Giuseppe Messina

Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease

BACKGROUND Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. METHODS We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. RESULTS After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). CONCLUSIONS The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).

Short and long-term safety of lenograstim administration in healthy peripheral haematopoietic progenitor cell donors: a single centre experience

Healthy donors (HDs) who were mobilized using lenograstim (LENO) and who were undergoing peripheral haematopoietic progenitor cell collection with apheresis (HPC-A) were enrolled in a surveillance protocol. In all, 184 HDs have been assessed with a median follow-up of 62 months (range 2–155). HDs received LENO at a median dose of 10 μg/kg (range 5–15). Bone pain was reported as the most frequent short-term adverse event (71.2%). Other commonly observed short-term symptoms included fatigue (19.0%), fever (5.4%), headache (27.7%), nausea (12.0%) and insomnia (22.3%). Spleen size increased in 4.3% of the donors. No vascular disorders or cardiac disease occurred. Long-term follow-up included monitoring of adverse events, neoplastic disease or other pathologies. Transit ischaemic attack occurred in one donor (39 months post-donation). One autoimmune event was reported at 28 months post-recombinant human granulocyte (rhG)-CSF (ankylosing spondylitis); one donor with a history of chronic obstructive pulmonary disease developed secondary polyglobulia (50 months post-rhG-CSF). One donor was diagnosed with lung cancer at 19 months post-donation. No haematological disease was observed. In conclusion, the short-term safety appears to be verified, whereas, although the study identified no increased risks of malignancy among HDs who received rhG-CSF, long-term safety requires more complete data sets, especially a longer follow-up and a larger number of HDs.

Pegfilgrastim compared with filgrastim after high‐dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients

Abstract:  We undertook a comparative study of Pegfilgrastim vs. Filgrastim after high‐dose melphalan and autologous peripheral blood stem cell transplantation (APBSCT) in multiple myeloma (MM) patients. Thirty‐seven consecutive patients were randomly assigned to receive a single 6 mg dose of Pegfilgrastim on day 1 post‐transplant (n = 18 patients) vs. daily subcutaneous injections of Filgrastim 5 μg/kg (n = 19 patients) starting on day 5 post‐transplant. The median duration of grade 4 neutropenia in the Pegfilgrastim and Filgrastim groups was 5 and 6 d, respectively (P = ns). The results for the two groups were also not significantly different for time to neutrophil and platelet recovery, but incidence of febrile neutropenia (61.1% vs. 100%, P = 0.003) and duration of febrile neutropenia (1.5 d vs. 4 d, P = 0.005), were lower in the Pegfilgrastim arm. After initial haematopoietic reconstitution, we observed significantly higher value of leukocytes × 109 L on day 15 (6.0 vs. 2.7, P = 0.004), in the Pegfilgrastim group compared with the Filgrastim group. This study shows that a single injection Pegfilgrastim can be used with safety and efficacy similar to those provided by daily injections of Filgrastim and it is associated with a decrease incidence of infectious events after APBSCT in MM patients.

Multicenter Experience Using Total Lymphoid Irradiation and Antithymocyte Globulin as Conditioning for Allografting in Hematological Malignancies

A non myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). To evaluate the effects of TLI-ATG in a multicenter study, 45 heavily pretreated patients, median age 51, with lymphoid (n = 38) and myeloid (n = 7) malignancies were enrolled at 9 centers. Twenty-eight patients (62%) received at least 3 lines of treatment before allografting, and 13 (29%) had refractory/relapsed disease at the time of transplantation. Peripheral blood hematopoietic cells were from HLA identical sibling (n = 30), HLA-matched (n = 9), or 1 antigen HLA-mismatched (n = 6) unrelated donors. A cumulative TLI dose of 8 Gy was administered from day -11 through -1 with ATG at the dose of 1.5 mg/kg/day (from day -11 through -7). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Donor engraftment was reached in 95% of patients. Grade II to IV acute GVHD (aGVHD) developed in 6 patients (13.3%), and in 2 of these patients, it developed beyond day 100. Incidence of chronic GVHD (cGVHD) was 35.8%. One-year nonrelapse mortality was 9.1%. After a median follow-up of 28 months (range, 3-57 months) from transplantation, median overall survival was not reached, whereas median event-free survival was 20 months. This multicenter experience confirms that TLI-ATG protects against GVHD and maintains graft-vs-tumor effects.

Bone Marrow Failure Associated with Herpesvirus 8 Infection in a Patient Undergoing Autologous Peripheral Blood Stem Cell Transplantation

We describe a fatal case of human herpesvirus 8-associated bone marrow failure in a patient who had received intense treatment for Hodgkin lymphoma and was undergoing bone marrow transplantation. Bone marrow failure was resistant to antiviral treatment and a second infusion of autologous stem cells. Human herpesvirus 8 infection continues to be a major concern in transplant recipients in critical condition.

Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant

Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3–4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09–2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04–2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03–2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98–2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post-transplant cyclophosphamide-based regimen can achieve better leukemia-free survival and graft-versus-host disease-free, relapse-free survival, lower incidence of graft-versus-host disease and non-relapse mortality as compared to anti-thymocyte globulin-based graft-versus-host disease prophylaxis in patients with acute myeloid leukemia.

Allogeneic stem cell transplantation in multiple myeloma: immunotherapy and new drugs

Introduction: Autologous (auto) stem cell transplantation (SCT) and the development of new drugs have improved the survival of multiple myeloma (MM) patients. By contrast, though potentially curative, the use of allogeneic (allo)-SCT is controversial. Areas covered: A review has been conducted to examine the current evidence for the use of allo-SCT in MM. We have examined novel cell therapies that may be exploited to induce myeloma-specific immune responses including the new promising frontier of chimeric antigen receptor (CAR)-T and -natural killer (NK) cells. Expert opinion: One of the major controversies facing researchers in exploring the allo approach is the remarkable recent treatment improvement observed with second- and third-generation proteasome inhibitors and immunomodulatory drugs, monoclonal antibodies and deacetylase inhibitors. Despite these great advances, the disease remains to be incurable and allo-SCT may still play a role in the cure of MM. We think that allo-SCT conserves a role in MM and its curative potential in high-risk patients should be explored in the setting of control clinical trials. Novel cell therapies such as CAR technologies may open new avenues of research toward a potential cure. Data from currently ongoing prospective studies will be helpful to clarify pending clinical questions.

The impact of early CD4+ lymphocyte recovery on the outcome of patients who undergo allogeneic bone marrow or peripheral blood stem cell transplantation.

BACKGROUND Different factors influence the clinical outcome of allogeneic transplants, the foremost being good immune recovery. MATERIALS AND METHODS The purpose of this study was to evaluate the influence of different factors, such as stem cell source, type of donor, conditioning regimen and acute graft-versus-host disease, on early lymphocyte recovery after transplantation. We then analyzed the impact of early CD4+ cell count on overall survival, transplant-related mortality and disease-related mortality. RESULTS Univariate analysis with Spearmans rho showed a significant correlation between early CD4+ cell recovery and overall survival, transplant-related mortality, stem cell source and type of donor. In multivariate analysis CD4+ cell count was significantly associated with (i) stem cell source, being higher in patients whose haematopoietic progenitor cells were obtained by apheresis than in those whose source of grafted cells was bone marrow, and (ii) type of donor, being higher in patients transplanted from sibling donors than in those whose graft was from an alternative donor. The ROC curve of CD4+ cell count indicated that a cut-off of 115 CD4+ cells/mL could differentiate groups with different outcomes. At 2 years follow-up, patients achieving this CD4+ cell count had significantly lower cumulative transplant-related mortality compared to patients who did not have this count (10%±4% versus 40%±8%, p=0.0026). At the 5-year follow-up, the overall survival rates were 77.5%±0.6% and 36%±7% (p=0.000) in patients with a CD4+ cell count ≥115/mL and in patients with CD4+ cell count ≤ 115/mL, respectively. CONCLUSION Early CD4+ cell recovery after allogeneic transplantation has a relevant impact on overall survival and transplant-related mortality and is influenced by two factors: stem cell source and type of donor.

Very Low Rate of Readmission after an Early Discharge Outpatient Model for Autografting in Multiple Myeloma Patients: An Italian Multicenter Retrospective Study

We analyzed the main modalities and clinical outcomes of the early discharge outpatient model in autologous stem cell transplantation (EDOM-ASCT) for multiple myeloma in Italy. EDOM-ASCT was employed in 382 patients, for a total of 522 procedures, between 1998 and 2012. Our study showed high homogeneity among centers in terms of inclusion criteria, supportive care, and in hospital readmission criteria. Overall, readmissions during the aplastic phase occurred in 98 of 522 transplantations (18.8%). The major extrahematological complication was neutropenic fever in 161 cases (30.8%), which required readmission in 76 cases. The incidence of severe World Health Organization grade 3 to 4 mucositis was 9.6%. By univariate analysis, fever, mucositis, altered renal function at diagnosis, second transplantation, and transplantation performed late in the course of the disease were significantly correlated with readmission, whereas fever, mucositis, altered renal function, and timing of transplantation remained the only independent predictors by multivariate analysis. Overall, transplantation-related mortality was 1.0%. No center effect was observed in this study (P = .36). The safety and low rate of readmission of the EDOM-ASCT in myeloma trial suggest that this strategy could be extended to other transplantation centers if a stringent patient selection and appropriate management are applied.

Low tolerance and high toxicity of thalidomide as maintenance therapy after double autologous stem cell transplant in multiple myeloma patients

Although a double autologous peripheral blood stem cell transplant (APBSCT) is an effective therapy for patients (pts) with multiple myeloma and extends progression‐free survival and overall survival, pts show a continued pattern of recurrent disease. The feasibility and tolerability of thalidomide (Thal) administered in the post‐transplantation period as maintenance therapy was tested in 17 pts at a dose of 100 mg/d starting between 3 and 5 months after the second transplantation and continuing either until toxicity precluded further therapy or until pts had disease progression. After a median administration of 13 months (range: 3–26), 76.5% (13 pts) failed to tolerate Thal because of: transiet ischemic attack (three pts), severe fatigue (two), neutropenia (one), piastrinopenia (one), severe opportunistic infectious (two), erectile impotence (one), gastointestinal toxicity (anorexia with weight loss one), peripheral neuropathy (two). After a median follow‐up of 36 months (range: 10–59) from the second transplant, 13 patients attained a CR + near CR (with a conversion rate from 47.1% to 76.5%). In conclusion, Thal as maintenance therapy after double ASCT is associated with low feasibility and high toxicity and could prevent a lengthy use of this antineoplastic agent.