Conclusions: DUV monotherapy had a manageable safety profile and demonstrated significantly impro... more Conclusions: DUV monotherapy had a manageable safety profile and demonstrated significantly improved clinical outcomes over OFA in CLL/SLL pts who had received ≥2 prior therapies, a population in need of additional targeted therapies.
EOI; 16 (76.2%) were MRD-negative (CR, n=15; partial response, n=1). The proportion of pts receiv... more EOI; 16 (76.2%) were MRD-negative (CR, n=15; partial response, n=1). The proportion of pts receiving >90% dose intensity during induction (n=34) and maintenance (n=27), respectively, was: G, 91.2% and 100%; LEN, 76.5% and 70.4%; and atezo, 71.9% and 85.2%. All treated pts had ≥1 adverse event (AE), 28 (73.6%) pts had a grade 3-4 AE, 12 (31.6%) had a serious AE, and 9 (23.7%) had an AE that led to discontinuation of any drug (induction, n=6; maintenance, n=3). Conclusions: CR rate at EOI for the chemo-free regimen GLEN -atezo is comparable with currently available treatment options in this indication and higher than with historical controls, with durable activity. The overall safety and tolerability profile is consistent with the known profiles for the individual drugs and for GLEN. Acknowledgment: Third-party medical writing assistance, under the direction of Franck Morschhauser, was provided by Zoe Toland and Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.
SummaryWe have examined the prognostic value of the levels in the blood of granulocyte elastase-α... more SummaryWe have examined the prognostic value of the levels in the blood of granulocyte elastase-α1-proteinase inhibitor (E-α1-PI) complex, tumor necrosis factor-α (TNF-α) and urokinase-type plasminogen activator (u-PA) in 35 patients with severe infection upon admission to an Intensive Care Unit. Fourteen patients died.No differences for E-α1-PI complex were found between survivors and nonsurvivors, but in all patients the levels on admission were eight-fold higher than the reference value.TNF-α levels, measured by immunoassay, on admission were four times higher in the nonsurvivors than in the survivors (p = 0.0003) and correlated with the severity of the disease (APACHE II score, r = 0.43, p <0.05). TNF-α was not detectable by bioassay.Total u-PA antigen (u-PA Ag), plasmin-activatable single-chain u-PA (scu-PA) and inactive, nonactivatable u-PA (u-PA#) were on admission all two-fold higher in the nonsurvivors (p = 0.0006, 0.003 and 0.0003, respectively), while normal in the sur...
Bulletin de la Société belge d'ophtalmologie, 1997
The Hermansky-Pudlak syndrome (HPS) associates oculocutaneous albinism with a haemorrhagic diathe... more The Hermansky-Pudlak syndrome (HPS) associates oculocutaneous albinism with a haemorrhagic diathesis and the accumulation of ceroid-like material in different tissues. HPS is not an uncommon type of albinism as it was diagnosed in 13.5% (8/59) of our autosomal recessive albinos. These eight patients were evaluated ophthalmologically and haematologically. Apart from the symptoms caused by the albinism, accompanying signs vary from ecchymoses to life threatening haemorrhages and death by associated restrictive lung disease. Recognition of this syndrome by the ophthalmologist can be of major importance in this serious and eventually fatal disorder.
Sepsis is often associated with hemostatic dysfunction. This study aimed to relate changes in fib... more Sepsis is often associated with hemostatic dysfunction. This study aimed to relate changes in fibrinolysis and coagulation parameters to sepsis and sepsis outcome. Urokinase-type plasminogen activator (u-PA) antigen, tissue-type plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor (PAI) type 1 antigen, PAI activity, antithrombin (AT) III activity, and protein C activity were measured in 24 patients suffering from sepsis or septic shock and the results were compared with those observed in 30 non-sepsis patients with severe infectious disease. The u-PA level was markedly increased in plasma of sepsis patients as compared to non-sepsis patients (11.5 +/- 9.4 versus 1.6 +/- 1.5 ng/ml, p less than 0.0001). PAI-1 antigen and t-PA activity showed a significant increase in sepsis patients (320 +/- 390 ng/ml versus 120 +/- 200 ng/ml, and 3.0 +/- 3.6 IU/ml versus 1.0 +/- 0.7 IU/ml, respectively, p less than 0.01). AT III was decreased in sepsis patients (58 +/- 2...
BI-505 is a fully human high-affinity IgG1 antibody, which was isolated from a highly diverse hum... more BI-505 is a fully human high-affinity IgG1 antibody, which was isolated from a highly diverse human phage-antibody library based on its functional ability to induce programmed cell death of tumor cells. BI-505 binds to intercellular adhesion molecule-1 (ICAM-1), suggesting a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope is strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 has potent macrophagedependent anti-myeloma activity. It has been shown to enhance survival in advanced disseminated murine models of myeloma compared with currently used treatments, and to inhibit primary myeloma cell growth and bone damage in an SCID-hu model when used in combination with lenalidomide and bortezomib. This first-inhuman study was conducted to determine the maximum tolerated dose (MTD) of BI-505 when given as a mono-therapy, and to characterize its safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with refractory/relapsed multiple myeloma. Research.
Since the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortez... more Since the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortezomib, the prognosis of multiple myeloma (MM) has significantly improved. These agents have been incorporated into numerous treatment schedules for newly diagnosed as well as more advanced MM patients. Hence, the therapeutic options for MM have become more complex and subject to rapid changes. The multiple myeloma study group (MMSG) of the Belgian Hematological Society has established recommendations for the treatment of MM as based on an extensive review of the literature which is also summarized in this paper. The recommendations are the result of a consensus opinion between hematologists with experience in the field and representing most hematology centers in Belgium. Where applicable, reimbursement criteria are also taken into account. The consensus recommendations should be a reference for use by clinical hematologists in daily practice.
There is resurgent interest in glucocorticoids (GCs) in the treatment of poor prognosis chronic l... more There is resurgent interest in glucocorticoids (GCs) in the treatment of poor prognosis chronic lymphocytic leukemia (CLL). Little is known however on how GCs induce apoptosis in CLL. Methylprednisolone (MP) induces apoptosis in ZAP-70 positive CLL more readily than in ZAP-70 negative CLL, which is in contrast to the effects of radiation and chemotherapy. The increased GC sensitivity of ZAP-70+ CLL was studied in relation to the expression status of ZAP-70 and the related signal transducing tyrosine kinase SYK. Both ZAP-70 and SYK were downregulated by GC treatment. Moreover, SYK was dephosphorylated by the phosphatase PTP1B of which the expression and translation levels were induced by GCs. Inhibition of PTP1B successfully restored ZAP-70 expression and SYK phosphorylation but did not interfere with GC-induced apoptosis. Therefore, the downregulation of ZAP-70 and P-SYK per se during treatment with GCs is not sufficient to induce apoptosis, and different mechanisms must therefore be responsible for the increased steroid sensitivity of ZAP-70+ CLL.
The EORTC Invasive Fungal Infections Cooperative Group (IFICG) conducted a prospective survey by ... more The EORTC Invasive Fungal Infections Cooperative Group (IFICG) conducted a prospective survey by questionnaire of all cases of invasive aspergillosis (IA) in cancer patients to ascertain current diagnostic and therapeutic approaches. All members of the IFICG were asked prospectively to complete a detailed questionnaire for each IA case identified in their institution over a 12-month period. One hundred and thirty questionnaires were returned. All cases were independently evaluated (DWD &amp; JC) and 123 were eligible. Cases came from 20 hospitals in eight countries and the number of cases per institution varied from 1-21. Acute myeloid leukaemia (AML) (60, 49%), acute lymphoblastic leukaemia (ALL) (21, 17%) and lymphoma (11, 9%) were the most frequent underlying diseases, and 16 (12%) patients had received an allogeneic bone marrow transplant. Pulmonary involvement was present in 87%, infection of sinuses/nose in 16% and brain in 8%. The chest radiograph was initially normal in 9% of those with primary pulmonary disease. The diagnosis was confirmed in 50%, probable in 31% and possible in 19%. The evidence for IA was on the basis of clinical and radiological features alone in 28%, with culture or histology in another 31% and 9%, respectively, and with both culture and histology in 29%. In three (2%) patients with diagnosis was based on culture or histology alone. Treatment was given to 120 patients (98%)-amphotericin B 75%, lipid-associated amphotericin B 36%, itraconazole 40%, flucytosine 12%, growth factors 33%, lobectomy 5%. At 3 months after diagnosis or first suspicion of IA, 44 (36%) patients were alive and 79 (64%) dead. Outcome was best in those with AML (30% death and 46% with a complete antifungal response or cure). Growth factors (mostly granulocyte colony stimulating factor) appeared not to influence outcome (P = 0.99). IA remains a considerable diagnostic and therapeutic challenge. No single diagnostic procedure was universally successful and a multifaceted approach including surgery is necessary. There was no discernable difference in outcome between initial therapy with amphotericin B, itraconazole or lipid-associated amphotericin B, although numbers are limited and the study was retrospective.
Human hemopoietic stem cells (HSC) have been shown to engraft, differentiate, and proliferate in ... more Human hemopoietic stem cells (HSC) have been shown to engraft, differentiate, and proliferate in the hemopoietic tissues of sublethally irradiated NOD/LtSZ scid/scid (NOD/SCID) mice. We used this model to study homing, survival, and expansion of human HSC populations from different sources or phenotype. We observed that CD34 ؉ cells homed specifically to bone marrow (BM) and spleen, but by 3 days after injection, survived only in the BM. These BM-homed CD34 ؉ cells proliferated intensively and gave rise to a 12-fold, 5.5-fold, and 4-fold expansion in 3 days for umbilical cord blood, adult mobilized peripheral blood, and adult BM-derived cells, respectively. By injection of purified subpopulations, it was demonstrated that both CD34 ؉ 38 ؉ and CD34 ؉ 38 ؊ umbilical cord blood HSC homed to the BM and expanded. Importantly, kinetics of expansion were different: CD34 ؉ 38 ؉ cells started to increase in cell number from day 3 onwards, and by 4 wk after injection, virtually all CD34 ؉ cells had disappeared. In contrast, CD34 ؉ 38 ؊ cells remained quiescent during the first week and started to expand intensively from the third week on. In this paper, we have shown that homing, survival, and expansion of stem cells are three independent phenomena important in the early phase of BM engraftment and that kinetics of engraftment differ between CD34 ؉ 38 ؉ and CD34 ؉ 38 ؊ cells.
Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a huma... more Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20+/CD22+ B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. Results In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) a...
... Abstract. 45th Annual Meeting of the American Society of Hematology, San Diego, CA, Dec 6-9,2... more ... Abstract. 45th Annual Meeting of the American Society of Hematology, San Diego, CA, Dec 6-9,2003 Abstract NO: 87. Related research. ... Robert Marcus, Kevin Imrie, Philippe Solal-Celigny, John V Catalano, Anna Dmoszynska, Jo??o C Raposo, et al. ...
Conclusions: DUV monotherapy had a manageable safety profile and demonstrated significantly impro... more Conclusions: DUV monotherapy had a manageable safety profile and demonstrated significantly improved clinical outcomes over OFA in CLL/SLL pts who had received ≥2 prior therapies, a population in need of additional targeted therapies.
EOI; 16 (76.2%) were MRD-negative (CR, n=15; partial response, n=1). The proportion of pts receiv... more EOI; 16 (76.2%) were MRD-negative (CR, n=15; partial response, n=1). The proportion of pts receiving >90% dose intensity during induction (n=34) and maintenance (n=27), respectively, was: G, 91.2% and 100%; LEN, 76.5% and 70.4%; and atezo, 71.9% and 85.2%. All treated pts had ≥1 adverse event (AE), 28 (73.6%) pts had a grade 3-4 AE, 12 (31.6%) had a serious AE, and 9 (23.7%) had an AE that led to discontinuation of any drug (induction, n=6; maintenance, n=3). Conclusions: CR rate at EOI for the chemo-free regimen GLEN -atezo is comparable with currently available treatment options in this indication and higher than with historical controls, with durable activity. The overall safety and tolerability profile is consistent with the known profiles for the individual drugs and for GLEN. Acknowledgment: Third-party medical writing assistance, under the direction of Franck Morschhauser, was provided by Zoe Toland and Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.
SummaryWe have examined the prognostic value of the levels in the blood of granulocyte elastase-α... more SummaryWe have examined the prognostic value of the levels in the blood of granulocyte elastase-α1-proteinase inhibitor (E-α1-PI) complex, tumor necrosis factor-α (TNF-α) and urokinase-type plasminogen activator (u-PA) in 35 patients with severe infection upon admission to an Intensive Care Unit. Fourteen patients died.No differences for E-α1-PI complex were found between survivors and nonsurvivors, but in all patients the levels on admission were eight-fold higher than the reference value.TNF-α levels, measured by immunoassay, on admission were four times higher in the nonsurvivors than in the survivors (p = 0.0003) and correlated with the severity of the disease (APACHE II score, r = 0.43, p <0.05). TNF-α was not detectable by bioassay.Total u-PA antigen (u-PA Ag), plasmin-activatable single-chain u-PA (scu-PA) and inactive, nonactivatable u-PA (u-PA#) were on admission all two-fold higher in the nonsurvivors (p = 0.0006, 0.003 and 0.0003, respectively), while normal in the sur...
Bulletin de la Société belge d'ophtalmologie, 1997
The Hermansky-Pudlak syndrome (HPS) associates oculocutaneous albinism with a haemorrhagic diathe... more The Hermansky-Pudlak syndrome (HPS) associates oculocutaneous albinism with a haemorrhagic diathesis and the accumulation of ceroid-like material in different tissues. HPS is not an uncommon type of albinism as it was diagnosed in 13.5% (8/59) of our autosomal recessive albinos. These eight patients were evaluated ophthalmologically and haematologically. Apart from the symptoms caused by the albinism, accompanying signs vary from ecchymoses to life threatening haemorrhages and death by associated restrictive lung disease. Recognition of this syndrome by the ophthalmologist can be of major importance in this serious and eventually fatal disorder.
Sepsis is often associated with hemostatic dysfunction. This study aimed to relate changes in fib... more Sepsis is often associated with hemostatic dysfunction. This study aimed to relate changes in fibrinolysis and coagulation parameters to sepsis and sepsis outcome. Urokinase-type plasminogen activator (u-PA) antigen, tissue-type plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor (PAI) type 1 antigen, PAI activity, antithrombin (AT) III activity, and protein C activity were measured in 24 patients suffering from sepsis or septic shock and the results were compared with those observed in 30 non-sepsis patients with severe infectious disease. The u-PA level was markedly increased in plasma of sepsis patients as compared to non-sepsis patients (11.5 +/- 9.4 versus 1.6 +/- 1.5 ng/ml, p less than 0.0001). PAI-1 antigen and t-PA activity showed a significant increase in sepsis patients (320 +/- 390 ng/ml versus 120 +/- 200 ng/ml, and 3.0 +/- 3.6 IU/ml versus 1.0 +/- 0.7 IU/ml, respectively, p less than 0.01). AT III was decreased in sepsis patients (58 +/- 2...
BI-505 is a fully human high-affinity IgG1 antibody, which was isolated from a highly diverse hum... more BI-505 is a fully human high-affinity IgG1 antibody, which was isolated from a highly diverse human phage-antibody library based on its functional ability to induce programmed cell death of tumor cells. BI-505 binds to intercellular adhesion molecule-1 (ICAM-1), suggesting a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope is strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 has potent macrophagedependent anti-myeloma activity. It has been shown to enhance survival in advanced disseminated murine models of myeloma compared with currently used treatments, and to inhibit primary myeloma cell growth and bone damage in an SCID-hu model when used in combination with lenalidomide and bortezomib. This first-inhuman study was conducted to determine the maximum tolerated dose (MTD) of BI-505 when given as a mono-therapy, and to characterize its safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with refractory/relapsed multiple myeloma. Research.
Since the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortez... more Since the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortezomib, the prognosis of multiple myeloma (MM) has significantly improved. These agents have been incorporated into numerous treatment schedules for newly diagnosed as well as more advanced MM patients. Hence, the therapeutic options for MM have become more complex and subject to rapid changes. The multiple myeloma study group (MMSG) of the Belgian Hematological Society has established recommendations for the treatment of MM as based on an extensive review of the literature which is also summarized in this paper. The recommendations are the result of a consensus opinion between hematologists with experience in the field and representing most hematology centers in Belgium. Where applicable, reimbursement criteria are also taken into account. The consensus recommendations should be a reference for use by clinical hematologists in daily practice.
There is resurgent interest in glucocorticoids (GCs) in the treatment of poor prognosis chronic l... more There is resurgent interest in glucocorticoids (GCs) in the treatment of poor prognosis chronic lymphocytic leukemia (CLL). Little is known however on how GCs induce apoptosis in CLL. Methylprednisolone (MP) induces apoptosis in ZAP-70 positive CLL more readily than in ZAP-70 negative CLL, which is in contrast to the effects of radiation and chemotherapy. The increased GC sensitivity of ZAP-70+ CLL was studied in relation to the expression status of ZAP-70 and the related signal transducing tyrosine kinase SYK. Both ZAP-70 and SYK were downregulated by GC treatment. Moreover, SYK was dephosphorylated by the phosphatase PTP1B of which the expression and translation levels were induced by GCs. Inhibition of PTP1B successfully restored ZAP-70 expression and SYK phosphorylation but did not interfere with GC-induced apoptosis. Therefore, the downregulation of ZAP-70 and P-SYK per se during treatment with GCs is not sufficient to induce apoptosis, and different mechanisms must therefore be responsible for the increased steroid sensitivity of ZAP-70+ CLL.
The EORTC Invasive Fungal Infections Cooperative Group (IFICG) conducted a prospective survey by ... more The EORTC Invasive Fungal Infections Cooperative Group (IFICG) conducted a prospective survey by questionnaire of all cases of invasive aspergillosis (IA) in cancer patients to ascertain current diagnostic and therapeutic approaches. All members of the IFICG were asked prospectively to complete a detailed questionnaire for each IA case identified in their institution over a 12-month period. One hundred and thirty questionnaires were returned. All cases were independently evaluated (DWD &amp; JC) and 123 were eligible. Cases came from 20 hospitals in eight countries and the number of cases per institution varied from 1-21. Acute myeloid leukaemia (AML) (60, 49%), acute lymphoblastic leukaemia (ALL) (21, 17%) and lymphoma (11, 9%) were the most frequent underlying diseases, and 16 (12%) patients had received an allogeneic bone marrow transplant. Pulmonary involvement was present in 87%, infection of sinuses/nose in 16% and brain in 8%. The chest radiograph was initially normal in 9% of those with primary pulmonary disease. The diagnosis was confirmed in 50%, probable in 31% and possible in 19%. The evidence for IA was on the basis of clinical and radiological features alone in 28%, with culture or histology in another 31% and 9%, respectively, and with both culture and histology in 29%. In three (2%) patients with diagnosis was based on culture or histology alone. Treatment was given to 120 patients (98%)-amphotericin B 75%, lipid-associated amphotericin B 36%, itraconazole 40%, flucytosine 12%, growth factors 33%, lobectomy 5%. At 3 months after diagnosis or first suspicion of IA, 44 (36%) patients were alive and 79 (64%) dead. Outcome was best in those with AML (30% death and 46% with a complete antifungal response or cure). Growth factors (mostly granulocyte colony stimulating factor) appeared not to influence outcome (P = 0.99). IA remains a considerable diagnostic and therapeutic challenge. No single diagnostic procedure was universally successful and a multifaceted approach including surgery is necessary. There was no discernable difference in outcome between initial therapy with amphotericin B, itraconazole or lipid-associated amphotericin B, although numbers are limited and the study was retrospective.
Human hemopoietic stem cells (HSC) have been shown to engraft, differentiate, and proliferate in ... more Human hemopoietic stem cells (HSC) have been shown to engraft, differentiate, and proliferate in the hemopoietic tissues of sublethally irradiated NOD/LtSZ scid/scid (NOD/SCID) mice. We used this model to study homing, survival, and expansion of human HSC populations from different sources or phenotype. We observed that CD34 ؉ cells homed specifically to bone marrow (BM) and spleen, but by 3 days after injection, survived only in the BM. These BM-homed CD34 ؉ cells proliferated intensively and gave rise to a 12-fold, 5.5-fold, and 4-fold expansion in 3 days for umbilical cord blood, adult mobilized peripheral blood, and adult BM-derived cells, respectively. By injection of purified subpopulations, it was demonstrated that both CD34 ؉ 38 ؉ and CD34 ؉ 38 ؊ umbilical cord blood HSC homed to the BM and expanded. Importantly, kinetics of expansion were different: CD34 ؉ 38 ؉ cells started to increase in cell number from day 3 onwards, and by 4 wk after injection, virtually all CD34 ؉ cells had disappeared. In contrast, CD34 ؉ 38 ؊ cells remained quiescent during the first week and started to expand intensively from the third week on. In this paper, we have shown that homing, survival, and expansion of stem cells are three independent phenomena important in the early phase of BM engraftment and that kinetics of engraftment differ between CD34 ؉ 38 ؉ and CD34 ؉ 38 ؊ cells.
Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a huma... more Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20+/CD22+ B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. Results In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) a...
... Abstract. 45th Annual Meeting of the American Society of Hematology, San Diego, CA, Dec 6-9,2... more ... Abstract. 45th Annual Meeting of the American Society of Hematology, San Diego, CA, Dec 6-9,2003 Abstract NO: 87. Related research. ... Robert Marcus, Kevin Imrie, Philippe Solal-Celigny, John V Catalano, Anna Dmoszynska, Jo??o C Raposo, et al. ...
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