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  • 1
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5810-5810
    Abstract: Introduction Tyrosine kinase inhibitor (TKi) has become the standard of care in patients (pts) with chronic myeloid leukemia (CML) and an unavoidable tool in the combined therapy for pts with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Nevertheless, because of resistance to TKI and side-effects, allogeneic stem cell transplantation (HSCT) remains the standard therapy of ALL Ph+ and of CML pts failing 1st line therapy with TKi, with failure or insufficient response or intolerance or mutations resistant to 2nd generation TKI, or in the advanced phase at diagnosis (accelerated phase and blast crisis). Unfortunately, despite greater remission with the use of TKi pre-transplant, HSCT transplant outcome have not improved largely due to high incidence of relapse after transplant. In the past decade several multi-institutional studies confirmed the feasibility and safety of post-HSCT imatinib administration as prophylactic or therapeutic strategy. Second and 3rd generation TKi administration after HSCT - targeting mutational status and according to pre-HSCT activity - is today under investigation. Methods Here we are reporting our experience in post-HSCT treatment with the 3rd generation TKi ponatinib in 5 pts (4 CML, 1 ALL Ph+) treated between 2011 and 2016 at our Institution. Pts data and information were collected from Institutional database and chapters revision. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results Pts and diseases features are reported in table 1. Stem cell source was peripheral blood in all cases, 3 pts were transplanted from a family mismatched donor (haplo), 1 from a family matched donor, 1 from a matched unrelated donor (MUD). The 3 haplo-transplanted pts previously underwent a MUD HSCT. All pts received a treosulfan based conditioning regimen and GvHD prophylaxis consisted on co-administration of MMF and rapamycin. Pre-transplant treatment for the ALL Ph+ consisted of chemotherapy combined with dasatinib, followed by a first MUD HSCT and dasatinib in maintenance. The patient relapsed 1 year after HSCT with documentation of mutation V299L. Ponatinib was introduced as salvage treatment to bridge second haplo HSCT. Pre-transplant treatment for the CML patients consisted of TKi therapy with combination of chemotherapy in case of uncontrolled progression of disease. Two pts received a first MUD HSCT but relapsed respectively 5 months and 4 years later. Four pts received ponatinib 45 mg daily before the last HSCT: one patient achieved sustained major molecular response, 3 pts obtained transient response. All pts were presenting 2nd generation TKi resistant mutation (ref table 1). Ponatinib was started at a median time of 157 days after HSCT (range, 117-583): in 3 cases as salvage treatment in overt relapse, while in one case as prophylaxis and one case as preemptive therapy. Acute GvHD was diagnosed in 4 pts before ponatinib administration, 2 of them also experienced chronic GvHD. No new cases of GvHD were observed after initiation of ponatinib. Immunosuppressive treatment and azoles treatment were discontinued before ponatinib in all but one patient who was under combined treatment for chronic GvHD: therapeutic drug monitoring was closely performed without evidence drug-drug interaction. Pts were regularly evaluated for toxicities. No serious adverse events were reported in our experience: we administered ponatinib at a median maximum dosage of 30 mg daily (range, 15-45 mg), for a median of 24 weeks (range, 4 - 116 weeks). Two pts required anti hypertension drugs. One patient was closely monitored for multifactorial liver cholestasis never requiring ponatinib discontinuation. At last evaluation one patient maintained the status of molecularly undetectable leukemia (follow-up post HSCT 30 months) and two pts obtained molecular response (follow-up post HSCT 25 months and 5 months). Two patients who received therapeutic ponatinib in overt relapse didn't respond and died for progressive disease. Conclusions Ponatinib is safe and well tolerated as bridge to HSCT and to maintain the disease control after transplant. Prophylaxis targeted therapy and pre-emptive therapy with ponatinib may lead the reduction of disease relapse for high-risk Ph+ leukemia. Disclosures Bonini: Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Ciceri:MolMed SpA: Consultancy.
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  • 2
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3442-3442
    Abstract: Introduction Voriconazoleis a second-generationtriazolebroad-spectrum antifungal agent indicated in adults and children aged 2 years and above as treatment of invasive aspergillosis, treatment ofcandidaemiain non-neutropenic patients (pts), treatment of fluconazole-resistant serious invasive Candida infections, treatment of serious fungal infections caused byScedosporiumspp. and Fusarium spp. Voriconazoleis associated with a broad spectrum of dermatologically adverse reactions: it seems to be responsible for a multistep process beginning with acute and chronicphototoxicity, followed by actinic keratosis (AK), and finally skin squamous cell carcinoma (SCC), especially if therapy is maintained. Strictphotoprotectionis mandatory; drug replacement by anothertriazolemust be discussed in case of acutephototoxicity.Voriconazolemust be stopped in pts with chronicphototoxicity, and a long-term dermatologic follow-up of skin lesions is required even after withdrawal. It is now established thatvoriconazoleis an independent risk factor for the development of cutaneous malignancy in lung transplant recipients. Recently, a retrospective study from the Mayo Clinic (WojenskiDJ et al, Transplant Infectious Disease 2015, 17, 250-58) confirmed the association betweenvoriconazoleand SCC also after allo-HSCT (allogeneic hematopoietic stem cell transplantation) and identified cumulative days ofvoriconazoleas a risk factor for SCC. Methods The current study seeks to analyze the correlation betweenvoriconazoleexposure and non-melanoma skin cancer (NMSC) in our Center, where it is available an intensive dedicated follow-up after allo-HSCT to prevent and early detect second solid tumors. Results We analyze data prospectively collected at our Long-Term Follow-Up clinic between 2011 and 2016 including 302 adult pts with a minimum follow-up of 24 months. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Baseline characteristics of the 302 pts are outlined in table 1. In total, 25 pts developed NMSC - median time from allo-HSCT 42 months (range, 9 months - 20 years) - median follow-up after NMSC diagnosis 2 years (range, 2 months - 12 years). The estimated cumulative incidence of NMSC at 3 years was 3.2% and at 5 years 6.2%. At the dermatological annual evaluation 3 pts were presenting AK, only one progress to basal cell carcinoma (BCC), the 2 pts with AK are under dermatological follow-up. All pts were treated withvoriconazolefor more than 180 days. In total 19 pts were diagnosed with BCC and 6 pts with SCC. Five pts with SCC and 17 with BCC were treated withvoriconazole, overall 16/22 (4 SCC) for more than 180 days. All pts were treated according to standard practice for NMSC, unfortunately 1 pts deceased due to SCC progression. Only 2 pts were diagnosed and treated for NMSC before transplantation. Six pts had antecedent acute GvHD and 8 pts had antecedent moderate to severe chronic GvHD. History ofvoriconazoleexposure, cumulative days ofvoriconazoleuse, gender, age at transplant, TBI based conditioning regimen, acute/chronic GvHD and skin cancer pre-transplant were considered for analysis. Age at transplant above 48 years (p 〈 0.0001),voriconazoleexposure (p 0.0088) and cumulative days ofvoriconazoleexposure greater than 180 days (p 0.0038) were associated with higher risk of NMSC. Conclusions Our experience confirms the correlation betweenvoriconazoleand occurrence of NMSC after allo-HSCT. Incidence of NMSC is higher than previously reported in registry reports, and the occurrence of NMSC in pts exposed tovoriconazoleseems to be precocious. This observation confirms the relevance of counseling and prevention of NMSC in patients benefiting fromvoriconazoleas a crucialmold-active antifungal prophylaxis and treatment. Disclosures Bonini: Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Ciceri:MolMed SpA: Consultancy.
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  • 3
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4362-4362
    Abstract: Introduction Allogeneic hematopoietic cell transplantation (HCT) is an effective therapeutic option for high-risk hematological malignancies; 80% of those who survive the first 2 years are expected to become long-term survivors. The prevalence of chronic health conditions approaches 75% among HCT survivors and that for severe or life-threatening conditions exceeds 20%. Patients and Methods A standardized follow-up of HCT survivors is applied at our Center, according to Jacie Standards. Here we report the analysis of data collected between July 2014 and July 2015 in 260 adult patients (pts) who underwent an HCT between 1992 and 2014. Data on 7 items - selected to monitor relevant comorbidities - were prospectively collected in our Institutional database. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results Pts characteristics are reported in table 1, median time of follow-up 4.4y (r1-22), cumulative follow-up 1404y; 13 pts deceased during the time of observation (6 due to disease relapse, 2 to late major infection, 2 to second cancer, 1 to GvHD, 1 to myocardial infarction, 1 unknown). - chronic Graft-versus-Host-Disease (c-GvHD): at a median follow-up of 43 months (r 16 months - 21 years) 84 (32%) pts are presenting c-GvHD features. According to NIH 2014 consensus criteria 23 cases were classified as mild, 32 moderate, 29 severe. Median number of involved organs 2 (r1-5), 39 pts were experiencing skin lesions, 55 eyes, 28 mouth, 19 joint and fascia, 18 lungs. Topical therapy was the treatment of choice for mild cases, while moderate and severe were treated with systemic therapy. The partnership with the lung specialist and the ophthalmologist was crucial for the management of lung and eyes GvHD. - Late infectious manifestation: 38 (15%) pts present late infection, 2 pts deceased due to major events. Of note pneumonia was reported in 12 pts, Varicella Zoster virus reactivation in 7, CMV late reactivation in 4 pts. - Second cancer screening was performed according to international guidelines. The incidence of new cases is 10% (26 pts) and 11 pts are actually under work-up for suspicious lesions. Non-melanoma skin cancer was the most frequent diagnosis (13 cases); 3 pts were diagnosed with cervix cancer, 2 with lung cancer. The prevalence of second cancer in our population is 18% (47 cases). All pts were treated according to standard for general population, 45/47 are alive. - Cardiovascular diseases were frequently observed in our setting: hypertension was documented in 36 pts, arterial diseases in 10 pts, cardiomyopathy in 28 pts. Overall 27% of pts were diagnosed with cardiovascular comorbidities. - Metabolic syndrome (MS) is reported as a very common complication in long-term survivors: 65 (25%) pts were presenting features of MS (3/5 among hypertension, dyslipidemia, raised fasting glucose, and central obesity). A concomitant thyroid dysfunction - requiring hormonal replacement - was present in 27/65 pts. - Secondary hemosiderosis was documented (with MRI and blood parameters) and treated in 39 pts (15%) - 8 pts received deferasirox while phlebotomy was used in 31. - Osteoporosis and bone loss were evaluated measuring bone mineral density using dual-energy X-ray absorptiometry; osteopenia was detected in 81 pts and osteoporosis in 42 (47%). Pts were evaluated in conjunction with the endocrinologist and treated according to the fracture risk score. According to donor source no difference were observed (Chi-square test - p ns) except for higher incidence of moderate/severe GvHD incidence in HLA identical sibling (p 0.0097) as compared to alternative donors. Discussion HCT survivors are at a defined relevant risk of developing long-term complications that have a direct impact on the morbidity and mortality.A multidisciplinary active screening within routine HCT long-term follow-up care is mandatory to enhance early diagnosis/treatment and overall outcome. The next challenge will be to enhance the primary prevention to reduce the incidence of preventable comorbidities. Table 1. patients characteristics N (range) Pts 260 Age At transplant 48y (10 - 76) At follow-up 54y (20 - 82) Male / Female 169 / 91 Diagnosis AML / ALL 106 / 33 MDS 27 HD / NHL 23 / 29 MM 14 CML 8 CLL 5 SAA / EPN 4 / 1 Others 10 Status at transplant CR / PD 169 / 91 Donor Haploidentical 100 HLA identical Sibling 76 Match Unrelated Donor 82 Cord Blood 2 Disclosures Bonini: MolMed S.p.A: Consultancy.
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  • 4
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 22, No. 3 ( 2016-03), p. S189-S190
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    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2016
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  • 5
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4400-4400
    Abstract: Background Optimization of pre-transplant risk assessment is a crucial issue to improve the allo-HSCT decision making process. Actually 3 major algorithms are in use in clinical practice: the EBMT risk score, the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and - more recently introduced - the refined Disease Risk Index (DRI). DRI was defined to calibrate HSCT outcome across studies and centers. It was developed as a tool to assign patients into risk groups based on disease type and status at the time of transplantation. The aim of the DRI is to provide a robust tool that can be used for prognostication, for the analysis and interpretation of retrospective data, whether conducted in single-center, multicenter, or registry settings, or within the context of the federally mandated center outcome reporting. The DRI can also be used for the stratification of patients entering prospective HCT clinical trials. DRI is not a fixed tool but instead it was conceived to be refined by the transplant community as new information becomes available. Here we are presenting the results of a retrospective study designed to evaluate the 3 aforementioned score in stratification and prognostication of transplant outcome after a haploidentical HSCT (haplo-HSCT). Patients and Methods We included 220 adult patients (pts - 138 male, 82 female) who underwent a haplo-HSCT for hematologic malignancies, between 2006 and 2014 and were reported to our Institutional database. Risk assessment score and outcome analysis included all consecutive pts receiving an haplo-HSCT as 1st allogeneic transplantation. Pts receiving haplo-HSCT as 2nd or 3rd HSCT were excluded from the present analysis. Median age was 49 years (range, 15-77). The cohort included a broad representation of diseases (138/220 acute leukemia, 30 Hodgkin lymphoma); 62 pts were in complete remission at transplant, 158 were presenting active disease. Conditioning regimens mostly rely upon the combination of treosulfan plus fludarabine (201/220) and total body irradiation (range 200 - 400 cGy) was utilized in 52 patients. GVHD prophylaxis consisted mostly of an mTor inhibitor (rapamycin) combined with mycophenolate mofetil. The majority of patients received peripheral blood stem cells from a family haploidentical donor as stem cell source, while only 4 patients received bone marrow transplant. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results The median follow-up for survivors was 37 months (r 6-107). The overall survival (OS) at 2-y was 35% and the transplant related mortality at 100-days 23%. The 2y OS according to EBMT / HCT-CI / DRI risk score are reported in table 1.a and figure 1. The evaluation of the HCT-CI impact after DRI stratification was able to show a significant difference in outcome showing better survival for pts with low DRI score and low HCT-CI score as expected (table 1.b). Discussion Refined DRI score and HCT-CI score predict survival after haplo-HSCT. The integrated application of refined DRI and HCT-CI may improve the definition of transplant eligibility for pts candidate to allogeneic HSCT form alternative donors including family haploidentical source. Table 1a. EBMT score 0-3 % pts 4-5 %pts 〉 5 %pts p 51% 17 34% 51 27% 32 0.07 HCT-CI score 0-2 3-4 〉 /= 5 48% 59 36% 31 0% 10 0.0001 DRI score Low-Intermediate High Very-High 61% 32 27% 51 5% 17 0.0001 Table 1b. HCT-CI 0-4 HCT-CI 〉 /=5 p DRILow-Intermediate 64% 0% 0.0001 DRIHigh-Very High 29% 0% Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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  • 6
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3492-3492
    Abstract: Introduction Pre-transplant risk assessment is a crucial issue to improve the HCT decision-making process. Several transplant-related models have been designed to optimize decision-making about suitable candidates for allogeneic HCT. The refined Disease Risk Index (DRI) was developed to stratify disease risk acrosshistologiesand HCT regimens. However, few recipients of haploidentical HCT were originally included in the DRI study cohorts. In 2015 a first large cohort of non-myeloablativehaploidentical HCT with post-transplant cyclophosphamide (PTCy) confirmed the validity of DRI also in this setting. Beside this, in the past few years the novel composite end point of GVHD-free, relapse-free survival (GRFS) after HCT spreads out. GRFS acknowledge that both survival and rates of grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death are clinically meaningful. GRFS therefore represents ideal recovery from HCT and a measure of cure without ongoing morbidity. Methods We analyzed risk-stratified GRFS according to the refined DRI in haploidentical HCT at our Center, where it was exploited - since 2006 - asirolimus-based,calcineurininhibitor-free prophylaxis of GvHD to allow the safe infusion of unmanipulated haploidentical HCT. We analyze data collected between 2006 and 2014 including 207 adult pts. Data were prospectively collected in Institutional database. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. All consecutive pts receiving a haplo HCT as 1st allogeneic transplantation were included - pts receiving haplo HCT as 2nd or 3rd HCT were excluded from the present analysis. Results Baseline characteristics of the 207 pts are outlined in table 1. With 4-year median follow-up, 4-year probabilities of transplant related mortality (TRM),relapse, progression-free survival (PFS), and overall survival (OS) were 25,8%, 42,5%, 31,7%, and 34,4%, respectively. Day-100 cumulative incidence of grade II-IV and III-IV acute graft-versus-host-disease (GvHD) were 30,1% and 15,5% respectively. The 4-year cumulative incidence of chronic GvHD was 33,5% (moderate-severe chronic GvHD 26,2%). Considering the composite end point of GRFS, for the entire population the 4-year GRFS was 17,8%. By refined DRI group, low-intermediate (n 69), high (n 105), and very high (n 33) risk groups had 4-year GRFS estimates of 31,1%, 13,7%, and 3,0% (p 〈 .0001), with corresponding 4-year OS estimates of 56,7%, 28,9%, and 6,1% (p 〈 .0001). On a multivariable Cox model we considered as covariates age, host/donor sex mismatch, host/donor CMV status, stem cell source, conditioning intensity, GvHD prophylaxis ATG-based versusPTCy-based, DRI stratification, HCT Comorbidity Index Score (HCT-CI). On multivariable analyses, the DRI was statistically significantly associated with GRFS, OS, PFS, relapse, TRM and grade II to IV acute GvHD (ref table 2). HCT-CI was statistically significantly associated with GRFS, OS, PFS and TRM. Conditioning intensity was associated with PFS and relapse, while GvHD prophylaxis (PTCyvs ATG) was only associated with OS. Interestingly no risk factors were clearly emerging for chronic GvHD. Conclusions The combination of a refined DRI and GRFS provide a valid tool to improve the HCT decision-making process and will help optimize patient outcomes. Disclosures Ciceri: MolMed SpA: Consultancy.
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  • 7
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 22, No. 12 ( 2016-12), p. 2250-2255
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    Publisher: Elsevier BV
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  • 8
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 5465-5465
    Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only cure for several patients with high-risk hematological malignancies. Recent advances in supportive therapies have significantly reduced the treatment-related mortality over the last decades. Nevertheless graft-versus-host disease (GvHD) still represents a major complication, and research is needed to achieve further progress in this area of transplantation. Moreover, although initial studies suggested relative equivalence, recent and large prospective studies showed higher rates of acute and chronic GvHD, and worse survival in allo-HSCT from unrelated donors (URD) compared with HLA-identical sibling donors. Following our encouraging results in haplodentical setting with the more recently post-transplantation cyclophosphamide (PTCy) and sirolimus as GvHD prophylaxis (Cieri et al, 2015), in this study we investigated whether the incorporation of low dose anti-thymocyte globulin (ATG) to PTCy and sirolimus GvHD prophylactic approach, may alleviate some of the increased alloreactivity associated with URD transplants. We retrospectively evaluated a cohort of 21 haematological patients receiving URD allo-HSCT in the San Raffaele Haematology and BMT Unit, from 2013 to 2015. All subjects had high-risk hematologic malignancies, with the most common diagnosis being myeloid diseases (52%). A total of 11 patients had active disease at HSCT, while 9 were in hematologic remission. Nine patients scored high according to disease risk index defined by Armand et al, 10 scored intermediate, while only 2 had a low disease score. Myeloablative conditioning consisted of treosulfan (14 g/m2/day) on days -6 to -4, fludarabine (30 mg/m2/day) on days -6 to -2, and melphalan (70 mg/m2/day) on days -2 and -1, followed by T-replete G-CSF-mobilized PBSCs (n=19) or BM grafts (n=2). Whether 12 patients received stem cells from HLA- matched URD (fully 10/10 HLA matched), the remaining 9 had one-locus HLA-mismatched from their donors. During conditioning patients received ATG-Fresenius 5 mg/kg per day IV on day -4 to -2. In vivo B-cell depletion was obtained by rituximab (i.v. 375mg/m2 given as a single dose on day -1). Postgrafting immunosuppression consisted of PTCy (50 mg/kg/day) on days 3 and 4. Sirolimus was given orally from day 5, and monitored to maintain a target therapeutic plasma level of 5-14 ng/ml. According to chimeric status and evidence of GVHD, the dosage of sirolimus was tapered during the second month post-transplantation, ending in complete withdrawal within the sixth month after HSCT. Mycophenolate mofetil (MMF) was initiated orally at 10 mg/kg t.i.d. on day 5 after HSCT, and withdrawn on day 30. Median follow up was 247 days (range 29-486) from HSCT. All patients were engrafted in a median time of 17 days (range, 14-51 days), with full donor chimerism achieved by day 30. Poor graft function was observed in 11 patients. Post-HSCT recovery of lymphocyte subsets was lengthy as compared to other unmanipulated HSCT, with a median time to CD3 〉 100/ml of 41 days (range, 22-389 days) by flow-cytometry, while 5 patients never reached immune reconstitution. All except one developed febrile neutropenia during aplasia. We observed a high rate of serious infections: severe pneumonia in 7 cases (5 required NIV, 4 were admitted to ICU), CMV reactivation in 13 (3 CMV disease), HHV6 reactivation in 10, BK virus haemorrhagic cystitis in 2 patients. Although the overall mortality associated with these complications was limited, as evidenced by a favourable NRM, it caused significant morbidity in patients and often required aggressive therapies, potentially contributing to poor graft function. The incidences of acute and chronic GVHD were low. A grade II-IV acute GvHD was reported in 10% patients, while five patients developed chronic GvHD (mild in 4 cases, only one moderate). Non-relapse mortality (NRM) at 100 days and 1 year was 4.8% and 20.7%, respectively. The estimated 1-year overall survival (OS) and relapse incidence were 51% and 22.5% respectively. Although limited by a small number of patients with relatively short follow-up, our study suggests that URD allo-HSCT with ATG, PTCy and sirolimus-based GvHD prophylaxis, can be very effective in preventing GvHD, but at the expense of delayed immune reconstitution and high rate of infectious complications, while warranting acceptable NRM and relapse incidence. Disclosures Bonini: MolMed S.p.A: Consultancy.
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  • 9
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5743-5743
    Abstract: Multidrug resistant Gram-negative (MDR-GN) bacteria are responsible for severe infections in immune-compromised hosts. Clinical outcome is often poor, especially in patients undergoing hematopoietic stem cell transplantation (HSCT) with mortality rates exceeding 50%. In patients with a documented pre-transplant MDR-GN bacterial infection, HSCT is usually regarded as a potentially harmful procedure, despite its curative potential. Recently, active surveillance strategies based on rectal swab evaluation have been recommended with the aim of early identification of MDR-GN carriers, although they are not routinely performed in every transplant center. After an Institutional outbreak of K. pneumoniae carbapenemase -producing (KPC-Kp) infections in our Centre in June 2012, we decided to start an Institutional programme of active surveillance. No patient was excluded from HSCT, despite a documented colonization. In this study, we retrospectively analysed the results of the active surveillance programme and the impact of a pre-transplant colonization on HSCT outcomes. From July 2012 to January 2016 (43 months), 362 consecutive patients (254 undergoing allogeneic HSCT (allo-HSCT) and 108 autologous HSCT (auto-HSCT) were examined. All patients had a pre-transplant rectal swab evaluable. Blood cultures were performed at each febrile episode. Neutropenic patients developing fever were treated according to internal antimicrobial guidelines, usually with multiple targeted antimicrobial therapy in case of a previously known MDR-GN bacterial colonization. Median follow-up was of 602 days. Pre-transplant carriers were 8% and 17% in auto-HSCT and allo-HSCT recipients, respectively. Both in auto-HSCT and allo-HSCT, 30% of carriers were colonized by KPC-Kp. Among auto-HSCT, the overall survival (OS) did not significantly differ in carriers versus non-carriers (86% vs 84% at 2 years; P=0.231). Moreover, neither transplant-related mortality (TRM) nor infection-related mortality (IRM) were significantly different among the two groups, being of 0% vs 4% at 100 days (P=0.32) and of 0% vs 2% at 100 days (P= 0.099), respectively. In allo-HSCT, the OS was not significantly influenced by the carrier status nor univariate (43% vs 50% at 2 years; P=0.091) or in multivariate analysis (HR 1.41; P=0.129). Furthermore, TRM and IRM were comparable in MDR-GN bacteria carriers versus non-carriers, being 31% vs 25% at 2 years (P=0.301) and 23% vs 14% at 2 years (P=0.304). A MDR-GN bacterial colonization was not an independent risk factor for TRM and IRM, with an hazard ratio (HRs) of 1.428 (P=0.268) and of 1.69 (P=0.215). Furthermore, we did not observe any significant variation in the incidence of severe acute GvHD when comparing carriers and non-carriers (HR 1.86; P=0.087). In multivariate analysis severe acute GvHD was the only independent factor for a worse OS, TRM and IRM ( HRs of 3.177 (P 〈 0.001), 7,933 (P 〈 0.001) and 18,690 (P 〈 0.001), respectively. We registered a total of 168 Gram-negative bloodstream infections (BSIs) and 41/168 (24%) were due to a MDR bacteria, of which 6/41 in auto-HSCT patients and 35/41 in allo-HSCT recipients. Extended spectrum β-lactamases (ESBL+) E. coli (39%) and KPC-Kp (24%) were most frequently isolated from blood cultures. Thanks to the early initiation of a combined antimicrobial therapy guided by the antimicrobial susceptibly test deriving from rectal swabs in patients developing neutropenic fever, we witnessed a significant reduction in 30-day MDR-GN bacteria-related mortality (0% for auto-HSCT and 17% for allo-HSCT patients). Noticeably, in our Center 30-day KPC-Kp-related mortality was only 30%. Our retrospective single-centre study was able to demonstrate that, both in auto-HSCT and allo-HSCT, a pre-transplant colonization status is not significantly associated with a reduced OS, nor with a reduced TRM and IRM. Moreover, the prompt initiation of an adequate empirical therapy based on information coming from rectal swab is able to reduce MDR-GN bacteria-related mortality and to improve the overall HSCT outcome. Disclosures Ciceri: MolMed SpA: Consultancy.
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  • 10
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2584-2584
    Abstract: Introduction:Haploidentical hematopoietic stem cell transplantation (HSCT) performed using T–replete BM grafts and post-transplantation cyclophosphamide (PT-Cy) has gained much interest in the transplantation community for the excellent toxicity profile, achieving outcomes equivalent to those of HSCT performed using matched related or unrelated donors (Bashey, JCO 2013). Nonetheless, relapse remains a major challenge with the use of this non-myeloablative regimen (Luznik, BBMT 2008). Thus, we investigated whether the use of PBSC graft, an intensified myeloablative conditioning and sirolimus instead of tacrolimus might help increasing the therapeutic index of this procedure. Patients and Methods:Here we report the results on 39 patients treated between Nov 2012 and June 2014. The median age was 56 years (range, 21–78). Diagnoses included AML (21), ALL (5), CML-BC (1), MDS (1), NHL (5), and HD (6). The majority (62%) of patients were not in disease remission at time of HSCT. Eight patients (20%) received a prior allo-HSCT. For the remaining patients who underwent haplo-PTCy as a first allogeneic transplant, 19 patients (61%) scored high/very high according to the CIBMTR disease score, 12 (39%) scored intermediate, while no patient had a low disease score. The median Sorror Comorbidity Index was 3 (range: 0-9). Conditioning consisted of treosulfan (14 g/m2/day) on days –6 to –4, fludarabine (30 mg/m2/day) on days –6 to –2, and melphalan (70 mg/m2/day) on days –2 and –1, followed by T-replete G-CSF-mobilized PBSC. Postgrafting immunosuppression consisted of PT-Cy (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days, and sirolimus for at least 3 months. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Cumulative incidence (CI) of non-relapse mortality (NRM) was calculated using relapse as a competing risk, for GvHD the competing risk was death. Results:PBSC grafts contained an infused median CD34/kg of 6.03 e6 (4.15–8.02 e7), CD3/kg 21.12 e7 (10.5–48.26 e7). All patients but 1 engrafted (97.5%), with a median time to neutrophil and platelet recovery of 18 days (range 13–45) and 19 days (9–65), respectively. Notably, the only patient with primary graft failure had a HLA-DP mismatch in HvG direction. Post-HSCT recovery of lymphocyte subsets was broad and fast: median time to CD3 〉 100/ml was 28 days (range: 8-97), to CD4 〉 200/ml 35 days (21-137) and to CD19 〉 0/ml 34 days (24-137). Circulating T cells comprised naïve and memory subsets, with a recovery of CD31+ recent thymic emigrants (RTEs) starting from day 30. All patients had a significantly higher proportion of circulating RTEs at day 30, 90 and 180 compared to their pre-HSCT levels, suggesting an improvement in their thymic function after HSCT. We observed a significant early increase in circulating Tregs at day 15 post HSCT. With a median follow-up for living patients of 327 days, the 1-year cumulative CI of NRM and relapse were 15% and 32%, respectively. Two of the 9 relapses were HLA-loss variants (Vago, NEJM 2009) occurring at a median time of 277 days post-HSCT. Classical relapses had instead an earlier occurrence (median time to relapse: 92 days, range 37-134). CI of acute GvHD grade II-IV and III-IV at 6 months were 18% and 8%, while CI of chronic GvHD at 12 months was 19%. Estimated 1-year probability of OS and DFS were 58% and 51%. Outcomes were particularly favorable in patients transplanted in CR (1-year OS 93%, DFS 95%) as compared to those of patients transplanted with active disease (1-year OS 37%, DFS 29%; p=0.005 and p=0.001, respectively). Importantly, stratification according to CIBMTR score held similar results: in patients with intermediate score, 1-year OS was 91% vs. 33% in patients with high/very high score (p=0.015); similarly, 1-year DFS was 92% vs. 34% (p=0.009). Conclusions: PT-Cy coupled to sirolimus allow the use of haploidentical PBSC grafts with low rates of GvHD, and intensified myeloablative regimen is a valid option for patients with aggressive/advanced hematologic malignancies. The acceptable rates of GvHD and NRM as well as the favorable immune reconstitution profile open the way for combining it with novel immunomodulatory or cellular therapies to improve DFS in patients at high risk for relapse who would benefit from further treatment intensification early after transplant. Disclosures Bonini: MolMed S.p.A.: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    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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