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Papers by Ulrich Pirron

The New England Journal of Medicine, Jan 29, 2015

Background Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical bene... more Background Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. Methods We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. Results

Journal of Clinical Oncology, May 20, 2012

TPS6643^ Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell prolif... more TPS6643^ Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation, significant morbidity, shortened life span and possible evolution to myelofibrosis and acute myeloid leukemia. Splenomegaly, debilitating constitutional symptoms, and frequent phlebotomy requirements are common in advanced disease. HU, an established first-line agent for cytoreduction, can be associated with cytopenias, aphthous and leg ulcers, and other side effects. Control of hematocrit is not always achieved with HU, and many patients are either intolerant of or become resistant to HU. JAK2 plays a key role in the pathophysiology of PV; nearly 100% of patients harbor either the JAK2V617F or JAK2 exon 12 mutations. In a phase 2 study in HU-resistant or -intolerant PV patients, ruxolitinib, a potent and selective inhibitor of JAK1/JAK2, was well tolerated and achieved rapid and durable clinical responses, including phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) and platelet (PLT) counts and disease-related symptoms. Methods: RESPONSE is a randomized (1:1), open-label, global phase 3 study (NCT01243944) designed to compare the safety and efficacy of ruxolitinib with best available therapy (BAT) in adult patients with PV who are resistant to or intolerant of HU (modified European Leukemia Net criteria) and require phlebotomy because of inadequate hematocrit control. Inclusion criteria have been amended to include patients who exhibit palpable splenomegaly with an MRI-confirmed volume of ≥ 450 cm3 (ie, approximately 2.5 x median normal volume; instead of ≥ 5 cm by palpation) and PLT > 100 x109/L; the requirement for either elevated WBC (> 15 x109/L) or PLT count (> 600 x109/L) was removed. The primary efficacy endpoint is the achievement of both phlebotomy independence and a ≥ 35% reduction in spleen volume after 32 weeks of treatment. Patients will be treated for 80 weeks to assess safety and durability of response. Patients randomized to BAT may be eligible to cross over to receive ruxolitinib after week 32. Enrollment is planned for 145 investigational sites (134 currently open), with a target of 200 patients.

Journal of Clinical Oncology, 2011

TPS203 Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell prolifer... more TPS203 Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation causing increased red cell mass, blood hyperviscosity, significant morbidity, shortened lifespan and possible evolution to acute myeloid leukemia. Splenomegaly, debilitating symptoms, leukocytosis, and thrombocytosis are common in advanced disease. HU, an established first-line agent for cytoreduction, can be associated with cytopenias, aphthous and leg ulcers and other side effects. Control of hematocrit is not always achieved with HU and many patients are either intolerant of or become resistant to HU; second line therapeutic options are limited with no drugs approved in this setting. Janus kinase (JAK) 2 plays a key role in the pathophysiology of PV; nearly 100% of patients harbor either the JAK2V617F gain-of-function mutation or a JAK2 exon 12 mutation. In a phase II study in HU-resistant or -intolerant PV patients, INC424, a potent and selective inhibitor of JAK1 and JAK2, was well tolerated and achieved rapid and durable clinical responses including phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell counts, platelet counts, and disease-related symptoms (Verstovsek S, et al. at 52nd ASH Annual Meeting; December 4-7, 2010. #313). METHODS RESPONSE, a global, open-label phase III trial ( NCT01243944 ), is designed to compare the efficacy and safety of INC424 to Best Available Therapy (BAT) in adult patients with PV who are resistant to or intolerant of HU (by ELN criteria), require phlebotomy due to inadequate hematocrit control, and exhibit palpable splenomegaly ≥ 5 cm below the costal margin with either leukocytosis > 15 x 109/L and/or thrombocytosis > 600 x 109/L. The primary efficacy endpoint, assessed after 32 weeks of treatment, is based on achieving both phlebotomy independence and a ≥ 35% reduction in spleen volume as measured by imaging. All patients will be treated for 80 weeks to assess safety and response durability. Patients randomized to BAT may be eligible to cross over to receive INC424 after week 32. Enrollment is now open globally with a target of 300 patients to be randomized 1:1 to INC424 or BAT.

Blood, 2013

Background Polycythemia vera (PV) is the most common of the myeloproliferative neoplasms and is c... more Background Polycythemia vera (PV) is the most common of the myeloproliferative neoplasms and is characterized by elevated hematocrit requiring phlebotomy, splenomegaly, a variety of symptoms and increased thrombotic risk. Ruxolitinib, a JAK1/JAK2 inhibitor, was well tolerated and achieved rapid and durable clinical responses in a phase 2 study of patients (pts) with PV who were resistant to or intolerant of hydroxyurea (HU). Pts experienced phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) counts, platelet (PLT) counts, and disease-related symptoms. Here, we describe the baseline (BL) characteristics and symptom burden of pts in a phase 3 study of ruxolitinib in pts with PV who are resistant to or intolerant of HU. Methods RESPONSE is a randomized (1:1), open-label, phase 3 study (NCT01243944) comparing the efficacy and safety of ruxolitinib with best available therapy (BAT) in pts with PV who are resistant to or intolerant of HU (modifi...

Journal of Clinical Oncology, 2014

7026 Background: PV is a myeloproliferative neoplasm characterized by increased erythrocytosis, d... more 7026 Background: PV is a myeloproliferative neoplasm characterized by increased erythrocytosis, disease-related symptom burden (eg, pruritus), and risk of vascular events (thrombosis and/or hemorrhage). Maintaining hematocrit (HCT) control is a key therapeutic goal. RESPONSE is the first phase 3 study to evaluate a JAK inhibitor (RUX) in treating PV. Methods: Phlebotomy (PBT)-dependent patients (pts) with splenomegaly (> 450 cm3) and HU resistance/intolerance were randomized 1:1 to RUX 10 mg bid or best available therapy (BAT). The primary endpoint was the proportion of pts who achieved both HCT control without PBT from wk 8 to 32 (with ≤ 1 PBT from wk 0 to 8) and a ≥ 35% reduction in spleen volume (SV) from baseline (BL) by MRI at wk 32. Key secondary endpoints included the proportion of pts who maintained the primary response at wk 48 and the proportion of pts who achieved complete hematologic response (CHR) at wk 32. Other endpoints were duration of response, symptom improvement by MPN-SAF diary, and s...

New Trends in Allergy III, 1991

The human low affinity receptor for IgE (Fc e RII), also known as the leukocyte differentiation a... more The human low affinity receptor for IgE (Fc e RII), also known as the leukocyte differentiation antigen CD23 [1], is a type II integral membrane glycoprotein of 45 kDa which is constitutively expressed on resting, β + /δ + B lymphocytes and is lost after isotype switch. Fc e RII/CD23 is also found on follicular dendritic cells, eosinophils, platelets, alveolar macrophages and can be induced on monocytes and Langerhans cells by IL-4. Two isoforms (CD23a and CD23b) differing in the N-terminal cytoplasmic part have been identified by molecular cloning. Soluble IgE binding fragments (sCD23) are released from CD23+ cells by proteolytic cleavage. Pleiotropic activities have been proposed for the Fc e RII/CD23 and its soluble derivatives. Although specific functions in IgE regulation have been described, the biological role of the CD23 molecule remains elusive. Two recently recognized characteristics of the Fc e RII/CD23 will be presented: 1) specific induction of CD23 on T-cells by allergens and 2) focusing of antigen via CD23.

European Journal of Immunology, 1990

IgE-dependent antigen focusing by human B lymphocytes is mediated by the low-affinity receptor fo... more IgE-dependent antigen focusing by human B lymphocytes is mediated by the low-affinity receptor for IgE* In this study we investigated the role of the low-affinity receptor for IgE (FcERII, CD23) on Epstein-Barr virus (EBV)-transformed human B cells in the uptake and presentation to T cells of antigen after complexing with IgE. Cloned EBV-transformed B cells were incubated for 5 h with (4-hydroxy-3-iodo-54trophenyl)acetyl (NIP)-haptenized tetanus toxoid (NIP-TT) or NIP-TT complexed with a chimeric human IgE/mouse anti-NIP monoclonal antibody (IgE x NIP-TT) and then contacted for 2 min with autologous cloned IT-specific T cells. Intracellular Ca2+ mobilization in T cells was determined as an early indicator of T cell activation. The antigen-presenting capacity of B cells was significantly increased by complexing the antigen with IgE. This effect could be selectively reversed in a dose-dependent manner by blocking the FceRII with an anti-CD23 monoclonal antibody. The IgE-mediated increased capacity for presenting antigen became particularly evident when B cells were incubated with NIP-TTor IgE x NIP-'IT for only 1 h at 4 "C, washed and then cultivated for 6 h at 37 "C allowing uptake and processing of the antigen.These results indicate a new role of the FceRII/CD23 molecules in the uptake of antigen by APC which might be of importance in the maintenance of an ongoing immune response against allergens.

The New England journal of medicine, Jan 29, 2015

Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in pati... more Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two gr...

The Journal of Heart and Lung Transplantation, 2004

Purpose: The potential utility of therapeutic drug monitoring (TDM) in optimizing the use of the ... more Purpose: The potential utility of therapeutic drug monitoring (TDM) in optimizing the use of the proliferation signal inhibitor everolimus was examined in a large double-blind trial of 213 stable lung transplant recipients comparing everolimus (3 mg/day) vs azathioprine (AZA, 1-3 mg/kg/day), in combination with Neoral (CsA microemulsion) and corticosteroids. 12-month efficacy results showed that everolimus was statistically significantly superior over AZA. The purpose of this investigation was to assess the future role of everolimus TDM in this population. Methods: Efficacy failure (FEV 1 decline Ͼ15%) and key safety events were descriptively compared for different average everolimus trough levels. Cox proportional hazard regression was used to assess the effect of everolimus exposure on efficacy. Results: Everolimus trough levels averaged 10 ng/mL initially, 9 ng/mL at month 1, and stabilized between 6 and 7 ng/mL for the remainder to month 12. Cox regression did not show a statistically significant effect of everolimus exposure on efficacy failure within the observed exposure range (p ϭ 0.162), with 13% for Cmin Ͻ5.8 ng/mL, 14% for 5.8-7.3 ng/mL, 14% for 7.4-9.9 ng/mL, and 23% for Ͼ9.9 ng/mL. Since only few patients had low everolimus trough levels, no minimal effective level could be identified. The incidence of hypercholesterolemia, hypertriglyceridemia and thrombocytopenia rose with increasing everolimus trough levels, whereas the incidence of high serum creatinine levels did not appear to be influenced by everolimus exposure. Median-Effect Analysis on Safety Parameters Response Everolimus C min (ng/mL)

The Journal of Heart and Lung Transplantation, 2003

isolated RV dysfunction and severe hemodynamic compromise at our institution. Overall survival, d... more isolated RV dysfunction and severe hemodynamic compromise at our institution. Overall survival, duration of mechanical support, post-RVAD hemodynamics, and RV function measured by echocardiography were analyzed. Results: Post-cardiotomy RV failure developed in patients after coronary artery bypass surgery alone or in combination with valve surgery (12), valvular surgery alone (5), aortic surgery (6), heart or lung transplantation (3), and pulmonary endarterectomy (4). Mean age was 58 Ϯ15 years and 17 (57%) were female. Initial operation was emergent in 22 (73%) cases. Centrifugal pumps were used in 29 and Abiomed pump in one patient. Overall, 17 (57%) patients died on the assist device: 3 from sepsis, 2 from stroke, and 12 from an inability to wean from the RV device. RVAD was successfully weaned in 13 (43%) patients with a median duration of 5 days (range 2-8). Ten survived to hospital discharge. At post-RVAD removal, mean pulmonary artery pressure was 25 Ϯ6 mmHg, cardiac output was 4 Ϯ2L, and central venous pressure was 16Ϯ3 mmHg. Echocardiogram after RVAD removal showed normal RV function in 2 patients and 11 demonstrated improvement of RV hypokinesis. Our most recent experience, from 1997 to present, demonstrated an improved postoperative survival of 44% compared to 18% from the five preceding years. Conclusion: Post-cardiotomy RV failure patients requiring mechanical support continue to have high mortality. Survival has improved over the last several years due to advances in pharmacological treatment and RVAD support. For patients successfully weaned from the RVAD, residual RV dysfunction is compatible with survival. More liberal use of RV mechanical support may be indicated for patients with acute RV failure.

The Journal of Heart and Lung Transplantation, 2004

devices with prior immunotherapy or patients with panel reactive antibodies of at least 25%. Endp... more devices with prior immunotherapy or patients with panel reactive antibodies of at least 25%. Endpoints: Primary: Incidence of biopsied and treated acute rejection, graft loss or death of EC-MPS compared with MMF during the first six months of treatment. Secondary: Acute rejection, biopsyproven rejection, treated acute rejection (with/without hemodynamic compromise), graft survival, patient survival, gastrointestinal safety and tolerability, frequency of adverse events and infections, laboratory data, vital signs. Results: Available results of 6-month data of eligible patients will be presented at the ISHLT Scientific Sessions.

The Journal of Heart and Lung Transplantation, 2006

Background: In this study we evaluated exposure, safety and efficacy data from an international t... more Background: In this study we evaluated exposure, safety and efficacy data from an international trial of everolimus. We sought to identify a tolerated and efficacious range for blood levels of this agent in maintenance lung transplant recipients. Methods: In a randomized, double-blind, multicenter trial, 213 maintenance lung transplant recipients received either everolimus 1.5 mg twice daily (n ϭ 101) or azathioprine 1 to 3 mg/kg/day (n ϭ 112) with cyclosporine and corticosteroids. At 15 visits over the first 2 years of the trial, we obtained 826 everolimus trough (C 0) blood samples. We used median-effect analysis to assess relationships between everolimus C 0 vs efficacy and safety responses. Results: Everolimus administration began at 1.5 mg twice daily and was progressively lowered over the first 2 months to an average of 1.2 Ϯ 0.4 mg twice daily, which was maintained thereafter. This dose yielded median C 0 levels of 6.6 ng/ml (10th to 90th percentiles: 2.8 to 11.8 ng/ml). Over this range of everolimus C 0 , freedom from a decline in pulmonary function with bronchiolitis obliterans syndrome and freedom from biopsy-proven acute rejection were both Ն88%. The incidence of increased cholesterol (Ͼ6.5 mmol/liter), increased triglycerides (Ͼ2.9 mmol/liter) and transiently decreased platelet count (Ͻ100 ϫ 10 9 /liter) rose significantly with increasing C 0. Infections and drug-related adverse events were not significantly related to exposure. Conclusions: A tolerated and efficacious concentration range for everolimus in maintenance lung transplantation appears to be 3 to 12 ng/ml when used in conjunction with cyclosporine and corticosteroids. This range should be prospectively assessed with possible refinement as more clinical experience is gained.

American Journal of Transplantation, 2006

Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce th... more Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double-blind clinical trial, 213 BOS-free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1-3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV 1 >15% [∆FEV 1 >15%], graft loss, death or loss to follow-up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of ∆FEV 1 >15%, ∆FEV 1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after lung transplantation.

The New England Journal of Medicine, Jan 29, 2015

Background Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical bene... more Background Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. Methods We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. Results

Journal of Clinical Oncology, May 20, 2012

TPS6643^ Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell prolif... more TPS6643^ Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation, significant morbidity, shortened life span and possible evolution to myelofibrosis and acute myeloid leukemia. Splenomegaly, debilitating constitutional symptoms, and frequent phlebotomy requirements are common in advanced disease. HU, an established first-line agent for cytoreduction, can be associated with cytopenias, aphthous and leg ulcers, and other side effects. Control of hematocrit is not always achieved with HU, and many patients are either intolerant of or become resistant to HU. JAK2 plays a key role in the pathophysiology of PV; nearly 100% of patients harbor either the JAK2V617F or JAK2 exon 12 mutations. In a phase 2 study in HU-resistant or -intolerant PV patients, ruxolitinib, a potent and selective inhibitor of JAK1/JAK2, was well tolerated and achieved rapid and durable clinical responses, including phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) and platelet (PLT) counts and disease-related symptoms. Methods: RESPONSE is a randomized (1:1), open-label, global phase 3 study (NCT01243944) designed to compare the safety and efficacy of ruxolitinib with best available therapy (BAT) in adult patients with PV who are resistant to or intolerant of HU (modified European Leukemia Net criteria) and require phlebotomy because of inadequate hematocrit control. Inclusion criteria have been amended to include patients who exhibit palpable splenomegaly with an MRI-confirmed volume of ≥ 450 cm3 (ie, approximately 2.5 x median normal volume; instead of ≥ 5 cm by palpation) and PLT &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 100 x109/L; the requirement for either elevated WBC (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 15 x109/L) or PLT count (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 600 x109/L) was removed. The primary efficacy endpoint is the achievement of both phlebotomy independence and a ≥ 35% reduction in spleen volume after 32 weeks of treatment. Patients will be treated for 80 weeks to assess safety and durability of response. Patients randomized to BAT may be eligible to cross over to receive ruxolitinib after week 32. Enrollment is planned for 145 investigational sites (134 currently open), with a target of 200 patients.

Journal of Clinical Oncology, 2011

TPS203 Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell prolifer... more TPS203 Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation causing increased red cell mass, blood hyperviscosity, significant morbidity, shortened lifespan and possible evolution to acute myeloid leukemia. Splenomegaly, debilitating symptoms, leukocytosis, and thrombocytosis are common in advanced disease. HU, an established first-line agent for cytoreduction, can be associated with cytopenias, aphthous and leg ulcers and other side effects. Control of hematocrit is not always achieved with HU and many patients are either intolerant of or become resistant to HU; second line therapeutic options are limited with no drugs approved in this setting. Janus kinase (JAK) 2 plays a key role in the pathophysiology of PV; nearly 100% of patients harbor either the JAK2V617F gain-of-function mutation or a JAK2 exon 12 mutation. In a phase II study in HU-resistant or -intolerant PV patients, INC424, a potent and selective inhibitor of JAK1 and JAK2, was well tolerated and achieved rapid and durable clinical responses including phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell counts, platelet counts, and disease-related symptoms (Verstovsek S, et al. at 52nd ASH Annual Meeting; December 4-7, 2010. #313). METHODS RESPONSE, a global, open-label phase III trial ( NCT01243944 ), is designed to compare the efficacy and safety of INC424 to Best Available Therapy (BAT) in adult patients with PV who are resistant to or intolerant of HU (by ELN criteria), require phlebotomy due to inadequate hematocrit control, and exhibit palpable splenomegaly ≥ 5 cm below the costal margin with either leukocytosis > 15 x 109/L and/or thrombocytosis > 600 x 109/L. The primary efficacy endpoint, assessed after 32 weeks of treatment, is based on achieving both phlebotomy independence and a ≥ 35% reduction in spleen volume as measured by imaging. All patients will be treated for 80 weeks to assess safety and response durability. Patients randomized to BAT may be eligible to cross over to receive INC424 after week 32. Enrollment is now open globally with a target of 300 patients to be randomized 1:1 to INC424 or BAT.

Blood, 2013

Background Polycythemia vera (PV) is the most common of the myeloproliferative neoplasms and is c... more Background Polycythemia vera (PV) is the most common of the myeloproliferative neoplasms and is characterized by elevated hematocrit requiring phlebotomy, splenomegaly, a variety of symptoms and increased thrombotic risk. Ruxolitinib, a JAK1/JAK2 inhibitor, was well tolerated and achieved rapid and durable clinical responses in a phase 2 study of patients (pts) with PV who were resistant to or intolerant of hydroxyurea (HU). Pts experienced phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) counts, platelet (PLT) counts, and disease-related symptoms. Here, we describe the baseline (BL) characteristics and symptom burden of pts in a phase 3 study of ruxolitinib in pts with PV who are resistant to or intolerant of HU. Methods RESPONSE is a randomized (1:1), open-label, phase 3 study (NCT01243944) comparing the efficacy and safety of ruxolitinib with best available therapy (BAT) in pts with PV who are resistant to or intolerant of HU (modifi...

Journal of Clinical Oncology, 2014

7026 Background: PV is a myeloproliferative neoplasm characterized by increased erythrocytosis, d... more 7026 Background: PV is a myeloproliferative neoplasm characterized by increased erythrocytosis, disease-related symptom burden (eg, pruritus), and risk of vascular events (thrombosis and/or hemorrhage). Maintaining hematocrit (HCT) control is a key therapeutic goal. RESPONSE is the first phase 3 study to evaluate a JAK inhibitor (RUX) in treating PV. Methods: Phlebotomy (PBT)-dependent patients (pts) with splenomegaly (> 450 cm3) and HU resistance/intolerance were randomized 1:1 to RUX 10 mg bid or best available therapy (BAT). The primary endpoint was the proportion of pts who achieved both HCT control without PBT from wk 8 to 32 (with ≤ 1 PBT from wk 0 to 8) and a ≥ 35% reduction in spleen volume (SV) from baseline (BL) by MRI at wk 32. Key secondary endpoints included the proportion of pts who maintained the primary response at wk 48 and the proportion of pts who achieved complete hematologic response (CHR) at wk 32. Other endpoints were duration of response, symptom improvement by MPN-SAF diary, and s...

New Trends in Allergy III, 1991

The human low affinity receptor for IgE (Fc e RII), also known as the leukocyte differentiation a... more The human low affinity receptor for IgE (Fc e RII), also known as the leukocyte differentiation antigen CD23 [1], is a type II integral membrane glycoprotein of 45 kDa which is constitutively expressed on resting, β + /δ + B lymphocytes and is lost after isotype switch. Fc e RII/CD23 is also found on follicular dendritic cells, eosinophils, platelets, alveolar macrophages and can be induced on monocytes and Langerhans cells by IL-4. Two isoforms (CD23a and CD23b) differing in the N-terminal cytoplasmic part have been identified by molecular cloning. Soluble IgE binding fragments (sCD23) are released from CD23+ cells by proteolytic cleavage. Pleiotropic activities have been proposed for the Fc e RII/CD23 and its soluble derivatives. Although specific functions in IgE regulation have been described, the biological role of the CD23 molecule remains elusive. Two recently recognized characteristics of the Fc e RII/CD23 will be presented: 1) specific induction of CD23 on T-cells by allergens and 2) focusing of antigen via CD23.

European Journal of Immunology, 1990

IgE-dependent antigen focusing by human B lymphocytes is mediated by the low-affinity receptor fo... more IgE-dependent antigen focusing by human B lymphocytes is mediated by the low-affinity receptor for IgE* In this study we investigated the role of the low-affinity receptor for IgE (FcERII, CD23) on Epstein-Barr virus (EBV)-transformed human B cells in the uptake and presentation to T cells of antigen after complexing with IgE. Cloned EBV-transformed B cells were incubated for 5 h with (4-hydroxy-3-iodo-54trophenyl)acetyl (NIP)-haptenized tetanus toxoid (NIP-TT) or NIP-TT complexed with a chimeric human IgE/mouse anti-NIP monoclonal antibody (IgE x NIP-TT) and then contacted for 2 min with autologous cloned IT-specific T cells. Intracellular Ca2+ mobilization in T cells was determined as an early indicator of T cell activation. The antigen-presenting capacity of B cells was significantly increased by complexing the antigen with IgE. This effect could be selectively reversed in a dose-dependent manner by blocking the FceRII with an anti-CD23 monoclonal antibody. The IgE-mediated increased capacity for presenting antigen became particularly evident when B cells were incubated with NIP-TTor IgE x NIP-'IT for only 1 h at 4 "C, washed and then cultivated for 6 h at 37 "C allowing uptake and processing of the antigen.These results indicate a new role of the FceRII/CD23 molecules in the uptake of antigen by APC which might be of importance in the maintenance of an ongoing immune response against allergens.

The New England journal of medicine, Jan 29, 2015

Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in pati... more Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two gr...

The Journal of Heart and Lung Transplantation, 2004

Purpose: The potential utility of therapeutic drug monitoring (TDM) in optimizing the use of the ... more Purpose: The potential utility of therapeutic drug monitoring (TDM) in optimizing the use of the proliferation signal inhibitor everolimus was examined in a large double-blind trial of 213 stable lung transplant recipients comparing everolimus (3 mg/day) vs azathioprine (AZA, 1-3 mg/kg/day), in combination with Neoral (CsA microemulsion) and corticosteroids. 12-month efficacy results showed that everolimus was statistically significantly superior over AZA. The purpose of this investigation was to assess the future role of everolimus TDM in this population. Methods: Efficacy failure (FEV 1 decline Ͼ15%) and key safety events were descriptively compared for different average everolimus trough levels. Cox proportional hazard regression was used to assess the effect of everolimus exposure on efficacy. Results: Everolimus trough levels averaged 10 ng/mL initially, 9 ng/mL at month 1, and stabilized between 6 and 7 ng/mL for the remainder to month 12. Cox regression did not show a statistically significant effect of everolimus exposure on efficacy failure within the observed exposure range (p ϭ 0.162), with 13% for Cmin Ͻ5.8 ng/mL, 14% for 5.8-7.3 ng/mL, 14% for 7.4-9.9 ng/mL, and 23% for Ͼ9.9 ng/mL. Since only few patients had low everolimus trough levels, no minimal effective level could be identified. The incidence of hypercholesterolemia, hypertriglyceridemia and thrombocytopenia rose with increasing everolimus trough levels, whereas the incidence of high serum creatinine levels did not appear to be influenced by everolimus exposure. Median-Effect Analysis on Safety Parameters Response Everolimus C min (ng/mL)

The Journal of Heart and Lung Transplantation, 2003

isolated RV dysfunction and severe hemodynamic compromise at our institution. Overall survival, d... more isolated RV dysfunction and severe hemodynamic compromise at our institution. Overall survival, duration of mechanical support, post-RVAD hemodynamics, and RV function measured by echocardiography were analyzed. Results: Post-cardiotomy RV failure developed in patients after coronary artery bypass surgery alone or in combination with valve surgery (12), valvular surgery alone (5), aortic surgery (6), heart or lung transplantation (3), and pulmonary endarterectomy (4). Mean age was 58 Ϯ15 years and 17 (57%) were female. Initial operation was emergent in 22 (73%) cases. Centrifugal pumps were used in 29 and Abiomed pump in one patient. Overall, 17 (57%) patients died on the assist device: 3 from sepsis, 2 from stroke, and 12 from an inability to wean from the RV device. RVAD was successfully weaned in 13 (43%) patients with a median duration of 5 days (range 2-8). Ten survived to hospital discharge. At post-RVAD removal, mean pulmonary artery pressure was 25 Ϯ6 mmHg, cardiac output was 4 Ϯ2L, and central venous pressure was 16Ϯ3 mmHg. Echocardiogram after RVAD removal showed normal RV function in 2 patients and 11 demonstrated improvement of RV hypokinesis. Our most recent experience, from 1997 to present, demonstrated an improved postoperative survival of 44% compared to 18% from the five preceding years. Conclusion: Post-cardiotomy RV failure patients requiring mechanical support continue to have high mortality. Survival has improved over the last several years due to advances in pharmacological treatment and RVAD support. For patients successfully weaned from the RVAD, residual RV dysfunction is compatible with survival. More liberal use of RV mechanical support may be indicated for patients with acute RV failure.

The Journal of Heart and Lung Transplantation, 2004

devices with prior immunotherapy or patients with panel reactive antibodies of at least 25%. Endp... more devices with prior immunotherapy or patients with panel reactive antibodies of at least 25%. Endpoints: Primary: Incidence of biopsied and treated acute rejection, graft loss or death of EC-MPS compared with MMF during the first six months of treatment. Secondary: Acute rejection, biopsyproven rejection, treated acute rejection (with/without hemodynamic compromise), graft survival, patient survival, gastrointestinal safety and tolerability, frequency of adverse events and infections, laboratory data, vital signs. Results: Available results of 6-month data of eligible patients will be presented at the ISHLT Scientific Sessions.

The Journal of Heart and Lung Transplantation, 2006

Background: In this study we evaluated exposure, safety and efficacy data from an international t... more Background: In this study we evaluated exposure, safety and efficacy data from an international trial of everolimus. We sought to identify a tolerated and efficacious range for blood levels of this agent in maintenance lung transplant recipients. Methods: In a randomized, double-blind, multicenter trial, 213 maintenance lung transplant recipients received either everolimus 1.5 mg twice daily (n ϭ 101) or azathioprine 1 to 3 mg/kg/day (n ϭ 112) with cyclosporine and corticosteroids. At 15 visits over the first 2 years of the trial, we obtained 826 everolimus trough (C 0) blood samples. We used median-effect analysis to assess relationships between everolimus C 0 vs efficacy and safety responses. Results: Everolimus administration began at 1.5 mg twice daily and was progressively lowered over the first 2 months to an average of 1.2 Ϯ 0.4 mg twice daily, which was maintained thereafter. This dose yielded median C 0 levels of 6.6 ng/ml (10th to 90th percentiles: 2.8 to 11.8 ng/ml). Over this range of everolimus C 0 , freedom from a decline in pulmonary function with bronchiolitis obliterans syndrome and freedom from biopsy-proven acute rejection were both Ն88%. The incidence of increased cholesterol (Ͼ6.5 mmol/liter), increased triglycerides (Ͼ2.9 mmol/liter) and transiently decreased platelet count (Ͻ100 ϫ 10 9 /liter) rose significantly with increasing C 0. Infections and drug-related adverse events were not significantly related to exposure. Conclusions: A tolerated and efficacious concentration range for everolimus in maintenance lung transplantation appears to be 3 to 12 ng/ml when used in conjunction with cyclosporine and corticosteroids. This range should be prospectively assessed with possible refinement as more clinical experience is gained.

American Journal of Transplantation, 2006

Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce th... more Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double-blind clinical trial, 213 BOS-free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1-3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV 1 >15% [∆FEV 1 >15%], graft loss, death or loss to follow-up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of ∆FEV 1 >15%, ∆FEV 1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after lung transplantation.