Immunomodulatory effects of unselected haematopoietic stem cells autotransplantation in refractory Crohn's disease.

BACKGROUND: Autologous haematopoietic stem cells transplantation (HSCT) has been shown to be effective in refractory Crohn's disease. AIM: We analysed the effects of HSCT on the immune response of patients treated for moderate-severe Crohn's disease, refractory or intolerant to multiple drugs. METHODS: Unselected peripheral blood stem cells were collected after mobilisation with cyclophosphamide (CTX) and G-CSF. The conditioning regimen included CTX and rabbit antithymocyte globulin. Blood samples for immunological analyses were collected at baseline, after mobilisation, and 3, 6 and 12 months after transplantation. Immunological analyses evaluated: (1) CD4(+)/CD25(high+)/FoxP3(+) regulatory T cells (T-regs); (2) Toll-like receptor 2-(TLR2) and TRL4-expressing monocytes (CD14(+) cells); (3) IL-12, IL-10, TNF-alpha-production by mitogen-stimulated CD14(+) cells and IFN-gamma production by CD4(+) T cells. Immunological results were compared with healthy donors and associated with clinical and endoscopic response during 12 months of follow-up. RESULTS: Overall, T-regs increased, whilst TLR4-expressing cells, as well as TNF-alpha and IL-10, all higher than healthy donors at baseline, significantly decreased after transplantation. Full responders at T(3) had higher T-regs and lower IFN-gamma and IL12. T-regs decreased and IL12 and TLR2 increased in the only relapsed patient. CONCLUSIONS: HSCT can induce and maintain clinical and endoscopic remission in refractory Crohn's disease, which is associated with immunomodulation.

A long-term follow-up analysis in adult acute myeloid leukemia patients after hematopoietic stem cell transplantation.

AIMS AND BACKGROUND: Over the last 17 years, 119 adult acute myeloid leukemia patients have undergone hematopoietic stem cell transplantation at our Center. STUDY DESIGN: Seventy patients in first complete remission received hematopoietic stem cell transplantation (28 allogeneic and 42 autologous HSCT) as late intensification after conventional chemotherapy; 38 patients received allogeneic hematopoietic stem cell transplantation in a more advanced phase. A reference group was built up by collecting 40 acute myeloid leukemia patients who received high-dose cytosine arabinoside as late intensification and whose complete remission lasted more than 10 months. RESULTS: Results of the study led to conclude that an earlier timing of allogeneic hematopoietic stem cell transplantation can be recommended in order to treat patients who would otherwise suffer an early relapse. CONCLUSIONS: The outcome of autologous hematopoietic stem cell transplantation in patients not in first complete remission supports the possibility of achieving good quality second complete remissions and suggests that autografting may be a life-saving strategy in selected acute myeloid leukemia patients with advanced disease.

Hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: a single-centre analysis.

The role of autologous or allogeneic hematopoietic stem cell transplantation (HSCT) in ALL is controversial because of its adverse risk/benefit ratio, and the main policy is to reserve it for high-risk patients. In our Institution, between 1984 and 2002, 40 patients received an allogeneic HSCT and 39 underwent autografting. The conditioning regimen included HD-Ara-C, HD-CTX and 10 Gy fractionated TBI. After allogeneic SCT in first CR, four patients relapsed, leading to a 10-year EFS chance of 78.3%; of the other patients, 5 are still in CR. After autografting in first CR, there was an early death, one secondary AML, one death in CR and six relapses, leading to a 10-year EFS chance of 44.4%; of the other patients, 6 are still in CR. Even considering the limited number of patients and the slow accrual rate, selection bias cannot be considered a sufficient explanation for the favorable outcome of allografting in first CR as the majority of the patients had adverse prognostic factors. It cannot be claimed that allogeneic SCT was performed in patients already cured, as the autografted patients had a notably worse outcome, and a 10-year EFS chance of about 80% is an uncommon finding even in standard-risk ALL patients. It might be inferred that the timing of SCT as late intensification, in addition to a rather aggressive conditioning regimen, helped to minimize the leukemic burden, thus favoring the expression of a GVL effect. Conversely, the results in more advanced disease phases are discouraging, due to poor quality CRs and inefficacy of GVL in managing large residual disease.

Harvesting of autologous blood stem cells after a mobilising regimen with low-dose cyclophosphamide.

Although high-dose cyclophosphamide (HD-CTX) is commonly used as a mobilising regimen for autologous peripheral blood stem cell (PBSC) collection, significant morbidity and insufficient harvesting may complicate the procedure. Alternative regimens and lower doses of cyclophosphamide (CTX) have been investigated as possible ways of overcoming these difficulties. Low-dose CTX (1.5 g/m2) was administered to 102 lymphoma patients as an autologous PBSC mobilising regimen. The collection of 6 x 10(6) CD34+ cells/kg was chosen as the target of the apheresis sessions, whereas 3 x 10(6)/kg were considered the minimum necessary to perform autologous stem cell transplantation (ASCT) safely. The apheretic sessions were started a median of eight days after CTX administration; a median of two aphereses was required. More than 6 x 10(6) CD34+ cells/kg were collected from 78 patients, between 3 and 6 x 10(6)/kg from 19, and fewer than 3 x 10(6)/kg from 5, two of whom underwent bone marrow harvesting and one a successful second PBSC harvesting session using the same mobilising regimen. Eighty-two patients underwent autografting, six of whom received a second transplant after relapse (five using autologous PBSCs coming from the first apheretic course). Low-dose CTX proved to be a safe and effective regimen for autologous PBSC mobilization and also compared favourably with alternative regimens in terms of the rate of harvesting insufficiency. This does not imply that low-dose CTX is the best mobilising regimen for all patients, and the identification of prognostic factors predicting mobilising potential may help in choosing the best individualised regimen.

Lethal pulmonary complications significantly correlate with individually assessed mean lung dose in patients with hematologic malignancies treated with total body irradiation.

PURPOSE: To assess the impact of lung dose on lethal pulmonary complications (LPCs) in a single-center group of patients with hematologic malignancies treated with total body irradiation (TBI) in the conditioning regimen for bone marrow transplantation (BMT). METHODS: The mean lung dose of 101 TBI-conditioned patients was assessed by a thorough (1 SD around 2%) in vivo transit dosimetry technique. Fractionated TBI (10 Gy, 3.33 Gy/fraction, 1 fraction/d, 0.055 Gy/min) was delivered using a lateral-opposed beam technique with shielding of the lung by the arms. The median lung dose was 9.4 Gy (1 SD 0.8 Gy, range 7.8--11.4). The LPCs included idiopathic interstitial pneumonia (IIP) and non-idiopathic IP (non-IIP). RESULTS: Nine LPCs were observed. LPCs were observed in 2 (3.8%) of 52 patients in the group with a lung dose < or = 9.4 Gy and in 7 (14.3%) of 49 patients in the >9.4 Gy group. The 6-month LPC risk was 3.8% and 19.2% (p = 0.05), respectively. A multivariate analysis adjusted by the following variables: type of malignancy (acute leukemia, chronic leukemia, lymphoma, myeloma), type of BMT (allogeneic, autologous), cytomegalovirus infection, graft vs. host disease, and previously administered drugs (bleomycin, cytarabine, cyclophosphamide, nitrosoureas), revealed a significant and independent association between lung dose and LPC risk (p = 0.02; relative risk = 6.7). Of the variables analyzed, BMT type (p = 0.04; relative risk = 6.6) had a risk predictive role. CONCLUSION: The mean lung dose is an independent predictor of LPC risk in patients treated with the 3 x 3.33-Gy low-dose-rate TBI technique. Allogeneic BMT is associated with a higher risk of LPCs.