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  • 1
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 34-35
    Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely utilized as a curative treatment for malignant and non-malignant hematological conditions. Fluoroquinolone prophylaxis (FQ-P) is demonstrated to reduce the rate of blood stream infections (BSI) caused by gram-negative bacteria (GNB) during allo-HSCT and increases overall survival (OS), making this approach the standard of care. The available data show that during the transplantation period, the intestinal microbiome diversity profoundly decreases, which is associated with a significant increase in transplant-related mortality (TRM), acute graft-versus-host disease (aGVHD) related mortality and decrease in OS. FQ-P is reported to be a dominant factor in the perturbation of the gut microbiota, leading some centers to omit or modify transplant antibiotic prophylaxis regimens. The aim of the present study has been to evaluate the effects of FQ-P omission on the prevalence of gram-negative bacteria blood stream infections (GNB-BSI), GNB susceptibility to antibiotic treatment, mortality of patients with sepsis and overall TRM. This retrospective single-center study included all consecutive patients, admitted to the Rambam Department of Hematology for allo-HSCT between 01.01.2017 and 31.12.2019. The fact that at our center, FQ-P in allo-HSCT recipients was discontinued on 01.12.2018 allowed comparison of the outcomes in patients treated with and without such prophylaxis. GNB-BSI events registered within 30 days of admission were analyzed. The proportion of first-time GNB-BSI, the antibiotic susceptibility profile, day 30 and day 90 mortality among patients with GNB-BSI were compared. The assessment also included day 30 and day 90 overall TRM, mortality related to sepsis and aGVHD. During the evaluated period, 189 patients underwent allo-HSCT and were included in the analysis. FQ-P was administered to 125 patients and omitted in 64 individuals. GNB-BSI events occurred in 23 (18.4%) patients receiving FQ-P and in 17 (26.6%) patients who did not receive it (p=0.19). GNB susceptibility to FQ, piperacillin/tazobactam and meropenem increased from 38.1% to 58.8%, from 60% to 70.6% and from 85.7% to 94.1%, respectively, after FQ-P had been stopped (p=non-significant, NS). 30-day and 90-day mortality among patients with GNB-BSI did not increase in the post-FQ-P period (Table 1). Day 30 and day 90 overall TRM rates were 10.6% and 18.9%, respectively, with FQ-P versus 13.5% and 21.9%, respectively, without FQ-P (p=NS). Before FQ-P was stopped, sepsis was the cause of death in 56% of events and aGVHD in 16% and after FQ-P was stopped, the corresponding values were 46% and 23%, respectively (p=NS). FQ-P omission has not significantly increased the rate of GNB-BSI or affected the profile of GNB susceptibility to antibiotic treatment in patients undergoing allo-HSCT. Moreover, it has not significantly changed day 30 and day 90 mortality either among patients with GNB-BSI or in the entire study population. FQ-P omission in allo-HSCT recipients appears to be safe and its implementation could contribute to the preservation of intestinal microbiome diversity, potentially leading to improved post-transplant outcome. The findings of this study need to be further evaluated in large randomized trials. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 2
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    Online Resource
    Informa UK Limited ; 2018
    In:  Leukemia & Lymphoma Vol. 59, No. 3 ( 2018-03-04), p. 610-616
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 59, No. 3 ( 2018-03-04), p. 610-616
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2018
    detail.hit.zdb_id: 2030637-4
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  • 3
    Online Resource
    Online Resource
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 1421-1421
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1421-1421
    Abstract: Data on pregnancy-associated acute myeloid leukemia (PA-AML) are scanty, coming from case reports and very small retrospective case series. The aim of the current study was to analyze reported maternal and fetal clinical characteristics and treatment decisions and provide a comprehensive basis for the development of guidelines for the management of women with PA-AML. Methods A systematic search of articles on PA-AML diagnosed during pregnancy or immediately after delivery, published between January 1967 and June 2013 in journals indexed in PubMed, was performed. Search terms of “acute leukemia”, “acute myeloid leukemia” and “acute promyelocytic leukemia” (APL) were crossed with terms “pregnancy”, “gestation” and “partum”. Additional potentially relevant reports referenced in reviewed articles were evaluated. Data on women's age, gestational stage, AML subtype, therapy, timing of its application, achieving complete remission (CR), survival status and fetal outcome (malformations, survival, birth weight) were recorded. Results One hundred and seventy three PA-AML cases, reported in 88 papers, were analyzed. AML was reported in 120 cases (69%) and APL in 53 cases (31%). The French-American-British (FAB) AML categorization, available for 59 non-M3 AML cases, showed the distribution of AML subtypes similar to that reported in non-pregnant women (M1 - 3%, M2 - 12%, M4 - 30%, M5 - 27%, M6 - 5%, M7 - 1%). Median age at diagnosis was 28 years (range 15-45). Thirty seven women (22%) were diagnosed during 1st trimester, 85 (50%) in 2nd and 47 (28%) in 3rd trimester. The trimester was not reported in 4 cases. One hundred and twenty five women received chemotherapy during pregnancy: 18 in whom therapy was started in 1st trimester, 81- in 2nd and 26 - in 3rd trimester. In 46 patients, treatment was administered either after elective abortion (n = 26), or after delivery of a live baby (n =20). Data on therapy were unavailable in 2 cases. Delay in therapy beyond 1 week (range 2-20) from diagnosis (n = 21) did not affect the overall survival (OS) compared to that obtained in women treated promptly (median 11.5 vs 10.5 months, respectively; p=0.572). Among patients for whom remission data were available (n=151), 82 (73%) treated during pregnancy, and 27 (70%) treated after delivery, achieved CR. Within a median follow-up of 9 months (range 0-300), median OS for the entire cohort was 10.5 months (9 for AML vs 15.5 for APL; p=0.001). A multivariate analysis showed APL to be the only independent predictive factor for an improved OS (p=0.037), while maternal age and treatment delay had no statistically significant impact on OS (p= 0.83 and 0.889, respectively). Notably, the OS of women with PA-AML tended to improve over time (19 months for women treated over the last 30 years vs 8 months for those treated earlier; p = 0.09) (Figure 1); however, it is still less than the median OS of 3 years reported in age-matched non-pregnant women (http://seer.cancer.gov). One hundred and forty seven pregnancies were evaluable for the fetal outcome (excluding elective abortions); 117 (80%) pregnancies ended in delivery of a live baby. Six pregnancies where fetuses were exposed to chemotherapy during the 1st (n=1) or 2nd (n=5) trimester resulted in delivery of malformed newborns; 28 pregnancies ended in fetal death (5 stillbirths, 13 intrauterine fetal deaths, 4 post-delivery deaths, 5 unplanned abortions, 1 cause unavailable). Fetal outcome was unavailable for 2 babies. The median birth weight was 2.3 Kg for the 89 babies with reported weight (range 1.7-5 Kg). Among the 83 babies for whom data about birth weight and pregnancy week were available, 59% had a weight appropriate for the gestational age, 30% were small for gestational age and 11% were large for gestational age. In 89% of cases where information was available, the delivery was pre-term. No case of fetal leukemia was reported. Conclusions Based on our retrospective analysis, the outcome of women diagnosed with AML during pregnancy appears to be worse than that reported in age-matched non-pregnant women. The survival rate of the fetuses exposed to chemotherapy is encouraging. The incidence of malformations is low and the birth weight of most newborns is appropriate for the gestational age. Therapy delay could be considered in some of these patients, but large registry-based studies are warranted to establish treatment recommendations for the management of PA-AML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 4081-4081
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 4081-4081
    Abstract: Heparanase activity is implicated in cell invasion, tumor metastasis and angiogenesis. Recently, we have reported that heparanase stimulates tissue factor (TF) expression in endothelial and cancer cells, resulting in elevation of coagulation activity (Nadir et al. JTH, 2006). We also found that heparanase releases tissue factor pathway inhibitor (TFPI) from endothelial and tumor cells, contributing to the local procoagulant balance (Nadir et al. TH, 2008). Heparanase was cloned from and is abundant in the placenta. We investigated the role of heparanase in the placenta, focusing on its effect on TF, TFPI, TFPI-2, and vascular endothelial growth factor-A (VEGF-A). Twenty formalin embedded samples of early pregnancy losses (weeks 5–10) were studied. Ten cases were miscarriages of women with thrombophilia and recurrent fetal losses, and ten control cases were pregnancy terminations. Applying real time RT-PCR and immunostaining for heparanase, TF, TFPI, TFPI-2, and VEGF-A it was found that in fetal losses related to thrombophilia the levels of heparanase, VEGF-A and TFPI-2 were significantly increased (2–3 fold) compared to placentas from controls. Next, JAR (human choriocarcinoma throphoblast) cells were transfected to overexpress the full length (65 kDa) heparanase or incubated with active (50+8 kDa) recombinant heparanase. Immunoblotting and real time RT-PCR showed that throphoblasts overexpressing or incubated with exogenous heparanase exhibited a 2–3 fold increase in TFPI and TFPI-2 in cell lysates both at the protein and mRNA levels, with no detectable effect on VEGF-A and TF. Accumulation of TFPI and TFPI-2 in the cell culture medium was increased 5–6 fold, exceeding the observed induction of TFPI and TFPI-2 gene transcription. Extracellular accumulation of TFPI and TFPI-2 was already evident 60 min following heparanase addition, prior to protein induction, indicating an active release of preformed proteins. These results indicate a regulatory effect of heparanase on TFPI and TFPI-2 in throphoblasts, suggesting a potential involvement in early miscarriages.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 5
    Online Resource
    Online Resource
    Georg Thieme Verlag KG ; 2014
    In:  Thrombosis and Haemostasis Vol. 112, No. 09 ( 2014), p. 466-477
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 112, No. 09 ( 2014), p. 466-477
    Abstract: Heparanase is implicated in cell invasion, tumour metastasis and angiogenesis. It forms a complex and enhances the activity of the blood coagulation initiator – tissue factor (TF). We describe new peptides derived from the solvent accessible surface of TF pathway inhibitor 2 (TFPI-2) that inhibit the heparanase procoagulant activity. Peptides were evaluated in vitro by measuring activated coagulation factor X levels and co-immunoprecipitation. Heparanase protein and/or lipopolysaccharide (LPS) were injected intra-peritoneally and inhibitory peptides were injected subcutaneously in mouse models. Plasma was analysed by ELISA for thrombin-antithrombin complex (TAT), D-dimer as markers of coagulation activation, and interleukin 6 as marker of sepsis severity. Peptides 5, 6, 7, 21 and 22, at the length of 11–14 amino acids, inhibited heparanase procoagulant activity but did not affect TF activity. Injection of newly identified peptides 5, 6 and 7 significantly decreased or abolished TAT plasma levels when heparanase or LPS were pre-injected, and inhibited clot formation in an inferior vena cava thrombosis model. To conclude, the solvent accessible surface of TFPI-2 first Kunitz domain is involved in TF/heparanase complex inhibition. The newly identified peptides potentially attenuate activation of the coagulation system induced by heparanase or LPS without predisposing to significant bleeding tendency.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2014
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  • 6
    Online Resource
    Online Resource
    Elsevier BV ; 2010
    In:  Thrombosis Research Vol. 125, No. 5 ( 2010-5), p. e251-e257
    In: Thrombosis Research, Elsevier BV, Vol. 125, No. 5 ( 2010-5), p. e251-e257
    Type of Medium: Online Resource
    ISSN: 0049-3848
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
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  • 7
    Online Resource
    Online Resource
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 378-378
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 378-378
    Abstract: Abstract 378 Background: Heparanase that is abundant in platelets and neutrophils is implicated in cell invasion, tumor metastasis and angiogenesis. Recently, we demonstrated that heparanase is directly involved in the regulation of the hemostatic system. Heparanase was shown to form a complex and enhance tissue factor (TF) activity, resulting in increased factor Xa production (Nadir et al, Haematologica, 2010). In the present study, the effect of heparanase on sepsis was investigated. Methods: ICR mice, heparanase knock-out mice and heparanase over-expression mice were studied. Sepsis was induced by intra-peritoneal injection of lipopolysaccharides (LPS). Four hours after injection, blood was obtained via temple plexus puncture followed by mice sacrificing. Levels of thrombin-antithrombin (TAT), D-Dimer and IL-6 were tested using ELISA. Plasma factor VII levels were evaluated using the Western blot analysis and fibrinogen levels in the lung, kidney and spleen were estimated by immunostaining. Results: Intra-peritoneal injection of heparanase (0.5μg/mg) compared to PBS injection, increased the TAT (p 〈 0.05) and D-Dimer (p 〈 0.05) levels, which were similar to the ones induced by LPS (5μg/mg), although the IL-6 levels did not rise and mice did not show signs of illness. Moreover, heparanase injection half an hour following LPS administration resulted in reduced levels of TAT, D-Dimer, fibrinogen and of factor VII (p 〈 0.001), increased levels of IL-1 (p 〈 0.001) and profuse blood leak from puncture, compatible with severe disseminated intravascular coagulation (DIC). Similarly, injection of LPS to heparanase knock-out mice led to lower levels of TAT (p 〈 0.001), D-Dimer (p 〈 0.001) and IL-6 (p 〈 0.001) compared to control mice, while injection of LPS to heparanase over-expression mice resulted in DIC. Conclusions: Heparanase is found to induce activation of the coagulation system without inflammatory response. It also contributes to laboratory enhancement of sepsis resulting in DIC. Inhibitors of heparanase may potentially attenuate morbidity and mortality in sepsis. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 8
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3893-3893
    Abstract: Rapid eradication of blasts from peripheral blood during induction therapy in AML is associated with remission and overall survival. We prospectively evaluated the value of a bone marrow (BM) examination on day 5 of induction therapy in unselected newly diagnosed AML patients assigned for intensive induction. Seventy nine patients were enrolled during a 29-months period in six medical centers in Israel. BM blasts were evaluated by two independent observers and in most cases with the support of FACS analysis. Induction protocols administrated were 3+7 with daunorubicin 60 or 90 mg/m2 or clofarabine 40mg/m2 for five days [58 (73%), 10(13%) and 11(14%) patients, respectively]. Patients’ median age was 59 (range 22-78) years. Among surviving patients the actual follow-up time was longer than 9 months in 25(48%) patients and longer than 12 months in 16 (30%) patients. Cytogenetic results are available for 70 patients [2(3%), 47(67) and 21(30%) with standard, intermediate and poor risk, respectively] . Flt3ITD mutation was present in 11(13.9%) patients and NPM1 mutation, in 12 who presented with normal karyotype and were negative for FLT3-ITD. Treatment protocol was not altered on the basis of day 5 BM examination which was repeated on day 12-14. Residual disease ( 〉 10% blasts) was detected and a re-induction protocol (repeat 3+7 at doses of 60 or 45mg/m2 at day 14 or clofarabine 30mg/m2 on day 21) was administered in 20(25%) patients. Overall, 50(72%) patients achieved remission (CR1). Post-remission therapies varied according to patient age and risk factors. Overall, 29(37%) patients underwent allogeneic stem cell transplantation. During the study period, 27(34.2%) patients succumbed, 5(6.3%) during induction, 8(10%) while in remission and 12(15%) following relapse. Day 5 blast counts higher than 10% of all BM nucleated cells predicted for the identification of residual leukemia on day 14 regardless of BM cellularity. Moreover, day 5 counts lower than 10% of all BM nucleated cells predicted for the achievement of CR1 with a single induction course. The 10% cutoff for BM day 5 blast count accurately identified these patients with a sensitivity of 80% and specificity of 74%. Kaplan Meir analysis demonstrated superior overall survival (OS) and lower relapse rate (figure 1a & b) of rapid responders than those with more than 10% blasts in day 5 BM. The 2-year anticipated OS is 80% and 35% (p=0.05), respectively. For the 50 patients who achieved CR1, the predicted 2-year relapse rate was as low as 8% for patients with a low day 5 BM blast count and 82% in the group of higher day 5 BM blasts (p=0.004).Figure 1Figure 1. Bone marrow day 5 aspiration was not always informative and in seven cases where biopsy was not available the blast content couldn’t be assessed. Of the 72 patients with a valid day 5 blasts count, 24 (33%) were rapid responders in whom blasts were less than 10% of BM nucleated cells. On day 14, a lower than 10%, blast count was recognized in 54% of patients. However, 11/16 (69%) of patients who despite high blast counts at day 5 had a low count at day 14, either failed to achieve remission or relapsed. Only 5 patients presented with a low blast count at day 5 had a day 14 blasts count higher than 10%. Rapid response on day 5 was not associated with age or molecular status; yet, there was a trend (p=0.08) towards lower frequency of poor cytogenetics among these patients. Surprisingly, mean presenting WBC was higher among rapid responders. Conclusion Bone marrow blast count on the fifth day of induction during chemotherapy is a powerful predictor of AML prognosis, irrespective of other pre-treatment risk factors. Larger studies, with longer follow up are required to determine its role in clinical management. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 9
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3935-3935
    Abstract: Introduction: Acute graft-versus-host disease (aGVHD) is a major limitation of allogeneic stem cell transplantation (alloSCT) due to associated morbidity and mortality. A search for biomarkers that predict its occurrence is continuously evolving. Regulatory T cells (T regs) have been shown to suppress the early expansion of alloreactive donor T cells and limit the capacity to induce GVHD without minimizing the graft-versus-leukemia (GVL) effect. Recently, the role of regulatory B cells (B reg) in GHVD was demonstrated, with exacerbation of GVHD in both donor and host mice lacking functional regulatory B cells. Semaphorin 3A (Sema3A) is an immunoregulatory molecule secreted by activated B, T and antigen presenting cells. It enhances suppressor ability of B and T regulatory cells by increased secretion of interleukin-10 (IL-10) and transforming growth factor β (TGF-β). The aim of the present study was to explore whether Sema3A expression on B reg and T reg cells from donors and/or recipients pre- or early post-transplantation can predict occurrence of aGVHD. Methods: Thirty four consecutive patients referred to alloSCT were included in the first study cohort. Additionally, 10 donor/recipient (D/R) pairs were enrolled. All participants signed informed consent. 20 cc of fresh peripheral blood were drawn from recipients at day -7 pre-alloSCT and upon WBC engraftment, as well as from their corresponding donors. Mononuclear cells were isolated using ficoll gradient separation and subjected to FACS analysis using monoclonal antibodies evaluating the level of Sema3A expression on B reg cells (CD19/CD25high/ Sema3A), T reg cells (CD4/CD25high/Sema3A) and natural killer (NK) cells (CD3/CD56). Cutoff for positive expression of Sema3A on regulatory cells was considered only if ≥20% of cells expressed the above phenotype of T, B cell and NK population. The FACS results correlated with occurrence of clinical aGVHD grade II-IV. Descriptive statistical analysis and student t test are used to describe results. Results: Overall, 44 recipients were analyzed. Median age at transplant was 49.9 (18-69), 34 were diagnosed with acute leukemia/MDS, 8 - lymphoproliferative and 2 - myeloproliferative diseases. All patients received peripheral mobilized stem cells. Myeloablative conditioning was administered to 33 and reduced intensity to 11 patients. GVHD prophylaxis consisted of standard cyclosporine and methotrexate. Twenty patients developed aGVHD grade II-IV, mostly grade II –III (80%). Recipient expression of Sema3A on B cells pre-transplant was higher in patients without aGVHD versus those with aGVHD (79.9% vs 69.5%, respectively; p 〈 0.005) while pre-transplant expression of Sema3A on T cells was similar in patients without and with aGVHD (57.3% vs 58.6%, respectively) (fig 1). Post-transplant, recipient expression of Sema3A on B and T cells was similar in patients without and with aGVHD (B cells: 84.1% vs 79.1%, T cells 62.6 vs 58.4, respectively) (fig 2). In donors, the expression of Sema3A on regulatory T cells was higher if their recipients did not develop aGVHD as compared to the expression in donors with recipients who developed aGVHD (51.0% vs 36.2%). Sema3A expression on regulatory B cells was not different in donors, no matter whether recipients did not or did develop aGVHD (52.2% vs 55.0%, respectively) (fig 3). Sema3A expression on NK cells was below our determined threshold. Conclusion: This is the first report of a correlation of Sema3A expression with the occurrence of aGVHD, opening a potentially important opportunity for early clinical intervention. Specifically, 1. Pre-transplant recipient Sema3A expression on B reg cells is significantly higher in patients who will not develop aGVHD. 2. Pre-transplant high expression of Sema3A on donor T reg cells is associated with a lower risk of aGVHD development in their corresponding recipients. 3. Sema3A expression on recipient T reg cells does not correlate with occurrence of aGVHD. Further studies with a larger patient cohort validation are needed to confirm the above findings. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 10
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5654-5654
    Abstract: Introduction: Acute lymphoblastic leukemia (ALL) and mixed phenotype acute leukemia (MPAL) in adults are associated with a cure rate of only 20 and with a tendency for relapse to the CNS. Total body irradiation (TBI)-based high dose therapy and allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for these patients, however, the median age for ALL in adults is 65 years and thus, majority of patients are not suitable candidates for high dose conditioning and HCT. Therefore, novel approaches are needed. Thiotepa is an alkylating lipophilic agent that result in achieving up to 100% cerebrospinal fluid levels and has been used in ablative regimens (total dose of 20 mg/kg), Christopoulos BBMT 2012. Methods: We aimed to test this regimen in patients with ALL/MPAL who were not eligible for a standard TBI-containing regimen and capped the thiotepa dose at 14 mg/kg (for patients given myeloablative regimen divided to 2 doses on Day -5 and -4) or at a dose of 10-12 mg/kg (in patients given a reduced intensity regimen). In addition patients were given BCNU at a dose of 400 mg/m^2 on Day -6 and fludarabine at a dose of 25 mg/m^2 on Day -6 to -4. We omitted entirely cranial irradiation, however Intrathecal (IT) therapy was allowed pretransplant (only) as per physician discretion. GVHD prophylaxis consisted of cycslosporine-methotrexate and ATG in cases of non-sibling donors. Results: Between July 2014 and June 2019, 22 patients from 3 centers in Israel were eligible for the protocol. Median follow up was 17 (range, 3-61) months. Median age at transplant was 51 (range, 22-68), Table. Majority of the patients (59%) had a CR1 with MRD negative disease . Ten patients (45%) were given a myeloablative regimen ( 〉 14 mg/kg of thiotepa) and 12 patients (55%) were given a reduced intensity regimen (10-12 mg/kg of thiotepa), majority (7 patients, 32%) because of age 〉 60 years. Eight patients (36%) had a sibling donor, 12 patients (55%) had an unrelated donor and 2 (9%) had a 1 antigen-mismatch unrelated donor. GVHD prophylaxis consisted for all patients cyclosporine and a short course of methotrexate.Three patients (14%) developed sinusoidal obstruction syndrome (1 patient, severe). 7 patients (32%) had microbiology documented infections and 16 patients (73%) had grade 3-4 mucositis. All patients who survived (n=18, 82%) had a day 30-whole marrow donor chimerism 〉 96%. Cumulative incidences of grade 2-4 and grade 3-4 acute GVHD at day 200 were 51%(95% CI 35%-62%) and 11%(95% CI 5%-24%), respectively. Cumulative incidence of 2 year-moderate-severe chronic GVHD was 52% (95% CI 41%-74%). Relapse occurred in only 3 patients and all occurred within 4 months from HCT with a 2 year cumulative incidence of 17%(95% CI 12%-21%). Cumulative incidences of non-relapse mortality at 30 days, 3 months and 2 years after HCT were 15%(95% CI 8%-17%), 24%(95% CI 12%-32%) and 24%(95% CI 12%-32%), respectively. At time of data extraction 14 patients were alive. Cumulative Incidences of 2-year overall survival for CR1 patients with MRD negative disease and for non-CR1 patients with MRD negative disease at HCT were 70%(95% CI 61%-87%) and 62%(95% CI 50%-73%), respectively (p=.59), Figure. Factors associated in cox regression model with decreased overall survival were CNS involvement at diagnosis (p=.06, HR=2.24) and older age (p=.045, HR=1.5), while disease status at HCT, having a sibling donor, and intensity of conditioning were not predictive. Conclusions: This study shows that a thiotepa based regimen has substantial activity in patients with ALL, even in those who are older than 60 years and in patients intelligible to TBI. Reduced doses of thiotepa may have comparable efficacy and a lower toxicity profile when compared to higher doses and should be further investigated in this cohort of patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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