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  • 1
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    Incidence, Risk Factors and Clinical Outcome Of Leukemia Relapses Due To Loss Of The Mismatched HLA Haplotype After Partially-Incompatible Hematopoietic Stem Cell Transplantation
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 918-918
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    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 918-918
    Abstract: Introduction Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) represents the best curative option for many patients with high-risk myeloid malignancies, mainly due to its potent immuno-mediated antileukemic effect. Still, post-transplantation relapse remains an unsolved issue. We and others described genomic loss of the mismatched HLA haplotype as a mechanism by which leukemic cells evade donor T cell-mediated immune pressure and cause clinical relapse after partially HLA-incompatible HSCT (Vago et al, N Engl JMed, 2009), but the actual incidence and risk factors of this phenomenon are to date largely unknown. Methods We analyzed retrospectively 224 consecutive partially HLA-mismatched HSCTs performed in our Institute in the last ten years (Unrelated Donor, UD: 60; Mismatched Related Donor, MMRD: 164) in patients affected by myeloid malignancies (Acute Myeloid Leukemia, AML: 173; Myelodisplastic Syndrome, MDS: 27, Myeloproliferative Neoplasms: 17; others: 7). All patients received myeloablative conditioning and infusion of donor T cells, either as part of the graft or as an add-back. Patients’ follow-up included bone marrow genomic HLA typing to identify HLA loss relapses. In selected cases of HLA loss relapse cryopreserved serial serum samples harvested after HSCT were analyzed for the eventual presence of anti HLA Class I or Class II antibodies. Results We documented 77 cases of relapse: 66 after MMRD and 11 after UD HSCT. Out of 77 relapses 21 (27%) were due to genomic loss of the mismatched HLA in leukemic cells. HLA loss occurred in 19 patients with AML, one with MDS and one with myelofibrosis. All the 21 cases of HLA loss occurred after MMRD HSCT (32%), so the analysis for putative risk factors were limited to this subgroup of transplants (n=164), comparing the frequencies of putative risk factors between patients with HLA loss and “classical” relapses (n=21 and 45, respectively). HLA loss relapses occurred significantly later than their classical counterparts (median time to relapse 307 vs 86 days, p 〈 0.0001) in this very high-risk population, suggesting that outgrowth of the mutant variants require a considerable lapse of time. None of the disease-related factors we addressed (amongst which disease subtype, cytogenetics, molecular profile and disease status at HSCT) correlated significantly with eventual HLA loss. Use of an unmanipulated T cell-repleted graft resulted to be a risk factor for HLA loss relapses (Chi2=6.36; p=0.01). Both acute (HR:4.67, CI 95%: 1.53-14.22; p=0.007) and chronic (HR: 1.71; CI 95%: 0.68-4.28; p=0.01) Graft-versus-Host Disease (GvHD) occurred more frequently in patients with HLA loss relapses. Intriguingly, HLA-C*04 was more frequent in the mismatched haplotype of patients with HLA loss as compared to those with classical relapse (Chi2= 8.07; p=0.04), possibly suggesting an higher immunogenicity of the allele, hinted also by a similarly higher frequency in patients who did not relapse (Chi2=2.77; p=0.096). In our series, predicted NK alloreactivity had no apparent impact on eventual HLA loss. In none of the five patients studied to date we could evidence circulating anti-HLA antibodies, suggesting that humoral immunity does not play a major role in this phenomenon. Since lymphocyte infusions from the original donor are expected to be inefficacious to treat HLA loss relapses, whenever fit these patients were candidate to re-transplantation from alternative donors, HLA-mismatched and putatively alloreactive against the relapsed leukemia. Still, outcome was poor, with 5 of 8 re-transplanted patients dying of transplant-related mortality and only one alive in complete remission at a follow-up of 18 months. Conclusions Genomic loss of the mismatched HLA haplotype is an extremely frequent mechanism of leukemia immune evasion and relapse after MMRD HSCT. It appears to be prompted by selective immune pressure mediated by donor-derived T cells, and accordingly occurs more frequently upon T cell-repleted transplants and in the presence of acute and chronic GvHD, clinical hallmarks of T cell alloreactivity. Conversely the role of NK and B cells in HLA loss needs further investigation, but appears to date less pronounced. Given the poor outcome of re-transplantation, mainly due to toxicity, novel diagnostic and therapeutic approaches are needed to anticipate the detection and improve the treatment of these frequent variants of leukemia relapse. Disclosures: Bordignon: MolMed SpA: Employment. Bonini:MolMed SpA: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.918.918
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 2
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    Allogeneic Transplantation with a Treosulfan-Fludarabine Conditioning Regimen Is Feasible and Effective in Elderly Patients with Refractory or Relapsed Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndrome (MDS); Preliminary Results From a Single Center Experience.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4318-4318
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4318-4318
    Abstract: Abstract 4318 Background the majority of AML and poor risk MDS cases in the elderly ( 〉 60 years) are resistant to induction chemotherapy or relapse after initial response; thereafter, most of these patients (pts) receive only supportive treatments, with an expected survival of few weeks. Allogeneic (allo) stem cell transplantation (SCT) could be the only potentially salvage strategy; actually, for the high probability of letal toxicites due to the conditioning regimen, acute graft-versus-host disease (aGvHD) and infections, these pts are rarely offered this procedure. Since 2005, we have transplanted 12 pts, age 〉 60, with refractory or relapsed AML/MDS, from an allogeneic donor. Data on feasibility and outcome are here reported. Aim to retrospectively evaluate data on alloSCT in elderly pts with refractory or relapsed AML and MDS, transplanted at our Institute. Patients and Methods period 9/2005 to 4/2009, 12 pts, median age 65 (61-72). Performance status (Karnofsky): median 90% (80-100), HCT-CI: median score 1 (0-4). Diagnosis (WHO): AML 3, AMLMD 4, RAEB2 2, MDS/MPD 2, therapy-related AML 1. Median number of chemo cycles before SCT: 2 (1-7), all pts received at least 1 cycle with intermediate or high-dose cytarabine, 2 pts also received an autologous SCT. Donors: matched sibling 2, matched unrelated 2, related haploidentical 7, cord blood 1. Disease status at SCT: primary refractory 7, relapsed 5. Conditioning regimen: treosulfan (TREO) 14 g/sqm for 3 days, fludarabine (FLU) 30 mg/sqm for 5 days, ATG 10 mg/kg for 3 days for SCT from alternative donors. GvHD prophylaxis: T-cell depletion in 2 cases, cyclosporine (CSA)/methotrexate in 7, rapamycin/mycophenolate mofetil (MMF) in 3. Results 11/12 (92%) pts engrafted and were in CR at day +30, with 95-100% donor chimerism (VNTR). Deaths within day 30 and day 100 were 0 and 3 (25%), respectively. Acute GvHD: 6 pts (55%), grade II (3) or III (3), only of skin in 3 cases, skin+liver in 1, only intestinal in 2. Relapses were 4 (36%). Overall TRM was 25% (3 pts), with all deaths due to infections during immunosuppression for aGVHD; 5 more pts died because of disease progression. Median OS from SCT of all 12 pts was 180 (56-1150) days, DFS (11 pts) was 128 (24-1114) days. At last follow-up (FU) 4 pts (33%) are alive, all in CR with a median FU of 406 (128-1150) days. Conclusions alloSCT proved to be feasible in our elderly pts with AML/MDS refractory to induction or relapsed after initial complete remission. Early letal toxicities, due to the conditioning treatment, were absent; aGVHD, infections and relapses were the principal causes of mortality. Up to now, prolonged survival ( 〉 1 year) free from disease has been obtained in 25% of pts; of the 4 pts alive in CR, only 1 is receiving immunosuppression (CSA), for chronic GVHD. In conclusion, the TREO-FLU association showed a reduced-toxicity profile in these frail pts and a substantial anti-leukemic effect. Better prevention of aGVHD should be obtained, expecially after SCT from alternative donors, possibly with the rapamycin/MMF combination, which we are currently investigating at our Institute. AlloSCT after TREO-FLU conditioning can be considered an effective option for AML/MDS elderly pts with active disease after failure of previous intensive treatments. Disclosures: bonini: MolMed S.p.A.: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.4318.4318
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 3
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    Pharmacokinetics (PK) Study Of Antithymocyte Globulins Fresenius (ATG-F) Prior To Allogeneic Stem Cell Transplantation: Implications For Timing Of Graft and Early Adoptive Immunotherapy Infusions
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4536-4536
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    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4536-4536
    Abstract: Antithymocyte globulins Fresenius (ATG-F) are purified, concentrated preparations of polyclonal immunoglobulin G from hyperimmune serum of rabbits immunized with human thymus activated lymphocytes. These immunoglobulins induce immunosuppression through T-cell depletion and immune modulation. The polyclonal nature of ATG-F is responsible for its effects on the immune system: T-cell depletion in blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis; modulation of molecules involved in leukocyte-endothelium interactions; induction of apoptosis in B-cell lineages; interference with dendritic cells. ATG-F administered before allogeneic hematopoietic stem cell transplantation (allo-HSCT) reduces the risks of graft rejection and graft-versus-host disease (GvHD), but the slow clearance of the xenoserum might delay immune reconstitution, increase the risk of disease relapse and impair the activity of a donor lymphocyte infusion (DLI) performed early after allo-HSCT. Methods We studied 24 patients with hematologic malignancies, who underwent allo-HSCT from familiar or unrelated donors, after a conditioning regimen based on myeloablative treosulfan and fludarabine. As graft rejection and GvHD prophylaxis, 17 patients received ATG Fresenius at the dose of 10 mg/kg over 16 hours at day -4,-3 and -2 before HSCT; 5 patients received in vivo T-cell depletion at the dose of 20 mg/kg at day -4,-3 and -2 before HSCT; 2 more patients received ATG Fresenius at the dose of 10 mg/kg much earlier before allo-HSCT (day -14, -13 and -12) since the treatment protocol included a donor DLI at day +3 after transplantation. We collected serum samples at different timepoints, from the first ATG dose to at least 3 weeks after HSCT. We used a flow cytometry-based assay to detect the concentration of free T-cell specific rabbit IgG (SRIgG) which corresponds to the serum biological activity against human T-lymphocytes, as opposed to the levels of unspecific rabbit IgG (RIgG) by ELISA, which lack anti-T-cell function. Results In our cohorts of patients we observed a concentration peak at 64 hours after the first ATG administration, corresponding to the end of the last immunoglobulin dose administration. Interestingly, patients who received the 20 mg/kg dose of serum reached four times higher levels of SRIgG, suggesting a non-linear correlation between the administered dose and the measured plasmatic peak concentrations. Moreover, the terminal elimination half life of SRIgG is significantly shorter than the one of RIgG: 14 vs 67 days (data not shown), indicating that, for the dose of 10 mg/kg, 10 days after HSCT, SRIgG titre has already reached sub-therapeutic levels. Conclusions Previous results indicated that in vivo specific activity of rabbit ATG Fresenius disappears from circulation around day +7 after their last administration (at the dose of 10 mg/kg, day -4, -3, 2). Based on our current data, we can suggest that residual specific anti-lymphocyte activity is dependent upon i. timing and ii. dosage of ATG administration, although this correlation might not be linear. According to these results, current policies of a fixed schedule for DLI infusion should be revisited and possibly adapted to each patient, based on specific conditioning protocols. Disclosures: Seitz: Fresenius Biotech GmbH: Employment. Martinius:Fresenius Biotech GmbH: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4536.4536
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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    Monitoring of Wilms' Tumor Gene 1 Levels Predict Early Relapse After Allogeneic Hematopoietic Stem Cells Transplantation in Patients with High Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 4102-4102
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4102-4102
    Abstract: Abstract 4102 Background: several approaches have been used in AML and MDS patients (pts) in Complete Remission (CR) to detect Minimal Residual Disease (MRD) and predict the risk of relapse. The Wilms' tumor gene 1 (WT1) is over-expressed in 〉 80% of AML and advanced MDS, making this molecule an ideal marker for MRD monitoring. We analyzed WT1 quantitative expression in pts at high risk of relapse who received an Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) at our Institute. Aim of the study: to analyze WT1 based MRD monitoring as a predictive marker of relapse in AML/MDS pts after allo-HSCT. Materials and methods: in this retrospective study we included 54 pts with high-risk disease (50 AML and 4 MDS) who underwent allo-HSCT (10 MRD, 13 MUD, 28 MMRD, 3 CB), mostly after a myeloablative treosulfan-based (51/54 pts) conditioning between November 2007 and January 2011. In all pts (54/54) WT1 was over-expressed in the presence of active disease. Post-transplant disease evaluations, including WT1 quantification, were performed monthly for the first six months, every three months until one year and then every six months. WT1 transcript levels were quantified in Bone Marrow (BM) by RQ-PCR, with TaqMan technology on RNA from mononucleated cells. The housekeeping gene ABL was used as control gene, with WT1 level being normalized to 10^4 copies of ABL per sample. The cut-off value for WT1 positivity in BM samples was 250 copies/10^4 copies of ABL. Results: at transplant 38 pts (70%) were in CR, 12 pts (22%) had refractory disease, in 4 pts (8%) BM was not evaluable and no leukemic blasts were detectable in the peripheral blood. Median follow up (FU) after allo-HSCT was of 18 months (range: 4–42). At day 30 after transplant hematologic and cytogenetic CR and full donor chimerism (STR) were documented in all 54 pts, with a median BM WT1 value of 118/10e4 ABL (range: 0–10118). 23/54 pts (43%) relapsed at a median time of 180 days after allo-HSCT (range: 60–780). Correlation of post-transplant clinical outcome and WT1 expression levels identified: 1) 24 pts in continuous CR until last FU and BM WT1 levels persistently negative; 2) 13 pts who relapsed and showed an increase of BM WT1 levels above 250 at a median time of 40 days (range: 20–80) before hematological relapse and lose of full donor chimerism; 3) 9 pts who relapsed with WT1 increase concomitant with hematological relapse. These pts missed one or more of planned disease evaluations before relapse; 4) 1 patient who relapsed without documentation of WT1 increase; 5) 7 pts who maintained the CR but showed a transient increase of BM WT1 above 250 at one or two consecutive point of FU with normalization at subsequent evaluations. In 3 of these 7 pts concomitant GvHD was documented and in 4 pts ongoing immunosuppression was discontinued shortly after WT1 data had been obtained. Conclusions: WT1 expression levels in BM are effective in predicting AML/MDS relapse after allo-HSCT thus anticipating the appearance of leukemic blasts and of host chimerism. Our data prompt the use of WT1 based MRD monitoring for tailoring ‘pre-emptive' therapeutic approaches based on exploitation of donor immunity and its putative Graft-versus-Leukemia effect. In several patents the time occurring between WT1 MRD positive results and the clinical recurrence of the disease was relatively short, thus in order to detect disease relapse in time for therapeutic intervention we suggest a monthly monitoring of WT1 levels at least for the first year after allo-HSCT. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.4102.4102
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    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 5
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    Management of Acute Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Comparison of Different Salvage Strategies
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 4463-4463
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    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4463-4463
    Abstract: Abstract 4463 Background: The prognosis of patients with acute leukemia (AL) relapsed after allogeneic stem cell transplantation (allo-SCT) is namely poor. The management relies on implementation of the Graf versus Leukemia (GvL) effect either by immunosuppression withdrawal or administration of Donor Lymphocyte Infusions (DLI); these measures are particularly effective if tumor burden is limited. In case of higher tumor burden, instead, other strategies can be exploited, such as cytoreductive chemotherapy (CT) and/or further allo-SCT with a different conditioning regimen or the use of a more mismatched donor. Aim: Analysis of variables associated with outcome and response to different salvage strategies in pts with AL relapsed after allo-SCT. Materials and methods: we performed a retrospective analysis of a cohort of 64 consecutive pts with AL transplanted at the San Raffaele Scientific Institute and relapsed during follow up. Chi-square analysis was used for the association between variables; Kaplan Meyer curves and Long-rank test were used for survival analyses. Results: Between 09/2003 and 10/2010, 64 pts relapsed after receiving allo-SCT (median time to relapse: 6 months, range: 1–38); 54/64 pts (84%) had overt hematological relapse, 10/64 pts (16%) MRD positivity and/or Mixed Chimerism (MC). Therapeutic options applied were DLI or second allo-SCT, preceded or not by reinduction CT. Ten pts with MRD positivity and/or MC received DLI as first choice strategy. Among them, 4 had a sustained CR (40%) and 6 progressed to overt relapse; in 5 cases an allo-SCT was performed, and 1 pt was rescued. Fifty-four pts presented with overt relapse: 14 received DLI as first line salvage therapy; 2/14 (14%) obtained durable CR; an allo-SCT was attempted in 5/12 pts who progressed, with success in one. Fourteen pts went directly to a further allo-SCT; among them, 1 (7%) obtained durable CR. The remaining 26 pts received allo-SCT after re-induction CT; 5 (19%) obtained sustained CR. A further allo-SCT, given as first-choice strategy or used as a rescue treatment after DLI failure, was followed by a longer OS compared to DLI only (median OS 328 vs. 187 days after relapse, p=0.03). Survival, in particular, was longer in pts receiving DLI or CT as “debulking” strategy before undergoing further allo-SCT (DLI only v.s. SCT only vs. SCT + debulking: Median OS 187 vs. 159 vs. 351 days after relapse, p=0.07). Of note, all the long-surviving patients changed donor for the second SCT (alive 31% vs. 0% p=0.02) Taken together, 24 pts were given DLI as fist choice strategy, and received a median of 2 DLI infusions (range 1–4), with a median dose of 1×10^6 CD3/Kg (range: 1×10^5–1×10^8 CD3/Kg); 5/24 pts (21%) developed acute GvHD (max grade III in a single case). In univariate analysis, variables with a tendency to be associated with response to DLI were: early disease at transplant (p=0.07), Reduced Intensity Conditioning (p=0.06) and the use of Rapamycin for the GvHD prophylaxis (p=0.1). Variables with a tendency to association of longer OS after DLI were MRD positivity and/or MC (p=0.01), response to first DLI (p=0.07) and time to relapse longer than 6 months (p=0.1). DLI doses associated with the best response (50%) were 1×10^7 CD3/Kg for MRD and MUD and 1×10^6 CD3/Kg for MMRD respectively. Of note, no association was observed between DLI doses and incidence of GVHD. Conclusions: DLI is a reasonable option to treat pts with MRD positivity or MC after allo-SCT. When CR is not achieved after the first DLI, anyway, the switch to a more aggressive approach such as a further allo-SCT should be considered. The association of DLI with low-dose CT or other immune-modulating agent should be further exploited. For pts in over relapse, a further allo-SCT, if feasible, offers the best opportunity of prolonging survival. A debulking strategy such as CT or DLI should be considered according to the characteristics of the pts and the disease. Disclosures: Bonini: MolMed: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.4463.4463
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 6
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    Ventilation Heterogeneity Of Peripheral Airways (Sacin*VT) Assessed By Nitrogen Multiple Breath Washout (N2-MBW) Is An Accurate and Sensitive Marker Of Bronchiolitis Obliterans Following Haematopoietic Stem Cell Transplantation Recipients
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4599-4599
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    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4599-4599
    Abstract: Bronchiolitis Obliterans (BO) initially affects terminal and respiratory bronchioles, a region of the lung largely unexplored by spirometry, which is only altered in advanced disease. In contrast, the Impulse Oscillation System (IOS) and the nitrogen multiple breath washout (N2-MBW) are techniques characterized by a high sensitivity to peripheral airway changes and potentially more suited to early detection of small airways disease. In a cross sectional study, a total of 161 patients, divided into 4 groups: healthy controls (n=41), bone marrow transplant candidates (n=47), haematopoietic stem cell transplantation (HSCT) recipients (n=65) and patients with chronic obstructive pulmonary disease (COPD; n=8), were assessed by IOS, N2-MBW, spirometry, body plethysmography and diffusing capacity for carbon monoxide (DLCO) in order to describe respiratory function changes in post-transplant patients without pulmonary graft versus host disease (GVHD) and in order to characterize the pattern of peripheral airway changes in BO. All subjects were able to perform IOS and N2-MBW without difficulty. Significant variables are illustrated in the table.ControlNo BOSpBOSpMSDMSDMSDRV/TLC %9714109240.04414422 〈 0.001DLCO %96880160.0024911 〈 0.001Scond* VT [l]0.020.010.030.02 〈 0.0010.020.01 〈 0.001Sacin* VT [l]0.050.020.130.09 〈 0.0010.370.20 〈 0.001Z5Hz [cmH2O/(l/s)]3.070.673.491.29NS4.932.460.017DR5-20Hz [cmH2O/(l/s)] 0.300.230.560.68NS1.250.960.016X5Hz [cmH2O/(l/s)]-0.950.21-1.130.77NS-2.271.980.002fR [1/s)] 10.632.5413.194.86NS20.346.39 〈 0.001Rperipheral [cmH2O/(l/s)]1.770.802.091.46NS3.703.060.026 Stem cell transplantation, even without respiratory complications, does not affect spirometry but appears to cause an increase in air trapping, a reduction in DLCO and enhanced ventilation inhomogeneity both in conductive (Scond*VT) and acinar (Sacin*VT) airways. Patients with BO (n=8) were characterized by further DLCO reduction, increase in oscillometric indices sensible to peripheral airways involvement (Z5Hz, DR5-20Hz, X5Hz, Resonant frequency and Rperipheral) and a further three-fold increase in Sacin* VT. Compared to patients with BO, COPD patients with the same degree of spirometric obstruction (FEV1/FVC 〈 0.7, FEV1 50% predicted) showed only half the increase in predicted Sacin*VT (p= 0.03). At a cut off of 321% of predicted value, Sacin* VT could distinguish the subjects with BO from recipients, with good accuracy (87%), sensibility (87.5%) and specificity (89.5%). We conclude that IOS and N2-MBW are simple tests able to detect changes following HSCT as well as those specific to Bronchiolitis Obliterans. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4599.4599
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 7
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    Cardiovascular Risk: Analysis of Known Factors in Patients After Treosulfan-Based Conditioning for Haploidentical and HLA-Identical Stem Cell Transplantation
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 4471-4471
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    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4471-4471
    Abstract: Abstract 4471 Allogeneic stem cell transplantation (HSCT) is an emerging risk factor for cardiovascular disease. Long-term survivors seem to be at higher risk for premature arterial vascular disease compared with sex- and age-matched population. In HSCT, pre-transplant treatments and the conditioning regimen play a key role in endothelial and organ damage. The use of immunosuppressant drugs to prevent graft-versus-host disease (GvHD) influences as well the development of cardiac disease. To better understand the impact of treosulfan-based conditioning regimens in leading to the emergence of cardiovascular disease, we retrospectively evaluated 94 consecutive patients who had survived longer than 1 year, transplanted at Our Institution between 2002 and 2010 (62 males – median age 46, range 14–69). For 48 patients an HLA-identical sibling was available, 6 patients found an unrelated donor while 40 patients underwent haploidentical HSCT from family donors. Forty-six patients received in vivo T-cell depletion and 72 B-cell depletion. GvHD prophylaxis was based upon cyclosporine + methotrexate for the HLA-identical transplants (48 – median EBMT risk score 3) whereas rapamycin + MMF were used for patients undergoing transplantation from HLA-haploidentical donors (35 – median EBMT risk score 4); 9 did not receive any immunosuppression because of application of suicide gene strategy as tool to prevent GvHD (median EBMT risk score 3). We compared clinical variables (i.e. GvHD, OS, TRM, major cardiac events and comorbidities) with biochemical and functional tests (i.e. cardiac function, lipid profile and ferritin levels) both before and 1 year after transplantation. After a median follow-up of 29 months, only 3 patients experienced a major cardiovascular event; no one experienced a late congestive heart failure. In all series, we found that ferritin levels significantly decrease after 1 year of follow-up, compared to pre-transplant values (P 〈 0.0001); viceversa, the lipid profile (total cholesterol, HDL and LDL fractions) remarkably increased (p 〈 0.05). Interestingly, the linear regression analysis for the overall survival showed no difference for both ferritin level and cholesterol level. Moreover, no significant variations were detected comparing cyclosporine versus rapamycin-treated patients, nor comparing patients with or without GvHD. Increased rates of cardiovascular disease are commonly associated to HSCT. In our experience, no differences were found in the incidence of cardiovascular events comparing different donor source or immunosuppressants. This suggests that haploidentical transplants are feasible and have similar cardiac toxicity than standard HLA-identical ones. Our analysis was surely limited by the short time of observation. In future, the evaluation of dynamic biomarkers on a greater series and on a longer follow-up will help us to identify a tailored schedule of cardiac monitoring after HSCT to prevent major lethal events in our patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.4471.4471
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Bone-to-Bone Stem Cell Infusion In Graft Failure After Haploidentical Hematopoietic Stem Cell Transplantation: Safety and Feasibility. Three Case Report
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4438-4438
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    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4438-4438
    Abstract: Abstract 4438 BACKGROUND: Graft Failure (GF) occurs in 5–27% of patients (pts) after allogeneic hamatopoietic stem cell transplant (HSCT) and is associated with high morbidity and mortality related to infections and hemorrhagic events. Graft function may be poor as result of graft rejection, primary disease relapse or Poor Graft Function (PGF). The incomplete recovery of blood counts is defined primary PGF and the decreasing blood counts after successful engraftment secondary PGF. Several factors may determine GF: disease risk and status, conditioning regimen, HSC source, HLA compatibility, T cell content, immunosuppression, GvHD, viral infections, drugs. GCSF and Rhu-EPO are readily available and effective in PGF but with no effects on platelets. Second transplantation from the same donor, with or without conditioning therapy, can boost the haematopoietic recovery in pts with GF. Unfortunately, both a second peripheral CD34+ mononuclear cells (MNC) mobilization and a marrow harvest in the operating room may be contraindicated early after the first donation as not safe for donors. Intrabone SCT can overcome the risk of graft failure even with a low number of CD34+ MNC, as it has been demonstrated in cord blood transplant. Here we investigate in three adult pts with GF a bone-to-bone boost (BBB) with a small marrow harvest from respective donors, unfit for a second conventional donation. AIM: to evaluate the feasibility of the BBB technique in 3 pts with graft failure. METHODS: pts were 2 males (57, 53 y) with PGF with a diagnosis of AML and CMML, respectively, and a female (44 y) with graft rejection and AML relapse. In the first two patients prolonged pancytopenia and hypoplastic marrow were documented, with diagnosis of primary PGF and secondary PGF, respectively, donor chimerism ranging from 80–100% (STR and HLA), without evidence of leukemia. In the third patient, after prolonged pancytopenia an AML relapse was documented with 89% blasts on bone marrow aspirate. In PGF patients no conditioning regimen was administered before the boost at day 30 and 72 after SCT, respectively. In the patient with AML relapse Melphalan 200 mg/mq was given 48 h before the infusion, at day 35 after SCT. The 3 donors were related, haploidentical. For the BBB procedure small quantities of bone marrow ( 〈 200ml) were collected from the posterior iliac crest bilaterally of the donors, at the bedside, during deep sedation and analgesya. Shortly after the unmanipulated marrow harvested was infused in superior-posterior iliac crest mono- or bilaterally, depending on the volume, during deep sedation and analgesya. In pt 1 Mononucleated cell (MNC) dose was 0.9 × 10^8/Kg for a volume of 166 ml. In pt 2 MNC dose was 0.4 × 10^8/Kg for a volume of 88 ml. In pt 3 MNC dose was 0.3 × 10^8/Kg for a volume of 140 ml. RESULTS AND CONCLUSION: In this cases the BBB technique proved feasible and safe for both the donor and the patient. Patient 1 received a second PBSC boost, without conditioning, 3 months after the BBB, and he's now alive, in CR, 13 months after the first transplant. Patient 2 died 3 months after the first transplant for pneumonia and sepsis. Patient 3 is alive, in CR, 4 months after the first HSCT. This practice can give the chance of HSC boost to patients with GF without the need of a GCSF mobilization for donors, with a minimal invasive operation. This can give the option to overcome and resolve infectious and hemorrhagic complications, bridging patients to further therapies and procedures. The intra-bone SCT may be a facilitating tool for microenvironment reconstitution, seeding and subsequent differentiation and may as well have a tolerogenic effect, through the mesenchymal stromal cells infused with the harvest. Further studies are necessary to assess the efficacy of this procedure. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.4438.4438
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
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  • 9
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    Antifungal Prophylaxis with Posaconazole in Allogeneic Hematopoietic Stem Cell Transplantation Using Sirolimus for Prevention of Graft-Versus-Host Disease
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 4335-4335
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    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4335-4335
    Abstract: Invasive fungal infections (IFI) have emerged as a leading cause of morbidity and infection-related mortality among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients over the past two decades. Several new drugs have recently been introduced as antifungal prophylaxis, supported by results of prospective randomized trials. In agreement with the international guidelines, a mold-active antifungal prophylaxis is strongly recommended in high-risk patients receiving allo-HSCT, considering efficacy, different pharmacokinetic, drug-drug interactions, and toxicity profile of the various antifungal drugs. Posaconazole, a triazole with broad-spectrum antifungal activity and a favorable toxicity profile, is the drug of choice for patients with graft versus host disease (GVHD). Consequently, posaconazole prophylaxis in allo-HSCT recipients is administered in combination with immunosuppressive drugs for GVHD prophylaxis and/or treatment, most commonly cyclosporine (CsA) or tacrolimus. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR), largely used for GVHD prevention and treatment, but extensively metabolized by CYP3A4. As posaconazole strongly inhibits CYP3A4 its coadministration with sirolimus is contraindicated by the manufacturer of posaconazole, and up to now poorly described in literature. In the San Raffaele Haematology and Bone Marrow Transplantation Unit, from 2010 to 2015, we retrospectively identified sixty-six patients that received posaconazole oral suspension as primary (n=43) or secondary (n=23) antifungal prophylaxis after allo-HSCT. The majority of patients were affected by acute leukaemia (67%), not in remission at time of allo-HSCT (55%), and with a previous allo-HSCT reported for 50% of them, carrying an high risk for developing a post-transplant IFI. Median follow up was 357 days (range 43-1884) after HSCT. Posaconazole administration was given for a median of 221 days (range 13-966). Thirty-two patients (49%) received posaconazole during engraftment phase, while 28 (42%) and 19 (29%) patients for IFI prophylaxis in the setting of acute or chronic GvHD respectively. A concomitant administration of sirolimus was performed in 49 patients (74%). Sirolimus concentrations were monitored two times a week, while posaconazole was controlled in patients' serum on a weekly basis, during the first two months of treatment. We observed a 55-70% steady-state dose reduction of sirolimus in 19 patients, after posaconazole introduction. Alternatively, patients with ongoing posaconazole prophylaxis received an initial empiric sirolimus dose reduction at 1 mg/day. The co-administration of posaconazole and sirolimus resulted safe. Discontinuation was reported mainly in patients with documented IFI, who required a change of the antifungal drug. No adverse events potentially associated with sirolimus overexposure (i.e. sinusoidal obstructive syndrome, sirolimus-related thrombotic microangiopathy) were reported, although one-third of the patients experienced a transient and moderate elevation of sirolimus serum levels in the first week of coadministration. In this analysis post-transplant IFI occurred in 14 cases. The risk of developing IFI was influenced by type of prophylaxis, resulting in 12% and 39% of IFI during primary and secondary prophylaxis respectively (p value 0.013; OR 4.89, CI 1.39-17.11). However the most significant and strong association was reported in concomitant with insufficient posaconazole serum levels ( 〈 0.5 ml/L), a known reported limitation of the oral solution formulation especially in patients with intestinal GVHD and/or diarrhea (p value 〈 0,0001; OR 35.14, CI 6.43-192). In patients with adequate posaconazole serum levels ( 〉 0.5 ml/L) the incidence of IFI was 5%, supporting the utility of therapeutic drug monitoring (TDM) in such conditions and generating interest for the use of the upcoming posaconazole tablets with improved bioavailability in allo-HSCT recipients. In our experience concurrent sirolimus and posaconazole use was well tolerated, with a 55% to 70% sirolimus dose reduction at posaconazole initiation and close monitoring of serum sirolimus and posaconazole trough levels in the first months of co-administration. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.4335.4335
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 10
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    Graft-Versus-Host Disease after Haploidentical Stem Cell Transplantation in High Risk Haematological Diseases: A 10-Years Evaluation at San Raffaele Scientific Institute
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2498-2498
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    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2498-2498
    Abstract: Introduction Haematopoietic stem cell transplantation (HSCT) is the only curative option for patients (pts) affected by high-risk haematological diseases (HRHD). However, the availability of a match donor is still an unmet-medical need. Recently alternative donor transplantations have been broadly exploited, reaching results similar to transplants from a well match donor. Anyway, whoever the donor is, the most important complication remains Graft-versus-Host Disease (GvHD). Aim of the study We evaluated incidence, characterization, stratification, treatment, treatment response and outcome at medium and long-term follow-up for both acute (a-) and chronic (c-) GvHD in haploidentical setting. We also evaluated the impact of the NIH consensus criteria on GvHD in a routine clinical application to confirm their feasibility in daily practice and not only in clinical trials use. Methods A population of 257 pts was selected from our Institutional database on the basis of their having an HRHD with indication to allogeneic HSCT and having received a HSCT from an haploidentical family donor without exclusion. HSCT were performed between January 2004 and December 2013 at our Center. No distinction between first HSCT or subsequent one was made, all consecutive haploidentical HSCT were captured. Results Time of median follow-up was 10 months; 1-year overall-survival (OS) was 46%, with better outcome for pts transplanted in complete remission (p 0.0001) confirming disease status as the leading factor for overall outcome. Transplant related mortality was estimated to be 30% at 1 year and the leading cause of death was infections. The 6-months a-GvHD incidence was 45% (119/257) - median day of presentation 21 post HSCT (range 8-89). Late-onset a-GvHD was documented in 15 pts. Grade I GvHD was documented in 33 pts (27.7%), grade II in 44 (37%), grade III-IV in 36 (30.3%) – 6 not evaluable. Skin was the most frequently involved organ (77.3%), both as single manifestation or combined. One-hundred and five pts received a first line therapy based on high-dose prednisone (2mg/Kg) and 37/105 completely abrogated the a-GvHD. At a 3-months evaluation 46% of affected pts showed complete resolution of a-GvHD, while the mortality rate was 29%. C-GvHD affected 69/257 pts and 1-year risk of onset was 25% - median day of presentation was 139 post HSCT (range 40-809) and 36/69 pts were off immunosuppressive therapy (52.3%) at presentation. According to onset presentation 53.7% were de novo, 24.6% progressive and 18.8% quiescent GvHD. Forty-one pts (59.5%) presented at declaration with overlap features. The most frequent involved organ was skin (grade I to III), as reported in 53 pts (76.8%). Skin lesions were usually accompanied with mouth lesions (35 pts – 50.7%), liver (23 pts – 33.3%) or eyes (27 pts – 39.1%) dysfunctions. The median number of involved organs was 3 (range 1-7). Mild c-GvHD was diagnosed in 10 pts (14.5%), who received topical therapy. Fifty-nine pts – diagnosed with moderate (32, 46.4%) or severe (27, 39.1%) - received a systemic treatment for c-GvHD: prednisone 1 mg/Kg alone or 0,5 mg/kg plus mTOR- or calcineurin-inhibitor for pts that were not likely to tolerate high dose steroid due to comorbidity (namely active infections, diabetes, cardiovascular diseases). At a 12-months evaluation the overall response was 48% (complete resolution 25%, partial resolution 23%), while the mortality rate was 36%. The Landmark analysis of OS at 3 months after HSCT shows that a-GvHD affected pts had a worse outcome (p= 0,068), on the contrary the Landmark analysis of OS at 18 months shows that c-GvHD did not associate with a worse outcome (p ns) but the follow up is still short. Confirming previous reports, overlap c-GvHD was related to worse survival in comparison with classic c-GvHD (p 0.0098). Conclusion Haploidentical HSCT is a valid and feasible option for pts in need of a transplant. GvHD is manageable after haploidentical HSCT, as in full matched setting. Better knowledge and insight in a/c-GvHD are providing advance in improving pts outcome. The NIH-consensus criteria are manageable in daily clinical practice and able to translate in a tailored approach to GvHD with benefit on general outcome. Further advance in the development of specific biomarkers for GvHD will provide additional crucial information for management, diagnosis and prognostication in GvHD. Figure 1 Figure 1. Disclosures Bonini: MolMed S.p.A.: Consultancy. Bordignon:MolMed: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2498.2498
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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