Bernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only ...on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center.
Thirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses.
Patients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies.
Regardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.
Bernard-Soulier syndrome is a very rare form of inherited thrombocytopenia that derives from mutations in GPIbα, GPIbβ, or GPIX and is typically inherited as a recessive disease. However, some years ...ago it was shown that the monoallelic c.515C>T transition in the GPIBA gene (Bolzano mutation) was responsible for macrothrombocytopenia in a few Italian patients.
Over the past 10 years, we have searched for the Bolzano mutation in all subjects referred to our institutions because of an autosomal, dominant form of thrombocytopenia of unknown origin.
We identified 42 new Italian families (103 cases) with a thrombocytopenia induced by monoallelic Bolzano mutation. Analyses of the geographic origin of affected pedigrees and haplotypes indicated that this mutation originated in southern Italy. Although the clinical expression was variable, patients with this mutation typically had a mild form of Bernard-Soulier syndrome with mild thrombocytopenia and bleeding tendency. The most indicative laboratory findings were enlarged platelets and reduced GPIb/IX/V platelet expression; in vitro platelet aggregation was normal in nearly all of the cases.
Our study indicates that monoallelic Bolzano mutation is the most frequent cause of inherited thrombocytopenia in Italy, affecting 20% of patients recruited at our institutions during the last 10 years. Because many people from southern Italy have emigrated during the last century, this mutation may have spread to other countries.
This prospective observational study aimed to verify the efficacy of erythropoietin zeta in the treatment of patients with low-risk myelodysplastic syndrome.
Patients with low/int-1 IPSS risk and ...serum erythropoietin level below 500 U/L were enrolled. Treatment consisted of erythropoietin zeta 40,000 U subcutaneously once a week. The primary endpoint was the erythroid response. According to Simon's two-stage statistical design, 36 patients were recruited. The median age was 75 years (range 56-83 years), male/female ratio was 1.1/1, median baseline serum erythropoietin was 57.9 U/L (range 9.4-475 U/L). 53% of patients had low-risk disease, while the remaining had Int-1 risk.
After 8 weeks, a significant response (rise in Hb levels of at least 1.5 g/dL) was achieved in 18 patients (50%) out of 36. However, 17 patients did not improve; 8/17 patients pursued the 40,000 U weekly schedule of erythropoietin zeta, and 4/8 (50%) of them reached the erythroid response after 16 weeks. Nine patients underwent dosage doubling (40,000 U twice per week), and 5/9 (55%) of them achieved the erythroid response.
Compared with data from the literature, this prospective study revealed that EPO-zeta is a safe and effective therapeutic option in low-risk MDS patients.
Abstract The revised IPSS (IPSS-R) was developed aiming at a better prognostication, taking into account patients treated with best supportive care. We herein validated this model on the basis of ...data from 1314 patients who received BSC only as well as patients who underwent induction chemotherapy ( n = 214) or allogeneic transplantation ( n = 167). We could demonstrate a clear distinction of the IPSS-R risk categories with regard to survival and risk of AML evolution in all patient cohorts. When comparing IPSS-R, IPSS, WHO prognostic scoring system (WPSS) and Duesseldorf score, the best results regarding the ability to predict survival were obtained by the IPSS-R.
Background and Aim: The emergence and dissemination of Carbapenemase producing Klebsiella pneumoniae (KPC) represent a serious threat to public health and is associated with high mortality rates in ...patients with hematologic malignancies. Several risk factors (prior exposure to or current use of antibiotics, extended stay in hospital, neutropenia, sharing a room with a know carrier etc) have been identified for colonization in hematological patients. However, data on how to contain their spread in haematological setting are still surprisingly limited. We carried out a prospective investigation to assess the prevalence of KPC colonization among hematologic patients, the impact of a strategy control to limit the spread and to evaluate the efficacy of an implementation of more extensive active surveillance.
Methods: Infections caused by multiresistant pathogens have been recorded in our Unit from January 2012 through June 2014. From January 2012 to July 2013, we developed an intensive control infection program, (Plan A): 1. Weekly colonization screening for KPC; 2. Educate healthcare personnel about KPC; 3. Promotion of hand hygiene 4. Physical separation of carriers from non-carriers 5. A double-carbapenem plus colistin therapeutic empiric regimen was given for blood stream infections. Since July 2013, we decided to implement additional measures, including (Plan B): 1. Drastic reduction in the number of beds. 2. 2% chlorhexidine body washing for colonized patients. 3. Ensure access to adequate hand hygiene stations (i.e., clean sinks and/or alcohol) and ensure they are well stocked with supplies (e.g. towels, soap, etc.) 4. Donning gown and gloves before entering the affected patient’s room and removing the gown and gloves and performing hand hygiene prior to exiting the affected patient’s room.
Results: Since January 2012 perianal swabs were detected weekly from 607 consecutive patients affected by hematologic malignancies, for a total of 1079 admissions and 12.284 days of hospital stay.KPC colonization was present in 47 out of 607 (7.7%) screened patients at some time during their (often multiple hospitalizations); 11 bloodstream infections were reported in 9 patients (23%). Three deaths (3/11, 27%) due to KPC were reported before implementation screening (overall mortality rate was 6.3 % of colonized patients). KPC-decolonisation was achieved in 13/47 pts (28 %) after a median duration of 88 days (range 20-118).Most patients who recovered from KPC infection or were just colonized by KPC went on to receive additional chemotherapy without any life threatening KPC infection occurring (only one patient reported two septic episodes). Since screening cultures or further clinical cultures identified a progressive increase KPCcolonized or -infected patients, we decided to implement additional measures (Plan B). Therefore, from fourth trimester 2013 of study, we have observed a progressive decrease in rate of new colonization: 2 patients (4.17%) vs 15 patients (30%) in the third trimester, and a very low rate was maintained until the second trimester of 2014( 3 patients -4%).
Conclusions: The prevalence of KPC colonization in our hospital is high among patients with hematologic diseases.An implementation of additional measures, sharing the patients in single bed-rooms and consequently limiting transfer of cases from other wards, was able to contain KPC colonization and infection.However, the success of our preliminary interventions should be monitored constantly; besides, to prevent the emergence and further spread of CRE, a coordinated regional control effort among healthcare facilities should be recommended.
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No relevant conflicts of interest to declare.
Relapsed/refractory AML patients have a poor prognosis; allogeneic hematopoietic stem cell transplantation (HSCT) is the only chance in this setting to achieve long-term disease-free survival (1). ...It was previously established the activity of clofarabine plus cytarabine in AML relapse (clofarabine dosed once daily for 5 days with 40 mg/m2 followed 4 hours later by ara-C at 1 g/m2 per day)(2).However, modifications of this combination in AML therapy of relapsed/refractory patients warrant further evaluation. Therefore, our goal was to determine the efficacy and safety of clofarabine at lower dosage followed by cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and to evaluate the capacity of this regimen as a bridge for HSCT.
Patients aged 18-65 years with refractory/relapsed AML were treated at the dose of clofarabine 30 mg/mq on days 1-5 and cytarabine 1000 mg/mq gg on days 1-5. We evaluated the complete remission rate (CRR), duration of remission (DOR) and overall survival (OS). Minimal residual disease (MRD) by molecular targeting was considered in all patients.
Twenty-five (25) patients aged 29-64 years (median 47), who were fit for allogenetic HCT, received one cycle of 30 minutes infusion of clofarabine 30 mg/mq, followed 4 hours later by 3 hours infusion of intermediate dose cytarabine 1000 mg/mq days 1-5. Only in the first three patients this schedule was followed by gentuzumab. Nine (36%) patients had refractory disease (seven after one induction regimen, one after two previous regimes, one after a prior hematopoietic stem cell transplant (HSCT); 16 (64%) patients were in their first (12 patients) or second relapse (4 patients); among the 12 patients in first relapse, 5 were from an allogeneic stem cell transplant. Fourteen patients (56%) achieved a complete remission (CR), seven (28%) was refractory and 4 (16%) died of treatment related mortality. Eleven (44%) patients underwent (9 in CR) to allogeneic transplants or DLI infusion (3 patients refractory, and 8 patients relapsed), only one patient underwent to autologous transplant. One patient, who was relapsed after prior HSCT, obtained a CR but he developed acute graft vs host disease after therapy and died in molecular CR*. Among all patients underwent HSCT after Clofa/Ara-c salvage, six patients (50%) are still alive and in complete remission, six patients (50%) died because of HSCT complications or AML relapse. The complete remission rate (CRR) was (56,00 %), the median Overall Survival was 5 months for all patients (range 1-38 M), 11 Months for those underwent to tranplantation and 1,5 Months for non transplanted group. Treatment was complicated by neutropenic fever (n=17), grade III-IV mucositis (n=2) , skin rush (n=4) grade II- III, hepatic transaminase elevations (n=2). Two (n=5) patient died before their disease status could be evaluated.
These preliminary results suggest that combination treatment with clofarabine 30 mg/mq and ARA-C 1000 mg/mq is effective in this particularly poor prognosis category of patients, resulting in an ORR very favorably, representing a potential “bridge” toward bone marrow transplant procedures (among the 14 patients who achieved a CR, twelve (85%) proceeded to HSCT, and six are still alive). The safety profile is acceptable in this relapsed/refractory population, and our results are very similar to previous regimes using higher clofarabine dosages. More studies with this combination in adults are warranted.
1 Estey E. Treatment of relapsed and refractory acute myeloid leukemia. Leukemia. 2000;14:476-479. 2. Faderl S et al, “Results of a pase 1-2 study of clofarabine in combination with cytarabine (ara-C)”Blood 2005
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No relevant conflicts of interest to declare.
Abstract 3612
The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 ...mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) combined with the same drugs, in previously untreated AML < 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm/d for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU/d s.c. for 5 days per month) during one year. A total of 577 pts were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done in eligible pts. From 9/1999 till 1/2008, 2005 pts were randomized (891 by EORTC-LG and 1114 by GIMEMA). In addition 104 pts (GIMEMA) were registered to receive SD-AraC (+etoposide+daunorubicine) in induction. Due to insufficient reporting, 3 centers, who recruited 63 pts, have been excluded from the analysis. After 1 or 2 courses of induction, CR was achieved in 1500 pts. Between 4/2000 and 5/2008 544 pts have been randomized for the IL-2 question, of whom 528 (222 EORTC, 306 GIMEMA) met the eligibility criteria and were included in the analysis: 263 in IL-2, 265 in Observation (Obs) arm; the remaining pts have not been randomized due to prolonged hypoplasia after consolidation or after auto-SCT, or refusal of the patient or a planned allo-SCT. The two groups were well balanced with respect to the above mentioned stratification factors. Due to prolonged pancytopenia after auto-SCT, severe organ damage or infection after auto-SCT, early relapse or patient refusal, 165 pts actually received IL-2 and 197 pts were adequately documented in the Obs arm. During the first 4 months 82% of the pts in the IL-2 arm received a mean daily dose of 6 × 106 IU and 62% of the pts received the maximally required 20 s.c. injections; the remaining stopped due to relapse (22%) or toxicity (16%). During the second 4 months, out of 103 pts 82% in the IL-2 arm received a mean daily dose of 6 × 106 IU and 76% of the pts received the maximally required 20 s.c. injections; the remaining stopped due to relapse (15%), toxicity/refusal (6%) or other reasons (2%). During the third 4 months, among 79 of the pts in the IL-2 arm 80% received a mean daily dose of 6 × 106 IU and 85% of the pts received the maximally required 20 s.c. injections. Grade 3–4 toxicity was more frequent in the IL-2 compared to Obs arm and consisted of hypersensitivity (3% vs 0%), fatigue (7.9% vs 1%), rigor/chills (6.1% vs 0%), arthralgia/myalgia (3.6% vs 0%).
For the total of 528 pts, the median follow-up from the 2nd randomization was 6 years. As of July 2011, a total of 308 events were reported: 150 (IL-2 arm) vs 158 (Obs arm); among them 277 relapses (137 vs 140) and 31 deaths without relapses (13 vs 18). The DFS from 2nd randomization was similar in the 2 groups: the 5-yr DFS rate was 44.2% (IL-2) vs 40.4% (Obs), hazard ratio (HR)=0.95, 95% CI (0.76,1.19), p=0.66. A total of 259 pts died: 128 (IL-2 arm) vs 131 (Obs. arm). The 5-yr overall survival rate was 52.2% (IL-2) vs 50.9% (Obs), HR=0.98, 95% CI (0.77,1.26), p=0.9. The initial remission induction treatment (received/randomized) did not have impact on the results after the 2nd randomization.
This study shows that, with a median follow-up of 6 years, low dose IL-2 maintenance does not lead to a prolonged DFS and overall survival in pts with AML in first complete remission treated in the EORTC-GIMEMA AML12 trial.
Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. de Witte:Novartis: Consultancy, Honoraria, Speakers Bureau.
Abstract▪2214▪This icon denotes a clinically relevant abstract
Bernard-Soulier syndrome (BSS) has been historically described as an autosomal recessive disease, and more than 50 different mutations ...have been identified in homozygous or double-heterozygous patients. However, a few reports have suggested that BSS may be occasionally transmitted in an autosomal-dominant fashion. In 2001, we described six Italian families that were previously diagnosed with Mediterranean macrothrombocytopenia and possessed the monoallelic c.515C>T transition in the GPIBA gene, which results in a p.Ala156Val substitution (Bolzano mutation) in GPIb alpha (Savoia et al, Blood 2001;97:1330–5)
Since 2001, we have searched for this mutation in all patients referred to us for a non-syndromic, autosomal dominant form of inherited macrothrombocytopenia of unknown origin. Screening for the c.515C>T mutation identified 42 carriers and genetic molecular testing in all of the available relatives indicated that this mutation was present in 61 additional individuals. When the 42 families described here are added to the 6 families previously described, our database of 210 pedigrees of inherited thrombocytopenia includes 48 families with monoallelic, dominant BSS caused by the Bolzano mutation; 22 of the pedigrees have MYH9-related disease, 21 have thrombocytopenia 2 caused by ANKRD26 mutations (Noris et al, Blood 2011;117:6673–80), and 10 pedigrees have the classic biallelic, recessive form of BSS (Savoia et al, Haematologica 2011;96:417-23). Our experience therefore indicates that the Bolzano mutation is the most frequent cause of inherited thrombocytopenia in Italy. Analyses of the geographic origin of affected pedigrees and haplotypes indicated that this mutation originated in southern Italy.
The bleeding tendency was variable, with 42% of the cases presenting recurrent, spontaneous hemorrhages that only rarely were severe (5 patients required medical intervention and platelet transfusions). 19 women delivered 32 children (vaginal and caesarean births) with no platelet transfusions, and excessive bleeding was reported in one case only. None of the patients experienced abnormal bleeding associated with dental extractions or surgery. Thrombocytopenia was usually mild (a few subjects even had normal platelet counts), and electronic counters overestimated the degree of platelet deficiency with respect to manual counting with optical microscopy in a Neubauer chamber (Table 1). Platelets were larger than normal in most patients, and their GPIb/IX/V content was 50% of controls. However, in vitro platelet aggregation in response to ristocetin 1.5 mg/mL was defective only in 22% of cases. The serum thrombopoietin level was two-fold greater than that of healthy subjects and similar to that observed in a case series of patients with ITP. Beta 1-tubulin polymorphisms, which have been associated with platelet size and function (Freson et al, Blood 2005;106:2356–62), did not explain the variation in clinical and laboratory features of our patients.
In conclusion, our study indicates that the monoallelic Bolzano mutation is a frequent cause of macrothrombocytopenia in Italy and that this mutation induces a mild form of BSS that is often misdiagnosed with ITP. Further analyses in other countries will reveal whether this form of the disease is exclusive to Italy or if it also affects other populations.Table 1Platelet count and size in patients with the Bolzano mutation in GPIb alpha.PatientsControlsmean±SD (range)Manual platelet count, x10e9/L114±36† (42–184)276±50 (170–420)Impedance platelet count, x10e9/L89±33**,† (21–147)255±53 (141–396)Optical platelet count, x10e9/L103±32*,† (21–162)280±54 (164–412)MPV, fL, by optical counter15±1.7† (9.7–17.8)8.2±0.8 (7.1–11.1)MPD, um, by optical microscopy3.6±0.5† (2.6–5.1)2.4±0.3 (1.9–3.4)*: p<0.05,**: p<0.001 compared to manual method;†: p<0.001 compared to normal subjects
Cattaneo:Eli Lilly Daiichi Sankyo: Honoraria; AstraZeneca: Honoraria, Research Funding.
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