Association of clinicopathological features of melanoma with total naevus count and a history of dysplastic naevi: a cross-sectional retrospective study within an academic centre.

BACKGROUND: High naevus count (HNC) (≥ 50 naevi) and presence of dysplastic naevi (DN) are risk factors for malignant melanoma (MM); however, MMs also occur in patients with low naevus count (LNC) (< 50 naevi) and in patients without DN. Little is known about differences between MMs in these groups. AIM: To characterize the clinicopathological differences between MMs in patients with HNC and those in patients with LNC, with or without biopsy-proven DN. METHODS: This was a cross-sectional retrospective chart review of 281 patients with MM seen between April 2013 and March 2014 at an academic pigmented lesion clinic (Boston, MA, USA). RESULTS: Patients with LNC MMs were diagnosed at an older age (51 vs. 41 years, P < 0.001, OR = 0.95, 95% CI 0.93-0.97), with more aggressive MM features, including greater Breslow thickness (1.1 vs. 0.8 mm, P = 0.01), more mitoses (2 vs. 1 mitoses/mm2 , P < 0.001), lower rate of superficial spreading subtype (58 vs. 78%, P < 0.01, OR = 2.57, 95% CI 1.31-5.03) and higher MM stage (P < 0.001), compared to patients with HNC. Patients with DN had similar trends as those in patients with HNC described above, and in addition, were more likely to have a truncal MM (55 vs. 39%, P < 0.01, OR = 1.97, 95% CI 1.22-3.18) with less ulceration (13 vs. 29%, P < 0.01, OR = 0.36, 95% CI 0.19-0.71). Patients without DN were more likely to have a history of a non-MM skin cancer (32 vs. 19%, P = 0.01, OR = 0.49, 95% CI 0.28-0.85) and an amelanotic MM (33 vs 21%, P = 0.03, OR = 0.55, 95% CI 0.31-0.96). CONCLUSIONS: Patients with LNC may develop MMs with more aggressive features at an older age than patients with HNC. A history of biopsy-proven DN reveals distinct MM differences compared to patients without DN.

Myeloid expression of the AP-1 transcription factor JUNB modulates outcomes of type 1 and type 2 parasitic infections.

Activation of macrophages is a key step in the initiation of immune responses, but the transcriptional mechanisms governing macrophage activation during infection are not fully understood. It was recently shown that the AP-1 family transcription factor JUNB positively regulates macrophage activation in response to Toll-like receptor agonists that promote classical or M1 polarization, as well as to the cytokine interleukin-4 (IL-4), which elicits an alternatively activated or M2 phenotype. However, a role for JUNB in macrophage activation has never been demonstrated in vivo. Here, to dissect the role of JUNB in macrophage activation in a physiological setting, mice lacking JUNB specifically in myeloid cells were tested in two infection models: experimental cerebral malaria, which elicits a pathological type 1 immune response, and helminth infection, in which type 2 responses are protective. Myeloid-restricted deletion of Junb reduced type 1 immune activation, which was associated with reduced cerebral pathology and improved survival during infection with Plasmodium berghei. Myeloid JUNB deficiency also compromised type 2 activation during infection with the hookworm Nippostrongylus brasiliensis, leading to diminished cytokine production and eosinophil recruitment and increased parasite burden. These results demonstrate that JUNB in myeloid cells shapes host responses and outcomes during type 1 and type 2 infections.

Effects of electron-cyclotron-resonance-heating-induced internal kink mode on the toroidal rotation in the KSTAR Tokamak.

It is observed that the magnitude of the toroidal rotation speed is reduced by the central electron cyclotron resonance heating (ECRH) regardless of the direction of the toroidal rotation. The magnetohydrodynamics activities generally appear with the rotation change due to ECRH. It is shown that the internal kink mode is induced by the central ECRH and breaks the toroidal symmetry. When the magnetohydrodynamics activities are present, the toroidal plasma viscosity is not negligible. The observed effects of ECRH on the toroidal plasma rotation are explained by the neoclassical toroidal viscosity in this Letter. It is found that the neoclassical toroidal viscosity torque caused by the internal kink mode damps the toroidal rotation.

Infectious complications associated with alemtuzumab use for allogeneic hematopoietic stem cell transplantation: comparison with anti-thymocyte globulin.

OBJECTIVES: To evaluate the incidence of infectious complications after receiving alemtuzumab as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in Korean patients. METHODS: From November 2004 to January 2006, 12 patients who received alemtuzumab-based conditioning regimens for allogeneic HSCT were evaluated retrospectively until death or until the end of the follow-up in July 2007; they were compared with 18 patients who received rabbit anti-thymocyte globulin (ATG)-containing conditioning regimens from January 2002 to January 2006. RESULTS: Post-engraftment infections occurred more frequently in the alemtuzumab recipients than in the ATG recipients; the mean number of infections, excluding cytomegalovirus (CMV) infections, per patient during the follow-up period was 2.6+/-1.4 vs. 1.0+/-0.8 (P=0.003), respectively. Although there was no statistical difference in the cumulative incidence of CMV infection between the 2 groups (91.7% vs. 55.6%, P=0.381), the alemtuzumab recipients had a higher incidence of CMV diseases (41.6% vs. 0%, P=0.0006) and a higher recurrence rate of CMV infection (90.0% vs. 27.3%, P=0.008) than did the ATG recipients, irrespective of the dose of alemtuzumab. Hemorrhagic cystitis (HC) (66.7% vs. 16.7%, P=0.009) and BK virus-associated HC (41.7% vs. 5.6%, P=0.026) developed more frequently in the alemtuzumab recipients. The all-cause mortality rate was not significantly different between the alemtuzumab and the ATG recipients (75% vs. 55.6%, P=0.28). CONCLUSION: Alemtuzumab recipients had a high incidence of CMV disease as well as BK virus-associated HC compared with the ATG recipients. The dose of alemtuzumab should be tailored to patients' risk; in addition, the implementation of the appropriate prophylaxis for CMV and early detection strategies for BK virus are recommended.

The activity of hematopoietic stem cell transplantation in Korea.

Since the first successful allogeneic hematopoietic SCT (HSCT) was performed in Korea in 1983, there has been a noticeable progress in both the quantity and quality of HSCT over 24 years. There are 38 HSCT centers in Korea and the number of both allogeneic and autologous HSCTs has been increasing every year. As of December 2006, a total of 9561 HSCTs have been carried out in Korea, including 5617 allogeneic (59%) and 3944 autologous HSCTs (41%). The main indications were acute leukemia (3979, 78% allogeneic); lymphoma (1244, 90% autologous); myeloma (939, 92% autologous) and aplastic anemia (938). Characteristically, severe aplastic anemia accounts for a considerable proportion of transplants (10%), compared with western countries. Recently, there has been a marked increase in the number of unrelated transplants and the usage of PBSCs. The pattern of infectious diseases associated with HSCT is quite different. The rapid expansion of unrelated donor pools worldwide has changed the outlook of an unrelated donor search in Korea.

Clinical impact of thrombotic microangiopathy on the outcome of patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

The impact of thrombotic microangiopathy (TMA) on outcome was studied in 148 patients with acute graft-versus-host disease (GVHD) (> or =grade II). The Blood and Marrow Transplant Clinical Trials Network's definition for TMA was used to diagnose definite TMA. Probable TMA was diagnosed when none of the features of nephropathy and neurologic abnormalities associated with definite TMA were present. Overall, TMA developed in 43 (29%) patients; 16 definite and 27 probable. The occurrence of TMA, the maximum grade of acute GVHD and initial treatment failure were associated with shorter overall and GVHD-specific survival. The development of probable as well as definite TMA affected the survival of patients with acute GVHD adversely. These results show the clinical impact of TMA on patients with acute GVHD, and suggest that the proposed definitions and grading of TMA may need to be modified.

Distribution of the minor histocompatibility antigens in Korean population and disparities in unrelated hematopoietic SCT.

Minor histocompatibility antigens (mHags) are polymorphic peptides presented to T lymphocytes restricted by the MHC molecule. It has been reported that disparities of mHags are a potential risk factor for GVHD after hematopoietic SCT (HSCT). Here we observed allelic frequencies of HA-1, -2 and -8 in 139 Korean healthy individuals using PCR-sequence-specific primers, and analyzed the correlation between disparity of these mHags and acute GVHD (aGVHD) in 54 patients who underwent HSCT from unrelated HLA-identical donors. The allelic frequencies in Korean healthy individuals were 39.6 and 60.4% for HA-1(H) and HA-1(R), 92.4 and 7.6% for HA-2(M) and HA-2(V), 36.7 and 63.3% for HA-8(R) and HA-8(P), respectively. The frequencies of mHags incompatibility known to be associated with aGVHD were 16.7% in HA-1, 0% in HA-2 and 25.9% in HA-8. However, the statistically significant association of aGVHD with these mHags incompatibility was not found between healthy donors and leukemia patients after unrelated HSCT. This first report about mHags in Koreans may be helpful in further defining the clinical impact of mHags disparities in HSCT and in comparing with other populations.

Anti-leukaemic role of acute GvHD after unrelated haematopoietic stem cell transplantation in intermediate- to high-risk acute myelogenous leukaemia.

Little is known about the role of acute GvHD (aGvHD) based on the concept of graft-versus-leukaemia effect (GVLE) after unrelated donor haematopoietic stem cell transplantation (uHSCT). We evaluated 67 uHSCTs performed with multinational unrelated donors for patients with AML. The median follow-up duration was 18 months (range 7-61). The majority of patients had intermediate- or high-risk cytogenetic findings. The conditioning regimen for most patients consisted of cyclophosphamide plus total body irradiation (n=56) with our standard GvHD prophylaxis containing tacrolimus plus a short course of methotrexate. The incidence of aGvHD and chronic GvHD was 50 and 52%, respectively. Eight patients (12%) have relapsed to date. The estimated overall disease-free survival (DFS) rate at 5 years was 67%. Notably fewer relapses were seen when aGvHD developed (P=0.008). Specifically, high-risk AML patients had a much lower relapse rate when they developed aGvHD (P=0.01), compared with the intermediate-risk group. Therefore, the development of aGvHD after uHSCT in AML patients is closely related to a lower relapse rate, probably in association with GVLE.

Patterns of C-reactive protein release following allogeneic stem cell transplantation are correlated with leukemic relapse.

The C-reactive protein (CRP) is an acute-phase protein produced by hepatocytes, and is a reliable marker of systemic inflammation, which is relevant to the release of the proinflammatory cytokines. The value of monitoring the CRP levels after stem cell transplantation (SCT) can identify patients at risk of treatment-related complications and mortality. Inflammatory cytokines facilitate donor T-cell activation via antigen presenting cells immediately after SCT. This study examined the relationship between the post-SCT CRP levels and a leukemic relapse. Fifty-four consecutively transplanted patients who relapsed after the allogeneic SCT were compared with nonrelapsing patients. The serum CRP levels were measured on day 0 and every 7 days thereafter until 4 weeks after the SCT. The mean CRP levels throughout the early post-SCT episode were significantly lower in the relapsing patients than in those who did not experience relapse (mean+/-s.e.: 26.8 +/- 6.3 vs 65.3 +/- 9.4 for first week, P = 0.001; 23.9 +/- 3.8 vs 44.6 +/- 6.6 for second week, P = 0.008). Univariate analysis showed that the CRP level on the first and second week, and graft-versus-host disease were significantly associated with a relapse. Multivariate analysis showed that the CRP level on the first week was the strongest independent variable predicting the risk of a relapse after SCT (P = 0.04). These results indicate that the serum CRP levels early after allogeneic SCT might display the graft-versus-leukemia (GvL) effect. CRP is a surrogate of the proinflammatory cytokine release that was not measured in this study. The GvL effect appears to be efficiently strengthened by the high CRP levels that may be reflecting T-cell activation.

Vascular endothelial growth factor (VEGF) is associated with reduced severity of acute graft-versus-host disease and nonrelapse mortality after allogeneic stem cell transplantation.

This study investigated whether or not there is a correlation between the changes in the serum levels of vascular endothelial growth factor (VEGF) and the outcome of allogeneic stem cell transplantation (allo-SCT). Eighty-five patients undergoing allo-SCT were prospectively studied. The serum VEGF levels were measured on days 0, +7 and +14 after transplantation. The VEGF levels decreased significantly on day +7 and recovered on day +14. The highest levels from day +7 through day +14 were categorized by cluster analysis, which were then correlated with the nonrelapse mortality (NRM). There was a significant correlation between a low VEGF level and the occurrence of severe acute graft-versus-host disease (GVHD) including grade III-IV (P=0.029). The 1-year probability of NRM in patients with a low VEGF level was 22.5% compared with 3.5% for those with a high VEGF level (P=0.024). Multivariate analysis revealed clinically defined infections (P=0.011), advanced disease (P=0.014) and a low VEGF cluster (P=0.05) to be significantly associated with the occurrence of NRM in the cohort. In conclusion, low VEGF levels after allo-SCT are associated with NRM with an exacerbated severity of acute GVHD. VEGF monitoring after a transplant might identify those patients at risk of severe transplant-related mortality.

Haplotype mismatched transplantation using high doses of peripheral blood CD34+ cells together with stratified conditioning regimens for high-risk adult acute myeloid leukemia patients: a pilot study in a single Korean institution.

A total of 11 high-risk Korean acute myeloid leukemia (AML) patients received stem cell transplantation from human leukocyte antigen (HLA) haploidentical donors. Specifically, for eight patients with 2-3 mismatched antigens and bidirectional vectors, we used a newly designed conditioning regimen that consists of total body irradiation, busulfex, ATG, and fludarabine. The median number of CD34+ cells infused was 15.4 x 10(6)/kg (range, 8-21.2). These patients received neither graft-versus-host disease (GvHD) prophylaxis nor post transplantation G-CSF. All of the patients who were followed up for a median of 6 months (range, 17 days-28 months) showed stable primary engraftment and had no acute GvHD or transplant-related mortality for 100 days post transplant. Three patients with high-risk or refractory disease eventually died in relapse, even with GvH-directed NK alloreactivity. However, the patients in complete remission (CR), with the exception of one patient who is alive at 18 months EFS, died at 4, 6, and 8 months post transplantation due to infections that were associated with delayed immune recovery. Our findings suggest that haploidentical transplantation represents a feasible treatment for patients with high-risk AML in CR, provided that a plan for the enhancement of immune recovery is implemented.

Impact of ABO incompatibility on outcome after allogeneic peripheral blood stem cell transplantation.

Few studies have addressed the incidence of graft-versus-host disease (GVHD) or survival after ABO-incompatible allogeneic peripheral blood stem cell transplantation (PBSCT). We analyzed the clinical outcome of ABO incompatibility after allogeneic PBSCT. A total of 89 consecutive adult patients with hematological diseases including 49 ABO-identical, 20 major, 15 minor, and five bidirectional ABO-incompatible transplants were enrolled from four medical centers in Korea. No significant difference in engraftment times, graft failure, or transfusion requirements between groups was noted. A clinical diagnosis of severe immune hemolysis or pure red cell aplasia was not made for any patient after transplantation. The incidence of acute or chronic GVHD did not statistically differ between groups. With a median follow-up duration of 13 months (range, 0.5-61 months), the 3-year overall survival estimates for the ABO-identical, major/bidirectional, and minor group were 44.6.0+/-9.0, 43.1+/-11.6, and 43.8+/-13.5%, respectively (P=0.8652), while the 3-year disease-free survival estimates were 33.8+/-7.6, 39.9+/-11.4, and 45.7+/-13.1%, respectively (P=0.8546). We observed that time to neutrophil, platelet, and red blood cell engraftment, transfusion requirements, incidence of acute or chronic GVHD, relapse, and survival were not influenced by ABO incompatibility after allogeneic PBSCT from HLA-matched sibling donors.

Acute lymphoblastic leukemia with maturation--a new entity with clinical significance.

The diagnosis of 'ALL with maturation' (ALLm) is proposed. One hundred and one patients with untreated ALL were entered into this study. The diagnosis of ALLm was made when more than 20% of all nucleated elements in the bone marrow showed maturation beyond prolymphocytes by light microscopic examination. The mature-appearing leukemic cells showed the same immunophenotype to remaining lymphoblasts. The number of ALLm cases was 19 (18.8%). The mean age at presentation of ALLm was 29 +/- 18, older than that of 18 +/- 16 of the remaining typical ALL (ALLt) (P = 0.015). Remission was induced with daunorubicin, vincristine, prednisone and L-asparaginase. Only two of 19 ALLm patients achieved CR after 4 weeks induction chemotherapy. In contrast, 57 of 82 (69.5%) ALLt patients achieved CR after the same induction chemotherapy. There was no significant difference in immunophenotype of ALLm compared with ALLt. Labeling index of DNA topoisomerase IIalpha (TopoLI) was studied by immunohistochemistry. Initial TopoLI of ALLm (221 +/- 147) was much lower than that of ALLt (609 +/- 262, P = 0.005). Furthermore, the remaining leukemic cells after chemotherapy were not labeled with anti-DNA topoisomerase IIalpha. The P53 protein was expressed in nine of 18 ALLm cases (50.0%) and P-glycoprotein was not expressed in ALLm cases. Twelve of 19 ALLm cases were studied for carrying bcr/abl fusion by karyotyping and/or fluorescent in situ hybridization. Only two cases revealed bcr/abl fusion. In conclusion, ALLm is a separate entity of ALL which has a very poor clinical course and is independent of other prognostic factors. The morphologically mature leukemic cells are in resting GO phase.

Effectiveness of rotor off fraction in allogeneic murine bone marrow transplantation with complete disparity of major histocompatibility.

Counterflow centrifugal elutriation (CCE) has been a highly efficient physical method for separating T cells from bone marrow (BM) without impairing cell function and yield. To investigate the usefulness of CCE, the hematopoietic potential as well as the level of T cell contamination in rotor-off (R/O) fraction of BM was studied using a murine bone marrow transplantation (BMT) model [C3H/He (H-2k)-->BALB/C (H-2d)]. The total recovery of cells after CCE procedure was 71.4%. Morphologically, R/O fraction contained abundant mononuclear cells and a few lymphocytes. The numbers of colony forming unit for granulocyte/monocyte (CFU-GM), Sca-1+ cells, and T cells were compared among four fractions of CCE (fractions at flow rate of 17, 25, 28 mL/min, and R/O fraction). The number of CFU-GM per 10(5) nucleated cells in each fraction were significantly higher in R/O fraction (331.3 +/- 34.4) compared to unfractionated marrow (UM) (21.1 +/- 1.3) and fraction of 17 mL/min (FR 17) (23.7 +/- 2.2 ) (chi2 = 0.0044). Neither fraction of 25 mL/min (FR 25) nor fraction of 28 mL/min (FR 28) contained CFU-GM colonies. The concentration of Sca-1+ cells in R/O fraction was significantly higher (1.96-fold) than UM (p < 0.05), and 80.0 +/- 10.1% of Sca-1+ cells in UM were recovered in R/O fraction; 88.1% of Thy-1.2+ T cells were eliminated in R/O fraction (p < 0.05). Mice receiving UM after lethal irradiation (875cGy) suffered from severe graft-versus-host disease (GVHD) and all five died within 7 days after BMT procedure (Group A). Of interest, mice receiving mixture of R/O fraction with lymphocyte-rich fraction (FR 25 plus FR 28) to equalize T cell number as UM, developed severe GVHD and four out of five died (probability of survival; 20%) (Group B). Mice receiving R/O fraction had mild GVHD and four out of five survived for at least 90 days (probability of survival; 80%) (Group C). In group C, probability of survival (p = 0.0006) was higher, and severity of GVHD (p = 0.0043) and progression rate of GVHD (p = 0.02) was lower. In conclusion, the elutriated R/O fraction cells of BM have the advantages of stable engraftment and tolerable GVHD in murine allogeneic BMT with complete major histocompatibility disparity. This could be directly applicable to patients with high risk of GVHD and graft failure in upcoming clinical trials.

Induction chemotherapy with idarubicin plus N4-behenoyl-1-beta-D-arabinofuranosylcytosine in acute myelogenous leukemia: a newly designed induction regimen--a prospective, cooperative multicenter study.

This report describes the results of induction chemotherapy with idarubicin (IDA) plus N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BH-AC), a newly designed induction regimen, in cases of previously untreated acute myelogenous leukemia (AML). The study was conducted by the Multicenter Clinical Study Group of the Korean Biologic Response Modifier Society (KBRMS). From March 1994 through January 1995, 40 patients were treated. The median age was 30 years (range, 15 months to 65 years), with a distribution according to the French-American-British (FAB) classification of one MO, nine MI, 15 M2, six M3, four M4, and five M5 patients. Remission induction therapy consisted of IDA 12 mg/m2 intravenously (i.v.) over 30 minutes daily on days 1 to 3, in combination with BH-AC 300 mg/m2 over 4 hours daily on days 1 to 7 (in patients aged 41 to 65 years, BH-AC dosage was decreased to 200 mg/m2/d). Complete remission (CR) was achieved in 30 patients (75%), 22 by the first induction therapy and eight by the second induction therapy. Ten patients (25%) failed to respond to therapy, six due to resistant disease and four due to death caused by aplasia. The time to CR was 30 days, the median granulocytopenic period was 19 days, and the thrombocytopenic period was 24 days. All nonhematologic side effects such as nausea, vomiting, mucositis, skin eruption, liver and cardiac dysfunction, and neurotoxicity, were transient and tolerable. These data indicate an efficacy comparable to that of other combinations of IDA (or other anthracyclines) with cytosine arabinoside (Ara-C) for remission induction in AML.

The short-term changes of bone mineral metabolism following bone marrow transplantation.

Organ transplantation is now the treatment of choice for many patients with life-threatening chronic diseases. A new set of side effects unique to these groups of patients has become recognized, and bone disease is one of these complications. However, little is known about the effects of myeloablative treatment followed by bone marrow transplantation (BMT) on bone mineral metabolism. We have prospectively investigated 31 patients undergoing BMT for hematologic diseases. Serum concentrations of calcium, phosphorus, creatinine, gonadotropins, sex hormones, and the biochemical markers of bone turnover were measured. The samples were collected before BMT and 1, 2, 3, 4, and 12 weeks, 6 months, and 1 year after BMT. Bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry before BMT and 1 year after BMT. The serum carboxy-terminal cross-linked telopeptide of type I collagen increased progressively until 4 weeks after BMT. Thereafter, it began to decrease and reached basal values after 1 year. Serum osteocalcin decreased progressively until 3 weeks after BMT. After that, it increased and reached basal values after 3 months. No distinct differences were observed in the serum biochemical turnover markers between males and females, or between patients who received total body irradiation and those who did not. One year after BMT, lumbar spine BMD had decreased by 2.2%, and total proximal femoral BMD had decreased by 6.2%. Eighty-six percent of the women (12/14) went into a menopausal state immediately after BMT. This was caused by high gonadotropin levels and low estradiol levels. In contrast, gonadotropin levels and testosterone levels did not change significantly in the male patients after BMT. In conclusion, the rapid impairment of bone formation and the increase in bone resorption, as shown by the biochemical markers in this study, might play a role in post-BMT bone loss.

Distribution of seven polymorphic markers and haplotypes within the human TNF gene cluster in Koreans.

We examined the distribution of polymorphic elements within the tumor necrosis factor (TNF) gene cluster in 133 normals and in 20 Korean families and compared our data with the results of Caucasians. The genotypes that are shown frequently are TNF a6 (33.8%), TNF b5 (46.6%), TNF c1 (79.3%), TNF d3 (34.6%), TNF e3 (86.5%), TNFB*2 (51.5%), and TNF(-308) A (91.4%). In comparison, TNFa 6 (33.8%), TNFa 13 (4.1%), TNFb 5 (46.6%), TNFd 1 (7.5%), TNFd 3 (34.6%), TNFe 3 (86.5%), TNFe 4 (6.8%), and TNF(-308) A (91.3%) were found more frequently in Koreans than Caucasians (p < 0.01). TNFa 14, TNFa 15, TNFd 8, and TNFe 4 alleles were found only in Korean controls. However, TNFb 6 and TNFb 7 alleles were not found in this study. From the TNF gene of TNFa, TNFb, TNFc, TNFn, TNF(-308), TNFd, and TNFe, 49 different TNF haplotypes were found in 20 Korean families. These data suggest that the TNF microsatellite haplotypes constitute a highly polymorphic system and that will provide useful information on the association between the TNF marker and the immune disease.

Preemptive treatment of minimal residual disease post transplant in CML using real-time quantitative RT-PCR: a prospective, randomized trial.

Immunotherapy in the form of donor lymphocyte infusions in early-phase relapse might be advantageous as it induces a higher response, but this may be offset by increased toxicity, especially during the early period after transplantation. Among 45 consecutive patients receiving an allograft for CML, 13 patients were diagnosed to have molecular relapse (MRel), as defined by real-time quantitative reverse transcriptase-polymerase chain reaction, and another four patients were diagnosed to have cytogenetic relapse (CRel) within 6 months. Patients with MRel were randomly assigned to either a 'no therapy' group (group A, n=6), in which immunotherapy was reserved until CRel, or an 'immunotherapy' group (group B, n=7). In group A, all MRel progressed to CRel, and molecular remission (MR) was achieved in four (67%) after immunotherapy. The remaining two patients died of extensive GVHD and fungal pneumonia. In group B, only two MRel progressed to CRel and the remaining five (71%) achieved MR. Two patients died in the absence or loss of response. In patients relapsing directly into CRel (n=4), immunotherapy induced MR in two patients (50%). Earlier intervention played a role in preventing disease progression but this effect was not translated into better survival, which could have been overcome by imatinib mesylate, which induced MR and cytogenetic remission in nonresponders without toxicity.

Successful allogeneic hematopoietic stem cell transplantation using triple agent immunosuppression in severe aplastic anemia patients.

Graft rejection in patients with severe aplastic anemia (SAA) following allogeneic hematopoietic stem cell transplantation (HSCT) is strongly associated with a large number of prior transfusions and with prolonged disease duration before transplant. We retrospectively analyzed the outcomes and the factor affecting these multitransfused SAA patients, who had received triple agent immunosuppression and high doses of stem cells to overcome rejection. In total, 113 patients with SAA who had a median 16 months (range 1-216) of disease duration were transplanted using HLA-matched sibling donors after conditioning with cyclophosphamide (CY), procarbazine (PCB), and ATG. Graft failure occurred in 16 of the eligible 113 patients, and with a median follow-up of 30 months (range, 1-80), probability of overall rejection was 15%. Specifically, the multitransfused patients who received high doses of stem cells with T-cell depletion showed the lowest rejection rate, 5.6%, compared with 30.3% in multitransfused patients with bone marrow stem cells alone (P=0.0310). Disease duration (P=0.0338) and the number of infused CD34+cells (P=0.0101) were associated with a high risk of graft rejection on multivariate analysis. ABO mismatch and the number of CD34+ cells were significant factors in the incidence of acute graft-versus-host-disease (GVHD). The incidence of chronic GVHD among patients with sustained engraftment was 13/109 (11.9%). With the same follow-up period, probability of disease-free survival for the entire group of patients at 6 years was 89% and the only factor associated with long-term survival was rejection (P=0.0241). These results suggest that allogeneic HSCT conditioned with triple agent immunosuppression, and specifically with high-dose stem cell return is probably an effective treatment for successful engraftment in SAA patients with a high risk of rejection.

Conditioning with high-dose cyclophosphamide may not be sufficient to provide a long-term remission of paroxysmal nocturnal hemoglobinuria following syngeneic peripheral blood stem cell transplantation.

A patient with paroxysmal nocturnal hemoglobinuria (PNH) received a syngeneic peripheral blood stem cell transplant (PBSCT) with high-dose cyclophosphamide (CY) conditioning. He had a reasonable engraftment and complete hematologic recovery. However, at 12 months after PBSCT, he became symptomatic and peripheral blood cells were almost entirely composed of glycosylphosphatidylinositol-anchored proteins deficient cells. This case suggests that high-dose CY may not exert a significant effect on PNH clones in the long term, although it had been effective in allogeneic BMT. In view of the possible autoimmune basis, it seems to be necessary to include other immunosuppressive therapy including ALG in addition to CY.