Dynamic prognostic value of the revised international prognostic scoring system following pretransplant hypomethylating treatment in myelodysplastic syndrome.

This study aimed to analyze the use of the revised International Prognostic Scoring System (IPSS-R) assessed after hypomethylating treatment (HMT) for patients with myelodysplastic syndrome (MDS) undergoing an allogeneic stem cell transplantation (SCT). Among 115 patients who received pre-SCT HMT, comparison analysis of the prognostic values between the IPSS-R at the time of HMT (IPSS-R@HMT) and at the time of SCT after HMT (IPSS-R@SCT) showed a significantly higher predictive power for overall survival (OS) of the latter. Alteration in IPSS-R risk occurred in 60%, while the patients with 'down-staged' IPSS-R@SCT showed better OS compared with those with 'unchanged' or 'up-staged' risk. On multivariate analysis in all 201 patients, IPSS-R@SCT, monosomal karyotype, treatment failure to pre-SCT treatment, and high hematopoietic cell transplantation-comorbidity index were independently associated with OS. Constructed using these factors, the MDS Transplantation Prognostic Scoring System (MTPSS) identified four risk groups with 4-year OS of 76.4% in low, 61.4% in intermediate-1 and 21.9% in intermediate-2 risk groups, whereas all in the high risk group died within 2 years after SCT (P<0.001). Our study emphasizes the need for further studies aiming to evaluate a transplantation prognostic model such as the MTPSS to make appropriate decisions for transplantation in MDS.

Comparable outcomes between younger (⩽40 years) and older (>40 years) adult patients with severe aplastic anemia after HLA-matched sibling stem cell transplantation using fludarabine-based conditioning.

Allogeneic stem cell transplantation from HLA-matched siblings (MSD-SCT) for elderly patients with severe aplastic anemia (SAA) is not a widely accepted first-line treatment. Recently, fludarabine, lower-dose cyclophosphamide and antithymocyte globulin conditioning (Flu/lower-dose Cy/ATG) with lower toxicities has been investigated. To determine whether this regimen can overcome the negative effects of age, we analyzed 117 adult patients with SAA who received MSD-SCT using Flu/lower-dose Cy/ATG, and compared outcomes between 63 younger age group (YAG; ⩽40 years) and 54 older age group (OAG; >40 years) patients. No primary graft failure was observed. Neutrophil engraftment was significantly faster in the YAG compared with the OAG (12 vs 13 days; P=0.04). The incidences of acute grade II-IV (9.5% vs 9.3% at day 100; P=0.42) and chronic GVHD (8.1% vs 9.5% at 5 years; P=0.80), secondary graft failure (20.8% vs 7.9% at 5 years; P=0.11) and transplant-related mortality (5.4% and 11.1% at 5 years; P=0.91) were not significantly different between the YAG and OAG. In addition, failure-free (73.7% vs 81.0% at 5 years; P=0.73) and overall survival rates (93.7% vs 88.9% at 5 years; P=0.20) were comparable. Our results suggest that MSD-SCT using Flu/lower-dose Cy/ATG may be a feasible first-line treatment even in older patients with SAA.

Impact of pretransplant red cell transfusion on outcome after allogeneic stem cell transplantation in adult patients with severe aplastic anemia.

The aim of this study was to evaluate the impact of pretransplant transfusion of packed red cells (PRCs) on outcome after allogeneic stem cell transplantation (SCT) in severe aplastic anemia (SAA). A total of 221 adult SAA patients receiving allogeneic SCT were analyzed. The patients were divided into two groups according to the amount of pretransplant transfusion before SCT: the low transfusion group (⩽32 PRC units, n=164) and the high transfusion group (>32 PRC units, n=57). The incidence of engraftment failure was not different between the two groups. The incidence of acute GvHD (grades II-IV) was higher in the high transfusion group than in the low transfusion group (P=0.04), and the incidences of chronic extensive GVHD were not significantly different (P=0.136). The high transfusion group had higher 5-year transplant-related mortality (TRM) (24.8% vs 6.8%, P<0.001) and lower overall survival (OS) (72.3% vs 91.9%, P<0.001) than those in the low transfusion group. Multivariate analysis revealed that the high transfusion group and unrelated donor type were independent prognostic factors affecting OS. These results indicate that a history of higher pretransplant transfusion of PRCs was associated with increased TRM and decreased OS, suggesting that iron overload had a negative impact on outcome after SCT in SAA.

MyD88 in donor bone marrow cells is critical for protection from acute intestinal graft-vs.-host disease.

To understand the role of myeloid differentiation factor 88 (MyD88) expressed by donor bone marrow (BM) in the pathophysiology of graft-vs.-host disease (GVHD), we investigated the effects of transplantation of MyD88-deficient T cell-depleted BM (MyD88KO TCD-BM) on the severity of GVHD. Transplantation with MyD88KO TCD-BM aggravated GVHD; serious gut damage was evident, with high infiltration of T cells into the intestines of recipients and markedly reduced expansion of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). MDSCs from MyD88KO mice were defective in inducing donor T-cell apoptosis and inhibiting T-cell proliferation. Supplementation of transplanted mice with MDSCs from wild-type mice, but not MyD88KO mice, attenuated GVHD severity with reduced intestinal T-cell infiltration in MyD88KO TCD-BM recipients. Pretreatment of BM donors with lipopolysaccharide to increase MDSC levels and MyD88 transcription in the TCD-BM transplant alleviated GVHD severity and intestinal T-cell infiltration. The T cell/MDSC ratios were correlated with intestinal GVHD severity in both animal models and human patients. This study indicates that MyD88-dependent MDSC expansion from donor BM is critical for protection against fatal intestinal GVHD.

Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation.

Emerging molecular studies have identified a subgroup of patients with unfavorable core-binding factor-positive (CBF)-AML who should be treated by intensified post-remission treatments. We analyzed 264 adults with CBF-AML from 2002 to 2011, and focused on 206 patients who achieved CR after standard '3+7' induction chemotherapy. Patients who achieved CR with an available donor were treated with allogeneic hematopoietic SCT (allo-HSCT, n=115) and the rest were treated with autologous (auto) HSCT (n=72) or chemotherapy alone (n=19). OS was not significantly different between CBFß/MYH11 (n=62) and RUNX1/RUNX1T1 (n=144), and auto-HSCT showed favorable OS compared with allo-HSCT or chemotherapy alone. Cytogenetic analysis identified that inv(16) without trisomy had a favorable OS and t(8;21) with additional chromosomes had an unfavorable OS, but multivariate analysis revealed those were NS. Patients with c-kit mutation showed inferior OS. For transplanted patients, residual post-transplant CBF-minimal residual disease quantitative PCR with higher WT1 expression at D+60 showed the worst OS with a higher incidence of relapse. Conclusively, we found that unfavorable CBF-AML can be defined with risk stratification using cytogenetic and molecular studies, and a careful risk-adapted treatment approach using frontline transplantation with novel therapies should be evaluated for this particular risk subgroup.

PBSC vs BM grafts with myeloablative conditioning for unrelated donor transplantation in adults with high-risk ALL.

Few studies are available that compare PBSC and BM from unrelated donors, especially in adult high-risk ALL. To determine which graft source is superior in adult high-risk ALL, we analyzed the long-term outcomes of 106 consecutive transplants from 8/8-matched or 7/8-matched unrelated donors (38 PBSC vs 68 BM). All patients received a uniform strategy of pre-transplant therapy, myeloablative conditioning and GVHD prophylaxis. At 5 years, PBSC transplants showed higher incidence of chronic GVHD than did BM transplants (74.3% vs 46.7%, P=0.001). PBSC transplants showed outcomes comparable to those of BM transplants for relapse (23.7% vs 28.1%), non-relapse mortality (18.4% vs 25.0%), disease-free survival (57.9% vs 46.9%) and OS (57.9% vs 50.0%). In a separate comparison of outcomes between the two graft sources according to the presence of a Ph chromosome, no significant advantage of PBSC over BM was found in both subgroups of patients. Our data suggest that the outcomes of unrelated donor transplantation are similar between PBSC and BM in adult high-risk ALL. Whether PBSC should be the preferred graft source for a specific subgroup of adult ALL needs to be further investigated.

Experimental demonstration of energy-chirp control in relativistic electron bunches using a corrugated pipe.

The first experimental study is presented of a corrugated wall device that uses wakefields to remove a linear energy correlation in a relativistic electron beam (a "dechirper"). Time-resolved measurements of both longitudinal and transverse wakefields of the device are presented and compared with simulations. This study demonstrates the feasibility to employ a dechirper for precise control of the beam phase space in the next generation of free-electron-lasers.

Experiences of t-PA use in moderate-to-severe hepatic veno-occlusive disease after hematopoietic SCT: is it still reasonable to use t-PA?

Hepatic veno-occlusive disease (VOD) remains one of the most severe complications of hematopoietic SCT (HSCT). Anticoagulation and thrombolytic therapies using tissue-plasminogen activator (t-PA) have been used, but are reported to be ineffective and are associated with significant bleeding complications. We analyzed 56 moderate-to-severe post HSCT hepatic VOD cases treated with t-PA. We analyzed clinical outcomes according to the maximal daily dose of t-PA (t-PAmax) and the severity of VOD. Patients were stratified by t-PAmax10 mg (n=37) vs t-PAmax>10 mg (n=19). A higher t-PAmax was associated with increased mortality. Bleeding complications were more likely at higher t-PAmax in both moderate and severe VOD (P=0.036, 0.063), especially if patients had concomitant use of anticoagulants (36.4% vs 13.3%). In moderate VOD, the response rate was 86.4% for t-PAmax10 mg/day and 80% for t-PAmax>10 mg compared with 33.3% and 7.1%, respectively, for severe VOD (P=0.106). The 5-year OS in moderate and severe VOD was 49% and 7%, respectively, and it was 32% for t-PAmax10 mg and 18% for t-PAmax>10 mg. Our data demonstrate that lower bleeding complications and bleeding-related deaths may result from strict limitations on the t-PAmax without concomitant use of anticoagulation therapy. However, the overall response and survival outcomes should be re-evaluated by a well-validated study in the future.

Infectious complications following allogeneic stem cell transplantation: reduced-intensity vs. myeloablative conditioning regimens.

BACKGROUND: In allogeneic stem cell transplantation (allo-SCT), reduced-intensity conditioning (RIC) is known for producing less regimen-related toxicity. However, whether or not RIC reduces the risk for infection and infection-related mortality (IRM) remains controversial. METHODS: We retrospectively analyzed infectious episodes and IRMs after allo-SCTs by time period and by the intensity of the conditioning regimen (RIC [n = 81] vs. myeloablative conditioning, MAC [n = 150]). RESULTS: The cumulative incidence of any kind of infection was lower in the RIC group through the entire period (72% vs. 87%; P = 0.007). The onset of infections was deferred in the RIC group as compared with the MAC group (P = 0.012). Bacteremia occurred less frequently in the RIC group through the entire period (5% vs. 14%; P = 0.044). However, the incidences of cytomegalovirus reactivation and disease, herpes zoster, virus-associated hemorrhagic cystitis, and invasive fungal infection were not different between the two groups. Furthermore, there was no difference in relapse-free survival and IRM between the two conditioning regimens. CONCLUSION: Careful monitoring and appropriate preventive/therapeutic strategies for infectious complications, comparable to those for allo-SCT recipients with MAC, should also be applied to those with RIC, especially after engraftment.

Risk and prognostic factors for acute GVHD based on NIH consensus criteria.

To investigate the risk factors for acute GVHD (aGVHD), based on NIH consensus criteria (NCC), we evaluated 775 patients who underwent allogeneic transplantation. Of them, 346 patients developed aGVHD by NCC, in whom we also analyzed factors affecting aGVHD-specific survival. The cumulative incidence of aGVHD was 44.7%, consisting of classic aGVHD (n=320) and late-onset (n=26). Multivariate analyses revealed that younger age (P=0.015), unrelated donors (P=0.004) and acute leukemia compared with other hematologic malignancies (P=0.005) were significant risk factors for aGVHD, whereas PBSCs showed no association (P=0.720). Multivariate analyses, with only aGVHD patients, revealed that late-onset aGVHD had superior aGVHD-specific survival to classic aGVHD (P=0.044), and identified the association of visceral organ involvement (P=0.002), severity of aGVHD at onset (P=0.035) and advanced disease status (P<0.001) with inferior aGVHD-specific survival. In conclusion, this study demonstrates the risk and prognostic factors for aGVHD by NCC with some differences with the previous reports that were based on old criteria. The difference in the risk factors according to different criteria will give insights about the pathophysiology of GVHD. The better prognosis of late-onset aGVHD than of classic aGVHD raises the necessity for prospective trials with a large cohort focusing on the onset time.

Matched-pair analysis to compare the outcomes of a second salvage auto-SCT to systemic chemotherapy alone in patients with multiple myeloma who relapsed after front-line auto-SCT.

The aims of this study were to investigate the outcomes of second salvage auto-SCT and to identify the impacts of a second auto-SCT compared with systemic chemotherapy alone on disease outcome. Data from 48 patients who underwent second auto-SCT were matched to 144 patients (1:3) who received systemic chemotherapy alone from the Korean Myeloma Registry. Groups were matched for nine potential prognostic factors and compared for treatment outcomes. The median age of matching-pairs at relapse was 55.5 years. A total of 156 patients (81%) received vincristine, doxorubicin and dexamethasone induction therapy before the first auto-SCT. Thirty-five patients (73%) in the second auto-SCT group received novel agent-based therapies before the second auto-SCT, and similar proportion in both groups received novel therapies after relapse of front-line auto-SCT. With a median follow-up of 55.3 months, patients who underwent a second auto-SCT had significantly better median OS (55.5 vs 25.4 months, P=0.035). In multivariate analysis for OS, <18 months time to progression after first auto-SCT, International Staging System III and salvage chemotherapy alone were independent predictors for worse OS. The outcomes of second auto-SCT appear to be superior to those of systemic chemotherapy alone. A randomized trial comparing both treatment strategies is required.

Survival benefits with transplantation in secondary AML evolving from myelodysplastic syndrome with hypomethylating treatment failure.

The prognosis for patients with myelodysplastic syndrome with hypomethylating treatment failure (MDS-HTF) has been known to be poor. However, the clinical outcomes and optimal treatment options for secondary AML evolving from MDS-HTF (sAML/MDS-HTF) are not well known. This retrospective analysis was conducted to evaluate the clinical outcomes and influences of treatment options on survival in 46 consecutive patients with sAML/MDS-HTF. The median OS rates were 1.4 months in the best supportive care group (n=15) and 9.4 months in the active treatment group (n=31). One-year OS rates were 13.3% and 36.8%, respectively (P=0.001). Active treatment (P<0.001), lower BM blast (<33%) at sAML (P=0.007), non-poor NCCN (National Cancer Comprehensive Network) cytogenetics (P=0.001) and good performance status (ECOG (Eastern Cooperative Oncology Group) 1) (P=0.024) were significant predictors affecting favorable OS in a multivariate analysis. Of the active treatment options, allo-SCT with prior chemotherapy (CTx) showed better OS compared with CTx only or SCT without CTx (P=0.019). Our analyses suggest that active treatment, particularly SCT following CTx, should be considered in patients with sAML/MDS-HTF if the patient is medically fit.

Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia.

We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinib-based chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n=33), late molecular responders (LMRs, n=35), intermediate molecular responders (IMRs, n=9) and poor molecular responders (PMRs, n=18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph-positive ALL transplants at a high risk of relapse.

Immunoglobulin D multiple myeloma: response to therapy, survival, and prognostic factors in 75 patients.

BACKGROUND: To analyze the clinical features, outcomes including efficacy of treatment, and prognostic factors of patients with immunoglobulin D multiple myeloma (IgD MM). DESIGN AND METHODS: Seventy-five patients diagnosed with IgD MM were selected from the Korean Myeloma Registry database (www.myeloma.or.kr). RESULTS: Median age was 57 years and the main presenting features were bone pain (77%). Renal function impairment and hypercalcemia were present in 40 (53%) and 20 (27%) patients. Sixty-seven patients (89%) had lambda light chains. Forty-eight patients (64%) were of stage III by International Staging System. Twenty-six patients (53%) had chromosomal abnormalities mostly by conventional cytogenetics. Thirty-nine patients (54%) were treated with vincristine, adriamycin, and dexamethasone chemotherapy; the overall response rate (ORR) of 56%. Sixteen patients (22%) received first-line chemotherapy including new drugs (bortezomib or thalidomide), with an ORR of 81%. At a median follow-up time of 28.6 months, median overall survival (OS) was 18.5 months. Age, extramedullary plasmacytoma, del(13) or hypoploidy, serum ß(2) microglobulin level, and platelet count were significant prognostic factors for OS. CONCLUSIONS: IgD MM is an aggressive disease that is usually detected at an advanced stage. Despite a positive initial response, survival after relapse was dismal. Intensive treatment strategies before and following stem cell transplantation may improve outcomes in younger patients.

Donor-specific differences in long-term outcomes of myeloablative transplantation in adults with Philadelphia-negative acute lymphoblastic leukemia.

We analyzed long-term outcomes of myeloablative stem cell transplantation (SCT) in 292 adults with Philadelphia (Ph)-negative acute lymphoblastic leukemia (ALL). Donors were related (RD; n=132), unrelated (URD; n=68; 30 well-matched (WM), 19 partially matched (PM), 19 mismatched (MM)) and autologous (AUTO; n=92). After a median follow-up of 85 months, the risk of relapse was higher for AUTO-SCT than for RD-SCT (P<0.001). MM-URD-SCT yielded higher risk of non-relapse mortality than RD-SCT (P=0.010). As a result, disease-free survival (DFS) at 5 years was inferior using AUTO (46.1%; P=0.010) or MM-URD (26.3%; P=0.036), whereas DFS from other donor sources was approximately equivalent (53.5% for RD, 63.3% for WM-URD and 57.0% for PM-URD). Other factors associated with poorer DFS included SCT beyond first complete remission (CR), older age and adverse cytogenetics. In a pairwise comparison of outcomes between RD-SCT and AUTO-SCT for patients in first CR, the inferiority of AUTO-SCT was observed, particularly in high-risk patients. Conversely, in standard-risk patients, AUTO-SCT yielded comparable outcomes to RD-SCT. SCT using RD, WM-URD or PM-URD may be considered the best donor sources for adult high-risk Ph-negative ALL.

Hematopoietic SCT activity in Asia: a report from the Asia-Pacific Blood and Marrow Transplantation Group.

The hematopoietic SCT (HSCT) activity in nine Asian countries/regions was surveyed to overview the current situation. Data of 58 113 HSCTs (allogeneic: 63% vs autologous: 37%) performed between 1986 and 2006 by 432 transplant teams were collected. The number of HSCTs has been increasing in the past two decades in most countries/regions. The increase in allogeneic HSCTs is greater than in autologous HSCTs. The proportion of unrelated donors among allogeneic HSCTs in 2006 varied widely from <1% (Iran and Vietnam) to 62% (Japan). The use of each stem cell source, that is, BM, PBSC, cord blood and others (including co-infusion of BM and PBSC), also varied widely (36, 58, 0.1 and 6% in HSCT from related donors, respectively, and 53, 11, 35 and 1% in HSCT from unrelated donors, respectively). HSCTs have been continuously increasing for all indications except for chronic myelogenous leukemia and solid tumors. Hemoglobinopathy is a common indication among non-malignant diseases in many Asian countries/regions except for China, Japan and Korea. This survey clearly shows the recent progress of HSCTs in Asia and also some differences in donor and stem cell selection and disease application among countries/regions.

HLA-matched sibling transplantation with BM and CD34(+)-purified PBSCs in adult patients with high-risk severe aplastic anemia to overcome graft rejection without an increase in GVHD.

The transplantation of a large number of stem cells can overcome graft rejection but with the increased risk of GVHD. In this study, we analyzed the outcome of 32 adult patients with acquired severe aplastic anemia (SAA) who were at a high risk for graft rejection, including multiple transfusions (median 147 units, range 20-680) and long disease duration (median 67 months, range 3-347), and who had received both BM and CD34(+)-purified PBSCs from an HLA-matched sibling donor to reduce graft rejection. T cells in PBSCs were depleted using a magnetic-activated cell sorting method (CliniMACS system). Conditioning regimens consisted largely of CY and antithymocyte globulin (ATG) with fludarabine (FLU) or procarbazine (PCB). With a median follow-up of 89 months, the 8-year probability of survival was 87.5%. Neutrophils and plts promptly recovered, and none of the patients developed graft failure. The cumulative incidences of acute and chronic GVHD were 9.4 and 18.0%, respectively. Sustained engraftment and excellent survival without an apparent increase in the rate of GVHD in high-risk patients using the current approach showed that high-dose SCT with both BM and CD34(+)-purified PBSCs may yield better outcomes in heavily transfused and/or allo-immunized patients with SAA.