[Show abstract][Hide abstract]ABSTRACT: Background: HPSE is an endo-ß-d-glucuronidase that trims the heparan sulfate (HS) chains of proteoglycans, releasing biologically active fragments of HS. HPSE activity impacts cell signaling, gene expression and promotes extracellular matrix remodeling within the tumor microenvironment; high HPSE expression is associated with enhanced tumor growth, angiogenesis and metastases in several cancer types. As a result of its tumor promoting activities, HPSE is a promising new and unexploited target for anti-cancer therapy. There is a single enzymatically active HPSE in humans and HPSE knockout mice appear to be healthy, thus therapeutic neutralization of HPSE activity would likely have limited negative side effects.
In MM preclinical models HPSE was shown to be a master regulator of aggressive tumor behavior. Preclinical evidence also indicates that HPSE promotes chemoresistance suggesting it plays a pivotal role in regulating myeloma response to therapy (Ramani VPC et al., AACR 2014, Abstract nr 1708).
In preclinical studies, bortezomib or melphalan were found to enhance HPSE expression and secretion. High HPSE expressing MM cells were less susceptible to the cytotoxic effects of those drugs. Likewise, a very significant increase in HPSE gene expression following chemotherapy was observed in patient-derived tumor samples, indicating a potential role for HPSE in regulating myeloma response to therapy. Roneparstat (SST0001), a 100% N-acetylated and glycol split heparin, is a potent HPSE inhibitor devoid of any significant anticoagulant activity. In an in vivo model of disseminated myeloma, Roneparstat in combination with either bortezomib or melphalan, significantly decreased both the number of animals with detectable tumor and the tumor burden when compared with animals treated with either of these drugs alone. In addition, studies in animal models of MM indicated that the mechanism of action of Roneparstat was consistent with it having anti-HPSE activity in vivo (reduced angiogenesis and diminished expression of HGF, VEGF and MMP-9 and diminished HPSE induced shedding of syndecan-1, a HS proteoglycan known to be a potent promoter of myeloma growth).
Patients and Methods: A First in Man, multicenter, international, phase I clinical study is currently ongoing in advanced heavily pre-treated refractory MM patients (pts) who have exhausted all available anti-MM therapies. Roneparstat is administered subcutaneously, with a starting flat dose defined according to ICH S9 guidelines. A schedule DX5W1,W2 Q28D is being tested. Each cohort plans 3 + 3 pts. A direct fluorescence method (Heparin Red assay) is used in pharmacokinetic studies along with aPTT, used as a surrogate (indirect) measurement of Roneparstat plasma concentration. The pharmacodynamic effect of the drug on the coagulation cascade and any antitumor effect are also evaluated.
Results: 15 pts have been enrolled to date. 5 cohorts (doses ranging from 25 to 200 mg/day) have been evaluated, while, a 400 mg cohort has just been opened. Five pts have received 1 cycle of therapy, six pts 2 cycles, one 3 cycles, one 5 cycles and one 9 cycles; one patient is currently on treatment, one is not evaluable. Roneparstat administration was found to be safe with only minimal transient side effects. No DLTs and no bleeding complications have been observed. Roneparstat has been well tolerated both systemically and locally. The only side effect observed was minor reactions (redness, bruising) at the injection site (in 6 pts, all grade 1). A decrease > 50% in the serum monoclonal component was observed in one patient, lasting for 6 cycles.
Conclusions: Preclinical studies in MM lines and animal models have demonstrated Roneparstat as a potent anti-myeloma compound, particularly when used in combination with other drugs. In the ongoing Phase I escalating dose study (n. pts = 15), Roneparstat administration (at a dose of up to 200 mg/day) was found to be safe with only minimal local side effects. Based on these results, Roneparstat, at a defined dose, in combination with other anti-myeloma agents, will be evaluated in relapsed/resistant MM pts.
[Show abstract][Hide abstract]ABSTRACT: TOURMALINE-MM1 (NCT01564537) showed a significant 35% improvement in progression-free survival (PFS) with IRd vs placebo-Rd (hazard ratio [HR] 0.742, p = 0.012) in pts with RRMM (Moreau et al, ASH 2015). Here we present an analysis of the efficacy and safety of IRd vs placebo-Rd by cytogenetic status. Methods: Pts with RRMM were randomized 1:1 to receive IRd or placebo-Rd. High-risk cytogenetic abnormalities were assessed at a central laboratory; cut-off values were based on false-positive rates of the FISH probes, and were 5%, 3%, and 3% for del(17p), t(4;14), and t(14;16), respectively. Post-hoc analyses were performed using different cut-offs for del(17p) and t(4;14). Results: Of 722 pts enrolled, 552 (76%) had cytogenetic results (97% central laboratory-confirmed), of whom 137 had high-risk abnormalities (75 IRd, 62 placebo-Rd). PFS was improved with IRd vs placebo-Rd in high- and standard-risk pts (Table); in high-risk pts, median PFS with IRd was similar to that in all pts and in standard-risk pts. PFS benefit with IRd vs placebo-Rd was consistent using different positivity cut-offs of 20% del(17p) (n = 59; median 21.4 vs 6.7 mos, HR 0.611), 60% del(17p) (n = 33; median 15.7 vs 5.1 mos, HR 0.49), and 10% t(4;14) alone (n = 59; median 18.5 vs 12.0 mos, HR 0.444). Median TTP with IRd vs placebo-Rd was 21.4 vs 12.0 mos and 20.6 vs 15.9 mos in high- and standard-risk pts. Overall response rate (CR+VGPR rate) with IRd vs placebo-Rd was 79% vs 60% (45% vs 21%) and 80% vs 73% (51% vs 44%) in high- and standard-risk pts. Rates of grade ≥ 3 AEs with IRd vs placebo-Rd were 66% vs 73% in high- and 75% vs 65% in standard-risk pts; rates of serious AEs were 42% vs 52% and 45% vs 47%, respectively. Conclusions: IRd showed substantial benefit vs placebo-Rd in RRMM pts with high-risk cytogenetic abnormalities, irrespective of the cut-offs used, with limited additional toxicity. Clinical trial information: NCT0156
No preview · Article · May 2016 · Journal of Clinical Oncology
[Show abstract][Hide abstract]ABSTRACT: The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32). According to several studies, this translocation represents a unique subset of patients with relatively favorable outcomes. Using combined analyses of morphology and fluorescence in situ hybridization (I-FISH), we examined the co-occurrence rates of t(11;14) with seven chromosomal aberrations (CAs): del(13q), del(17p), del(1p), gain(1q), multiple gains(1q), del(16q) and del(IGH), and assessed the effect of the different combinations on patient outcomes, with overall survival (OS) as the main outcome measure. Bone marrow samples and clinical data from 212 MM patients with t(11;14) were analyzed. At least two additional CAs were found in 35% (75/205) of patients and a strong correlation between specific CAs. The occurrence of three CAs (multiple gains of (1q) (HR=6.94, P=0.001), del(1p) (HR=4.47, p=0.008) and del(IGH) (HR=2.38, p=0.002)) exerted a profoundly deleterious effect on median OS compared with patients with t(11;14) only. Del(17p) and del(13q) have also exerted a deleterious effect albeit to a lesser extent (HR=2.05, P=0.07 and HR=1.81, P=0.03, respectively). Compared with t(11;14) alone, the addition of certain CAs lead to worse outcomes. These findings may have important clinical and biological implications. Patients with coexisting adverse lesions and t(11;14) may be considered high-risk and managed accordingly. This article is protected by copyright. All rights reserved.
No preview · Article · May 2016 · Genes Chromosomes and Cancer
[Show abstract][Hide abstract]ABSTRACT: Over the past decade, transplantation of peripheral blood hematopoietic cells has increased and is now the predominant graft source for related or unrelated adult allogeneic hematopoietic stem cell transplantation. At the same time, increasing numbers of patients are receiving reduced intensity conditioning prior to hematopoietic stem cell infusion. In prior work utilizing smaller patient numbers and limited data, reduced intensity conditioning peripheral blood stem cell transplantation was shown to be non-inferior to reduced intensity conditioning bone marrow transplantation for acute leukemia. A recent, large registry analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation showed peripheral blood grafts result in superior outcomes compared to bone marrow after reduced intensity conditioning regimens for acute leukemia. The T-cell replete peripheral blood stem cell allografts are associated with significant graft-versus-leukemia benefits that are important drivers of improved leukemia free survival and overall survival. However, an increased risk of chronic graft-versus-host disease after peripheral blood grafts is concerning and long term follow-up comparing peripheral versus bone marrow grafts after reduced intensity conditioning regimen is needed. Further assessment of the long standing risks should be undertaken in an effort to better understand whether the risk of chronic graft-versus-host disease among peripheral blood graft recipients translates into continued graft-versus-leukemia effects and long-term remissions and cures, or, results in late morbidity and mortality.
No preview · Article · Apr 2016 · Experimental hematology
[Show abstract][Hide abstract]ABSTRACT: Despite their favorable prognosis, 10-20% of acute promyelocytic leukemia (APL) patients relapse. Reinduction therapy is often followed by autologous hematopoietic cell transplantation (auto-HCT). Arsenic trioxide (ATO) has become part of standard reinduction and is often followed by auto-HCT. Data on patients in CR2 were collected from two large transplant registries (Center for International Blood and Marrow Transplant Research (CIBMTR) and European Group for Blood and Marrow Transplant (EBMT)) and two specialty referral centers. The outcome of patients in CR2 who received only ATO-based therapy as reinduction was retrospectively compared with those who got an auto-HCT, with or without ATO. Prognostic factors included age, disease risk, extramedullary disease and duration of CR1. Of 207 evaluable patients, the median age was 31.5 years, 15.3% had extramedullary disease and median WBC at diagnosis was 4.8 × 10(9)/L. Sixty-seven patients received ATO alone and 140 underwent auto-HCT. The groups were comparable for age, gender, extramedullary disease, risk group and duration of CR1. At 5 years, overall survival (OS) was 42% and 78% for the ATO-only and auto-HCT groups, respectively (P<0.001). In addition, OS was associated with longer duration of CR1 (P=0.002), but not with disease risk at diagnosis. These data suggest that auto-HCT for APL patients in CR2 results in better OS than ATO-based therapy alone.Bone Marrow Transplantation advance online publication, 18 April 2016; doi:10.1038/bmt.2016.96.
No preview · Article · Apr 2016 · Bone Marrow Transplantation
[Show abstract][Hide abstract]ABSTRACT: Disease relapse is the commonest cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplasia yet treatment options for such patients remain limited. Azacitidine is an important new therapy in high risk myelodysplasia and acute myeloid leukaemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of Azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukaemia (n=116) or myelodysplasia (n=65). 69 patients received additional donor lymphocyte infusions. 46 of 157 (25%) assessable patients responded to Azacitidine therapy: 24 (15%) achieving a complete remission and 22 (14%) a partial remission. Response rates were higher in patients transplanted in complete remission (p= 0.04) and those transplanted for myelodysplasia (p= 0.023). In patients who achieved a complete remission the 2 year overall survival was 48% versus 12% for the whole population. Overall survival was determined by time to relapse post-transplant > 6 months (p= 0.001) and percentage of blasts in the bone marrow at time of relapse (p= 0.01). The concurrent administration of donor lymphocyte infusions did not improve response rates or survival. An Azacitidine relapse prognostic score was developed which predicted 2 year overall survival ranging from 3-37% (p=0.00001). We conclude Azacitidine represents an important new therapy in selected patients with acute myeloid leukaemia/myelodysplasia who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required.
[Show abstract][Hide abstract]ABSTRACT: Increasing numbers of patients are receiving haplo-identical stem cell transplantation (haplo-SCT) for treatment of acute leukemia with reduced intensity (RIC) or myeloablative (MAC) conditioning regimens. The impact of conditioning intensity in haplo-SCT is unknown.Methods
We performed a retrospective registry-based study comparing outcomes after T-replete haplo-SCT for patients with acute myeloid (AML) or lymphoid leukemia (ALL) after RIC (n = 271) and MAC (n = 425). Regimens were classified as MAC or RIC based on published criteria.ResultsA combination of post-transplant cyclophosphamide (PT-Cy) with one calcineurin inhibitor and mycophenolate mofetil (PT-Cy-based regimen) for graft-versus-host disease (GVHD) prophylaxis was used in 66 (25 %) patients in RIC and 125 (32 %) in MAC groups. Patients of RIC group were older and had been transplanted more recently and more frequently for AML with active disease at transplant. Percentage of engraftment (90 vs. 92 %; p = 0.58) and day 100 grade II to IV acute GVHD (24 vs. 29 %, p = 0.23) were not different between RIC and MAC groups. Multivariable analyses, run separately in AML and ALL, showed a trend toward higher relapse incidence with RIC in comparison to MAC in AML (hazard ratio (HR) 1.34, p = 0.09), and no difference in both AML and ALL in terms of non-relapse mortality (NRM) chronic GVHD and leukemia-free survival. There was no impact of conditioning regimen intensity in overall survival (OS) in AML (HR = 0.97, p = 0.79) but a trend for worse OS with RIC in ALL (HR = 1.44, p = 0.10). The main factor impacting outcomes was disease status at transplantation (HR ≥ 1.4, p ≤ 0.01). GVHD prophylaxis with PT-Cy-based regimen was independently associated with reduced NRM (HR 0.63, p = 0.02) without impact on relapse incidence (HR 0.99, p = 0.94).Conclusions
These data suggest that T-replete haplo-SCT with both RIC and MAC, in particular associated with PT-Cy, are valid options in first line treatment of high risk AML or ALL.
No preview · Article · Mar 2016 · Journal of Hematology & Oncology
[Show abstract][Hide abstract]ABSTRACT: Models for prediction of allogeneic hematopoietic stem transplantation (HSCT) related mortality partially account for transplant risk. Improving predictive accuracy requires understating of prediction limiting factors, such as the statistical methodology used, number and quality of features collected, or simply the population size. Using an in-silico approach (i.e., iterative computerized simulations), based on machine learning (ML) algorithms, we set out to analyze these factors. A cohort of 25,923 adult acute leukemia patients from the European Society for Blood and Marrow Transplantation (EBMT) registry was analyzed. Predictive objective was non-relapse mortality (NRM) 100 days following HSCT. Thousands of prediction models were developed under varying conditions: increasing sample size, specific subpopulations and an increasing number of variables, which were selected and ranked by separate feature selection algorithms. Depending on the algorithm, predictive performance plateaued on a population size of 6,611-8,814 patients, reaching a maximal area under the receiver operator characteristic curve (AUC) of 0.67. AUCs' of models developed on specific subpopulation ranged from 0.59 to 0.67 for patients in second complete remission and receiving reduced intensity conditioning, respectively. Only 3-5 variables were necessary to achieve near maximal AUCs. The top 3 ranking variables, shared by all algorithms were disease stage, donor type, and conditioning regimen. Our findings empirically demonstrate that with regards to NRM prediction, few variables "carry the weight" and that traditional HSCT data has been "worn out". "Breaking through" the predictive boundaries will likely require additional types of inputs.
[Show abstract][Hide abstract]ABSTRACT: One of the major projects of the Worldwide Network for Blood and Marrow Transplantation (WBMT) is to promote hematopoietic stem cell transplantation (HSCT) in emerging countries in the world. For these countries, HLA haploidentical HSCT (haplo-HSCT) from family members is an attractive approach because of its cost effectiveness. To learn the current status, including recent trends, of haplo-HSCT, the WBMT invited speakers from major transplant centers in 3 regions (Asia, Europe, and North America) to present at its annual WBMT Joint Session. This article represents the direct reports from these 3 speakers in addition to introductions by 2 WBMT speakers who address data from the Global Transplant Activity survey. It must be emphasized, however, that certain promising results of haplo-HSCT presented in this article were obtained at well-experienced institutes.
No preview · Article · Mar 2016 · Biology of Blood and Marrow Transplantation
[Show abstract][Hide abstract]ABSTRACT: Allogeneic hematopoietic cell transplantation (allo-HCT) with an HLA-identical sibling donor is the best post-remission treatment for patients with non good-risk acute myeloid leukemia (AML) in first complete remission (CR)(1). For patients who lack an HLA-identical sibling donor, transplantation with an 8/8 or a 7/8 HLA-matched unrelated donor, an HLA-haploidentical donor, or an unrelated umbilical cord blood (UCB) are considered as valid alternatives(1). This article is protected by copyright. All rights reserved.
No preview · Article · Feb 2016 · European Journal Of Haematology
[Show abstract][Hide abstract]ABSTRACT: Purpose. From a global perspective, the rates of allogeneic hematopoietic cell transplantation (allo HCT) are closely related to the economicstatus of acountry. However, apotential association with out come has not yet been documented. The goal of this study was to evaluate effects of health care expenditure (HCE), Human Development Index (HDI), team density, and center experience on non relapse mortality (NRM) after HLA-matched sibling alloHCT for adults with acute lymphoblastic leukemia (ALL). Patients and Methods. A total of 983 patients treated with myeloablative alloHCT between 2004 and 2008 in 24 European countries were included. Results. In a univariate analysis, the probability of day 100 NRM was increased for countries with lower current HCE (8% vs. 3%; p = .06), countries with lower HDI (8% vs. 3%; p = .02), and centers with less experience (8% vs. 5%; p = .04). In addition, the overall NRM was increased for countries with lower current HCE (21% vs. 17%; p = .09) and HDI (21% vs. 16%; p = .03) and for centers with lower activity (21%vs.16%;p = .07). Inamultivariate analysis, the strongest predictive model forday100NRMincluded currentHCE greater than the median (hazard ratio [HR], 0.39;p = .002).The overall NRM was mostly predicted by HDI greater than the median (HR, 0.65; p = .01). Both lower current HCE and HDI were associated with decreased probability of overall survival. Conclusion. Both macroeconomic factors and the socioeconomic status of a country strongly influence NRM after alloHCT for adults with ALL. Our findings should be considered when clinical studies in the field of alloHCT are interpreted.
[Show abstract][Hide abstract]ABSTRACT: Background Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. Methods We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. Results After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). Conclusions The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275 .).
Full-text · Article · Jan 2016 · New England Journal of Medicine