Early results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is a promising method of improving the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both effective against metastatic gastric cancer. This report clarified the impact of these regimens on early endpoints, including the pathological responses, chemotherapy-related toxicities, and surgical results. METHODS: Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as NAC. Patients then underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was the 3-year overall survival. RESULTS: Between October 2011 and September 2014, 132 patients were assigned to receive CS (n = 66; 33 in 2 courses and 33 in 4 courses) or DCS (n = 66; 33 in 2 courses and 33 in 4 courses). The respective major grade 3 or 4 hematological toxicities (CS/DCS) were leukocytopenia (14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet reduction (3.1%/1.5%). The rate of pathological response, defined as a complete response or < 10% residual cancer remaining, was 19.4% in the CS group and 15.4% in the DCS group, and 15.6% in the two-course group and 19.0% in the 4-course group. The R0 resection rate was 72.7% in the CS group and 81.8% in the DCS group and 80.3% in the two-course group and the 74.2% in the four-course group. No treatment-related deaths were observed. CONCLUSIONS: Our results do not support three-drug therapy with a taxane over two-drug therapy, or any further treatment beyond two cycles as an attractive candidate for the test arm of NAC.

Minimally invasive video-assisted thoracoscopic lobectomy for better clinical outcomes in peripheral T1NO lung cancer.

It is an unresolved issue whether various thoracotomies affect clinical outcomes. In addition, a wide variety of technical approaches of video-assisted thoracic surgery depend on the facility. We reviewed 152 consecutive patients with clinical T1N0M0 lung cancer that underwent three types of lobectomy with systematic mediastinal lymphadenectomy in a single institute: 46 conventional thoracotomies (OPEN), 50 anterolateral small thoracotomies mainly using the thoracoscope as a light guide (ASSIST), and 56 minimum thoracotomies in which only a thoracoscope view was used (PURE). Total discharge from the chest drainage tube, length of hospital stay, and post-thoracotomy pain were significantly less in PURE than in OPEN and ASSIST. The results of mediastinal lymphadenectomy were equivalent. The 3-year survival rates were also similar among the three groups. We conclude that good clinical outcomes, especially reduced post-thoracotomy pain, seemed to correlate with the lesser degree of destruction of the chest wall with the identical quality as an acceptable cancer operation in PURE.

Significance of additional high-dose cytarabine in combination with cyclophosphamide plus total body irradiation regimen for allogeneic stem cell transplantation.

The combination of cyclophosphamide (CY) and total body irradiation (TBI) has been used as a standard conditioning regimen for allogeneic transplantation. Several studies showed an advantage of adding high-dose cytarabine (HDCA) to this regimen. To clarify the significance of additional HDCA, we conducted a retrospective multicenter study and compared the clinical results of these two regimens. From June 1985 to March 2003, 219 patients with hematological malignancies underwent allogeneic transplantation after conditioning with CY+TBI 12Gy (n=73) or CA+CY+TBI 12Gy (n=146). Engraftment, overall survival, transplant-related mortality (TRM), relapse rate and incidence of graft-versus-host disease (GVHD) were compared according to risks and donors. Addition of HDCA had no impact on the relapse rate in all subgroups, and it was associated with lower TRM among standard-risk patients after related transplantation, and with higher TRM and worse survival among standard-risk patients after unrelated transplantation. The incidence of acute GVHD was not significantly different between the two regimens, and HDCA resulted in a higher incidence of chronic GVHD among standard-risk patients after related transplantation. In summary, addition of HDCA is not beneficial for high-risk patients, and is not recommended for standard-risk patients receiving unrelated transplantation.

Multicenter phase II trial of combination chemotherapy with weekly paclitaxel and 5-fluorouracil for the treatment of advanced or recurrent gastric carcinoma.

The aim of this study was to investigate the efficacy and safety of combination chemotherapy with weekly paclitaxel and 5-fluorouracil (5-FU) as first-line treatment in patients with advanced or recurrent gastric carcinoma. A total of 65 patients were treated with the following regimen, administered every 28 days; 5-FU 600 mg/m2 by 24-hour continuous infusion from days 1 through 5, and weekly paclitaxel 80 mg/m2 by 3-hour intravenous infusion on days 8, 14, and 21. A total of 272 cycles were conducted with a median of 4 (2-13) cycles per case. Out of 57 patients with measurable disease by RECIST criteria, there were 2 complete responses (3.5%), 20 partial responses (35.1%) and 25 cases with stable disease (43.9%). The overall response rate was 38.6% (95%CI: 26.0-51.2%). The median survival time and 1-year survival rates were 329 days and 47.4%, respectively. Both hematologic and non-hematologic toxicities were well tolerated.

Clinical studies on a new screening assay for anticancer agents using nude mice and isotopic evaluation.

A new screening assay for anticancer agents was established using an in vivo nude mouse model. Assessment of the chemosensitivity of individual human tumors was determined by [3H]thymidine incorporation by the treated tumors. Three hundred and thirty tumors derived from cancer patients were transplanted into nude mice s.c. and treated with anticancer agents. Mitomycin C, 5-fluorouracil, cyclophosphamide, and doxorubicin were used in the present studies. In 270 of 330 cancers, chemosensitivity was evaluated by this method (evaluable rate, 81.8%). The rate of positive sensitivity against all tumors was 21.9% in mitomycin C, 12.2% in 5-fluorouracil, 27.4% in cyclophosphamide, and 23.6% in doxorubicin, respectively. The tumor sensitivity to anticancer agents varied according to the type of cancer. Retrospective and prospective clinical studies were performed to determine the usefulness of the nude mouse-isotope assay for the prediction of tumor sensitivity. The 24-month survival rates of 24 gastric cancer patients treated with tumor-sensitive agents was significantly higher than that of 28 patients treated with tumor-resistant agents. The end results after chemotherapy in far-advanced and inoperable terminal cases of gastrointestinal cancers was also investigated, prospectively. Out of 19 cases, the 50% survival time of 11 patients treated with tumor-sensitive agents was longer than that of eight patients treated with tumor-resistant agents. From prospective correlative studies carried out on 25 patients, this assay correlated with clinical responses (overall agreement, 76.0%; P less than 0.05) with specific agreements of sensitivity and resistance of 37.5 and 94.1%, respectively. From these results, it seems reasonable to conclude that nude mouse-isotope assay is a screening assay to identify appropriate agents for the treatment of patients with cancer. However, there is still a need to develop a better protocol in this assay, especially for antimetabolites, and to continue research in order to find more sufficient assays to predict clinical sensitivity to anticancer agents.

New xenografts of human megakaryoblastic cell line (MEG-01) for evaluating anti-tumor agents.

A human megakaryoblastic cell line (MEG-01) was successfully transplanted into athymic nude mice. MEG-01 cells (5 x 10(7)) were inoculated subcutaneously in KSN-nu/nu mice, none of which were pretreated with irradiation or chemotherapeutic agents. All mice developed solid tumors at the site of injection after incubation for 10-14 days reaching a size of 200-400 mm2 (product of cross-sectional diameters) after 30 days. These tumors, designated as MEG-01/nu, were transplanted into other nude mice. The transplanted tumors infiltrated the liver and spleen, and leukemic megakaryoblastic cells appeared in the blood of some transplanted mice. Cells resuspended from MEG-01/nu tumors exhibited almost the same megakaryocytic characteristics as the original MEG-01 cells, and underwent in vitro differentiation to a mature form of megakaryocyte upon addition of phorbol diesters. MEG-01/nu was evaluated for sensitivity to cytosine arabinoside, vincristine, and daunorubicin in vitro and in vivo. Daunorubicin exhibited significant anti-tumor activity against MEG-01/nu in vivo, while cytosine arabinoside did so in vitro. Vincristine showed no activity against these cells. This cell line may provide a useful model for testing the in vivo efficacy of anti-tumor agents and immunotoxins, and for studying the pathophysiological mechanisms of human megakaryoblastic leukemia.

Reconstitution of peripheral blood lymphocyte subsets in the long-term disease-free survivors of patients with acute myeloblastic leukemia.

The number of long-term survivors of patients with acute myeloblastic leukemia (AML) has increased as a result of the progress of chemotherapy. We examined the recovery of peripheral blood lymphocytes (PBL) subset after chemotherapy to clarify the reconstitution of the immune system in AML. Thirty patients with AML in complete remission (CR) were entered into the study. There were 12 males and 18 females; one M0, six M1, 14 M2, three M3, two M4 and four M5 according to FAB classification. The age ranged from 21 to 78 years (median age, 46 years) and the duration of disease-free survival after completion of chemotherapy ranged from 5 to 122 months (median, 35 months). The chemotherapy was performed according to the protocol designed by the Japan Adult Leukemia Study Group (JALSG). PBL subsets were analyzed by flow cytometry with the use of monoclonal antibodies against CD2, CD3, CD4, CD5, CD8, CD16, CD20, CD45RA, CD56, CD57 and HLA-DR. There was a significant positive relationship between the absolute number of CD4+, CD45RA+ CD4+ cells and the duration of time post-therapy and a significant negative relationship between %CD5+ B, CD56+ cells and the duration of time post-therapy. The appearance of autoantibodies (rheumatoid factor and anti-DNA antibody) tended to increase after 2 years, however, there was no relationship between CD5+ B cells and the frequency of rheumatoid factor. These findings demonstrate that patients in CR have a low number of CD4+ and CD45RA+ CD4+ T cells at an early period after chemotherapy and that each subset recovered to a normal level in 2 years. %CD5+ B and CD56+ cells gradually decreased and returned to their normal level after 4 years. There were high numbers of DR+ T cells and NK cells for a long time, suggesting that activated T cells and NK cells may play a role in the immune surveillance system after chemotherapy.

Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate.

The effect of graft-versus-host disease (GVHD) on relapse incidence and survival has been analyzed in several studies, but previous studies included heterogeneous patients. Therefore, we analyzed the data of 2114 patients who received unmanipulated bone marrow graft from an HLA-identical sibling donor with a GVHD prophylaxis using cyclosporin A and methotrexate. Among the 1843 patients who survived without relapse at 60 days after transplantation, 435 (24%) developed grade II-IV acute GVHD. Among the 1566 patients who survived without relapse at 150 days after transplantation, 705 (47%) developed chronic GVHD. The incidence of relapse was significantly lower in patients who developed acute or chronic GVHD, but disease-free survival (DFS) was significantly inferior in patients who developed acute GVHD. A benefit of 'mild' GVHD was only seen in high-risk patients who developed grade I acute GVHD. The strongest association between GVHD and a decreased incidence of relapse was observed in patients with standard-risk acute myelogenous leukemia/myelodysplastic syndrome. In conclusion, the therapeutic window between decreased relapse and increased transplant-related mortality due to the development of GVHD appeared to be very narrow.

Studies on graft versus host (GvH) reactions. I. Impairment of hemopoietic stroma in mice suffering from GvH disease.

The hematologic changes were described in the adult (C57BL/6 x C3H/He) F1 hybrid mice suffering from graft versus host (GvH) disease induced with 10(8) parental (C3H/He) lymph node (PLN) cells. Progressive decreased in numbers of leucocytes, granulocytes, erythrocytes and reticulocytes was observed from day 7 to 14 of GvH disease. Thrombocytopenia was not so remarkable. A histologic study revealed and extremely hypoplastic marrow. The number of colony forming units (CFUs)/femur decreased progressively from day 5 to 14. When the femurs, removed from the diseased mice at various intervals after the PLN cell injection, were implanted subcutaneously into other hosts for 7 weeks in order to evaluate the hemopoietic stroma to support the hemopoietic stem cells, the progressive decrease in CFUs number in the implanted femurs was also observed from day 5 to 14. There was a dose relation between the number of PLN cells injected and the reduction of CFUs number either in the femurs in situ or the implanted femurs. It is thus concluded that the impairment of hemopoietic stroma results form F1 hybrid disease, i.e., GvH disease and can be one of the major causes of the depletion of hemopoietic cells resulting in pancytopenia.

Origins of hemopoietic and stromal cells in subcutaneous femur implants.

The origin of spleen colony-forming units (CFUs) and fibroblastoid colony-forming cells (CFUF) repopulating the marrow of femurs subcutaneously implanted in syngeneic and semi-syngeneic mice was studied by making use of a chromosome marker for CFUs and a cytotoxicity test for CFUF. The CFUs present in implants during first 4 weeks were of a mixture of those from the donor and the host, and thereafter, were exclusively of host origin. On the other hand, the colony growth of CFUF from the marrow of C57BL/6 femurs grafted in B6CBAF1 mice remained almost totally unaffected by treatment with C57BL/6 anti-B6CBAF1 serum as late as 40 weeks after implantation. Quite similar results were obtained from the marrow-depleted femur implants. It is concluded from the present studies that chimeric marrow consisting of hemopoietic cells of host origin and stromal cells of donor origin can repopulate the femurs within a matter of several weeks after subcutaneous implantation.

Age-related changes in the function of hemopoietic stroma in mice.

Hemopoietic function of the marrow and splenic stroma in C57BL/6 mice aging from 2 to 24 months were evaluated with the use of subcutaneous implantation method. Although there was no significant difference in the concentration as well as the total number of CFU(S) in femoral marrows between aged and young mice, the rates of CFU(S) repopulation in the femoral marrows from aged donors were significantly lower than in those from young donors when grafted subcutaneously in the 2 month-old syngeneic hosts. On the other hand, the femoral marrow grafts from 2 month-old donors were constantly repopulated irrespective of the age of the hosts. An essentially similar finding was obtained in the study of spleen grafts. It is suggested that the defective hemopoiesis, if any, in aged mice is primarily caused by the changes in hemopoietic stroma rather than those in hemopoietic stem cells.

Antineoplastic effect of erbstatin on human mammary and esophageal tumors in athymic nude mice.

The growth of MCF-7, a human mammary carcinoma, in athymic nude mice was inhibited by intraperitoneal administration of erbstatin for 14 days in combination with an iron chelator, foroxymithine, which inhibits the decomposition of erbstatin. Another human mammary carcinoma, Br-10, was not affected. Foroxymithine alone had no anti-tumor activity. In four esophageal tumors, erbstatin retarded tumor growth. There were no side-effects in any erbstatin-treated group. Levels of epidermal growth factor receptors were not changed throughout treatment with erbstatin at any dose. Erbstatin, a tyrosine kinase inhibitor, may have an antineoplastic effect against human mammary and esophageal tumors.

Pulmonary hypertension associated with pulmonary occlusive vasculopathy after allogeneic bone marrow transplantation.

BACKGROUND: Pulmonary vasculature abnormalities, including pulmonary veno-occlusive disease, have been demonstrated in marrow allograft recipients. However, it is often difficult to make a correct diagnosis of pulmonary lesions. METHODS: An open lung biopsy was performed on a patient who developed severe pulmonary hypertension after bone marrow transplantation for T-cell lymphoma. RESULTS: An open lung biopsy specimen demonstrated pulmonary arterial occlusion due to intimal fibrosis and veno-occlusion. The most striking alteration was partial to complete occlusion of the small arteries by fibrous proliferation of the intima. CONCLUSION: High-dose preparative chemotherapy and radiation before transplantation are thought to have contributed to the development of vasculopathy in this patient, because arterial occlusion by intimal fibrosis and atypical veno-occlusion are often associated with lung injury due to chemoradiation. An open lung biopsy is essential for diagnosing pulmonary vascular disease presenting signs compatible with posttransplantation pulmonary hypertension.

The chemopreventive role of ursodeoxycholic acid in azoxymethane-treated rats: suppressive effects on enhanced group II phospholipase A2 expression in colonic tissue.

Great interest has been focused on the chemoprevention of colonic carcinogenesis by oral administration of ursodeoxycholic acid (UDCA) because its administration reportedly reduces the incidence of colon cancer in animal experiments. To elucidate the precise role of UDCA in the chemoprevention of azoxymethane-induced colon carcinogenesis, we examined the expression levels of group II phospholipase A2 in the colonic tissue of UDCA-treated and untreated rats and correlated the levels with the findings of aberrant crypt foci, putative preneoplastic lesions. Twelve weeks after azoxymethane exposure, the total number of aberrant crypt foci in 0.4% UDCA-fed rats and 1% UDCA-fed rats was significantly decreased compared to the untreated animals. The mucosal concentrations of PGE2 and 6-keto PGF1alpha were significantly lower in the UDCA-treated rats than in untreated rats. In correlation with lowering, the enhanced activity, protein mass and mRNA levels of group II phospholipase A2 were significantly attenuated in the UDCA-treated animals. The chemopreventive role of UDCA in colon carcinogenesis may lie in its modulation of the arachidonate metabolism in colonic mucosa.

Biochemical modulation of Doxorubicin using an isoprenoid derivative, N-1379 - plasma transmembrane potential as a target site.

A new isoprenoid derivative, N-1379, was evaluated as a modulating agent of doxorubicin (DOX)-induced anticancer efficacy. The level of plasma transmembrane potential, measured using DiOC6(3), correlated with cellular sensitivity to DOX in K562 myelogenous leukemia, SH101 stomach, and PH101 pancreatic cancer cells. Non-toxic N-1379 increased the cellular transmembrane potential and DOX efficacy for three cell lines. The modulation of membrane function was accompanied by increases of DOX accumulation and S/G(2)M phase population in these cells. Overexpression of a 170 kD plasma membrane glycoprotein (GP-170) was not observed in any cells examined. We suggest therefore that interaction between electronegative transmembrane potential and positive charge of DOX may be linked to intracellular DOX accumulation. N-1379 may augment DOX efficacy through its increasing effect on plasma membrane potential independently of GP-170 overexpression.

Necrotizing tubulointerstitial nephritis associated with adenovirus infection.

We report 10 autopsy cases of necrotizing tubulointerstitial nephritis induced by adenovirus (ADV). Hemorrhagic, necrotizing tubulitis with intranuclear inclusion bodies was observed in the kidneys of five bone marrow transplant recipients and five patients treated with intensive chemotherapy for malignancies (four cases of leukemia and one case of lung cancer). It was histopathologically demonstrated that necrobiotic tubular cells had inclusion-bearing cells of three types: "smudge cells," Cowdry A intranuclear inclusion cells, and full-type intranuclear-containing cells. Immunofluorescent examination with anti-ADV antibody demonstrated specific fluorescence on the affected tubular cells of all 10 kidneys. Specific antigens for ADV type 11 were also revealed in all but one case by an immunofluorescent test using type-specific antiserum and convalescent serum containing high titer antibody to this serotype. Electron microscopy revealed intranuclear crystalline arrays of viral particles, 75 to 80 nm in diameter, in each of the seven cases examined. Extrarenal involvement, indicated by ADV-induced cytopathologic change, was confined to bladder or prostate. Hemorrhagic cystitis was recorded in all the bone marrow transplant cases as well as in one leukemia case. Adenovirus type 11 was isolated from urine in all five cases tested during these episodes. Renal failure was ascribed to ADV infection in two of five patients who died from renal dysfunction. The presence of hemorrhagic cystitis and localization of invasive infection in urogenital organs suggested that renal infection might occur by ascending route from the bladder. We propose that ADV should be added as a viral agent to the pathogenetic list of tubulointerstitial nephritis.

Superior survival of blood and marrow stem cell recipients given maternal grafts over recipients given paternal grafts.

During the reproductive period, mothers and offspring exchange hematopoietic cells and develop a form of immunological tolerance bidirectionally. To examine whether previous experience of such communication has any remote effect when maternal hematopoietic cells are later transplanted to the children, we retrospectively compared the outcomes of blood and marrow stem cell transplantation from maternal donors (n = 46) to those from paternal donors (n = 50) by using the database of the Japanese nationwide surveys for adult hematopoietic cell transplants between 1990 and 1998. At 5 years, recipients of maternal hematopoietic cells had a significantly higher overall survival than patients receiving paternal grafts (60% vs 32%, P = 0.006). Although no significant difference was observed in the occurrence of severe acute GVHD (grade > or =III) and the relapse of malignant diseases between two groups, the probability of non-relapse treatment-related mortality was significantly lower after maternal donor transplants. Furthermore, multivariate analysis revealed that parental donor type was the only factor significantly associated with overall survival. In conclusion, our analysis indicates superior survival of maternally donated recipients in hematopoietic stem-cell transplantations from biological parents. This finding has important implications in the selection of alternative familial donors, and warrants further prospective analysis of parental donor transplantations.

Busulfan, cyclophosphamide and total body irradiation as conditioning for allogeneic bone marrow transplantation for acute and chronic myeloid leukemia.

Fifty patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) underwent allogeneic bone marrow transplantation between October 1988 and January 1997. Patients received 8 mg/kg of busulfan (BU) with 120 mg/kg of cyclophosphamide (CY) followed by 10 Gy of total body irradiation (TBI). Twenty consecutive patients with AML in first remission (n = 9) or CML, in chronic phase (n = 11) entered the study (group I). Thirty consecutive patients with advanced myeloid malignancies including AML (n = 19) and CML (n = 11) also entered the study (group II). The probability of leukemia-free survival at 5 years was 85% for group I patients and 50% for group II patients. Severe regimen-related toxicities occurred in 16% of patients (two in group I, six in group II). The most common sites affected by severe toxicities were lung (n = 6), liver (n = 2) and heart (n = 2). The relapse rate was higher for patients allografted in advanced stages of disease (O% at 5 years for group I and 28% for group II). These results suggest that BU + CY + TBI is a very effective conditioning regimen in patients with myeloid malignancies.

Veno-occlusive disease of the liver after allogeneic bone marrow transplantation in children with hematologic malignancies: incidence, onset time and risk factors.

One hundred and forty children with hematologic malignancies undergoing allogeneic BMT were reviewed in order to clarify the incidence, onset time, and risk factors for veno-occlusive disease (VOD) of the liver. Thirty-eight patients (27.1%) developed VOD diagnosed according to the Seattle clinical criteria. Seventeen patients developed VOD within 20 days of transplantation (early-onset) and in 21 patients developed after day 20 (late-onset) including eight patients with histological confirmation. Late-onset VOD occurred from day 21 to day 508 (median day 39). Moderate or severe VOD developed in 11 early-onset and 13 late-onset patients. Death occurred in eight early-onset and 10 late-onset patients. Serum albumin and cholinesterase levels prior to the start of pretransplant conditioning were significantly lower in early-onset VOD than in late-onset VOD. Multivariate analysis showed that low serum albumin levels (< or =3.7 g/dl) prior to the start of pretransplant conditioning was most strongly associated with the development of VOD. Donor mismatch (other than HLA-matched relatives), use of minocycline, and a long interval (> or =13 months) between diagnosis and BMT were also significantly associated with the development of VOD. In contrast, use of fosfomycin was associated with a decreased risk. Our data suggest that hepatic function reserve is important in the development and onset time of VOD. Veno-occlusive disease of the liver is a complication which may occur a long time after transplantation.

Allogeneic myeloablative transplantation for patients aged 50 years and over.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been performed mainly for young patients due to concern about the high incidence of treatment-related mortality (TRM). Recent advances to reduce TRM by using peripheral blood stem cells or nonmyeloablative conditioning regimens have increased the age limit for this procedure, and correctly identifying the indication for transplant is essential for older patients. In this study, we analyzed data from 398 patients aged 50 or over selected from 5147 patients, who received conventional allogeneic HSCT (c-HSCT). Patients aged 50 or older showed inferior outcomes for TRM and overall survival (OS). Mulitivariate analyses confirmed that an age of 50 or over was an independent risk factor for TRM (P<0.0001) and OS (P<0.0001). Among patients aged 50 or older, increasing age remained an adverse factor for OS (P=0.0213). Regimens including total-body irradiation (TBI) correlated with a higher risk of TRM and a lower OS for older patients (P=0.0095 and 0.0303, respectively). These findings indicate that allogeneic c-HSCT should be offered to patients over 50 years only if the increased risk of TRM is acceptable, and that a non-TBI regimen is preferable when the transplant is performed.