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•An improved pegaspargase-modified MRD and risk-oriented regimen was prospectively tested in adults aged 18-65 years with Ph–ALL/LL.•Three-year survival rates were >60% with HCT or chemotherapy, further improved by MRD negativity and age ≤40 years.

In this retrospective study, we evaluated long-term survival and late effects in 137 patients affected by thalassemia major (TM) who received an allogeneic hematopoietic cell transplantation (HCT). Median age at HCT was 10.1 years. After a median follow-up of 30 years, 114 (83.2%) patients are living and 108 (78.8%) are cured. The cumulative incidence of nonrelapse mortality and thalassemia recurrence was 9.5% at 1 year and 10.2% at 39 years respectively. The 39-years cumulative incidence of overall survival and disease-free survival were 81.4% and 74.5%. One hundred twenty-three patients who survived more than 2 years after HCT were evaluated for late effects concerning hematological disorders, iron burden, growth, obesity, diabetes mellitus, thyroid and gonadal function, eye, heart, liver, lung, kidney, gastrointestinal, neurologic and psychiatric system, osteoarticular system, secondary solid cancer (SSC), performance status, and Covid-19 infection. Fertility was preserved in 21 males whose partners delivered 34 neonates and 25 females who delivered 26 neonates. Fifteen cases of SSC were diagnosed for a 39-year cumulative incidence of 16.4%. HCT represents a definitive cure for the majority of TM patients at the price, however, of a non-negligible early and late mortality which in the long run affects survival and disease-free survival.

The aim of this retrospective study was to determine the incidence and the clinical outcome of secondary oral cancer (SOC) and to assess potential risk factors in a large cohort of patients (n= 908), who received allogeneic hemopoietic cell transplantation (HCT) either for a malignant (n= 733) or nonmalignant hematologic disease (n= 175). The median follow-up of 438 transplant survivors was 17 years. Twelve patients developed SOC at a median of 13.5 years since HCT and at a median age of 47 years. The 35-year cumulative incidence function of SOC development was 3.47%. In univariate analysis, factors associated with increased incidence of SOC were reduced intensity conditioning and chronic graft-versus-host disease (cGvHD). On multivariate analysis, nonmalignant disease and duration of oral cGvHD ≥15 months were independent risk factors for SOC development. Nonmalignant disease recipients had 3.94× higher than expected rate of SOC (95% confidence interval, 1.50–10.39%, p= 0.0055). Recipients whose oral cGvHD persisted for more than ≥15 months had 58.6× higher than expected rate of SOC (95% confidence interval, 13.3–258.1%), p< 0.0001). This study demonstrates that oral cGvHD and a diagnosis of nonmalignant hematologic disease are strong risk factors in the SOC development.

Purpose To test the feasibility of using hospital discharge records (HDR) to monitor frequency indicators of hematologic malignancies (HM) in Abruzzo, an Italian region without a cancer registry.Methods Hospital discharge records contain a primary diagnosis field for principal disease and 5 secondary diagnosis fields for other diseases related or not to the principal diagnosis. In order to build patient indicators of HM—non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), multiple myeloma (MM), and leukemia (acute lymphoblastic leukemia [ALL], chronic lymphoid leukemia [CLL], acute myeloid leukemia [AML], and chronic myeloid leukemia [CML])—residents with first ICD-9-CM code 200-208 in any HDR field, or only in primary field, were identified.Results Among 3,955 patients with first diagnosis of HM registered in primary or secondary fields of HDR in the 2009-2013 period, and never recognized in 2005-2008 (791/year) (60.5/100,000), patients with first HM only in primary field were 2,304 (461/year) (35.2/100,000): 42% were NHL, 34% leukemia, 16% MM, 8% HL. Patient percentage of 461/791/year (58%) (64% among ordinary HDR and 49% in day-hospital HDR) was 35% for CLL (28/81), 47% for MM (74/152), 50% for CML (16/32), 57% for HL (36/63), 62% for NHL (194/314), and 82% for ALL (18/22) and AML (64/78).Conclusions Applying the cancer registries national rate, expected new diagnoses of HM in Abruzzo are about 620/year (46.4/100,000), compared to HDR estimates of 461 and 791/year (primary/all diagnoses fields: 58%). Since this percentage varies between 35% and 82%, our findings on the 2 methods seem useful for a validation process in the starting Cancer Registry.

To assess in multiple sclerosis (MS) the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) vs mitoxantrone (MTX) on disease activity measured by MRI.

Eighty patients with high-risk hematologic malignancies underwent unmanipulated, G-CSF–primed BM transplantation from an haploidentical family donor. Patients were transplanted in first or second complete remission (CR, standard-risk: n = 45) or in > second CR or active disease (high-risk: n = 35). The same regimen for GVHD prophylaxis was used in all cases. The cumulative incidence (CI) of neutrophil engraftment was 93% ± 0.1%. The 100-day CIs for II-IV and III-IV grade of acute GVHD were 24% ± 0.2% and 5% ± 0.6%, respectively. The 2-year CI of extensive chronic GVHD was 6% ± 0.1%. The 1-year CI of treatment-related mortality was 36% ± 0.3%. After a median follow-up of 18 months, 36 of 80 (45%) patients are alive in CR. The 3-year probability of overall and disease-free survival for standard-risk and high-risk patients was 54% ± 8% and 33% ± 9% and 44% ± 8% and 30% ± 9%, respectively. In multivariate analysis, disease-free survival was significantly better for patients who had standard-risk disease and received transplantations after 2007. We conclude that unmanipulated, G-CSF–primed BM transplantation from haploidentical family donor provides very encouraging results in terms of engraftment rate, incidence of GVHD and survival and represents a feasible, valid alternative for patients with high-risk malignant hematologic diseases, lacking an HLA identical sibling and in need to be urgently transplanted.

Eighty patients with high-risk hematologic malignancies underwent unmanipulated, G-CSF–primed BM transplantation from an haploidentical family donor. Patients were transplanted in first or second complete remission (CR, standard-risk: n = 45) or in > second CR or active disease (high-risk: n = 35). The same regimen for GVHD prophylaxis was used in all cases. The cumulative incidence (CI) of neutrophil engraftment was 93% ± 0.1%. The 100-day CIs for II-IV and III-IV grade of acute GVHD were 24% ± 0.2% and 5% ± 0.6%, respectively. The 2-year CI of extensive chronic GVHD was 6% ± 0.1%. The 1-year CI of treatment-related mortality was 36% ± 0.3%. After a median follow-up of 18 months, 36 of 80 (45%) patients are alive in CR. The 3-year probability of overall and disease-free survival for standard-risk and high-risk patients was 54% ± 8% and 33% ± 9% and 44% ± 8% and 30% ± 9%, respectively. In multivariate analysis, disease-free survival was significantly better for patients who had standard-risk disease and received transplantations after 2007. We conclude that unmanipulated, G-CSF–primed BM transplantation from haploidentical family donor provides very encouraging results in terms of engraftment rate, incidence of GVHD and survival and represents a feasible, valid alternative for patients with high-risk malignant hematologic diseases, lacking an HLA identical sibling and in need to be urgently transplanted.

Do some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]–matched, n = 941) or HLA-identical sibling donor (n = 3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P < .001) and relapse (RR, 1.50; P < .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P < .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.

Do some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]–matched, n = 941) or HLA-identical sibling donor (n = 3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P< .001) and relapse (RR, 1.50; P< .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P< .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an alternative treatment to patients with high-risk acute leukemia lacking a human leukocyte antigen-matched donor. We analyzed 173 adults with acute myeloid leukemia (AML) and 93 with acute lymphoblastic leukemia (ALL) who received a haplo-HSCT in Europe. All grafts were T cell–depleted peripheral blood progenitor cells from a direct family or other related donor. At transplantation, there were 25 patients with AML in CR1 (complete remission 1), 61 in more than or equal to CR2, and 87 in nonremission, and 24 with ALL in CR1, 37 in more than or equal to CR2, and 32 in nonremission. Median follow-up was 47 months in AML and 29 months in the ALL groups. Engraftment was observed in 91% of the patients. Leukemia-free survival at 2 years was 48% plus or minus 10%, 21% plus or minus 5%, and 1% for patients with AML undergoing transplantation in CR1, more than or equal to CR2, and nonremission, and 13% plus or minus 7%, 30% plus or minus 8%, and 7% plus or minus 5% in ALL patients, respectively. In conclusion, haplo-HSCT can be an alternative option for the treatment of high-risk acute leukemia patients in remission, lacking a human leukocyte antigen-matched donor.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an alternative treatment to patients with high-risk acute leukemia lacking a human leukocyte antigen-matched donor. We analyzed 173 adults with acute myeloid leukemia (AML) and 93 with acute lymphoblastic leukemia (ALL) who received a haplo-HSCT in Europe. All grafts were T cell–depleted peripheral blood progenitor cells from a direct family or other related donor. At transplantation, there were 25 patients with AML in CR1 (complete remission 1), 61 in more than or equal to CR2, and 87 in nonremission, and 24 with ALL in CR1, 37 in more than or equal to CR2, and 32 in nonremission. Median follow-up was 47 months in AML and 29 months in the ALL groups. Engraftment was observed in 91% of the patients. Leukemia-free survival at 2 years was 48% plus or minus 10%, 21% plus or minus 5%, and 1% for patients with AML undergoing transplantation in CR1, more than or equal to CR2, and nonremission, and 13% plus or minus 7%, 30% plus or minus 8%, and 7% plus or minus 5% in ALL patients, respectively. In conclusion, haplo-HSCT can be an alternative option for the treatment of high-risk acute leukemia patients in remission, lacking a human leukocyte antigen-matched donor.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for patients with relapsed acute myeloid leukemia. In this retrospective, multicenter study, we analyzed the outcome of 63 children (median age, 7 y; range, 0.2 to 17) who received unmanipulated allo-HSCT in second complete remission. Either a matched family donor or an unrelated donor was used in 29 (46) and 34 (54) patients, respectively. The stem cell source was bone marrow in 53 children (84), peripheral blood in 7 (11), and cord blood in 3 patients (5). Preparative regimen included total body irradiation in 25 patients (40). The 5-year estimates of overall survival and leukemia-free survival were 53 95 confidence interval (CI) 39-66 and 49 (95 CI 35-63), respectively, whereas the cumulative incidence of relapse and transplant-related mortality (TRM) were 26 (95 CI 16-41) and 25 (95 CI 15-40), respectively. In multivariate analysis, the use of a matched family donor predicted a better probability of LFS relative risk (RR) 2.29, P0.05. Both chronic graft-versus-host disease occurrence and age at diagnosis greater than 11 years were associated with an increased TRM (RR 8.08, P0.04 and RR 4.38, P0.05, respectively). These results indicate that allo-HSCT is a procedure able to rescue a significant proportion of children with acute myeloid leukemia in second complete remission, especially if an human leukocyte antigen-compatible relative is employed as donor. Both leukemia recurrence and TRM contributed to treatment failure. Optimization of donor selection and of strategies for both prophylaxis and treatment of graft-versus-host disease may improve the results of unrelated donor allo-HSCT.

Hematopoietic stem cell transplantation (HSCT) has been proposed for the treatment of severe multiple sclerosis (MS). In a phase 2 multicenter study we selected 19 non–primary progressive MS patients showing high disease activity on the basis of both brain magnetic resonance imaging (MRI) and sustained clinical deterioration despite conventional treatments. After stem cell mobilization with cyclophosphamide (CY) and filgrastim, patients were conditioned with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), cytosine arabinoside, etoposide, and melphalan (BEAM) followed by antithymocyte globulin (ATG). Unmanipulated peripheral blood stem cells (PBSCs) were then infused. No maintenance treatment was administered with a median follow-up of 36 months (range, 12 to 72 months). All patients showed clinical stabilization or improvement; 3 subsequently deteriorated, 1 beyond the baseline. No MRI active lesions were detected after the HSCT except in 1 patient who showed a new lesion at 4.5 years. Infections were limited and restricted to 3 months after HSCT. Health-related quality of life was assessed through the 54-item MS quality of life (MSQOL-54) questionnaire, showing a statistically significant improvement in both composite scores and in most of the individual domains. HSCT is able to induce a prolonged clinical stabilization in severe progressive MS patients, resulting in both sustained treatment-free periods and quality of life improvement.

Hematopoietic stem cell transplantation (HSCT) has been proposed for the treatment of severe multiple sclerosis (MS). In a phase 2 multicenter study we selected 19 non–primary progressive MS patients showing high disease activity on the basis of both brain magnetic resonance imaging (MRI) and sustained clinical deterioration despite conventional treatments. After stem cell mobilization with cyclophosphamide (CY) and filgrastim, patients were conditioned with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), cytosine arabinoside, etoposide, and melphalan (BEAM) followed by antithymocyte globulin (ATG). Unmanipulated peripheral blood stem cells (PBSCs) were then infused. No maintenance treatment was administered with a median follow-up of 36 months (range, 12 to 72 months). All patients showed clinical stabilization or improvement; 3 subsequently deteriorated, 1 beyond the baseline. No MRI active lesions were detected after the HSCT except in 1 patient who showed a new lesion at 4.5 years. Infections were limited and restricted to 3 months after HSCT. Health-related quality of life was assessed through the 54-item MS quality of life (MSQOL-54) questionnaire, showing a statistically significant improvement in both composite scores and in most of the individual domains. HSCT is able to induce a prolonged clinical stabilization in severe progressive MS patients, resulting in both sustained treatment-free periods and quality of life improvement.

Treatment of chronic granulomatous disease (CGD) with myeloablative bone marrow transplantation is considered risky. This study investigated complications and survival according to different risk factors present at transplantation. The outcomes of 27 transplantations for CGD, from 1985 to 2000, reported to the European Bone Marrow Transplant Registry for primary immunodeficiencies were assessed. Most transplant recipients were children (n = 25), received a myeloablative busulphan-based regimen (n = 23), and had unmodified marrow allografts (n = 23) from human leukocyte antigen (HLA)–identical sibling donors (n = 25). After myeloablative conditioning, all patients fully engrafted with donor cells; after myelosuppressive regimens, 2 of 4 patients fully engrafted. Severe (grade 3 or 4) graft-versus-host disease (GVHD) disease developed in 4 patients: 3 of 9 with pre-existing overt infection, 1 of 2 with acute inflammatory disease. Exacerbation of infection during aplasia was observed in 3 patients; inflammatory flare at the infection site during neutrophil engraftment in 2: all 5 patients belonged to the subgroup of 9 with pre-existing infection. Overall survival was 23 of 27, with 22 of 23 cured of CGD (median follow-up, 2 years). Survival was especially good in patients without infection at the moment of transplantation (18 of 18). Pre-existing infections and inflammatory lesions have cleared in all survivors (except in one with autologous reconstitution). Myeloablative conditioning followed by transplantation of unmodified hemopoietic stem cells, if performed at the first signs of a severe course of the disease, is a valid therapeutic option for children with CGD having an HLA-identical donor.

Treatment of chronic granulomatous disease (CGD) with myeloablative bone marrow transplantation is considered risky. This study investigated complications and survival according to different risk factors present at transplantation. The outcomes of 27 transplantations for CGD, from 1985 to 2000, reported to the European Bone Marrow Transplant Registry for primary immunodeficiencies were assessed. Most transplant recipients were children (n = 25), received a myeloablative busulphan-based regimen (n = 23), and had unmodified marrow allografts (n = 23) from human leukocyte antigen (HLA)–identical sibling donors (n = 25). After myeloablative conditioning, all patients fully engrafted with donor cells; after myelosuppressive regimens, 2 of 4 patients fully engrafted. Severe (grade 3 or 4) graft-versus-host disease (GVHD) disease developed in 4 patients: 3 of 9 with pre-existing overt infection, 1 of 2 with acute inflammatory disease. Exacerbation of infection during aplasia was observed in 3 patients; inflammatory flare at the infection site during neutrophil engraftment in 2: all 5 patients belonged to the subgroup of 9 with pre-existing infection. Overall survival was 23 of 27, with 22 of 23 cured of CGD (median follow-up, 2 years). Survival was especially good in patients without infection at the moment of transplantation (18 of 18). Pre-existing infections and inflammatory lesions have cleared in all survivors (except in one with autologous reconstitution). Myeloablative conditioning followed by transplantation of unmodified hemopoietic stem cells, if performed at the first signs of a severe course of the disease, is a valid therapeutic option for children with CGD having an HLA-identical donor.

One hundred nine patients with hematologic malignancies, undergoing bone marrow transplants (BMT) from unrelated donors, were randomized in 2 consecutive trials to receive or not to receive antithymocyte globulin (ATG) in the conditioning regimen, as follows: (A) 54 patients (median age, 28 years; 39% with advanced disease) were randomized to no ATG (n = 25) versus 7.5 mg/kg rabbit ATG (Thymoglobulin; Sangstat, Lyon, France) (n = 29) ; (B) 55 patients (median age, 31 years, 71% with advanced disease) were randomized to no ATG (n = 28) versus 15 mg/kg rabbit ATG (n = 27). Grade III-IV graft-versus-host disease (GVHD) was diagnosed in 36% versus 41% (P = .8) in the first and in 50% versus 11% (P = .001) in the second trial. Transplant-related mortality (TRM), relapse, and actuarial 3-year survival rates were comparable in both trials. In fact, despite the reduction of GVHD in the second trial, a higher risk for lethal infections (30% vs 7%; P = .02) was seen in the arm given 15 mg/kg ATG. Extensive chronic GVHD developed overall more frequently in patients given no ATG (62% vs 39%;P = .04), as confirmed by multivariate analysis (P = .03). Time to 50 × 109/L platelets was comparable in the first trial (21 vs 24 days; P = .3) and delayed in the ATG arm in the second trial (23 vs 38 days;P = .02). These trials suggest that (1) 15 mg/kg ATG before BMT significantly reduces the risk for grade III-IV acute GVHD, (2) this does not translate to a reduction in TRM because of the increased risk for infections, and (3) though survival is unchanged, extensive chronic GVHD is significantly reduced in patients receiving ATG.

One hundred nine patients with hematologic malignancies, undergoing bone marrow transplants (BMT) from unrelated donors, were randomized in 2 consecutive trials to receive or not to receive antithymocyte globulin (ATG) in the conditioning regimen, as follows: (A) 54 patients (median age, 28 years; 39% with advanced disease) were randomized to no ATG (n = 25) versus 7.5 mg/kg rabbit ATG (Thymoglobulin; Sangstat, Lyon, France) (n = 29); (B) 55 patients (median age, 31 years, 71% with advanced disease) were randomized to no ATG (n = 28) versus 15 mg/kg rabbit ATG (n = 27). Grade III-IV graft-versus-host disease (GVHD) was diagnosed in 36% versus 41% (P= .8) in the first and in 50% versus 11% (P= .001) in the second trial. Transplant-related mortality (TRM), relapse, and actuarial 3-year survival rates were comparable in both trials. In fact, despite the reduction of GVHD in the second trial, a higher risk for lethal infections (30% vs 7%; P= .02) was seen in the arm given 15 mg/kg ATG. Extensive chronic GVHD developed overall more frequently in patients given no ATG (62% vs 39%;P= .04), as confirmed by multivariate analysis (P= .03). Time to 50 × 109/L platelets was comparable in the first trial (21 vs 24 days; P= .3) and delayed in the ATG arm in the second trial (23 vs 38 days;P= .02). These trials suggest that (1) 15 mg/kg ATG before BMT significantly reduces the risk for grade III-IV acute GVHD, (2) this does not translate to a reduction in TRM because of the increased risk for infections, and (3) though survival is unchanged, extensive chronic GVHD is significantly reduced in patients receiving ATG.

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P?=?.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P?=?.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P?=?.05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings.

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P= .01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P= .07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P= .05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings.

24 patients with severe aplastic anemia were given marrow grafts from related donors other than HLA‐identical siblings. 2 patients received cyclophosphamide (CY) plus total body irradiation (TBI) as part of their preparative regimen. The remaining 22 received CY only, with or without other immunosuppressive agents. All donor/recipient pairs were genotypically identical for one HLA haplotype and had variable numbers of similar antigens on the unshared haplotypes. 6 patients received marrow from donors who were HLA‐A, B, DR, Dw phenotypically matched. All 6 are currently engrafted and surviving, 3 after having had Acute Graft‐Versus‐Host Disease (AGVHD) and 4 with Chronic Graft‐Versus‐Host‐Disease (CGVHD). The remaining 18 patients received HLA partially‐incompatible grafts. Of 17 partially‐matched patients evaluable for engraftment, 10 had failure of engraftment or graft rejection; all died of infectious complications. Of the 7 mismatched patients achieving sustained engraftment, all developed grade II–IV AGVHD. 6 of 11 patients who survived more than 100 d after transplant had CGVHD. Currently, 2of 18 patients who were mismatched for 1 or more loci survive with hematological recovery. This study shows that patients with refractory severe aplastic anemia who have a phenotypically‐matched donor clearly benefit from a marrow transplant using only CY for conditioning. Those with partially‐matched donors are at high risk for graft rejection and may need additional immunosuppression such as CY plus TBI to facilitate engraftment. For those who engraft, more effective prophylactic and/or treatment measures for AGVHD are needed to improve survival.

Attempts to identify an early and discriminating marker of acute graft-versus-host disease (aGvHD) have been unsuccessful. The levels of soluble CD4 and soluble CD8 in serum correlate with T cell subset activation and may be important in monitoring and characterizing immunological processes. We determined serum soluble CD4 (sCD4) and sCD8 levels with a two-site sandwich enzyme immunoassay on patients' serum samples collected prior to bone marrow transplantation and weekly after transplantation until day +28. No significant increment of sCD4 was documented in each determination. sCD8 rose significantly before diagnosis or development of maximal clinical symptoms in patients with grade II–III aGvHD than grade 0–I aGvHD [at day +21—median value 447 IU/ml; range 94–713; versus 1136 IU/ml, range 790–1416P=0.002); at day +28—median value 443 IU/ml, range 73–992, versus 1164 IU/ml, range 625–1960P=0.005)]. On the day of marrow infusion the sCD8 levels were significantly higher in patients who subsequently developed grade II–III than in patients with grade 0–I aGvHD (median value 155 IU/ml, range 10–332, versus 350 IU/ml, range 283–830;P=0.003). Careful monitoring of sCD8 is a useful tool for a prompt aGvHD diagnosis and may be used in a clinical bone marrow transplantation setting.

In high-risk acute leukemia patients undergoing HLA haploidentical T cell-depleted tranplantation, we demonstrated that adoptive immunotherapy with donor T regulatory cells (Tregs; 2x106/kg) co-infused with conventional T cells (Tcon; 1x106/kg ) provided significant protection from acute graft-versus-host disease (aGvHD) and was associated with an almost complete control of leukemia relapse (graft versus leukemia effect, GvL) (Di Ianni et al., Blood 2011; Martelli et al., Blood 2014; Ruggeri et al., ASH 2018). In the present study we investigated whether Tregs interact with bone marrow (BM) and peripheral blood (PB) dendritic cells (DCs) and whether such interaction is responsible for GvHD protection and GvL effect. Twenty six patients (median age 54 ; 20 AML; 4 ALL; 2 MDS) transplanted between July 2016 and April 2019 were evaluated up to one year after the transplant. BM and PB DCs (using CD123 for plasmocitoid DC-pDC; CD11c for myeloid DC-mDC; CD80/CD86 for costimulatory molecules) and T cells (CD3/CD4/CD8; CD4/CD25/CD127; CD28/PD-1/TIM3) were analysed by flow-cytometry. DCs were also sorted and analysed by RT-PCR for a panel of genes involved in activation (IL-6; TNF-a; IL-12; CCR7; NOTCH ligands) vs tolerigenic (TGF-beta; PD-1/PDL1; IDO; IL-10; ICOS) pathways. To study the effects of DCs on T cell proliferation, pre-activated (with GM-CSF at 50 ng/ml, IL-4 at 800 U/ml and TNF-a at 50 ng/ml for 18 hrs) BM and PB CD1c+DCs were co-cultured for 96 hrs with autologous CFSE labelled BM and PB CD3+ cells at a DC:CD3 ratio of 1:10. mDC numbers were significantly higher in BM than PB during the first 6 months after transplant. BM-derived mDCs expressed higher levels of the co-stimulatory receptor CD86. No differences emerged in pDCs. RT-PCR showed an activation signature in BM-DCs (significantly higher IL-6 level) and a tolerigenic signature in PB-DCs (significantly higher TGF-beta and PDL-1 levels). BM-derived CD8+T cells displayed a higher expression of the co-stimulatory receptor CD28 than PB-derived CD8+T cells (30.3±18.8 vs 9.2±4.9; p<0.05 ). In contrast, the expression of the immune checkpoint inhibitor PD-1 was significantly higher in both PB-derived CD4 (69%±29 vs 24±11) and CD8 (65±25 vs 4±3; p<0.05) T cells than BM-derived T lymphocytes. T cells from both BM and PB did not express the T cell exhaustion marker TIM-3. CD3/CFSE+-DCs co-cultures showed a T cell proliferation rate that was significantly higher in BM than in PB (25±7.2 vs 6.7±8.7; p<0.05). These data show that haploidentical transplantation with Treg/Tcon immunotherapy promotes the reconstitution of DCs with an activating signature in the BM and a tolerigenic signature in the PB. Human peripheral blood Tregs that are used for adoptive immunotherapy are largely CD45RO+ and express low level of CxCR4 bone marrow homing receptor. When infused in immunodeficient mice they migrate to the periphery (spleen, gut, liver) but are unable to home to the bone marrow (Ruggeri et al., ASH 2018). In conclusion, Tregs/DC interaction induce tolerance in the periphery (and may protect from GvHD). In the BM, in the absence of Tregs, DCs activate alloreactive Tcon and may favour killing of the leukemic targets. Therefore, Tregs/DC interactions may contribute to the separation between GvL effect and GvHD in the Treg based haploidentical transplantation.

No relevant conflicts of interest to declare.

Robinson: Sandoz: Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Beelen:Medac: Consultancy, Other: Travel Support. Finke:Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Corradini:Amgen: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer.

Introduction

Introduction

Foà: ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau.

No relevant conflicts of interest to declare.

CMV represents one of the most serious life-threatening complications of allogeneic stem cell transplantaion (allo-SCT). Pre-emptive treatment with anti-CMV drugs is highly effective, but toxicity and repetitive reactivation of CMV represent a major challenge in the clinical practice. The use of anti-CMV specific immunoglobulins (Megalotect) is controversial.

Introduction. Polycythemia Vera (PV) is a myeloproliferative neoplasm (MPN) whose major features are peripheral erythrocytosis and increased thrombotic risk, affecting morbidity and mortality. Essential Thrombocythemia (ET), a MPN characterized by high platelet generation rate, has been shown to be associated with a reduction in von Willebrand factor (vWf) large multimers and activity which depends on platelet turnover (Lancellotti et al, JTH 2015;13:1226-37). The acquired vWf type 2A defect in ET is thought to influence bleeding rate. Data on vWf and on a possible acquired von Willebrand deficiency in PV are less clear. Previous studies included PV patients with marked thrombocytosis, with bleeding history or included treated and untreated patients, with heterogeneous results. Therefore, the phenotypic features of vWf in PV patients with well-controlled haematocrit, routinely accessing the outpatient clinics remain largely undefined. In addition, whether the acquired vWf defect is similar between PV and ET remains poorly defined.

Soverini: Bristol-Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Bocchia: Novartis: Other: Travel grant; Celgene: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Cuneo: Abbvie: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Roche: Honoraria, Other: Advisory Board. Bonifacio: Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Falini: Roche: Research Funding. Galieni: Takeda: Other: Advisory Board; Abbvie: Other: Advisory Board. Foà: Sandoz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Baccarani: Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Gadolinium based contrast agents (GBCA) are used in magnetic resonance imaging (MRI) in order to improve the detection and the characterization of pathophysiologic processes. Many studies have reported an association between increased signal intensities (SI) on unenhanced T1-weighted MRI images in different brain regions and the history of repeated intravenous administrations of GBCAs in patients with normal renal function. We conducted a prospective study aimed to evaluate signal changes in the dentate nucleus (DN), globus pallidus (GP), pons, and thalamus (normalized to the deep cerebellum white matter) in T1-MRI images after serial injections of Gadobutrol for the study of the heart in patients with thalassemia.

Hematopoietic cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers (SSC). There is limited information about the incidence of SSC following HCT for patients with thalassemia major (TM).

Chronic lymphocytic leukemia (CLL) is a B cell disorder characterized by constitutive NOTCH1 activation. NOTCH1mutations are recurrently associated with CLL providing a new clonal marker to track CLL origin. To investigate CLL-initiating cells, we assessed NOTCH1mutational status and signaling in hematopoietic stem (HSCs) and progenitor cells from CLL bone marrow. We collected a total of 29 bone marrow (BM) samples including 22 CLL patients and 7 healthy donors (HDs). BM cells were sorted into CD34+CD38- HSCs (purity 94.23% ± 3.04% ) and CD34+CD38+ progenitor fraction (98.12% ± 1.34%). While Sanger sequencing analysis of the NOTCH1failed to detect alterations in CD34+/CD38- HSCs, AS-PCR and Droplet digital PCR (ddPCR) indicated the presence of small HSCs mutated clones in 57% of cases. Altogether, these data confirm that NOTCH1mutation is an early event in CLL hematopoiesis. The analysis of CD34+/CD38+ progenitors detected the NOTCH1mutation in the majority of samples (66%). The NOTCH1mutational burden progressively increased along specific stages of HSC differentiation (6.4%± 4.7 in CD34+CD38- to 14.9%±11.3 in CD34+CD38+CD10+CD19+ cells, 22.7%±6.5 in CD34-CD38+CD10+CD19+ cells and 40.5%±4.3 in neoplastic CD5+CD19+ cells). This suggests that the NOTCH1lesion is selected and expands during HSC differentiation toward a B neoplastic cell, thus strengthening the hypothesis that the genetic alteration is an initial event associated with the stepwise malignant transformation of CLL. Conversely, CD34+ cells (1x106) from CLL patients carrying the mutation, when transplanted into NOD/SCID/IL2Rgnull (NSG) mice generated a mature CLL phenotype (the median percentage of CD5+CD19+ cells in hCD45+ cells was 38.5% and 43.8% in BM and spleen respectively) lacking NOTCH1 mutation (as showed by AS-PCR assay performed on enriched hCD45 cells). This data is more in line with the hypothesis that this genetic abnormality is acquired at the mature B cell stage as an additional leukemogenic event to transform into clinical CLL. Thus, we analyzed the NOTCH1 signaling status in HSCs and progenitor cells of NOTCH1-mutated and unmutated CLL samples. The flow-cytometric analysis of the active NOTCH1-ICN protein level showed unmutated and mutated CLL has a significantly higher NOTCH1-ICN level than HDs samples in both CD34+/CD38- HSCs and CD34+CD38+ (73.4%±22.9 and 83%±16.4 vs 33.3%±14.8; 94.4%±7.3 and 92.8%±4.3 vs 47.9%±13.8, p<0.01 and p<0.001, respectively). c-MYC expression was found significantly higher in HSCs cells from NOTCH1 mutated and unmutated CLL samples compared to HD (3.5±0.7 and 2.6±0.08 vs 1.3±0.1). Western blot analysis of the expression levels of the NOTCH1-TM subunit revealed that HSCs from mutated and unmutated CLL patients always expressed the NOTCH1-TM protein, compared to HDs where NOTCH1-TM was either absent or expressed at lower levels. The present study indicated that the pool of CD34+ cells, including HSC and progenitor compartments, have NOTCH1 aberrantly expressed and activated in CLL patients compared to HDs demonstrating a common nonmutational NOTCH1 activation occurring early in CLL hematopoiesis. This selective pressure might contribute to the onset of specific NOTCH1mutations in a DNA context that is prone to spontaneous microdeletion. These data represent a rationale for the use of therapies targeting the NOTCH1 signaling in CLL aimed to inhibit the survival of CLL-initiating cells.

Background and purpose of the study:Chronic myeloproliferative neoplasms (cMPN) are clonal diseases resulting from the transformation of a multi-potent hematopoietic stem cell that leads to overactive hemopoiesis and bone marrow fibrosis [Tefferi et al., Am. J. Hematol. 2008; 83(6): 491-7].

New treatments options introduced during recent decades have improved the survival of multiple myeloma(MM)patients.Managing the complications of the disease and its treatment, such as infections become more important as MM-patients survive longer. Infections are a significant cause of morbidity and a leading cause of death in MM-patients.Effect of novel therapies on the risk of infection remains to be established and new trials on prophylactic measures are needed.These advances have transformed myeloma into a chronic condition, with multiple relapses resulting in cumulative immunosuppression and higher risk of infection. In addition to the immunodeficiency related to myeloma, the type of anti-myeloma therapy used also plays a role in the development of infectious events.We aimed to study the development of severe infectious events of grade 3-4 requiring often hospitalization in a group of patients under treatment at diagnosis as well as at relapse. We evaluated the impact of the type of anti-myeloma therapy and of the disease features on patients' infectious complications in the context of novel agents.We retrospectively reviewed data from 195 myeloma patients diagnosed from 1999 to 2016 in order to assess type and outcome of infections (Table 1). 7 of these were life-threatening (3 viral interstitial pneumonias and 4 gram negative sepsis)and 103 have resulted in discontinuation of therapy(respectively 73 bacterial, 10 fungal,18 viral and 2 parasitic-infectious-complications). We focus on time of occurrence and number of prior therapeutic lines and on disease biological aggressiveness.Our aim was to define risk-factors and to organize an effective antimicrobial prophylaxis strategy in our cohort of patients.In our analysis 30 patients presented a FUO(fever of unknown origin)without isolation of pathogens.They were 19 elderly-patients and 11 young in a neutropenic phase after chemotherapy. They showed defervescence following antibiotic therapy with piperacillin-tazobactam.165 patients presented infectious complications with a well-known etiology (Figure 1): 100 bacterial, 45 viral, 15 fungal and 5 parasitic infections. Pathogens isolated were:Candida-Albicans followed by C.Parapsylosis and Aspergillus-Flavus among fungal infections,E.Coli,Klebsiella-Pneumoniae and Pseudomonas-aeruginosa between bacterial complications,CMV,HSV,HZV in viral manifestations and Leishmanias among parasitic-events.Advanced age is a meaningful risk-factor togheter with biologically aggressiveness and relapse condition. The majority of patients were older than 65 years (125 as 76%) in a relapse setting (125 as 77%).Kind of anti-myeloma therapy used also plays a role in the development of infection. Specifically the predominant part of patients developing fungal infections(13 as 89%)showed neutropenia after chemotherapy or previous therapy with Imids. The majority of patients with viral infections(39 as 87%) presented lymphopenia and previous therapies bortezomib-based.Bacterial infections have shown mostly prevalent in neutropenic-phases (88 as 88%) usually in relapse phases (78 as 78%)or in hypogammaglobulinemic patients(68 as 68%).Finally most of parasitic infections have been shown after high doses steroid treatment and with more than 2 of therapeutic lines(100%).Severe infections represent a significant comorbidity in MM, often underestimated, in all phases of the disease expecially in refractory/relapsed patients.Immunoglobulin-replacement-therapy or antibiotic-prophylaxis may possible have a protective-role in high risk old patients with high ISS stage and aggressive disease. Variety of factors underlies susceptibility to infections including defects of innate and adaptive-immunity(neutropenia,hypogammaglobulinemia).Need for antimicrobial-prophylaxis depends on risk for and seriousness of infections.Based on our experience,in the first three-months of therapy with IMIDs we now begin prophylactic antibacterial and antifungal therapy (quinolone and fluconazole).All patients treated to date(30 in total)did not require therapy-discontinuation.High-risk-patients should receive antimicrobial-prophylaxis and trials on prophylactic-measures are needed.Key to the management of infection is the understanding of the specific risk factors and periods in order to perform a risk adjusted prophylactic and treatment strategies.

Background and purpose of the study:Several reports have documented that histone deacetylase inhibitors induce neoplastic cells to undergo growth arrest, differentiation and/or apoptotic cell death. Among these agents, Givinostat inhibits proliferation of cells bearing the JAK2V617Fmutation [Guerini et al., Leukemia 2008 Apr; 22(4): 740-7; Calzada et al., Exp. Hematol. 2012; 40 (8): 634-45]. In two phase II studies conducted in patients with chronic myeloproliferative neoplasms (cMPN), Givinostat was generally well tolerated at the maximum administered dose (150 mg/day) [Rambaldi et al., Br. J. Haematol. 2010; 150 (4): 446-55; Finazzi et al., Br. J. Haematol. 2013;161(5):688-94]. To formally assess the safety and tolerability, Maximum Tolerated Dose (MTD) and preliminary efficacy of Givinostat in patients with JAK2V617Fpositive Polycythemia Vera (PV), this two-part, multicenter, open label, non-randomized, phase Ib/II study dose was conducted.

Foà: Ariad: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau. Garderet:Takeda: Consultancy; Amgen: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy.

Efficace: TEVA: Consultancy, Research Funding; Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; Lundbeck: Research Funding. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Angelucci:Novartis oncology, celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lo Coco:Teva: Consultancy, Honoraria, Speakers Bureau; Lundbeck: Honoraria, Speakers Bureau; Novartis: Consultancy; Baxalta: Consultancy; Pfizer: Consultancy.

Newly significant advances have been made in diagnosis and treatment of multiple-myeloma (MM).Until recently,MM was defined by presence of end-organ-damage,specifically hypercalcemia, renal-failure, anemia and bone-lesions(CRAB-features).

Introduction

No relevant conflicts of interest to declare.

Background:

No relevant conflicts of interest to declare.

Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gaidano:Novartis: Honoraria, Other: Advisory boards; Celgene: Research Funding; Karyopharm: Honoraria, Other: Advisory boards; Roche: Honoraria, Other: Advisory boards; Morphosys: Honoraria, Other: Advisory boards; GlaxoSmithKline: Honoraria, Other: Advisory boards; Amgen: Honoraria, Other: Advisory boards; Janssen: Honoraria, Other: Advisory boards. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Patriarca:Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Di Raimondo:Janssen-Cilag, Celgene: Honoraria. Hájek:Janssen-Cilag: Honoraria; Celgene, Merck Sharp & Dohme: Consultancy, Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

Oliva: Celgene: Other: Advisory Board, Speakers Bureau; Amgen: Consultancy; Novartis: Speakers Bureau.