and anti-GP Ib/IX. Prospective studies are required to understand the impact of different GP-specific platelet aabs on the clinical course of ITP including, anti-GP V. Disclosures Rummel: Celgene: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria. Bakchoul:Aspen Germany gGmbH, CLS Behring, Stago gGmbH: Honoraria; German Research Society (DFG): Research Funding; Robert Bosch gGmbH: Research Funding.

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Association between Megakaryocyte Abnormalities on Bone Marrow Smear and Response to Thrombopoietin Receptor Agonists in Adult Patients with Primary Immune Thrombocytopenia

Blood ◽

10.1182/blood-2021-151435 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3160-3160

Author(s):

Ondine Walter ◽

Agnès Ribes ◽

Johanne Germain ◽

Jean-Baptiste Rieu ◽

Thibault Comont ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Adult Patients ◽

Second Line ◽

Bone Marrow Smear ◽

Advisory Committees ◽

Thrombopoietin Receptor

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease due to peripheral destruction but also impaired central production of platelets. Autoimmune reaction directed against megakaryocytes (MKs) has been described, and may explain morphological abnormalities of MKs observed in some patients with primary ITP. Thrombopoietin receptor agonists (TPO-RAs) are indicated as second-line treatments for ITP, but no predictive factors of response used in clinical routine practice has been demonstrated. The utility of systematic bone marrow smears (BMS) at ITP diagnosis is discussed. Howerer, it is usually recommended before second-line treatments. Two studies have suggested an association between MK abnormalities and response to corticosteroids in primary ITP, but none have investigated this association for TPO-RAs. This study aimed to investigate the association between MK abnormalities and response to TPO-RAs in adult patients with primary ITP. Methods: The source of population was the CARMEN registry. The CARMEN (Cytopénies Auto-immunes: Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) with incident ITP in routine visit or hospital stay. ITP was defined by international definition (platelet count <100 x 10 9/L and exclusion of other causes of thrombocytopenia). The study population consisted in all patients included in the CARMEN registry between June 2013 and March 2018 with primary ITP, treated by TPO-RA and with a BMS before initiating TPO-RA. We excluded the patients with a number of MKs <10 MK on the BMS. Morphological abnormalities were established based on literature and defined by consensus among 3 expert cytologists (AR, JBR and VDM). All MKs present on each smear were analyzed. MKs were categorized by the presence of dysplasia (monolobed MK and/or separated nuclei and/or microMKs), and according to their stage of maturation (basophilic, granular and thrombocytogenic). All patients' medical charts were reviewed by two experts in ITP (OW and GM) to determine the response to TPO-RAs. Response was defined by a platelet count between 30 and 100 G/L with at least a doubling of basal platelet count according to the international definition. In case of subsequent exposure to both TPORAs in a single patient, response was defined by response to at least one TPO-RA in the main analysis. We performed a subgroup analysis by TPORAs. Results: During the study period, 451 patients with incident ITP were included in CARMEN-registry. Among them, 105 had been treated by TPO-RAs, including 65 with BMS before the exposure to TPORA. We then excluded 20 patients with secondary ITP and 7 with less than 10 MKs on the BMS. We finally included 38 patients in the analysis. Median age at diagnosis was 71 years (interquartile range - IQR: 31 - 94) and 34.2% were women. Thirty-three patients were treated with eltrombopag, 17 with romiplostim including 13 who were exposed to both TPORAs. Thirty-four (89.4%) achieved response. The median number of MKs analyzed per patient was 137 (IQR: 50 - 265). All results are presented in Table 1. In the main analysis, there was no significant difference in the median percentage of dysplastic MKs in responders (4.0%, 95% confidence interval - CI: 2.3 - 6.4) and non-responders (4.5%, 95% CI: 0.7 - 7.1). There was a trend for a higher proportion of granular MKs (4.5%, 95% CI: 3 - 6) and basophilic MKs (30.1%, 95% CI: 21.9 - 39.1) in non-responders comparing to responders (granular: 2.0%, 95% CI: 0 - 4.1; basophilic: 21.3%, 95% CI: 11.4 - 40.7). Results were similar in the subgroup of patients treated with eltrombopag (data not shown; the low number of patients treated with romiplostim precluded any analysis). Conclusion: In this study, neither MK abnormalities nor the pattern of MK maturation stages were significantly associated with response to TPO-RAs. These results do not support a systematic bone marrow smear in patients with primary ITP to look for morphological predictive factors of response to TPO-RA. Figure 1 Figure 1. Disclosures Comont: AstraZeneca: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees.

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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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IPH4102; An Anti-KIR3DL2 Monoclonal Antibody in Refractory Sezary Syndrome: Results from a Multicenter Phase 1 Trial

Blood ◽

10.1182/blood-2018-99-118021 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 684-684 ◽

Cited By ~ 1

Author(s):

Martine Bagot ◽

Pierluigi Porcu ◽

Basem M. William ◽

Maxime Battistella ◽

Maarten Vermeer ◽

...

Keyword(s):

Quality Of Life ◽

Monoclonal Antibody ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Advisory Committees ◽

Multicenter Phase ◽

Equity Ownership

Abstract Aims: Sezary Syndrome (SS) is the most aggressive form of cutaneous T cell lymphoma (CTCL), characterized with high blood involvement and expression of Killer cell immunoglobulin like receptor 3DL2 (KIR3DL2). IPH4102 is a first-in-class monoclonal antibody that targets KIR3DL2. Very limited effective treatment options are available for SS patients with refractory disease. We conducted a phase 1 study testing IPH4102 in patients with refractory CTCL. Here we report results from the SS subset. Methods: IPH4102-101 study is a multicenter phase I trial composed of a dose escalation and cohort expansion portions that evaluated IPH4102 in patients with refractory CTCL. Key eligibility criteria included failure of ≥ 2 prior systemic therapies. KIR3DL2 testing was performed for all patients at baseline and at different time points throughout the study. IPH4102 was given Q1w x 4 weeks, followed by Q2w x 10 weeks then Q4w until disease progression or unacceptable toxicity. Primary endpoint is safety. Main 2ry endpoints include best global response (BGR) using the Olsen criteria, progression-free survival (PFS), duration of response (DOR), quality of life (QOL) and biomarker analyses. Results: The study included 35 SS patients, 20 in the dose escalation and 15 in the cohort expansion, with a median age of 70 years (37-90). Median time from initial SS diagnosis to starting IPH4012 was 22.8 months. Nineteen patients (54%) received IPH4102 as ≥ 4th line of systemic therapy and 7 (20%) were previously treated with mogamulizumab. Thirteen patients (37%) had lymph node involvement as per investigator assessment and based on radiological examination while 7 patients (20%) had evidence of large cell transformation. KIR3DL2 expression was observed in either skin or blood in 33 patients (94%) and in both in 28 patients (80%). Most common adverse events (AEs) were asthenia (26%), peripheral edema (26%), and fatigue (23%), which were all grade 1-2. Possibly related grade ≥ 3 AEs were observed in 7 patients (20%), and only 2 patients (6%) stopped treatment for an AE. Table 1 shows BGR and response by compartment. Overall response rate was 42.9% [95% CI: 28.0% - 59.1%], with median time to response of 4.8 months. Median DOR and PFS were 5.6 months [95% CI: 3.2-not reached] and 12.8 months [95% CI: 8.1-not reached], respectively. Mogamulizumab pretreated patients showed BGR, median DOR and PFS of 42.9%, 13.8 and 20.9 months, respectively. Quality of life assessment was performed using the Pruritus VAS score andSkinDex29. Patients with CR, PR or SD showed marked improvement overtime of all evaluated parameters including SkinDex29 global, symptoms, emotional, and functional scores. Biomarker analysis showed progressive decrease in CD4/CD8 ratio in responding patients. The decrease of KIR3DL2+ expressing cells in skin evaluated by immunohistochemistry at week 5 and 14 was able to predict BGR (AUC=0.749, 0.714, respectively). Figure 1 shows reduction in KIR3DL2 expressing cells at week 5 and week 14 in a patient who had PR as BGR. To date, 9 patients are still ongoing treatment. Updated clinical and correlative research analyses will be presented at the meeting. Conclusions: IPH4102 is highly effective in patients with refractory SS. It induces meaningful clinical activity and improves quality of life placing it as an encouraging treatment option for these patients. Further development in SS and other T-cell malignancies is underway. Disclosures Bagot: Actelion: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Porcu:Innate Pharma: Consultancy. Khodadoust:Innate Pharma: Research Funding. Sicard:Innate Pharma: Employment, Equity Ownership. Azim:Innate Pharma: Employment, Equity Ownership. Kim:miRagen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Galderma: Research Funding; Tetralogic: Research Funding; Neumedicine: Consultancy, Research Funding; Soligenix: Research Funding; Portola: Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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An Insight into the Impact of Hemophilia a on Daily Life According to Disease Severity: A Preliminary Analysis of the CHESS II Study

Blood ◽

10.1182/blood-2020-136952 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-3

Author(s):

Declan Noone ◽

Francis Nissen ◽

Tao Xu ◽

Tom Burke ◽

Sohaib Asghar ◽

...

Keyword(s):

Board Of Directors ◽

Disease Severity ◽

Research Funding ◽

Hemophilia A ◽

Daily Life ◽

Social Activity ◽

Publicly Traded ◽

Advisory Committees ◽

On Demand ◽

The Impact

Introduction: Hemophilia A (HA) is a congenital bleeding disorder caused by a deficiency in clotting factor VIII (FVIII). There are currently limited data on the impact of HA on daily life. Here we examine the impact of HA on the daily life of adult persons with HA (PwHA) without current FVIII inhibitors according to disease severity. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey II (CHESS II) is a retrospective, burden-of-illness study in adults with mild, moderate, and severe HA or hemophilia B (defined by endogenous FVIII/IX [IU/dL] relative to normal; mild, 5-<40%; moderate, 1-5%; severe, <1%); this analysis includes only PwHA. Male participants (aged ≥18 years) diagnosed with HA (without FVIII inhibitors) at least 12 months prior to clinical consultation were enrolled from Denmark, France, Germany, Italy, the Netherlands, Romania, Spain, and the UK. Data on clinical outcomes and healthcare resource utilization were captured via electronic case report forms disseminated to hemophilia specialists. PwHA completed a paper-based questionnaire utilizing 5-point Likert scales to assess the disease burden on their daily life. Overall, 12 months' retrospective data were examined. Informed consent was obtained and the study was approved by the University of Chester ethical committee. Results: Of 258 PwHA completing questionnaires, 15.9% (n=41), 27.9% (n=72), and 56.2% (n=145) had mild, moderate, and severe HA, respectively. Of those with severe HA, 60.0% were currently receiving FVIII prophylaxis (standard of care for severe HA); in comparison, 4.9% and 6.9% of those with mild and moderate HA were receiving prophylaxis (Table 1). Treatment adaptation in anticipation of physical or social activity was reported by 19.5%, 23.6%, and 38.6% of those with mild, moderate, and severe HA, respectively. Over a third of participants with mild (36.6%) and moderate (44.4%) HA, and 64.8% of those with severe HA (58.6% with severe HA receiving on-demand treatment and 69.0% receiving prophylaxis) agreed or strongly agreed that HA had reduced their physical activity (Figure 1). Overall, 38.9% of those with moderate HA and 58.6% of those with severe HA (63.8% with severe HA receiving on-demand treatment and 55.2% receiving prophylaxis) agreed or strongly agreed that their HA had reduced their social activity; this was less pronounced in mild HA (9.8%). Additionally, 31.7%, 36.1%, and 64.1% of those with mild, moderate, and severe HA (62.1% with severe HA receiving on-demand treatment and 65.5% receiving prophylaxis) agreed or strongly agreed that their HA had caused them to miss opportunities. Correspondingly, frustration due to HA was felt by 19.5%, 34.7% and 57.9% (56.9% with severe HA receiving on-demand treatment and 58.6% receiving prophylaxis) of people, respectively. When asked whether they believed their daily life was compromised due to their hemophilia, 24.4%, 37.5%, and 63.4% of those with mild, moderate, and severe HA, respectively, agreed. Pain, as reported by the physician, was noted in 36.6% of people with mild HA (100% was reported as 'mild'); in people with moderate HA, pain was reported as 'mild', 'moderate', and 'severe' in 44.4%, 20.8%, and 1.4% of PwHA, respectively. In people with severe HA, pain was reported as 'mild', 'moderate', and 'severe' in 39.7%, 27.6%, and 8.6% for those receiving on-demand treatment, and 37.9%, 32.2%, and 8.0% for those receiving prophylaxis, respectively. Conclusions: In all disease severity groups, there was a notable group of PwHA that felt that they have had to reduce their physical and social activity, have had fewer opportunities and are frustrated due to their disease. While the impact on daily life is most pronounced in people with severe HA (including those receiving on-demand treatment and those receiving prophylaxis), it is also apparent in mild and moderate HA, indicating that there may be an unmet medical need in these groups. Disclosures Noone: Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; Research Investigator PROBE: Research Funding; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees. Nissen:F. Hoffmann-La Roche Ltd: Current Employment; Actelion: Consultancy; Novartis: Research Funding; GSK: Research Funding. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Burke:University of Chester: Current Employment; HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Asghar:HCD Economics: Current Employment. Dhillon:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; HCD Economics: Current Employment. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Khair:Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Haemnet: Membership on an entity's Board of Directors or advisory committees.

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A Longitudinal Prospective Study Evaluating the Effects of Eltrombopag Treatment On Bone Marrow in Patients with Chronic Immune Thrombocytopenia: Interim Analysis At 1 Year.

Blood ◽

10.1182/blood.v120.21.2195.2195 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2195-2195 ◽

Cited By ~ 2

Author(s):

Russell K. Brynes ◽

Attilio Orazi ◽

Raymond S.M. Wong ◽

Kalpana Bakshi ◽

Christine K Bailey ◽

...

Keyword(s):

Bone Marrow ◽

Trabecular Bone ◽

Board Of Directors ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Employment Equity ◽

Advisory Committees ◽

Study Results ◽

Equity Ownership ◽

Chronic Immune Thrombocytopenia

Abstract Abstract 2195 Introduction: Eltrombopag (epag), a thrombopoietin receptor agonist (TPO-RA), increases platelet counts in patients with chronic immune thrombocytopenia (cITP). TPO-RAs have been associated with varying degrees of increases in bone marrow reticulin (Brynes 2011; Ghanima 2011). Due to lack of pretreatment evaluations, the incidence and clinical significance of these findings have not been established. Inconsistencies in specimen preparation, staining, and analysis across institutions further confound conclusions. The purpose of this 2-year (y) study (NCT01098487) is to assess for bone marrow fibrosis (reticulin and/or collagen) in patients treated with epag for cITP. Baseline and 1y findings are presented. Methods: Bone marrow biopsies are being collected at baseline (before treatment with epag) and at 1 and 2y of treatment. Specimens are centrally processed and stained for reticulin (silver) and collagen (trichrome) and undergo central independent pathology review of cellularity; megakaryocyte, erythroid, and myeloid quantity and appearance; trabecular bone quality; reticulin grade; and presence of collagen (European Consensus scale-MF; Thiele 2005). Results: Baseline and 1y (10–14 months) data are available for 101 patients. Median age is 42y (18–78); 70 patients are female; 50% are Caucasian/European, 22% are East Asian, and 29% are Central South Asian. Median time since ITP diagnosis is 4.2y (0.2–45.7). All patients had received prior ITP therapy, and 8 patients had received prior TPO-RA treatment (epag [7], romiplostim [1]), the last dose ≥6 months before enrollment. At baseline, 91 patients had reticulin grade 0 (MF-0), 10 MF-1, and 0 MF≥2. At 1y, 59 patients had MF-0, 38 MF-1, 3 MF-2, and 1 MF-3 (Figure). Compared with baseline, there was no change at 1y in MF grade in 61 patients, a decrease by 1 grade in 3, an increase by 1 grade in 35, and an increase in 2 or 3 grades in 1 patient each (Table). Three patients had collagen at 1y (1 patient each with MF-1, MF-2, and MF-3). None of the 4 patients with MF≥2 had adverse events or hematologic abnormalities considered related to impaired bone marrow function, and none withdrew due to bone marrow findings. Among the 8 patients with prior TPO-RA treatment, all had baseline reticulin of MF-0 and none had collagen; at 1y, 6 remained MF-0, 1 was MF-1, and 1 MF-3 (collagen demonstrated). Cellularity was normal in 83% and 80% of patients at baseline and 1y, respectively. Other than normalization of erythroid lineage numbers, no changes occurred in marrow cellular composition. In 3 of 4 patients with MF≥2, cellularity was increased at 1y. Trabecular bone thinning was found at baseline in 28 patients (the majority with prior steroid use) and 51 patients at 1y. Discussion: 10% of patients had MF-1 at baseline. After 1y of treatment, no increase or a mild increase in reticulin was observed in 63% and 35% of patients. No patient with MF≥2 (n=4) had clinical signs or symptoms indicative of bone marrow dysfunction and none withdrew from the study. Results were similar to those reported for EXTEND, an eltrombopag extension study (median treatment duration >2 years; Brynes 2011). Conclusion: These data suggest that treatment with epag is generally not associated with clinically relevant increases in bone marrow reticulin or collagen. The potential association of TPO-RAs and increased bone marrow reticulin needs further study. Disclosures: Brynes: GlaxoSmithKline: Research Funding. Orazi:GlaxoSmithKline: Research Funding. Wong:Roche: Research Funding; MSD: Research Funding; Johnson & Johnson: Research Funding; Bayer: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; GlaxoSmithKline: Research Funding; Bristol-Myers Squibb: Research Funding. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

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Thrombosis in Immune Thrombocytopenia Patients with Antiphospholipid Antibodies: A Meta-Analysis

Blood ◽

10.1182/blood.v126.23.1051.1051 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1051-1051

Author(s):

Guillaume Moulis ◽

Alexandra Audermard-Verger ◽

Laurent Arnaud ◽

Cécile Luxembourger ◽

François Montastruc ◽

...

Keyword(s):

Venous Thrombosis ◽

Board Of Directors ◽

Antiphospholipid Antibodies ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Data Extraction ◽

Meta Analysis ◽

Random Effect ◽

Sensitivity Analyses ◽

Advisory Committees

Abstract Background: Thrombosis during immune thrombocytopenia (ITP) management is a critical issue. Among suspected risk factors for thrombosis in ITP patients, the role of antiphospholipid antibodies (aPL) is controversial. We performed a systematic review and a meta-analysis to investigate risk of thrombosis with lupus anticoagulant (LA), anticardiolipin (aCL) and anti-β2GP1 antibodies in primary ITP. Methods: Literature search was computed on Medline, Cochrane and ISI Web of Sciences by two independent investigators from January 1st 1980 to December 31st 2014. Unpublished studies were searched in meeting abstracts of the American Society of Hematology, the European Haematology Association, the American College of Rheumatology and the European League Against Rheumatism. Inclusion criteria were observational studies including primary ITP patients where presence of aPL was documented (LA, aCL or anti-β2GP1 antibodies). We assessed the occurrence of thrombotic events in these studies. Two investigators performed data extraction. All authors were contacted in order to confirm or provide complementary data if needed. Study quality was assessed using the NewCastle-Ottawa (NOS) scale. The main analysis assessed the risk of all thromboses (arterial or venous) associated with the presence of LA, aCL or anti-β2GP1 antibodies. Sensitivity analyses were performed, restricted to the best quality studies. We also also stratified the risk of arterial and venous thrombosis separately. Random effect (Der Simonian & Laird) models were used. Heterogeneity was assessed using the I2 index. Odds ratio (OR) and their 95% confidence intervals (95%CI) were computed. Publication bias was searched using Egger's test and funnel plot. Results: Searching in electronic databases retrieved 776 citations, completed by 12 additional studies from unpublished literature. Out of them, 44 studies were identified for a full-length text review. Eventually, 10 cohort studies totalizing 1010 patients were selected (9 with LA, 6 with aCL, 2 with anti-β2GP1 antibody dosages). Five studies were prospective and 5 retrospective. The median NOS score was 6 (range: 4-8). The pooled OR for the risk of all thromboses associated with LA positivity was 6.11, 95%CI [3.40-10.99] (I2 =0%, Egger's test: p=0.37). It was 2.13, 95%CI [1.11-4.12] with aCL (I2 =0%, Egger's test: p=0.14). Sensitivity analyses restricted to studies with quality score ≥6 led to similar results. The OR for arterial thrombosis was 5.52, 95%CI [2.40-12.70] with LA and 2.12, 95%CI [0.84-5.33] with aCL. The OR for venous thrombosis was 5.13, 95%CI [2.31-11.40] with LA and 2.00, 95%CI [0.83-4.81] with aCL. Only two studies assessed the risk of thrombosis associated with anti-β2GP1 antibody positivity, with high heterogeneity (I2 =81%). Consequently, no pooled OR was computed. Conclusions: This meta-analysis demonstrates that aPL positivity in ITP patients is a risk factor for thrombosis. The risk was three times higher with LA than with aCL. It was similar for arterial and venous thromboses. For practicing clinicians, our results imply that systematic aPL determinations should be performed in ITP, since aPL positivity and associated thrombosis risk should influence the choice of treatment. Disclosures Michel: Roche: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Godeau:Roche: Research Funding; Amgen: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Iron Overload Is Highly Prevalent in All Disease Severity States in Pyruvate Kinase Deficiency (PKD)

Blood ◽

10.1182/blood.v128.22.2430.2430 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2430-2430

Author(s):

Eduard J van Beers ◽

Wilma Barcellini ◽

Stefan W. Eber ◽

Janet L Kwiatkowski ◽

Jennifer A Rothman ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Disease Severity ◽

Research Funding ◽

Chelation Therapy ◽

Iron Status ◽

Compound Heterozygous ◽

Advisory Committees ◽

Cardiac Iron ◽

Significant Difference

Abstract Background: PKD causes a defect in glycolysis resulting in a hereditary non-spherocytic hemolytic anemia. The prevalence of iron overload is not well described for PKD. Aim: We aim to describe the demographic features and prevalence of iron overload in transfusion dependent and transfusion independent patients with PKD. Methods: Between March 2014 and April 2016, 203 patients enrolled on the PKD Natural History Study at 29 IRB approved sites. All patients were confirmed to have two compound heterozygous or homozygous mutations in the PKLR gene. Children < 1 year of age (n=9) were excluded from this analysis, because elevated ferritin levels are less reliably related to iron overload. Patients were designated with iron overload at the time of enrollment if the plasma ferritin was >1000 ng/mL or the patient was on chelation therapy at any time during the prior 12 months. Patients were designated with having had iron overload if a MRI ever showed liver iron content (LIC) >3 mg/g dry weight or if they had ever received chelation therapy. Tests of association were performed using Fisher's exact test (categorical) and Wilcoxon rank sum test (continuous). Linear associations between variables were measured by Pearson correlation coefficient. P-values <0.05 were considered statistically significant. Results: Of the 194 patients, 111 (57%) were adults ≥18 years and 83 (43%) were children. The median age of enrollment was 20.6 y (range: 1.3-69.9). Splenectomy had been performed in 65% (126/194). Screening ferritin levels were available for 72% (140/194) and LIC for 32% (62/194). At enrollment, 48% (70/147) had iron overload as defined by ferritin and/or current chelation. Using the LIC criterion, iron overload had been present at some point in 86% (95/110) of patients. Ferritin positively correlated with LIC (n=45); r=0.62, p<0.0001. However, of 29 patients with an LIC measurement and a mean ferritin <1000 ng/mL, 15 (52%) had a LIC >3 mg/g DW. Baseline characteristics in patients with and without iron overload are shown in the Table. Notably, even in patients that were never regularly transfused and had a hemoglobin (Hb) >8.7 g/dl, the prevalence of iron overload was 26% (8/31). The frequency of iron overload was significantly higher in patients who had a prior splenectomy (p<0.0001), even after controlling for transfusion history (p<0.0001). Age was associated with iron overload (p=0.046); although, the age range of patients with iron overload was broad (1.3-69.9 years). The frequency of iron overload was significantly higher in those with a lower baselineHb(p=0.004) and higher bilirubin (p=0.03). Data on cardiac iron status was available for 66 patients.Only 2 had cardiac iron overload (defined as T2*<20ms); they were age 5 (T2* 17.8ms, LIC 5 mg/g) and 22 years (T2* 19.7ms, LIC 14 mg/g) at the time of the MRI. Of the 194 patients, 52 (27%) were from the Pennsylvania Amish community. These patients were managed differently than the non-Amish, in that only 2% of the Amish patients were on iron chelation therapy in the 12 months prior to enrollment compared with 43% among the non-Amish cohort. In addition, the Amish had a significant higher prevalence of splenectomy (96% vs 52%, p<0.0001) and proportion who had been historically transfused (79% vs 32%, p<0.0001). Despite these differences, the Amish patients had a lower prevalence of iron overload (34% vs. 51%). There was no significant difference inHbor enrollment age between the Amish and non-Amish cohorts. Conclusion: Iron overload is a common, serious complication in PKD, regardless of age, disease severity, or transfusion status. Although ferritin correlates with LIC for the PKD population overall, at the individual patient level, ferritin is not a good predictor of LIC and a ferritin <1000 ng/ml does not exclude hepatic iron overload. Therefore, we recommend that all patients with PKD starting at age 1 year should be screened annually for iron overload using ferritin and, at least once, using MRI. Disclosures Barcellini: Agios: Consultancy. Neufeld:Novartis: Consultancy. Morton:Agios Pharmaceuticals: Research Funding. Yaish:Octapharma: Other: Study investigator. Kuo:Agios Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Other: unrestricted educational grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:bluebird bio: Consultancy, Research Funding; Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mast: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Amgen: Research Funding. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Effects of Anti-Glycoprotein Antibodies on Response of Immune Thrombocytopenia Patients to Thrombopoietin Receptor Agonists and on Megakaryocytes Viability

Blood ◽

10.1182/blood.v126.23.1048.1048 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1048-1048

Author(s):

Marina Izak Karaev ◽

Alexandra Kruse ◽

Margaret Morrisey ◽

Heyu Ni ◽

Zhu Guangheng ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Treatment Option ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Advisory Committees ◽

Thrombopoietin Receptor Agonists ◽

Platelet Counts ◽

Thrombopoietin Receptor ◽

Equity Ownership

Abstract Background Immune Thrombocytopenia (ITP) is a bleeding disorder due to a combination of increased platelet destruction and reduced production, often secondary to anti-platelet/megakaryocyte antibodies. The presence of antibodies to glycoproteins (GP) IIb/IIIa (integrin αIIbβ3) and GPIb/IX, detected in majority of ITP patients, may correspond to different responses to treatment, i.e., anti-GPIb is associated with more severe disease, and less responsive to intravenous immunoglobulins and steroids. Thrombopoietin Receptor Agonists (TPO-RA) increase platelet production by stimulation of megakaryopoesis. Predictors of response to TPO-RA and influence of antibody profile on response are currently unknown. In our previous study we investigated Absolute Immature Platelet Fraction (A-IPF) prior to TPO-RA treatment and did not find a correlation between A-IPF, anti-GP antibodies, and platelet counts. The aims of this study were to further investigate: 1. The role of anti-GP antibodies in response to TPO-RA; 2. Effect of patients' antibodies on megakaryocyte (MK) viability, maturation, apoptosis and formation of proplatelets (in vitro); 3. The influence of patients' clinical characteristics on response to TPO-RA. Materials and Methods 91 patients with persistent or chronic ITP, were treated at Weill Medical College of Cornell University until January 2015 with TPO-RAs: 52 patients received eltrombopag, 22 romiplostim and 17 avatrombopag. Serum samples of 84 patients were analyzed for the presence of anti-GP by MAIPA assay as previously described. Patients with baseline platelet counts less than <30x109/L were defined as responders to TPO-RA if the average of their six median monthly platelet counts was ≥50x109/L and doubled from average baseline counts (prior to TPO-RA). Patients with baseline platelet counts 30-50x109/L were responders if the average platelet count was ≥75x109/L. MKs were derived from human umbilical cord blood stem cells as previously described. Cells were grown using SFEM medium, adding on day 0 of culture 50 ng/ml recombinant TPO and aliquots of serum of ITP patients or healthy controls. The percentages of immature (CD41+/CD42-), mature (CD41+/CD42+), viable and apoptotic MKs were analyzed by flow cytometry on day 12. Apoptosis was analyzed by measuring Mitochondrial Outer Membane Potential (MOMP) and Phosphatidyl Serine (PS) externalization. MKs were considered apoptotic if they had positive staining for PS externalization, viable if positive for MOMP, and dead if positive for 7-Aminoactinomycin D (7AAD). Proplatelet formation by MKs was analyzed by microscopy. Statistical analysis using unpaired T-test and Pearson correlation test were performed. Results Ninety-one patients were included, 40 male (44%) and 51 female (56%), with a median age of 37.4 years (range 2-87). Median duration of ITP before TPO-RA treatment was 8 years (range 0.3-45). The 18/91 (19.8%) non-responders to TPO-RA were not different from the 73/91 responders in age, gender, number of prior treatments, duration of ITP, and past splenectomy. The presence of either or both anti-GP antibodies was correlated with average lower platelet counts on TPO-RA: 82.3 x109/L versus 123x109/L in patients without detected antibodies ("neither") (p=0.003). However, the response to TPO-RA was not influenced by the type of antibody: in patients with anti-GPIb the average platelet count was 76.1x109/L, and with anti-GPIIb/IIIa 80.7x109/L (Figure 1). In culture, excess dead MKs were found in anti-GPIb group and antiGPIb&antiGPIIb/IIIa group compared to "neither" group (p=0.0013 and p=0.027 respectively) and comparing antiGPIb&antiGPIIb/IIIa to control (p=0.0025). We did not observe changes in the degree of MK apoptisis or in MK maturation in the presence of serum antibodies. In cultures treated with serum of patients having anti-GPIb, less proplatelets were detected comparing to control (p=0.044) or to "neither" (p=0.0039). We conclude that patients with anti-GP antibodies respond less to TPO-RA, however there is no difference in response to TPO-RA between patients having anti-GPIb and anti-GPIIb/IIIa, unlike responses to other treatment modalities (e.g., steroids or immunoglobulins). TPO-RA could be a preferable treatment option in ITP patients having anti-GPIb. Figure 1. Average 6-months platelet counts of TPO-RA-treated ITP patients divided into groups by presence of antibody/ies. Figure 1. Average 6-months platelet counts of TPO-RA-treated ITP patients divided into groups by presence of antibody/ies. Disclosures Off Label Use: Eltrombopag, romiplostim and avatrombopag are a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. In some preliminary studies these medicines found as safe and effective treatment option in children and adolescents. Bussel:amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Novartis: Consultancy, Research Funding; Genzyme: Consultancy; BiologicTx: Research Funding; Ligand: Consultancy, Research Funding; Eisai: Consultancy, Research Funding; Shionogi: Consultancy, Research Funding; momenta: Consultancy; Protalex: Consultancy; Symphogen: Consultancy.

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Effect of Timing of Monoclonal Antibody Therapy on the Time to Next Treatment and Response Rate in Heavily Pre-Treated Patients with Myeloma Who Separately Received Both Daratumumab and Elotuzumab-Based Regimens

Blood ◽

10.1182/blood-2018-99-115663 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3258-3258 ◽

Cited By ~ 2

Author(s):

Melody R. Becnel ◽

M Laura Rubin ◽

Ranjit Nair ◽

Elisabet E. Manasanch ◽

Hans C. Lee ◽

...

Keyword(s):

Monoclonal Antibody ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Antibody Therapy ◽

Additional Patient ◽

Cancer Center ◽

Monoclonal Antibody Therapy ◽

Advisory Committees ◽

Significant Difference

Abstract Introduction Notable advances have been made in multiple myeloma management (MM) in recent years. The monoclonal antibodies daratumumab (dara) and elotuzumab (elo) are integral in the management of relapsed/refractory MM and are moving into the frontline setting for transplant ineligible patients. Despite many trials evaluating the efficacy of these agents, there is no consensus on the optimal integration of these agents into the current paradigm of MM management. There is a paucity of data to guide the selection of one antibody over the other, and little is known about whether the use of one prior antibody alters the efficacy of other agents in subsequent lines of therapy. We retrospectively analyzed MM patients treated with both elo and dara during the course of their disease to assess whether the sequence of elo followed by dara or dara followed by elo led to better outcomes. Methods We reviewed the records of MM patients ≥ 18 years old who received both dara and elo at any time during treatment at MD Anderson Cancer Center. We evaluated the time to next treatment (TTNT), defined as the start date of one treatment to the start of the next treatment, and the overall response rate (ORR) (partial response or greater) to dara and elo. TTNT and ORR were calculated for dara when administered as the first antibody during treatment and to dara when administered as the second antibody (elo given during prior lines of treatment). We evaluated TTNT and ORR when elo was administered as the first antibody during treatment and to elo when administered as the second antibody (dara given during prior lines of treatment). The association with categorical patient variables (age, race, immunoglobulin class, number of prior lines of therapy, agent co-administered with the second monoclonal antibody given) was analyzed using Fisher exact tests. Outcomes were estimated using the Kaplan-Meier method and differences in survival among groups were assessed using two-sided log-rank tests. Results We identified 56 patients treated with both dara and elo. We excluded 6 for missing data; 56% of the 50 patients were male; 70% were Caucasian; 56% with IgG subclass paraprotein; 66% kappa light chain restricted. Patients were heavily pre-treated; most with >5 lines of therapy prior to initiation of dara or elo. Elo was the first agent received in 64% of patients. Independent of treatment order, the ORR to elo and dara were 72% and 88% respectively. When elo was administered prior to dara (elo first), the ORR was 78%, and 61% when administered after dara (elo second). When dara was administered prior to elo (dara first), the ORR was 89%, and 88% when administered after elo (dara second). There was no statistical difference in ORR (78% vs 89%) for the initial antibody given, but there was a significant difference in ORR (61% vs. 88%) to the agent given second (p=0.04). Of the variables assessed, only the antibody class had a statistically significant association with outcomes; IgG was associated with better responses when elo was administered as the second agent. TTNT analysis included 47 (of 50) evaluable patients. With elo given first, median TTNT was 6.28 months, and 2.23 months when given second. With dara given first, median TTNT was 8.97 months and 4.60 months when given second. There was no statistically significant difference in TTNT for either the first or second agent administered. There was a statistically significant improvement in TTNT in Caucasian patients compared to other races when elo was given first, but no other clinical factor association was statistically significant. Conclusions Our data, though retrospective and single-center, demonstrate that responses to dara are similar whether administered as the first or second monoclonal antibody used in the treatment of MM. However, prior treatment with dara negatively impacts responses to elo in subsequent lines of therapy. Similarly, independent of the sequence of administration, TTNT was prolonged with dara compared to elo. Our findings suggest that elo followed by dara may be the preferred sequence of monoclonal antibody therapy as responses to elo decreased when administered after dara, but responses to dara were stable irrespective of elo administration. These findings warrant further investigation particularly as dara is now being used more often in the frontline setting. Further evaluation is also needed to determine any association with additional patient factors such as cytogenetics. Disclosures Lee: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Thomas:Amgen Inc: Research Funding; Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Array Pharma: Research Funding; Acerta Pharma: Research Funding. Orlowski:Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Poseida: Research Funding.

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MRI-Derived Radiomics of Hemophilic Arthropathy Is Associated with Severity of Joint Disease

Blood ◽

10.1182/blood-2021-151003 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2958-2958

Author(s):

Bolin Song ◽

Vidya Sankar Sankar Viswanathan ◽

Jonathan Nutt ◽

Lin Li ◽

Navid Faraji ◽

...

Keyword(s):

Board Of Directors ◽

Disease Severity ◽

Severity Score ◽

Research Funding ◽

Joint Disease ◽

Disease Severity Score ◽

Advisory Committees ◽

Hemophilic Arthropathy ◽

Mri Scans ◽

History Of

Abstract Introduction Joint bleeding resulting in synovial hypertrophy and articular cartilage damage are the hallmarks of hemophilic arthropathy. Early prophylaxis with extended half-life factor products and non-factor replacement therapies reduce joint bleeds but do not provide complete protection from development of arthropathy. MRI is the gold standard imaging technique to diagnose and monitor arthropathy in hemophilia. MRI changes that are associated with joint bleeding and development of arthropathy, however, are not sensitive enough to detect early changes in the synovial membranes after sub-clinical bleeding. Radiomics, the computerized extraction of sub-visual attributes from imaging scans can detect early changes of hemophilic arthropathy and help in more accurate characterizations of severe joint disease. The goal of this project was to develop and compare MRI radiomics with the International Prophylaxis Study Group (IPSG) score, an established MRI joint disease scale, in assessing the severity of joint disease. Methods After IRB approval, knee MRI scans of 17 hemophilia patients with a history of joint bleeding and 12 age-matched healthy controls were included in this study. Manual annotations were performed in consensus by a board-certified musculoskeletal radiologist to include the prefemoral fat, suprapatellar fat pad and bursa . To ensure that the signal intensities from different cases were in tissue-specific correspondence, a landmark-based histogram transformation was used to align MRI signal intensity distributions across all cases. 560 radiomic features capturing MRI pixels texture heterogeneity (Gabor wavelets, Laws texture, Haralick and GoLIAGe co-occurrence patterns) were subsequently extracted on all MRI slices with ROI for all the cases. Top 2 radiomic features (F 2) for differentiating between abnormal joint changes and control were selected by Minimum Redundancy Maximum Relevance (mRMR) algorithm with 100 iterations of 3-fold cross-validation. Consensus hierarchical clustering was then applied on F 2, from which two patient clusters were generated. A disease severity score was calculated based on historical lifetime bleed events in the joint, designation of target joint status, and history of surgical synovectomy. A previously described 17-point MRI IPSG score was also calculated by 2 independent reviewers. Both the IPSG score and the F 2 were then fit into a linear regression model separately as predictors whereas the disease severity score was set to be the response variable. The Akaike's Information Criteria (AIC) and the root mean square error (RMSE) were used to evaluate the model fitness and the likelihood ratio (LR) test was applied for model comparison. Results The dataset consisted of 17 males with moderate and severe hemophilia ranging in age from 10-55 years. The median disease severity score was 2 (0-11) and the median IPSG MRI Score was 2 (0-11). The top 2 radiomic features F 2, a Gabor wavelet feature and a Lawshc texture feature, yielded an AUC of 0.94 and an accuracy of 0.9 for differentiating between hemophilic joint changes and healthy control patients. Unsupervised clustering demonstrated good separation between the two classes (Fig panel A and B). The radiomic-based linear regression model (AIC: 86.67; RMSE: 2.86) was significantly better than the IPSG score-based model (AIC: 94.24; RMSE: 3.66) in joint disease severity characterizations (LR, p = 0.0083, Fig panel C). Conclusions Radiomic analysis of knee MRI in hemophilia patients with history of joint bleeding is correlated with the severity of joint disease. Our study demonstrates the feasibility of developing and utilizing a radiomics based tool to detect the severity of joint damage in a small population of knee joint hemophilic arthropathy. We plan to perform an Independent validation of the radiomics signature in a larger dataset of hemophilia joint MRI scans Figure 1 Figure 1. Disclosures Madabhushi: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers-Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Caris: Consultancy; Aiforia: Consultancy; Philips: Research Funding; AstraZeneca: Research Funding; Boehringer-Ingelheim: Research Funding; Bristol Meyers-Squibb: Research Funding. Ahuja: Sanofi: Membership on an entity's Board of Directors or advisory committees; XaTek, Inc: Patents & Royalties; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: DSMB member .

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