Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly ...diagnosed, chronic-phase chronic myeloid leukemia (CML).
A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day.
The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib.
This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.
The phase 3 ALFA-0701 trial demonstrated improved outcomes with fractionated-dose gemtuzumab ozogamicin (GO) combined with standard chemotherapy vs. standard chemotherapy alone in adults with de novo ...acute myeloid leukemia (AML). We examined post-transplant outcomes and occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients who received hematopoietic stem cell transplantation (HSCT) as follow-up therapy in ALFA-0701. Patients aged 50-70 years were randomized to standard chemotherapy with or without GO (3 mg/m2 on days 1, 4, and 7 of induction and day 1 on each of two consolidation courses). Allogeneic HSCT was recommended for patients in first complete remission with matched (related or unrelated) donor, except those with core-binding factor AML or normal karyotype and either NPM1+/FLT3-ITDwt or CEBPA+ AML. Eighty-five patients (GO: n = 32; control: n = 53) received HSCT in first complete remission or after relapse/primary induction failure. Three patients (GO: n = 2; control: n = 1 received GO as follow-up therapy) developed VOD/SOS after HSCT or conditioning. Post-transplant survival, non-relapse mortality, and relapse were not different between arms. Results indicate fractionated-dose GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant VOD/SOS or mortality and thus does not preclude the use of HSCT as consolidation treatment.
The randomized, phase III ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival ...(EFS) in adults with
acute myeloid leukemia (AML). Here we report an independent review of EFS, final overall survival (OS), and additional safety results from ALFA-0701. Patients (n=271) aged 50-70 years with
AML were randomized to receive conventional front-line induction chemotherapy (3+7daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m
on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/m
/day on day 1) according to their initial randomization. The primary end point was investigator-assessed EFS. Secondary end points included OS and safety. A blinded independent review confirmed the investigator-assessed EFS results August 1, 2011; hazard ratio (HR) 0.66; 95% Confidence Interval (CI): 0.49-0.89; 2-sided
=0.006, corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin
control arm. Final OS at April 30, 2013 favored gemtuzumab ozogamicin but was not significant. No differences in early death rate were observed between arms. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated AML. (Trial registered at
).
Summary
Bosutinib is an oral, dual SRC/ABL1 tyrosine kinase inhibitor for resistant/intolerant chronic myeloid leukaemia (CML). We assessed the efficacy and safety of bosutinib 500 mg/d (n = 250) ...versus imatinib 400 mg/d (n = 252) after >24 months from accrual completion in newly diagnosed chronic phase (CP)‐CML (Bosutinib Efficacy and Safety in Newly Diagnosed CML trial BELA). Cumulative complete cytogenetic response (CCyR) rates by 24 months were similar (bosutinib, 79%; imatinib, 80%); cumulative major molecular response (MMR) rates were 59% for bosutinib and 49% for imatinib. Responses were durable; 151/197 vs. 172/204 and 125/153 vs. 117/131 responders remained on treatment and maintained CCyR and MMR, respectively. Since the 12‐month primary analysis, no new accelerated‐/blast‐phase transformations occurred with bosutinib; four occurred with imatinib. Early response (BCR‐ABL1/ABL1 ≤ 10%, 3 months) was associated with better CCyR and MMR rates by 12 and 24 months (both arms). Gastrointestinal events and liver function test elevations were more common, and neutropenia, musculoskeletal events and oedema were less common with bosutinib. Discontinuations due to adverse events were more common with bosutinib versus imatinib (most commonly alanine aminotransferase elevation: 4% vs. <1%); most occurred within the first 12 months. Cardiovascular adverse events were similar in both arms. Bosutinib continues to demonstrate good efficacy and manageable tolerability in newly diagnosed CP‐CML patients.
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Introduction: The randomized phase 3 ALFA-0701 study demonstrated improved outcomes with the addition of gemtuzumab ozogamicin (GO) to standard 7+3 chemotherapy in patients with de novo acute ...myeloid leukemia (AML; Castaigne et al, Lancet 2012). 85 of 271 patients in the study received hematopoietic stem cell transplantation (HSCT) at any time during study. Here we describe transplant characteristics and compare survival and veno-occlusive disease (VOD) outcomes in these patients.
Methods: Patients aged 50-70 years with de novo AML who received standard chemotherapy treatment (daunorubicin and cytarabine) with the addition of GO (GO arm) or alone (control arm) and underwent HSCT as part of the open-label, randomized phase 3 ALFA-0701 study were included in this analysis. Patients who experienced complete remission could be considered for allogeneic HSCT according to performance status, age, the existence or not of a related donor, and cytogenetic and molecular risk categories. Allogeneic HSCT was considered for patients in the European LeukemiaNet (ELN) intermediate 2 or adverse risk group. The type of pre-transplant conditioning regimen was left to the discretion of the transplant center. An interval of 2 months between the last dose of GO and HSCT was recommended. Post-transplant survival was defined as the time from HSCT to death due to any cause. Data on VOD events were extensively collected from screening up to the patient's death or the data collection cutoff date (November 1, 2013), whichever occurred first.
Results: A total of 32 patients in the GO arm and 53 patients in the control arm underwent HSCT (Table). All patients received allogeneic HSCT except for 1 patient in the control arm who received autologous HSCT. In the GO arm, 17 patients received HSCT in first remission, 2 after induction failure, and 13 after relapse. In the control arm, 22 patients received HSCT in first remission, 9 after induction failure, and 22 after relapse. Median (range) age was 60 (51-67) years in the GO arm and 59 (50-69) years in the control arm, and 47% and 45% were male, respectively. The distribution of ELN risk classification was similar for the GO vs control arm, respectively (favorable/intermediate: 63% vs 72%; adverse: 28% vs 25%). Only 1 patient in the control arm who received GO as follow-up therapy received transplant <2 months after the last GO dose.
As of April 30, 2013, 18 (56%) patients in the GO arm and 28 (53%) in the control arm had died: 7 and 16 of these deaths were attributed to disease progression/relapse, and 4 and 7 were attributed to graft versus host disease, respectively. Median post-transplant survival was 21.4 months in the GO arm vs 17.1 months in the control arm, with 3-year survival probability (95% confidence interval CI) of 39% (22-57) vs 45% (31-58), respectively (hazard ratio HR=0.97). Median post-transplant survival was not yet reached in the GO arm vs 19.2 months in the control arm for patients who received HSCT while in first remission, with 3-year survival probability (95% CI) of 53% (28-73) vs 46% (24-64), respectively (HR=0.71; Figure). In patients who received HSCT after relapse or induction failure, median post-transplant survival was 14.5 vs 10.5 months in the GO vs control arm, with 3-year survival probability (95% CI) of 21% (4-48) vs 44% (26-61), respectively (HR=1.42).
In all, 3 patients in the GO arm and 2 in the control arm (both of whom received GO as follow-up therapy) developed VOD; 3 of these cases (2 in GO arm; 1 in control arm) occurred post-transplant. All but 1 patient fully recovered.
Conclusions: Similar post-transplant outcomes were observed in patients with AML treated with standard chemotherapy with and without GO. The use of GO was not associated with an excess of VOD events after HSCT. The results suggest that the administration of GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant mortality and thus does not preclude the use of transplant as consolidation treatment following induction or salvage treatment.
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Benner:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Castaigne:Pfizer: Honoraria, Research Funding.
The RCS rat presents an autosomal recessive retinal pigment epithelium dystrophy characterized by the outer segments of photoreceptors being phagocytosis-deficient. A systematic genetic study allowed ...us to restrict the interval containing the rdy locus to that between the markers D3Mit13 and D3Rat256. We report the chromosomal localization of the rat c-mer gene in the cytogenetic bands 3q35-36, based on genetic analysis and radiation hybrid mapping. Using a systematic biocomputing analysis, we identified two strong related candidate genes encoding protein tyrosine kinase receptors of the AXL subfamily. The comparison of their expression patterns in human and mice tissues suggested that the c-mer gene was the best gene to screen for mutations. RCS rdy− and RCS rdy+ cDNAs were sequenced. The RCS rdy− cDNAs carried a significant deletion in the 5′ part of the coding sequence of the c-mer gene resulting in a shortened aberrant transcript encoding a 20 amino acid peptide. The c-mer gene contains characteristic motifs of neural cell adhesion. A ligand of the c-mer receptor, Gas6, exhibits antiapoptotic properties.
Abstract The phase 3 ALFA-0701 trial demonstrated improved outcomes with fractionated-dose gemtuzumab ozogamicin (GO) combined with standard chemotherapy vs. standard chemotherapy alone in adults ...with de novo acute myeloid leukemia (AML). We examined post-transplant outcomes and occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients who received hematopoietic stem cell transplantation (HSCT) as follow-up therapy in ALFA-0701. Patients aged 50–70 years were randomized to standard chemotherapy with or without GO (3 mg/m2 on days 1, 4, and 7 of induction and day 1 on each of two consolidation courses). Allogeneic HSCT was recommended for patients in first complete remission with matched (related or unrelated) donor, except those with core-binding factor AML or normal karyotype and either NPM1+/FLT3-ITDwt or CEBPA+ AML. Eighty-five patients (GO: n = 32; control: n = 53) received HSCT in first complete remission or after relapse/primary induction failure. Three patients (GO: n = 2; control: n = 1 received GO as follow-up therapy) developed VOD/SOS after HSCT or conditioning. Post-transplant survival, non-relapse mortality, and relapse were not different between arms. Results indicate fractionated-dose GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant VOD/SOS or mortality and thus does not preclude the use of HSCT as consolidation treatment.
It is important to understand the development of the normal retinal vascular system, because it may provide clues for understanding the mechanisms underlying the neovascularization associated with ...several retinopathies of infancy and adulthood. However, little is known about normal human ocular vascularization. VEGF is a key growth factor during vascular development and one of its receptors, KDR, plays a pivotal role in endothelial cell proliferation and differentiation. The purpose of this study was to analyze VEGF and KDR gene expression patterns during the development of the human eye during the embryonic and fetal stages.
The gene expression of VEGF and KDR was analyzed by in situ hybridization in 7-week-old embryos and in 10- and 18-week-old fetuses. In addition, we performed VEGF and KDR immunohistochemistry experiments on 18-week-old fetus tissue sections.
These results clearly demonstrated that the levels of VEGF and KDR transcripts are correlated during the normal development of the ocular vasculature in humans. The complementarity between the patterns of VEGF and KDR during the early stages of development suggests that VEGF-KDR interactions play a major role in the formation and regression of the hyaloid vascular system (HVS) and in the development of the choriocapillaris. In later stages (i.e., 18-weeks-old fetuses), the expression of KDR seems to be linked to the development of the retinal vascular system. VEGF and KDR transcripts were unexpectedly detected in some nonvascular tissues-that is, in the cornea and in the retina before the development of the retinal vascular system.
The expression of VEGF and KDR correlates highly with the normal ocular vascularization in humans, but VEGF may also be necessary for nonvascular retinal developmental functions, especially for the coordination of neural retinal development and the preliminary steps of the establishment of the definitive stable retinal vasculature.
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