FLANG salvage chemotherapy is an effective regimen that offers a safe bridge to transplantation for patients with relapsed or refractory acute myeloid leukemia.

The efficacy of fludarabine in combination with an intermediate dose of cytosine arabinoside, mitoxantrone, and G-CSF (FLANG; fludarabine 30 mg/m(2)/day, cytosine arabinoside 1 g/m(2)/day, mitoxantrone 10 mg/m(2)/day, and G-CSF 300 µg/day for 5 days) was evaluated in patients with refractory or relapsed acute myelogenous leukemia (AML). Between January 2004 and December 2006, 27 patients with relapsed or refractory AML were enrolled in the present study. In total, 14 patients had experienced an early relapse, 10 had experienced a late relapse, and the remaining three (11%) had developed primary refractory leukemia at the time of study entry. Most patients (n = 17, 63%) had post-transplant relapse, and 10 of them relapsed after allogeneic hematopoietic stem cell transplantation (SCT). After FLANG treatment, 15 patients (56%) achieved a complete response (CR), and three patients died during reinduction chemotherapy. After achieving a CR, eight patients received SCT (seven allogeneic (sibling = 4, unrelated = 2, and haploidentical familial = 1) and one autologous SCT), one received donor lymphocyte infusion, three received consolidation chemotherapy, and the remaining three refused further therapy. Eight patients were alive during continuous CR, with an event-free survival (EFS) rate of 30% after a median follow-up of 42.1 months. The survival outcome of patients who received SCT was remarkable (EFS of 75%). Additionally, no toxicity severe enough to preclude transplantation was evident after or during FLANG. The findings of the present study suggest that FLANG salvage chemotherapy is an effective regimen and that it offers a safe bridge to SCT. Furthermore, this regimen prompts efforts to proceed to SCT as post-remission therapy for patients in greater than first CR.

Favorable outcomes of intravenous busulfan, fludarabine, and 400 cGy total body irradiation-based reduced-intensity conditioning allogeneic stem cell transplantation for acute myelogenous leukemia with old age and/or co-morbidities.

Traditional transplant conditioning regimens have a limiting factor regarding co-morbidities or old age. Therefore, reduced-intensity conditioning (RIC) regimens have been increasingly used. To define the role of RIC in AML with old age (>or=55 years) and/or co-morbidities (HCT-CI scores >or=2), we analyzed patients who received allogeneic stem cell transplantation (SCT) with Flu/Bu/TBI 400 cGy/+/-antithymocyte globulin (ATG) conditioning regimen. Seventeen men and 15 women were enrolled. The median age was 45 years (range 17-65 years). All patients were in first (n = 25) or second (n = 7) complete remission before undergoing allogeneic SCT. Patients were transplanted from HLA-mismatched unrelated donors (n = 5), matched unrelated donors (n = 10), and matched sibling (n = 17). Calcineurin inhibitor and a short course of standard dose methotrexate were used to prevent graft-versus-host disease (GVHD). All patients achieved engraftment. At a median follow-up of 18 months (range 4-40) for survivors, the estimated 2-year rates of overall survival, event-free survival, transplantation-related mortality, and relapse were 66, 63, 26, and 16%, respectively. The incidence of acute (grades II-IV) and chronic GVHD by NIH consensus criteria was 34.4 and 62.5%. This study suggests that the Flu/Bu/TBI 400 cGy or Flu/Bu/TBI 400 cGy/ATG-based conditioning regimens maybe a feasible therapeutic approach for AML with old age and/or co-morbidities.

Cytomegalovirus ventriculoencephalitis after unrelated double cord blood stem cell transplantation with an alemtuzumab-containing preparative regimen for Philadelphia-positive acute lymphoblastic leukemia.

Despite the prophylaxis and preemptive strategies using potent antiviral agents, cytomegalovirus (CMV) remains a major infectious cause of morbidity and mortality in allogeneic stem cell transplantation (SCT) recipients. Delayed immune reconstitution after SCT, such as cord blood and T-cell depleted SCT with the use of alemtuzumab, has been associated with an increased frequency of CMV disease as well as CMV reactivation. CMV disease involving central nervous system is an unusual presentation in the setting of SCT. We report a case of CMV ventriculoencephalitis after unrelated double cord blood SCT with an alemtuzumab-containing preparative regimen for Philadelphia-positive acute lymphoblastic leukemia.

A case report of the second de novo acute myeloid leukemia (AML) following allogeneic stem cell transplantation in a patient with the first AML.

Secondary leukemia occurring after hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) is rare. Secondary AML usually follows autologous and not allogeneic transplants. When a new leukemia develops in a patient successfully treated with an allogeneic HSCT, the possibility of a de novo or secondary leukemia from either the donor or recipient should be considered. We present a case initially diagnosed as de novo AML without a cytogenetic abnormality. The patient was successfully treated with an HLA-matched sibling allogeneic HSCT. However, more than six years later, AML developed again and was associated with new complex cytogenetic abnormalities. After a second HSCT, the patient has been followed without serious complications. Considering the allogeneic setting, the newly developed cytogenetic abnormalities, a relatively long latent period, and the good clinical course after the second allogeneic HSCT, this case might represent a second de novo AML following successful treatment of the first AML.

High levels of B cell activating factor during the peritransplantation period are associated with a reduced incidence of acute graft-versus-host disease following myeloablative allogeneic stem cell transplantation.

B cell activating factor (BAFF), also known as B cell survival and activation factor, is associated with autoimmune disease and chronic graft-versus-host disease (cGVHD). T cells are known to be modulated by soluble BAFF (sBAFF). Considering the possible association of sBAFF with T cell as well as B cell function, sBAFF during the peritransplantation period may affect the development of acute GVHD (aGVHD). To test this hypothesis, we evaluated 45 patients who had undergone myeloablative (MA) allogeneic stem cell transplantation (SCT) for hematologic malignancy. Serum sBAFF levels were measured before conditioning and on day 0, day +7, and day +14. Thirty-three of the 45 patients (cumulative incidence, 73%) developed aGVHD between 16 days and 98 days posttransplantation. Repeated-measures analysis of variance revealed significantly lower sBAFF levels during the peritransplantation period in patients with aGVHD than in those without aGVHD (P=.001). Receiver operating characteristic curve analysis revealed that sBAFF levels at every time point were available for the prediction of aGVHD development, and that patients with a sBAFF level >43 pg/mL at each time point (which could ensure 75% sensitivity and 73%-82% specificity for the prediction of aGVHD at every time point) had a significantly lower cumulative incidence of aGVHD. This study is the first to demonstrate that sBAFF level during the peritransplantation period not only may be predictive of aGVHD, but also may have a protective effect against aGVHD in humans. Further investigation is needed to confirm our findings.

Bone marrow T cells are superior to splenic T cells to induce chimeric conversion after non-myeloablative bone marrow transplantation.

BACKGROUND/AIMS: The bone marrow functions not only as the primary B-lymphocyte-producing organ but also as a secondary lymphoid organ for CD4 and CD8 cell responses and a site of preferential homing and persistence for memory T cells. Bone marrow T (BM-T) cells are distinguished from peripheral blood T cells by surface phenotype, cytokine secretion profile, and immune functions. In this study, we evaluated the alloreactive potential of donor lymphocyte infusion (DLI) using BM-T cells in mixed chimerism compared to that using spleen T (SP-T) cells. METHODS: Cells were prepared using established procedures. BM-T cells were obtained as a by-product of T-cell depletion in BM grafting and then cryopreserved for subsequent DLI. We performed DLI using BM-T cells in allogeneic mixed chimera mice on post-BMT day 21. RESULTS: When the same dose of T cells, 5-10x10(5) (Thy1.2+), fractionated from BM and spleen were administered into mixed chimeras, the BM-T group showed complete chimeric conversion, with self-limited graft-versus-host disease (GVHD) and no pathological changes. However, the SP-T group showed persistent mixed chimerism, with pathological signs of GVHD in the liver and intestine. CONCLUSIONS: Our results suggest that DLI using BM-T cells, even in small numbers, is more potent at inducing chimeric conversion in mixed chimerism than DLI using SP-T cells. Further study is needed to determine whether cryopreserved BM-T cells are an effective cell source for DLI to consolidate donor-dominant chimerism in clinical practice without concerns about GVHD.

Comparison of quantitative cytomegalovirus real-time PCR in whole blood and pp65 antigenemia assay: clinical utility of CMV real-time PCR in hematopoietic stem cell transplant recipients.

Successful preemptive therapy for cytomegalovirus (CMV) infection in transplant patients depends on the availability of sensitive, specific, and timely diagnostic tests for CMV infection. Although the pp65 antigenemia assay has been widely used for this purpose, real-time quantification of CMV DNA has recently been recognized as an alternative diagnostic approach. However, the guidelines for antiviral therapy based on real-time quantitative polymerase chain reaction (RQ-PCR) have yet to be established. From November 2004 to March 2005, a total of 555 whole blood samples from 131 hematopoietic stem cell transplant (HSCT) recipients were prospectively collected. RQ-PCR was conducted using an Artus CMV LC PCR kit (QIAGEN). Both qualitative and quantitative correlations were drawn between the two methods. Exposure to the antiviral agent influenced the results of the two assays. Additionally, the discrepancy was observed at low levels of antigenemia and CMV DNA load. Via ROC curve analysis, the tentative cutoff value for preemptive therapy was determined to be approximately 2x10(4) copies/mL (sensitivity, 80.0%; specificity, 50.0%) in the high risk patients, and approximately 3x10(4) copies/mL (sensitivity, 90.0%; specificity, 70.0%) in the patients at low risk for CMV disease. Further study to validate the optimal cutoff value for the initiation of preemptive therapy is currently underway.

Retrospective comparison of bortezomib-containing regimens with vincristine-doxorubicin-dexamethasone (VAD) as induction treatment prior to autologous stem cell transplantation for multiple myeloma.

OBJECTIVE: Patients with multiple myeloma (MM) achieving high-quality responses, defined as a complete response (CR) and a very good partial response (VGPR) after transplant, benefit from high-dose therapy followed by autologous stem cell transplantation (ASCT). Induction pre-transplantation treatment with vincristine, doxorubicin and dexamethasone (VAD) is currently being replaced by new targeted agents with high anti-myeloma activity. The use of these novel agents may increase the CR + VGPR rate before ASCT, which may improve post-transplantation responses and survival. METHODS: We performed a retrospective analysis of 69 patients with MM who received bortezomib-containing regimens (n = 30) or VAD (n = 39) before collection of peripheral blood stem cells and ASCT. RESULTS: Objective response rate (at least a partial response) prior to ASCT was documented in 27 (90%) of 30 and 31 (81.6%) of evaluable 38 patients with bortezomib-containing regimens and VAD, respectively. The difference between the two groups was not significant (P = 0.494). However, the high-quality response rate with VGPR or more in the bortezomib group was significantly higher compared with the VAD group (66.7% vs. 34.2%, respectively, P = 0.006). The superiority of bortezomib-containing regimens in the high-quality response rate remained significant for only the newly diagnosed patients (n = 16, P = 0.008). The engraftment data as well as stem cell harvesting were comparable between the two groups. The major bortezomib-related toxicities were thrombocytopenias and peripheral neuropathies; toxicities of VAD were hematologic and infectious. After ASCT, the difference between the two groups did not reach the level of statistical significance with respect to progression-free survival and overall survival (P = 0.498 and 0.835, respectively). CONCLUSIONS: The results of this retrospective comparison of bortezomib-containing regimens with the VAD as induction treatment prior to ASCT for MM provided a demonstration of the superiority of bortezomib therapy in terms of achieving a high-quality response. However, survivals following ASCT did not differ according to the induction regimens.

Successful prevention of acute graft-versus-host disease using low-dose antithymocyte globulin after mismatched, unrelated, hematopoietic stem cell transplantation for acute myelogenous leukemia.

In this study, we investigated the effects of low-dose antithymocyte globulin (ATG, thymoglobulin) in the prevention of acute graft-versus-host disease (aGVHD) in mismatched, unrelated hematopoietic stem cell transplantations (uHSCTs) in patients with the single disease entity of acute myelogenous leukemia (AML). Patients (n = 103) with a variable risk for AML who received uHSCTs from available Asian and Caucasian donors were enrolled. First, we compared HLA-matched (group 1, n = 54) and HLA-mismatched (group 2, n = 49) transplantation patients. Then, we divided the patients in group 2, who had received transplants from allele(s)/antigen-mismatched donors, into 2 subgroups: patients who used ATG (group 3, n = 24) and those who did not (group 4, n = 25). To prevent the development of aGVHD, the patients in group 3 received ATG at a dose of 1.25 mg/kg body weight per day for 2 consecutive days, together with our standard regimen of methotrexate (MTX) and tacrolimus. The median CD34(+) cell infusion was 4.2 x 10(6)/kg (range: 1.2-34.4). The median patient age was 41 years (range: 16-57), and the median follow-up duration of patients who were event-free survivors was 23 months (range: 2-72). The overall incidences of aGVHD and chronic GVHD (cGVHD) were 38% and 56%, respectively. Of 48 evaluable patients in group 2, 10 (21%) developed moderate to severe aGVHD (grades II-IV). In contrast, 2 (8%) of the 24 patients in group 3 and 7 (29%) of the 24 evaluated patients in group 4 required therapy for aGVHD (grades II-IV; P = .038). The incidence of cGVHD was not different between groups 3 and 4. The estimated probabilities of overall survival (OS) and event-free survival (EFS) at 2 years for group 2 were 55% and 44%, respectively. In comparison, the estimated probabilities of OS and EFS at 2 years for groups 3 and 4 were 68% versus 38% (P = .043) and 58% versus 38% (P = .103), respectively. The overall cumulative incidence of nonrelapse mortality (NRM) was 29% in group 2. The cumulative incidence of NRM differed markedly between group 3 (16%; 95% confidence interval [CI], 4%-28%) and group 4 (44%, 95% CI, 34%-54%) (P = .013). We found no difference in cytomegalovirus (CMV) reactivation between groups 3 and 4. These results suggest that in mismatched uHSCT, a low dose of ATG (total 2.5 mg/kg) may prevent moderate to severe aGVHD, with comparable rates of relapse and CMV reactivation and a greatly decreased rate of NRM.

Pulmonary tuberculosis after hematopoietic stem cell transplantation: radiologic findings.

AIM: To determine the radiologic features of pulmonary tuberculosis in hematopoietic stem cell transplant (HSCT) recipients. MATERIALS AND METHODS: Between January 1996 and December 2005, 10 patients with pulmonary tuberculosis were analyzed. Chest radiographs were available in all of these patients and chest computed tomography (CT) scans were available in 7 patients. We retrospectively analyzed each patient's chest radiographic and CT findings. RESULTS: On chest radiography (n=10), the most common abnormalities were air-space consolidation (100%) and nodules (80%). Parenchymal lesions appeared mixed with other findings (80%). The most common mixed pattern was nodules with consolidations (80%). Parenchymal lesions were multilobar (80%), patchy (70%), or bilateral (80%). Evidence of a zonal predominance was not seen. On chest CT scans (n=7), the most common parenchymal lesions were consolidation (100%), nodules (71%), tree-in-bud appearance (43%), and ground-glass opacity (43%). Parenchymal lesions seen on CT scans also appeared mixed (86%) and multilobar in distribution (100%). Significant zonal predominance was not noted on CT scans. Cavity was noted in 14% of the study patients and lymphadenopathy was noted in 71% of these patients on CT scans. CONCLUSIONS: The radiologic features of pulmonary tuberculosis in HSCT recipients were nodules or air-space consolidation. Most of the abnormalities were mixed with other findings and had multilobar distribution, however, a lobar predilection was not seen. Awareness of radiologic findings of pulmonary tuberculosis in HSCT recipients may help the diagnosis of pulmonary tuberculosis.

The extent of minimal residual disease reduction after the first 4-week imatinib therapy determines outcome of allogeneic stem cell transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: Previously, the authors demonstrated the positive impact of imatinib on the outcome of allogeneic stem cell transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). Here, the authors analyzed for risk factors that affect transplantation outcome, and they focused particularly on the prognostic relevance of minimal residual disease level at each treatment stage. METHODS: Fifty-two patients with newly diagnosed Ph-positive ALL who completed allogeneic stem cell transplantation following imatinib therapy were enrolled in this study. For minimal residual disease monitoring, 548 marrow samples were analyzed by a real-time quantitative polymerase chain reaction assay. RESULTS: After the first 4-week imatinib therapy, 11 patients (21.2%) achieved molecular remission, and the remaining 41 patients had a reduction in BCR-ABL transcript levels (median, 3.21 log) from baseline value. The frequency of achieving a reduction in BCR-ABL transcript levels of at least 3 log at this stage was 36 (69.2%). Forty-eight (92.3%) of the 52 patients received stem cell transplantation during first complete remission. With a median follow-up of 49 months after stem cell transplantation, the 4-year relapse rate and disease-free survival rate were 21.2% and 69.8%, respectively. A reduction in BCR-ABL transcript levels of at least 3 log after the first 4-week imatinib therapy was identified as the most powerful predictor of lower relapse (12.1% vs 45.1%, P = .011) and better disease-free survival (82.1% vs 41.7%, P = .009) rates. CONCLUSIONS: Prospective assessment of the extent of minimal residual disease reduction after the first 4-week imatinib therapy may allow the authors to identify subgroups of Ph-positive ALL transplants at high risk of relapse.

Bortezomib in combination with conventional chemotherapeutic agents for multiple myeloma compared with bortezomib alone.

BACKGROUND: Recent studies have demonstrated synergy between bortezomib and a number of conventional cytotoxic agents. This study examined whether or not the speed of the response, progression and safety from a combination treatment of bortezomib with common chemotherapeutic drugs is superior to bortezomib monotherapy. METHODS: Fifty-seven patients with relapsed, refractory multiple myeloma (MM) who had received at least two cycles of treatment including bortezomib were enrolled in this study. The median age was 56 (35-79) years and 49.1% were male. Thirty-two patients were treated with bortezomib alone and 25 were treated with chemotherapeutic agents that were given in combination with bortezomib. The monoclonal immunoglobulin (mIg) or free light chain (FLC) concentrations were determined in the sera before and after two cycles of bortezomib treatment. The adverse events were assessed and graded according to the NCI Common Toxicity Criteria (version 2.0). RESULTS: Thirty-one of the 57 patients (54.4%) attained an early objective response (EOR) after the second bortezomib treatment, defined as a >/=50% decrease in the serum mIg or FLC concentration. Improvements in the response were observed when common chemotherapeutic agents were added to bortezomib monotherapy. In patients who received bortezomib combined with chemotherapeutic agents, 19 out of 25 patients (76%) showed an EOR, whereas 12 out of 32 patients (37.5%) given bortezomib monotherapy achieved an EOR after the second cycle of bortezomib treatment (P = 0.004); the median decrease from the baseline in the paraprotein level was 74.6 +/- 5.9 and 39.7 +/- 4.2%, respectively (P = 0.003). A statistically significant elevation of serum lactic dehydrogenase (P = 0.007) and alkaline phosphatase (P = 0.027) from baseline within two cycles of bortezomib treatment was observed in responding patients. With the combination treatment, peripheral neuropathy of >/=Grade II occurred in 12 out of 25 patients (48%) compared with 12 of 32 (37.5%) in those given bortezomib alone (P = 0.589). The median time to progression of disease was similar in the two groups (359 +/- 43.5 versus 365 +/- 103.5, P = 0.688). The multivariate Cox regression model showed that a high serum albumin and low beta2-microglobulin are favorable factors for the progression-free survival following bortezomib treatment. CONCLUSIONS: Bortezomib in combination with common chemotherapeutic agents is more active in the treatment of relapsed, refractory MM than with bortezomib alone. However, more effective post-bortezomib treatment is needed to reduce the rate of disease progression particularly in patients with high tumor burden.

The activating killer cell immunoglobulin-like receptors as important determinants of acute graft-versus host disease in hematopoietic stem cell transplantation for acute myelogenous leukemia.

BACKGROUND: We investigated the influence of killer cell immunoglobulin-like receptor (KIR) genes, based on the genotypes of inhibitory or activating KIR, in stem cell recipients with acute myelogenous leukemia and their human leukocyte antigen-matched sibling donors on acute graft-versus host disease (GVHD) after hematopoietic stem cell transplantation. METHODS: We studied 53 consecutive donor-recipient pairs to determine the impact of KIR genotypes and their bidirectional KIR interactions. RESULTS: All activating KIR genes in donors were important factors for determining outcome in a manner distinctive for each gene studied. Specifically, the 2DS2 gene and the 2DS4*003 allele were closely correlated with acute GVHD. The 2DS1 gene was associated with a better long-term survival, even if present only in the donor and not the recipient. The 2DS3-2DS5 dual genes were more often involved in a variety of transplant-related complications. CONCLUSIONS: In conclusion, these factors may help predict transplant outcomes and aid in our understanding of immunogenetic specificity.

Gemtuzumab ozogamicin in combination with attenuated doses of standard induction chemotherapy can successfully induce complete remission without increasing toxicity in patients with acute myeloid leukemia aged 55 or older.

BACKGROUND: In this study, the effectiveness and safety of combining gemtuzumab ozogamicin (GO) with an abbreviated schedule of standard induction chemotherapy were assessed in 37 patients (aged > or =55) yr with previously untreated acute myeloid leukemia (AML). METHODS: GO was administered at a dose of 6 mg/m(2) as a single 2-h intravenous infusion on day 1. Following GO, an abbreviated schedule of induction chemotherapy consisting of idarubicin (12 mg/m(2)/d, days 2-4), and N4-behenoyl-1-beta-arabinofuranosyl cytosine (300 mg/m(2)/d, days 2-6) was given. RESULTS: Thirty-seven patients were treated with GO in combination with chemotherapy. Complete remission (CR) and CR with incomplete platelet recovery were achieved in 28 patients (75.7%) and one patient (2.7%) respectively. Two patients (5.4%) died during induction and two patients (5.4%) with grade 4 treatment emergent adverse effects during chemotherapy did not complete induction chemotherapy. The majority of toxicities were mild and manageable. Severe myelosuppression was universal with significantly prolonged thrombocytopenic period. In total, 25 patients who received consolidation treatment, 19 patients remain alive at the time of analysis. Thirteen patients had undergone hematopoietic stem cell transplantation, three are preparing for transplantation and seven are receiving their consolidation chemotherapy course. CONCLUSION: Although only a relatively small number of cases were included in this preliminary study and the follow-up duration was short, frontline GO in combination with attenuated conventional chemotherapy was found to be effective and feasible in elderly patients with AML.

Allogeneic stem cell transplantation in first complete remission enhances graft-versus-leukemia effect in adults with acute lymphoblastic leukemia: antileukemic activity of chronic graft-versus-host disease.

The aim of the present study was to identify graft-versus-leukemia effects and the factors that affect outcome in 201 adults with acute lymphobalstic leukemia who received myeloablative allogeneic stem cell transplantation from matched sibling or unrelated donors (1995-2004). One hundred seventy-eight (88.6%) of these patients had high-risk criteria, and 151 (75.1%) patients were transplanted in first complete remission (CR). All patients received unmodified stem cell grafts (185 bone marrow and 16 peripheral blood) following total- body irradiation-containing myeloablative preparations. Graft-versus-host disease (GVHD) prophylaxis was uniformly attempted by administering calcineurin inhibitor plus methotrexate. After a median follow-up of 63 months (range: 25+ to 139+ months) for surviving transplants, disease-free survival at 5 years was 47.8% for all patients and 60.3% for patients in the first CR. No difference in transplantation outcome was observed between sibling and unrelated transplants in the first CR. The most powerful predictive factor affecting transplantation outcome was disease status at transplantation (the first CR versus beyond the first CR, P<.001). Chronic GVHD (cGVHD), especially limited type, was also found to have a significant antileukemic effect. Interestingly, the influence of cGVHD on relapse risk was prominent in patients with chromosomal translocations or normal cytogenetics.

Successful interim therapy with imatinib prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute myeloid leukemia.

OBJECTIVES: Imatinib (Glivec, STI571) has been successfully used in patients with chronic myelogenous leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome (Ph). We used imatinib interim therapy for four consecutive patients with newly diagnosed Ph+ acute myeloid leukemia (AML). We monitored the patient status for minimal residual disease by real-time quantitative polymerase chain reaction. METHODS AND RESULTS: Imatinib was administered on an interim schedule after each chemotherapy course. After the first imatinib cycle, all patients remained in sustained complete hematologic remission (CHR) with a decrease in the breakpoint cluster region of the Abelson oncogene locus transcript. All patients received a second imatinib cycle following consolidation and showed sustained CHR, including two cases with complete molecular remission. All cases underwent hematopoietic stem cell transplantation (HSCT) in favorable condition, and are still alive with a leukemia-free status at 6, 6, 9, and 25 months after HSCT. CONCLUSIONS: As a first-line interim therapy, imatinib appears to be a useful treatment strategy to provide a bridge to HSCT in patients with Ph+ AML. Further studies with a larger patient population and longer follow-up are needed for accurate assessment of the impact of imatinib on the long-term outcome of transplantation for patients with Ph+ AML.

Unrelated donor bone marrow transplants for severe aplastic anemia with conditioning using total body irradiation and cyclophosphamide.

The outcome of unrelated donor bone marrow transplantation for aplastic anemia is inferior to that of sibling donor bone marrow transplantation because of a higher rate of transplant-related mortality (TRM), which is closely associated with the intensity of pretransplant conditioning to overcome graft rejection. We conducted a prospective trial with an intermediate to high dose of total body irradiation (TBI) in combination with a fixed dose of cyclophosphamide (120 mg/kg) to use for pretransplant conditioning for unrelated donor bone marrow transplantation in adult aplastic anemia. The number of patients who received doses of 1200, 1000, and 800 cGy of TBI were 5, 9, and 26, respectively. The corresponding probabilities of overall survival (OS) at 3 years were 40%, 44%, and 92%, respectively. The incidence of regimen-related toxicity with grade III-IV and graft rejection in the patients who received a dose of 800 cGy of TBI were 0 of 26 patients. The significant factors associated with OS were the TBI dose (800 cGy vs. >or=1000 cGy; P = .001), chronic graft-versus-host disease (less than or equal to limited vs. extensive; P = .013), the method of HLA typing for the donor-recipient matching (serologic typing vs. DNA-based typing; P = .006), and the transfusion amount before transplantation (90 units; P = .020).

The beneficial effect of chronic graft-versus-host disease on the clinical outcome of transplantation with fludarabine/busulfan-based reduced-intensity conditioning for patients with de novo myelodysplastic syndrome.

Allogeneic hematopoietic stem cell transplantation following reduced-intensity stem cell transplantation (RIST) has enabled the treatment of older or medically infirm patients with myeloid malignancies; however, determining the value of RIST outcomes for myelodysplastic syndrome (MDS) is difficult because of the heterogeneity of the diseases included in most trials. To define the role of RIST in MDS, we performed RIST for 22 consecutive patients who had de novo MDS as classified by World Health Organization (WHO) criteria and who received an allograft with fludarabine/busulfan (Busulfex) or fludarabine/Busulfex/antithymocyte globulin (ATG) conditioning. Nineteen patients (86.4%) achieved engraftment. At a median follow-up of 18.9 months (range, 13.1-24.8 months), the estimated 2-year rates of overall survival, event-free survival (EFS), transplantation-related mortality, and relapse were 78.7%, 67.7%, 12.6%, and 22.5%, respectively. Acute graft-versus-host disease (GVHD) greater than grade II developed in 3 patients (15.8%). Chronic GVHD developed in 10 patients (55.6%), none of whom received ATG as a conditioning regimen. Variables influencing EFS were chronic GVHD, marrow blasts before transplantation, and the WHO criteria. The present study clarifies the benefits of the fludarabine/Busulfex-based conditioning regimen for de novo MDS diagnosed according to the WHO criteria and shows that chronic GVHD appears to have a beneficial effect on survival rates, which are strongly associated with graft-versus-tumor effects.

The inhibition of T-cells proliferation by mouse mesenchymal stem cells through the induction of p16INK4A-cyclin D1/cdk4 and p21waf1, p27kip1-cyclin E/cdk2 pathways.

Mesenchymal stem cells (MSCs) have been shown to down-regulate T-cell responses. However, the mechanisms underlying remain unknown. In this study, we report that BALB/c bone marrow-derived MSCs inhibit the proliferation of allogeneic T-cells in mixed lymphocyte reactions (MLR), This inhibition is dependent on cell-cell contact, and do not induce apoptosis. Furthermore, cell-cycle analyses reveal that T-cells, in the presence of MSCs, are arrested in the G0/G1 phase through. The blockage of phosphorylation of retinoblastoma protein (Rb), mediated by the p16(INK4A)-cyclin D1/cdk4 complex and p21(waf1), p27(kip1)-cyclin E/cdk2 complex pathway. Our results suggest that MSCs may perform a crucial function in the maintenance of immune homeostasis, via direct regulation of the clonal expansion of activated T-cells. The novel T-cell regulatory mechanism exhibited by MSCs may prove useful in a variety of therapeutic applications.