Anti-ADAMTS13 Inhibitor Boosting During Plasma Exchange Therapy Often Causes an Intractable Acquired Idiopathic TTP

Abstract Abstract 1086 Introduction: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder, characterized by classic “pentad”. Since 1998, it has been characterized by severe deficiency of ADAMTS13 activity (ADAMTS13:AC), due to genetic abnormalities or acquired autoantibodies (ADAMTS13:INH) to this enzyme. A drug-induced form of TTP, ticlopidine-associated (tc)- TTP, is also associated with severe deficiency of ADAMTS13:AC and ADAMTS13:INH, although unlike acquired idiopathic (ai)-TTP, spontaneous relapses do not occur. A first-line treatment of ai-and tc-TTP is plasma exchange (PE) that remarkably reduced the mortality. However, a certain population of the ai-TTP patients experiences a new drop in platelet count during the treatment. In 2011, we have reported that these ai-TTP patients were frequently associated with a tremendous increase of ADAMTS13:INH titers with PE, and termed “inhibitor boosting” (Isonishi et al. ISTH 2011). However, no systematic studies on this topic have been done. In this study, we analyzed ADAMTS13:INH boosting in Japan-Nara TMA registry. Patients and Methods: Between Jan 2004 and Dec 2011, 215 patients were diagnosed with ai-TTP (100 males/115 females) and 14 tc-TTP (7m/7f) in our registry. For analyzing of ADAMTS13:INH boosting, we evaluated patients in whom both ADAMTS13:AC and ADAMTS13:INH were analyzed more than 3 times within 14 hospital days after PE initiation (selected patients). The number of selected patients with ai-TTP was 56 (24m/32f) and tc-TTP was 5 (3m/2f). Assays for ADAMTS13:AC and ADAMTS13:INH were performed by chromogenic act-ELISA, and the ADMTS13:INH titers were expressed by the Bethesda units (BU). ADAMTS13:INH boosting was defined by fulfilling the followings: 1) patients must have ADAMTS13:INH titer of more than 1 BU/ml before PE; 2) ADAMTS13:INH levels increased more than those before PE, during PE or within 14 days after PE initiation. Autoantibody titers for anti-ADAMTS13 IgG, IgM, and IgA isotypes and IgG1-4 subclasses were determined as previously described (Ferrari et al, JTH 2009). Results: (1) Frequency of the boosting: In ai-TTP, 174 out of 215 (81%) patients showed severely decreased ADAMTS13:AC under 0.5% of the normal. All 56 selected ai-TTP patients had severe deficiency of ADAMTS13:AC, of which ADAMTS13:INH boosting was identified in 23 patients (23/56, 41%). The frequency of inhibitor boosting versus the inhibitor titers before PE was the followings: 4/17 (24%) with ADAMTS13:INH titers of 1-<2 BU/ml, 11/20 (55%) with ADAMTS13:INH titers of 2-<5 BU/ml, 4/10 (40%) with ADAMTS13:INH titers of 5-<10 BU/ml, and 4/7 (57%) with ADAMTS13:INH titers of · 10 BU/ml. In contrast, no patients had the boosting in the selected 5 tc-TTP patients. (2) Characterization of inhibitor autoantibodies: We analyzed the anti-ADAMTS13 immunoglobulin isotypes and IgG subtypes in 8 selected patients with ai-TTP (6 with the boosting, and 2 without) and 2 patients with tc-TTP. All 6 ai-TTP patients with boosting exhibited IgG antibodies, and 3 had additional IgA antibodies; none had IgM antibodies. As for the IgG subclasses, the following combinations were found: G1 alone (one patient), G1+G2 (one patient), G1+G2+G4 (three patients), and G1+G4 (one patient). On the other hand, among 2 ai-TTP patients without boosting, both had IgG antibodies, one had the additional IgA antibodies, and none had IgM antibodies. As for the IgG subclasses, the following combinations were found: G1 alone (one patient), and G1+G2+G4 (one patient). Thus, we did not identify any specific difference between patients with versus without the ADAMTS13:INH boosting. Further, in 2 tc-TTP patients, both had IgG+IgA antibodies. As for the IgG subclasses, one patient had G1+G2+G4, and the other had G1+G2+G3. (3) Effect of rituximab: Five ai-TTP patients with the boosting were treated with rituximab (375 mg/m2weekly 3–5 times), which remarkably suppressed high levels of ADAMTS13:INH and achieved clinical remission. Conclusion: In this study, we identified that ai-TTP patients with severe deficiency of ADAMTS13:AC with ADAMTS13:INH titers more than 2 BU/ml before PE are prone to develop the inhibitor boosting during PE, and that rituximab therapy is potentially very useful in this setting, due to suppression of IgG autoantibodies. Interestingly, the inhibitor boosting was not seen in tc-TTP patients with severe deficiency of ADAMTS13:AC with its autoantibodies. Disclosures: Matsumoto: Alexion Pharma: Membership on an entity's Board of Directors or advisory committees. Plaimauer:Baxter BioScience: Employment. 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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Characteristics of quinine- and quinidine-induced antibodies specific for platelet glycoproteins IIb and IIIa

Blood ◽

10.1182/blood.v77.12.2668.2668 ◽

1991 ◽

Vol 77 (12) ◽

pp. 2668-2676 ◽

Cited By ~ 63

Author(s):

GP Visentin ◽

PJ Newman ◽

RH Aster

Keyword(s):

Immune Response ◽

Platelet Membrane ◽

The Other ◽

Membrane Glycoprotein ◽

Igg Antibodies ◽

Drug Induced ◽

Disulfide Bonding ◽

Platelet Membrane Glycoprotein ◽

Drug Dependent

Abstract Recent studies have shown that antibodies characteristic of quinine- and quinidine-induced thrombocytopenia sometimes recognize the platelet membrane glycoprotein (GP) complex IIb/IIIa in addition to their well known target, GPIb/IX. We have investigated the frequency with which drug-induced antibodies bind to GPIIb/IIIa and the nature of their target epitopes. In studies of sera from 13 patients sensitive to quinidine or quinine, we found that 10 contained IgG antibodies specific for both GPIb/IX and GPIIb/IIIa, two reacted with GPIb/IX alone, and one reacted with GPIIb/IIIa alone. In all cases, the presence of drug was required for binding of IgG to target GPs. By immunoabsorption, we found that each of five polyspecific sera contained at least two different antibodies, one reactive with GPb/IX and the other with GPIIb/IIIa. Further studies with eight drug- dependent antibodies (DDAb) specific for GPIIb/IIIa showed that three recognized the GPIIb/IIIa complex only, one recognized GPIIb alone, and three recognized GPIIIa alone. The eighth serum appeared to bind to both GPIIIa alone and to an epitope determined by the GPIIb/IIIa complex. The three antibodies specific for GPIIIa alone also reacted with GPIIIa deglycosylated with endo-H, and with the major (61 Kd) fragment obtained by chymotryptic digestion of GPIIIa but failed to react with reduced GPIIIa. These findings demonstrate that, in drug- induced, immunologic thrombocytopenia, the anti-platelet immune response is typically directed against epitopes on both GPIb/IX and GPIIb/IIIa. The three DDAb we studied that were specific for GPIIIa alone recognize epitopes resistant to chymotrypsin and endo-H treatment that are dependent on intrachain disulfide bonding.

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Pseudothrombocytopenia: an immunologic study on platelet antibodies dependent on ethylene diamine tetra-acetate

Blood ◽

10.1182/blood.v59.1.157.157 ◽

1982 ◽

Vol 59 (1) ◽

pp. 157-161 ◽

Cited By ~ 105

Author(s):

JG Pegels ◽

EC Bruynes ◽

CP Engelfriet ◽

AE von dem Borne

Keyword(s):

Ethylene Diamine ◽

Igg Antibodies ◽

Immunofluorescence Test ◽

Igm Antibodies ◽

Platelet Antibodies ◽

Group Specificity ◽

Iga Antibodies ◽

Ethylene Diamine Tetra Acetate

Abstract Antibodies specifically reacting with platelets only in the presence of EDTA, by the platelet immunofluorescence test, were found in the serum of 20 patients with pseudothrombocytopenia due to in vitro EDTA- dependent platelet agglutination. These antibodies reacted optimally at 0–4 degree C. In 19 patients, IgG antibodies were detected; in 8 patients, IgM or IgA antibodies were also found. In one patient, only IgM antibodies were found. In 14 patients, the IgG antibodies were IgG1, but IgG2, IgG3, and IgG4 antibodies were also seen in 7 patients. The reaction of platelets with the antibodies was detectable in the presence of Na2EDTA, the K, Ca, and Mg salts of EDTA, and K2EGTA. F(ab')2 or F(ab') fragments of the IgG antibodies reached as strongly as the intact antibodies, indicating that the reaction is dependent on the antibody-combining site. The EDTA-dependent antibodies did not show platelet-group specificity. However, platelets from patients with Glanzmann disease did not react with the antibodies.

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The distribution of antibodies to HHV-6 compared with other herpesviruses in young children

Epidemiology and Infection ◽

10.1017/s095026880004824x ◽

1990 ◽

Vol 105 (3) ◽

pp. 603-607 ◽

Cited By ~ 16

Author(s):

T. J. Farr ◽

G. B. Harnett ◽

G. R. Pietroboni ◽

M. R. Bucens

Keyword(s):

Young Children ◽

Cord Blood ◽

Western Australia ◽

Age Groups ◽

The Other ◽

Early Age ◽

Rapid Rise ◽

Igg Antibodies ◽

Blood Samples ◽

Igm Antibodies

SUMMARYSera from 141 infants aged 0–12 months were examined for IgG antibodies to HHV-6, HSV, CMV, VZV and EBV and for HHV-6 specific IgM. Following the decline in maternal antibody, antibody to HHV-6 was found to rise by 5–6 months and approached the level found in adults by 11–12 months. In contrast the antibody rates for the other herpesviruses were much slower to rise, especially in the case of CMV and EBV. HHV-6 IgM antibodies were detected mainly in age groups showing a rapid rise in antibody to HHV-6. HHV-6-IgM was not detected in 235 cord blood samples. The data suggest that HHV-6 infection is acquired horizontally, at a very early age in Western Australia.

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A Large-Pore IEF Gel Electrophoresis Separates the Complex in Both of ADAMTS13 Bound to VWF and to the IgG Autoantibodies From the Unbound in Plasma Milieu

Blood ◽

10.1182/blood.v118.21.1160.1160 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1160-1160

Author(s):

Masanori Matsumoto ◽

Ayami Isonishi ◽

Yuji Hori ◽

Masaki Hayakawa ◽

Kenji Soejima ◽

...

Keyword(s):

Board Of Directors ◽

Gel Electrophoresis ◽

Von Willebrand Disease ◽

Adamts13 Activity ◽

Advisory Committees ◽

Normal Plasma ◽

Large Pore ◽

Severe Deficiency ◽

Type 3 ◽

Von Willebrand

Abstract Abstract 1160 Backgrounds and Aims: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder caused by a deficiency of ADAMTS13 activity due to its gene mutations (Upshaw-Schulman syndrome), and/or acquired autoantibodies to this enzyme. ADAMTS13 specifically cleaves the peptide bond between Tyr1605 and Met1606 within the A2 domain of von Willebrand factor (VWF). Recent studies with immunoprecipitation methods using anti-VWF antibody coated beads indicated that a small portion (3–4% of the total) of plasma ADAMTS13 is bound to VWF (Feys HB et al. JTH 7:2088, 2009). This experiment determined the amount of ADAMTS13 bound to VWF in an indirect fashion, but the complex may dissociate during washing procedures or by conformation change after binding to the antibody. Thus, we used an isoelectric focusing (IEF) to separate the complex in a direct fashion. However, the molecular size of VWF-ADAMTS13 complex is assumed to be enormously huge, and therefore a regular polyacrylamide IEF gel does not properly work. So, we employed a large-pore composite IEF gel consisting 0.75% agarose and 1.25% polyacrylamide containing 2% of Pharmalyte (pI range 3.0–10). By this method followed by western blot detection using a non-neutralizing anti-ADAMTS13 monoclonal antibody (WH2-11-1), we identified that an ADAMTS13-VWF complex is detected as a sharp band at pI 7.4. The specificity of this band was identified by a lack in plasma of type 3 von Willebrand disease (VWD), and a new emergence of the band in type 3 VWD plasma spiked with purified VWF (Hori et al, 57th ISTH meeting, P-MO-479). We applied this IEF analysis to detect the complex of ADAMTS13-its autoantibodies. Patients and Methods: ADAMTS13 activity was measured by chromogenic act-ELISA, and acquired idiopathic (ai-) TTP with severe deficiency of ADAMTS13 activity due the presence of its autoantibodies is a target in this study. VWF and ADAMTS13 were purified from normal plasma. A large-pore composite IEF gel electrophoresis was performed as previously described. Results and Discussion: Two forms of ADAMTS13, unbound (pI 5.3) and bound (pI 7.4) to VWF in a volume of 10 uL normal plasma (NP), were directly identified on the IEF gel followed by western blotting (Fig. left). Each plasma of type 3 VWD or USS lacked the complex (VWF-ADAMTS13) band with pI 7.4, but it was generated in vitro just after spiking the purified VWF or ADAMTS13 to the respective deficient plasma by the IEF (Fig. not shown). Next, when a volume of 3uL NP was analyzed, only one band with pI of 5.3 (5.1–5.5) was observed. In ai-TTP patients with severe deficiency of ADAMTS13 activity (<3% of the control), plasma had no or faint band of ADAMTS13 (Fig. middle). However, when we mixed the equal volume of patient plasma with ai-TTP with severe deficiency of ADAMTS13 activity and NP, the results on IEF gel showed appearance of 3 major bands with pIs of 5.3, 5.9 and 6.5, together with other many minor bands, and the unbound (free) ADAMTS13 almost disappeared (Fig. right). Then, the IgG purified from patient plasma of ai-TTP was mixed with NP or purified ADAMTS13, the complex band had a pI of 5.9 (5.5–6.3). These results indicated a possibility that the IEF analysis could be used to detect the autoantibodies to ADAMTS13, regardless of the neutralizing or non-neutralizing counterparts, in a totally different fashion to the enzyme immunoassay. Disclosures: Matsumoto: Alexion Pharma: Membership on an entity's Board of Directors or advisory committees. Soejima:The Chemo-Sero-Therapeutic Research Institute: Employment. 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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Consolidation with Vtd Significantly Improves the Complete Remission (CR) Rate Following Vtd Induction and Single Autologous Stem Cell Transplantation (auto) in Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v120.21.3096.3096 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3096-3096

Author(s):

Xavier Leleu ◽

Benjamin Hebraud ◽

Guillemette Fouquet ◽

Murielle Roussel ◽

Denis Caillot ◽

...

Keyword(s):

Board Of Directors ◽

Incidence Rate ◽

Relapse Rate ◽

Research Funding ◽

The Other ◽

Newly Diagnosed ◽

Phase 3 ◽

Advisory Committees ◽

Induction Regimen

Abstract Abstract 3096 Background. Several studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However there are limitations to these studies, especially that no data is available regarding the role of VTd consolidation in the context of bortezomib-triple based VTd induction regimen followed by a single auto. At completion of therapy, the response rate (ORR, PR and better) was 89%, VGPR+CR rate 74%, CR rate 29%, relapse rate and median PFS was 53% and 26 months (median F-up 32 months) in the VTd arm of the phase 3 IFM2007-02 trial conducted for newly diagnosed MM (Moreau et al, Blood 2012). In this study, only a minority of patients had received a consolidation or maintenance. On the other hand, Cavo et al. (Blood 2012) reported 97.5%, 92%, 61%, 39% 3-year progression and 62% estimated 5-year PFS (F-up 43 months) respectively in the VTd arm. VTd was given as induction before and consolidation after double auto in this upfront GIMEMA phase 3 trial (Cavo et al, Lancet 2010). We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen). Method. This study has included a first group of 121 newly diagnosed MM from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto upfront, aged less than 65 and treated with VTd-auto-VTd regimen. The second cohort included MM treated with VTd-auto without consolidation from the IFM2007-02 trial (n=76). A third cohort comprised MM that received upfront a triplet Vd-based combination induction (VCd, VRd) -auto without consolidation (n = 40). Results. In the whole study, the median age was 56 years, the sex ratio was 1,49, 50% had ISS 2 and 3, 22% had adverse FISH [t(4;14); del17p] (similar in the 3 groups). Overall, the ORR was identical in the 3 cohorts at completion of therapy, 104 (86%), 72 (94%) and 32 (80%) for the cohort 1 to 3, respectively. Nevertheless, the CR rate was significantly greater in patients that received a consolidation (cohort 1), as compared to the cohorts 2 and 3 that did not receive any consolidation, 59 (53%) vs. 26 (34%) and 13 (32.5%), respectively (p=0.0001). Interestingly, the CR rates were identical at the end of the induction in the 3 cohorts, 13%, 15% and 22.5%, respectively. With a median follow-up of 25 months, the incidence rate of relapse was significantly greater in the cohort 2 and 3 versus 1, further demonstrating the importance of the consolidation, 25 (21%), 42 (55%) and 13 (32.5%) patients (p=0.0001), respectively; and 9 (8%), 6 (8%) and 8 (20%) had died in cohorts 1 to 3 (p=0.07). The median (95%CI) PFS was not reached in cohort 1, and was 32 (28;36) months and 30 (26;33) months in cohort 2 and 3, respectively. Importantly, 54.5%, 32% and 32% of patients were free of relapse at 32 months in the 3 cohorts, respectively. Similar data were obtained for TTP. The median (95%CI) OS was not significantly different in cohorts 1 to 3, although not reached for the first 2 cohorts and 38 (33;43) months for the 3rdcohort. The 3-year survival was 84%, 91% and 76%, respectively (p=ns). A longer follow up will certainly demonstrate greater survival end points benefit in favor for consolidation. The safety profile of the cohort that contained a consolidation was superimposable to that of the remaining 2 cohorts without consolidation. The incidence rate of hematological EIs of grade 3 and 4 was 4%, 6% and 8% in the 3 cohorts (p=ns), respectively. The incidence rate of neuropathy grade 1–2 and 3–4 was 5% and 2% in the cohort 1 with consolidation, but only 1% occurred during the consolidation. This data compares favorably to the 3% reported in the cohort 2 (Moreau et al. Blood 2012). We have also observed 9 (9%) thromboembolic events (TE), 8 of venous type and 1 arterial. None of them happened during the consolidation, and again, this incidence rate if superimposable to that reported in the IFM2007-02 vTd cohort. Conclusion. This study showed an impressive increase in CR rate in relation to the consolidation that translated into a lower relapse rate. This study also demonstrated that the VTd regimen, used both as induction and consolidation, in the context of a single auto upfront in MM, significantly contributed to improve clinical outcomes with an acceptable toxicity profile. VTd-auto-VTd compared very favorably to the other upfront protocols, and may become in the near future a standard of care in newly diagnosed patients with Myeloma. Disclosures: Leleu: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Onyx: Honoraria, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau. Off Label Use: Pomalidomide. Roussel:celgene: Honoraria; janssen: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

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Polatuzumab Vedotin Combined with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) for Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Updated Results of a Phase Ib/II Study

Blood ◽

10.1182/blood.v128.22.1853.1853 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1853-1853 ◽

Cited By ~ 5

Author(s):

Hervé Tilly ◽

Franck Morschhauser ◽

Nancy L Bartlett ◽

Jeff Sharman ◽

Corinne Haioun ◽

...

Keyword(s):

Febrile Neutropenia ◽

Board Of Directors ◽

Research Funding ◽

Motor Dysfunction ◽

The Other ◽

Phase 2 ◽

Advisory Committees ◽

Phase Ib ◽

E Coli ◽

Genetics Research

Abstract Introduction: Previously reported results from an ongoing study of polatuzumab vedotin (PoV), an antibody drug conjugate (ADC) containing the anti-mitotic MMAE targeting CD79b, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) demonstrated an acceptable safety profile in patients (pts) with previously untreated DLBCL. The dose escalation (esc) phase established a recommended phase 2 dose of PoV at 1.8 mg/kg. We report updated safety and efficacy results for this multicenter, open-label Phase Ib/II study of PoV combined with R-CHP in previously untreated DLBCL pts (ClinicalTrials.gov NCT01992653). Methods: In the esc phase of this study, pts aged 60-80 years, with newly diagnosed or relapsed/refractory B-cell NHL were given PoV intravenously 1.0, 1.4, or 1.8 mg/kg with R-CHP every 21 days for a total of 6 or 8 cycles. In the dose expansion (exp) phase, pts were restricted to those with previously untreated DLBCL and aged 18-80 years. Investigator assessments for anti-tumor activity by Cheson 2007 were performed following 4 cycles of study treatment (tx) and at the end of study tx (EOT). Patients: DLBCL patient characteristics as of February 5, 2016 are included in Table 1. The majority of the subjects were IPI 4-5. Results: Of the 36 safety evaluable pts, the most common adverse events (AEs) in > 20% of pts were fatigue (36%) and diarrhea (30%), nausea (31%), and neutropenia (25%). 44% had at least one Gr 3/4 AE including neutropenia (22%), febrile neutropenia (14%), hypertension (8%), thrombocytopenia (4%), leukopenia (4%), oral fungal infection (4%), dysphagia (4%), vomiting (4%), asthenia (4%), fatigue (4), decreased appetite (4%), hyponatremia (4%), malnutrition (4%), chylothorax (4%), back pain (4%), motor dysfunction (4%), and confusional state (4%). Serious AEs were reported in 33% of pts, with 17 different events. These included 4 episodes of febrile neutropenia, 2 of neutropenia, 2 of pneumonia, and 1 each of E. coli UTI, oral fungal infection, hyponatremia, malnutrition, chylothorax, pulmonary embolism, pyrexia, pathologic femur fracture, and worsening of rheumatoid arthritis. 33% of pts experienced peripheral neuropathy (PN). The reported terms included PN, paresthesia, muscular weakness, neuralgia, and motor dysfunction. All neurologic AEs attributed to PoV were Gr 1 except one PN that was Gr 2 and improved to Gr 1 after PoV dose reduction. There were 2 pts that discontinued study treatment due to AEs (one with a Gr 2 tremor who is still in CR, and the other with Gr 2 UTI who ultimately progressed) while 5 (14%) had PoV dose reductions (2 PN, 2 neutropenia, 1 weight decrease and asthenia). No Gr 5 AEs were reported among the exp cohort. At the time of this report, response assessments were available in 26 pts. All pts in the esc phase have completed study tx and 8 in exp cohort have completed study tx. Interim and EOT PET response is summarized in Table 2. Among the 2 pts that developed progressive disease in the exp phase, one pt had a new axillary lesion and subsequently died despite salvage tx; the other patient had a CR at interim evaluation, but stopped all tx after 5 cycles due to E. coli UTI and subsequently developed recurrent disease. Conclusions: Early results show that PoV plus R-CHP has an acceptable safety profile in pts with previously untreated DLBCL. Although the protocol-specified MTD was not formally reached, the recommended phase 2 dose of PoV was established at 1.8 mg/kg based on the overall safety and tolerability profile at that dose. The pts treated at the phase 2 dosing were strongly weighted in the high risk category by IPI and in that context, efficacy is promising and will be updated at the time of presentation. Disclosures Morschhauser: Janssen: Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Bartlett:Gilead: Consultancy. Sharman:Gilead: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding. Haioun: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; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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. Kolibaba:Celgene: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Cell Therapeutics: Research Funding; GSK: Research Funding; Novartis: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Research Funding; Pharmcyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding. Chen:Seattle Genetics: Consultancy. Jones:Genentech, Inc.: Employment. Penuel:Genentech/Roche: Employment. Lee:Genentech, Inc.: Employment. Salles:Gilead: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mundipharma: Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding.

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SARS-CoV-2 serological testing using electrochemiluminescence reveals a rapid onset of seroconversion in severe COVID-19 patients

10.1101/2020.06.28.20141838 ◽

2020 ◽

Cited By ~ 1

Author(s):

A Munitz ◽

L Edry-Botzer ◽

M Itan ◽

R Tur-Kaspa ◽

D Dicker ◽

...

Keyword(s):

Antibody Response ◽

Host Response ◽

Nuclear Protein ◽

Humoral Response ◽

Rapid Onset ◽

Human Antibody ◽

Igg Antibodies ◽

Igm Antibodies ◽

Viral Antigens ◽

Iga Antibodies

AbstractDespite ongoing efforts to characterize the host response toward SARS-CoV-2, a major gap in our knowledge still exists regarding the magnitude and duration of the humoral response. We report the development of a rapid, highly specific and sensitive electrochemiluminescent assay for detecting IgM, IgA, and IgG antibodies toward two distinct SARS-CoV-2 antigens namely, the receptor binding domain (RBD) and the nuclear protein (NP). Whereas IgM antibodies toward RBD were detected at early stages of the disease, IgM antibodies against NP did not develop. Analysis of the antibody response in mild versus moderate/severe patients revealed a rapid onset of IgG and IgA antibodies, specifically in moderate/severe patients. Finally, we observed a marked reduction in IgM/IgA antibodies and to lesser extent, IgG, over time. We provide a comprehensive analysis of the human antibody response, and has major implications on our understanding and monitoring of SARS-CoV-2 infections, as well as finding effective vaccines.One Sentence SummaryUsing a newly developed assay to detect anti-SARS-Cov-2 IgM, IgG and IgA antibodies we reveal a rapid onset of IgG and IgA antibodies towards distinct viral antigens, specifically in moderate/severe COVID-19 patients,

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Shift to Anti-Fibrinolysis on the Administration of L-Asparaginase (L-Asp) during Induction Therapy for Pediatric Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v128.22.5156.5156 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5156-5156

Author(s):

Takashi Ishihara ◽

Keiji Nogami ◽

Tomoko Matsumoto ◽

Yasufumi Takeshita ◽

Akitaka Nomura ◽

...

Keyword(s):

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

The Other ◽

Induction Phase ◽

Advisory Committees ◽

Chugai Pharmaceutical ◽

Hepatic Synthesis ◽

Coagulation And Fibrinolysis

Abstract Introduction: Thromboembolism is a serious complication associated with ALL. The use of central venous catheter and treatment protocols involving corticosteroids and L-Asp is assumed as important thrombogenic factors at the induction phase. In particular, L-Asp has profound effects on hepatic synthesis of pro-, anti-coagulant and fibrinolytic factors. In this study, we hypothesized that change of coagulation and fibrinolytic function contributes to hyper-coagulation condition during the induction phase with L-Asp. In order to clarify this, we evaluated the dynamic change in coagulation and fibrinolysis by simultaneous measurement of both thrombin and plasmin generation assay (T/P-GA). Patients: Twenty-seven pediatric patients with newly diagnosed ALL were enrolled from Aug. 2014 to Oct. 2015 at 3 hospitals in Japan. All cases had no thrombotic predisposition. Eighteen cases (66.7%) (BCP-ALL; n=17, T-ALL; n=1) received Berlin-Frankfürt-Münster (BFM)-95 oriented induction therapy included prednisolone (and dexamethasone for T-ALL), vincristine, daunorubicin, and E.coli L-Asp (a total of 8 doses of 5,000 U/m2). The others (BCP-ALL; n=8, T-ALL; n=1) received Japan Association of childhood Leukemia Study (JACLS) ALL02 oriented induction therapy included prednisolone, dexamethasone, vincristine, daunorubicin, cyclophosphamide and E.coli L-Asp (a total of 6 doses of 6,000 U/m2). Methods: The individual hemostatic parameters were monitored by fibrinogen (Fbg), FDP, AT, TAT and PIC. Additionally, the global functions of coagulation and fibrinolysis were evaluated using T/P-GA established by our group [Matsumoto et al. TH 2013]. This assay was initiated by the addition of a mixture of optimized concentrations of tissue factor and tissue-type plasminogen activator. Thrombin and plasmin generation were monitored simultaneously using individual fluorescent substrates in separate microtiter wells. Standard curves were set using purified alpha-thrombin and plasmin. Patients' plasmas were collected at the following points, T0; pre-phase of L-Asp, T1; intermittent phase of L-Asp, T2; post-phase of L-Asp, and T3; post-induction phase. Endogenous potentials of thrombin generation (T-EP) for coagulant activity and plasmin peak levels (P-Peak) of plasmin generation for fibrinolytic activity were selected as parameters for evaluation in this study. A ratio of T-EP and P-Peak of patients' plasmas to those of control normal plasma were calculated. Results: All cases obtained first remission, and none of them developed coagulopathy. Six cases received FFP transfusion for low Fbg level, whilst 21 cases received AT supplement for low AT level. Fbg showed a median of 170, 99.0, 99.0 and 328 mg/dl at T0, T1, T2 and T3, respectively, whilst the other individual parameters showed relatively unchanged. T-EP revealed a median of 1,126, 1,059, 1,175, 1,343 and 1,132 nM, whilst P-Peak showed a median of 6.67, 4.54, 4.12, 5.50 and 5.77 nM for T0, T1, T2, T3 and control plasma, respectively, indicating the elevated T-EP ratios and reduced P-Peak ratios (Fig. 1). The most significant difference in both ratios demonstrated a median of 1.5-fold (range, 1.0 to 2.6) at T2, consistent with the lowest Fbg levels. The FFP transfusion group showed significantly lower T-EP ratios than non-transfusion group at T1 (a median of 0.87 vs. 1.01, P=0.041) and T2 (a median of 0.96 vs. 1.07, P=0.009), whilst P-Peak ratios revealed no significant changes. The AT supplement group showed no significant changes of both ratios. Conclusion: The results from decreased Fbg and unchanged FDP might reveal the hepatic synthesis disorder of Fbg, whilst the results from T/P-GA showed that their hemostatic dynamics appear likely to be thrombotic tendency, since their coagulation state was hyper-coagulation and anti-fibrinolysis at post-phase of L-Asp. These results suggest that the impaired balance of coagulation and fibrinolysis due to L-Asp therapy might play an important role of a thrombotic complication at induction phase. On the other hand both conventional FFP transfusion and AT supplement therapy might not dramatically repair this unbalance state. A further research would be required to examine the role of coagulant and fibrinolytic function using T/P-GA in the pathogenesis of coagulopathy associated with L-Asp therapy in order to establish the optimal supportive therapy. Figure 1 The Changes of Both T-EP and P-Peak Ratios Figure 1. The Changes of Both T-EP and P-Peak Ratios Disclosures Nogami: F. Hoffmann-La Roche Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sysmex Corporation: Patents & Royalties, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Matsumoto:Sysmex Corporation: Patents & Royalties, Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties, Research Funding. Shima:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sysmex Corporation: Patents & Royalties, Research Funding.

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Potential immunological markers for diagnosis and therapeutic assessment of toxocariasis

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652011000200001 ◽

2011 ◽

Vol 53 (2) ◽

pp. 61-65 ◽

Cited By ~ 15

Author(s):

Guita Rubinsky-Elefant ◽

Sumie Hoshino-Shimizu ◽

Cristina Miuki Abe Jacob ◽

Maria Carmen Arroyo Sanchez ◽

Antonio Walter Ferreira

Keyword(s):

Molecular Weight ◽

Toxocara Canis ◽

The Other ◽

Low Molecular Weight ◽

Therapeutic Assessment ◽

Igg Antibodies ◽

Follow Up Study ◽

Immunological Markers ◽

Iga Antibodies

In human toxocariasis, there are few approaches using immunological markers for diagnosis and therapeutic assessment. An immunoblot (IB) assay using excretory-secretory Toxocara canis antigen was standardized for monitoring IgG, IgE and IgA antibodies in 27 children with toxocariasis (23 visceral, three mixed visceral and ocular, and one ocular form) for 22-116 months after chemotherapy. IB sensitivity was 100% for IgG antibodies to bands of molecular weight 29-38, 48-54, 95-116, 121-162, >205 kDa, 80.8% for IgE to 29-38, 48-54, 95-121, > 205 kDa, and 65.4% for IgA to 29-38, 48-54, 81-93 kDa. Candidates for diagnostic markers should be IgG antibodies to bands of low molecular weight (29-38 and 48-54 kDa). One group of patients presented the same antibody reactivity to all bands throughout the follow-up study; in the other group, antibodies decayed partially or completely to some or all bands, but these changes were not correlated with time after chemotherapy. Candidates for monitoring patients after chemotherapy may be IgG antibodies to > 205 kDa fractions, IgA to 29-38, 48-54, 81-93 kDa and IgE to 95-121 kDa. Further identification of antigen epitopes related to these markers will allow the development of sensitive and specific immunoassays for the diagnosis and therapeutic assessment of toxocariasis.

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The Impact of Allogeneic Hematopoietic Cell Transplantation (alloHCT) on the Outcome of Poor-Risk Non-Hodgkin Lymphoma (NHL): A Retrospective Intent-to-Transplant (ITT) Analysis

Blood ◽

10.1182/blood-2019-128352 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3328-3328 ◽

Cited By ~ 1

Author(s):

Lorenz Selberg ◽

Peter Stadtherr ◽

Sascha Dietrich ◽

Thomas Luft ◽

Andrea Bondong ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

The Other ◽

Advisory Committees ◽

Unrelated Donors ◽

The Impact

Although alloHCT is an accepted salvage treatment in defined settings of poor-risk NHL, its potential benefit in these indications remains controversial because virtually all published studies are uncontrolled and restricted to patients who were actually able to undergo transplantation. Here, we aimed at assessing the impact of alloHCT by measuring its outcome from the time of donor search indication rather than from the time of transplant, thereby taking into account those patients who fail to proceed to allografting for any reason. Study design and patients : In a single centre retrospective analysis, course and outcome of all patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PTCL) who were considered as having an alloHCT indication according to accepted guidelines between 2004 and 2018 were recorded. Primary endpoint was overall survival (OS) from start of donor search. A key secondary endpoint was comparison of OS from the 3-month landmark by donor availability. Accepted donors were matched related donors (MRD), 10/10 matched unrelated donors (MUD), 9/10 compatible unrelated donors (MMUD), and mismatched related donors (MMRD), with haplo donors being used at our institution only since 2014. Results : Altogether a donor search was initiated in 187 patients (DLBCL 32%, FL 17%, MCL 23%, PTCL 28%). Median age was 54 (19-69) years with 74% being male. Within a median time from diagnosis to search initiation of 1.1 (0.1-19) years, a median of 4 (1-9) treatment lines had been administered, including an autoHCT in 50%. 69% of the patients had active disease at the time of search initiation. Only 2 patients underwent donor search in 1st remission (for Richter transformation and hepatosplenic T cell lymphoma, respectively). With a median follow-up of 6.2 (0.6-15.9) years, OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 25%, 44%, 52%, and 50%, respectively (Fig 1). 171 patients (91%) were alive at the 3-month landmark. For these, an MRD (20%), MUD (44%), MMUD (25%), or MMRD (7%) could be identified in 96% of the cases. AlloHCT was performed in 72% of all 187 patients, and in 79% of the patients alive at the 3-month landmark, with a significantly lower rate in DLBCL (69%) compared to the other entities. In patients who were actually transplanted, 5-year OS from landmark for DLBCL, FL, MCL and PTCL was 32%, 63%, 62%, and 62%, respectively, whereas only 5 of the 36 patients (14%) alive at the 3-month landmark not undergoing alloHCT for any reason survived long term. Due to the low rate of unsuccessful searches, donor vs no-donor landmark survival analyses were not possible. Conclusions: Despite donor search now being successful in virtually all cases, 20-30% of those patients intended for alloHCT for NHL will never proceed to transplant. However, long-term OS by ITT does not seem substantially worse than alloHCT outcome observed in registry studies restricted to patients actually transplanted, with DLBCL appearing inferior to the other 3 entities. Patients surviving the 3-month landmark but not undergoing alloHCT for any reason have a poor outlook. These results may serve as benchmark for novel therapeutic options entering the NHL treatment landscape. Disclosures Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.

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