Emilio Paolo Alessandrino

Allogeneic Hematopoietic Stem-Cell Transplantation for Patients 50 Years or Older With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia

PURPOSE This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients. PATIENTS AND METHODS We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC). RESULTS The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival. CONCLUSION Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.

WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).

We evaluated the impact of World Health Organization (WHO) classification and WHO classification-based Prognostic Scoring System (WPSS) on the outcome of patients with myelodysplastic syndrome (MDS) who underwent allogeneic stem cell transplantation (allo-SCT) between 1990 and 2006. Five-year overall survival (OS) was 80% in refractory anemias, 57% in refractory cytopenias, 51% in refractory anemia with excess blasts 1 (RAEB-1), 28% in RAEB-2, and 25% in acute leukemia from MDS (P = .001). Five-year probability of relapse was 9%, 22%, 24%, 56%, and 53%, respectively (P < .001). Five-year transplant-related mortality (TRM) was 14%, 39%, 38%, 34%, and 44%, respectively (P = .24). In multivariate analysis, WHO classification showed a significant effect on OS (P = .017) and probability of relapse (P = .01); transfusion dependency was associated with a reduced OS (P = .01) and increased TRM (P = .037), whereas WPSS showed a prognostic significance on both OS (P = .001) and probability of relapse (P < .001). In patients without excess blasts, multilineage dysplasia and transfusion dependency affected OS (P = .001 and P = .009, respectively), and were associated with an increased TRM (P = .013 and P = .031, respectively). In these patients, WPSS identified 2 groups with different OS and TRM. These data suggest that WHO classification and WPSS have a relevant prognostic value in posttransplantation outcome of MDS patients.

Adverse events occurring during bone marrow or peripheral blood progenitor cell infusion: analysis of 126 cases

Bone marrow (BM) and/or peripheral blood progenitor cells (PBPC) given after high-dose chemo-radiotherapy are commonly cryopreserved. Re-infusion of the thawed product can cause cardiovascular and other complications. We compared two groups of adult patients receiving autologous BM or PBPC transplant to assess the incidence of adverse events occurring during infusion. Fifty-one patients received BM, and 75 PBPC. The two groups were comparable in respect of age, total volume infused, quantity of dimethylsulfoxide (DMSO) and number of polymorphonuclear neutrophils. Patients receiving PBPC had a higher number of nucleated cells per kg of body weight; those in the BM group received a significantly greater quantity of red cells. Non-cardiovascular complications occurred in 19% and 8% of patients rescued by BM and PBPC respectively. The incidence of hypertension was 21% in the BM and 36% in the PBPC group. Asymptomatic hypotension was more frequent in PBPC patients (P < 0.001). bradyarrhythmia was noticed in two of 75 pbpc patients and in 14 of 51 bm patients (P < 0.001). in the former group one patient had heart block; he died of renal failure 10 days later. bradycardia and hemoglobinuria were more common in patients receiving bm where a higher concentration of red cells was present (P < 0.001). since bradyarrhythmias may be a life-threatening complication we advise continuous careful monitoring during infusion of thawed bm. the strong correlation between bradycardia and red blood cell contamination suggests the use of purified products with a very low red cell content.

Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study

Background Transfusion-dependency affects the natural history of myelodysplastic syndromes. Secondary iron overload may concur to this effect. The relative impact of these factors on the outcome of patients with myelodysplastic syndrome receiving allogeneic stem-cell transplantation remains to be clarified. Design and Methods We retrospectively evaluated the prognostic effect of transfusion history and iron overload on the post-transplantation outcome of 357 patients with myelodysplastic syndrome reported to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry between 1997 and 2007. Results Transfusion-dependency was independently associated with reduced overall survival (hazard ratio=1.48, P=0.017) and increased non-relapse mortality (hazard ratio=1.68, P=0.024). The impact of transfusion-dependency was noted only in patients receiving myeloablative conditioning (overall survival: hazard ratio=1.76, P=0.003; non-relapse mortality: hazard ratio=1.70, P=0.02). There was an inverse relationship between transfusion burden and overall survival after transplantation (P=0.022); the outcome was significantly worse in subjects receiving more than 20 red cell units. In multivariate analysis, transfusion-dependency was found to be a risk factor for acute graft-versus-host disease (P=0.04). Among transfusion-dependent patients undergoing myeloablative allogeneic stem cell transplantation, pre-transplantation serum ferritin level had a significant effect on overall survival (P=0.01) and non-relapse mortality (P=0.03). This effect was maintained after adjusting for transfusion burden and duration, suggesting that the negative effect of transfusion history on outcome might be determined at least in part by iron overload. Conclusions Pre-transplantation transfusion history and serum ferritin have significant prognostic value in patients with myelodysplastic syndrome undergoing myeloablative allogeneic stem cell transplantation, inducing a significant increase of non-relapse mortality. These results indicate that transfusion history should be considered in transplantation decision-making in patients with myelodysplastic syndrome.

Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R

Approximately one-third of patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (HSCT) are cured by this treatment. Treatment failure may be due to transplant complications or relapse. To identify predictive factors for transplantation outcome, we studied 519 patients with MDS or oligoblastic acute myeloid leukemia (AML, <30% marrow blasts) who received an allogeneic HSCT and were reported to the Gruppo Italiano Trapianto di Midollo Osseo registry between 2000 and 2011. Univariate and multivariate survival analyses were performed using Cox proportional hazards regression. High-risk category, as defined by the revised International Prognostic Scoring System (IPSS-R), and monosomal karyotype were independently associated with relapse and lower overall survival after transplantation. On the other hand, older recipient age and high hematopoietic cell transplantation-comorbidity index (HCT-CI) were independent predictors of nonrelapse mortality. Accounting for various combinations of patients age, IPSS-R category, monosomal karyotype, and HCT-CI, the 5-year probability of survival after allogeneic HSCT ranged from 0% to 94%. This study indicates that IPSS-R risk category and monosomal karyotype are important factors predicting transplantation failure both in MDS and oligoblastic AML. In addition, it reinforces the concept that allogeneic HSCT offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages.

Persistent Symptomless Human Metapneumovirus Infection in Hematopoietic Stem Cell Transplant Recipients

Sequential nasopharyngeal aspirates from patients without respiratory symptoms undergoing hematopoietic stem cell transplantation (HSCT) were tested for genomic RNA of human metapneumovirus (hMPV). Persistent hMPV infection was documented in most of them and confirmed by virus isolation. hMPV infection etiology was also evaluated during the same period in samples from pediatric patients with acute respiratory diseases (ARDs). Sequence analysis of hMPV in HSCT recipients documented infection by hMPV genotype A and strong interhost similarity; this pattern differs from that observed in pediatric patients with ARDs. The data indicate that HSCT recipients may frequently develop symptomless hMPV infection.

Human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection

Human cytomegalovirus infection is the most frequent viral complication in patients undergoing hematopoietic stem cell transplantation. Pre-transplant human cytomegalovirus serostatus of the recipient is the main trigger for specific T-cellreconstitution. Background Human cytomegalovirus infection is the most frequent viral complication in patients undergoing hematopoietic stem cell transplantation. We investigated the development of human cytomegalovirus-specific T cells in adult recipients of hematopoietic stem cell transplants. Design and Methods From May 2003 through October 2006 a total of 45 patients were monitored for human cytomegalovirus-specific T-cell reconstitution. Human cytomegalovirus-infected autologous dendritic cells were used as a stimulus to detect interferon-γ-producing human cytomegalovirus-specific CD8+ and CD4+ T cells during the first year after transplantation. Interleukin-2 production by specific T cells was also determined. Figure 1. Probability of HCMV infection development and HCMV-specific CD4+ and CD8+ T-cell immunity reconstitution. A: cumulative incidence curves of HCMV infection according to donor (D) and recipient (R) HCMV-serostatus. B: cumulative incidence curves of HCMV infection and HCMV-specific CD8+ and CD4+ T-cell reconstitution (i.e. corresponding to a specific T-cell number greater than 0.4 cells/μL blood). C: cumulative incidence curves of HCMV-specific CD8+ T-cell reconstitution according to D/R HCMV-serostatus. D: cumulative incidence curves of HCMV-specific CD4+ T-cell reconstitution according to D/R HCMV-serostatus. Results Human cytomegalovirus infection was detected in the blood of 39/45 patients at a median of 29 days after transplantation. Human cytomegalovirus-specific T-cell reconstitution followed reactivation of latent human cytomegalovirus infection at a median time of about 2 months after transplantation. Only donor human cytomegalovirus-seronegativity and bone marrow as a stem cell source were found to delay specific T-cell reconstitution significantly. Levels of three CD8+ and one CD4+ human cytomegalovirus-specific T-cells/μL blood had a positive predictive value of around 80% for identifying patients able to control human cytomegalovirus infection spontaneously. Five patients who received high doses of steroids for treatment of graft-versus-host disease developed human cytomegalovirus infection requiring pre-emptive treatment despite high levels of interferon-γ-producing T cells in response to human cytomegalovirus. Specific interleukin-2 production was not detected in patients with human cytomegalovirus infection requiring treatment, while 90% of patients who spontaneously controlled human cytomegalovirus infection had T cells that produced interleukin-2 and interferon-γ. Conclusions Pre-transplant human cytomegalovirus infection of the recipient is a major factor driving human cytomegalovirus-specific immune reconstitution. Control of human cytomegalovirus infection likely requires the presence of both interferon-γ and interleukin-2 producing T cells. Corticosteroid treatment may favor active viral replication even in patients with specific T cells.

A sequence of immuno‐chemotherapy with Rituximab, mobilization of in vivo purged stem cells, high‐dose chemotherapy and autotransplant is an effective and non‐toxic treatment for advanced follicular and mantle cell lymphoma

Summary. Options for relapsed/refractory indolent lymphoma include chemotherapy, immunotherapy and high‐dose therapy with autologous support. The best combination of these approaches, however, is not defined. We treated 10 patients with relapsed/refractory follicular (n = 7) or mantle cell lymphoma (n = 3) using chemotherapy, immunotherapy, high‐dose therapy and autotransplant in a sequence of four phases, each designed to play a specific role in tumour eradication. After the debulking with VACOP‐B (doxorubicin, cyclophosphamide, etoposide, vincristine, prednisone, bleomycin) (phase 1), 9/10 patients responded but none achieved a molecular response. After the immuno‐chemotherapy phase, which combined Rituximab with vincristine and cyclophosphamide, seven patients were in complete response (CR) and three in good partial response (PR), and all those with a molecular marker of disease showed a disappearance of the signal from marrow and blood. Phase 3, which coupled high‐dose cytarabine with Rituximab, was effective in mobilizing an adequate number of progenitor cells that were polymerase chain reaction negative in all informative cases. Phase 4 consisted of high‐dose therapy with autologous support followed by two doses of Rituximab. Autograft was performed in nine patients. The haematopoietic recovery was as expected. This sequence of chemotherapy, immuno‐chemotherapy, stem cell mobilization with in vivo purging and autotransplant, organized in four blocks of treatment, was simple to administer and devoid of toxic effects. It permits rapid attainment of clinical and molecular response and enables the harvest of lymphoma‐free peripheral blood progenitor cells even in heavily pretreated patients with relapsed or refractory disease.

Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. METHODS We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. FINDINGS Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Grays test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). INTERPRETATION In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. FUNDING Agenzia Italiana del Farmaco.

Hepatitis reactivation and liver failure in haemopoietic stem cell transplants for hepatitis B virus (HBV)/hepatitis C virus (HCV) positive recipients: a retrospective study by the Italian group for blood and marrow transplantation

Summary:Hepatitis B virus/hepatitis C virus (HBV/HCV) positive patients undergoing haemopoietic stem cell transplantation (HSCT) are at risk of hepatitis reactivation and fatal liver failure: we have conducted a retrospective study to assess the risk in 20 Italian transplant centres. A total of 90 patients infected with HBV (n=33) or HCV (n=57) receiving allogeneic (n=36) or autologous (n=54) haemotopoietic stem cell transplant (HSCT) between 1996 and 2000 were reviewed. The biochemical profiles and outcomes of infection-related liver disease were also analysed. The risk of death at 2 years was comparable when considering type of infection (3% for HBV vs 8% for HCV, P=0.6) or type of HSCT (7% for allogeneic vs 5% for autologous HHSCT, P=0.34). Hepatitis reactivation followed by resolution was more frequent in HCV+ than in HBV+ patients receiving an allograft (100% vs 16%, P=0.004). In HBV+ cases, risk of reactivation was comparable after autologous or allogeneic transplantation (66 vs 81%, P=0.3), but liver disease was more severe and occurred earlier in the autologous group. Our results indicate that HBV and HCV infection should not be taken as an absolute contraindication for HSCT and the risk of life-threatening liver complications are similar after allogeneic or autologous transplants.