Autologous Peripheral Blood Stem Cell Transplantation Research Articles

Effect of autologous peripheral blood stem cell transplantation in 13 patients with AML1/ETO (+) acute myeloid leukemia

This study was purposed to analyse the clinical efficacy of autologous peripheral blood stem cell transplantation (APBSCT) in 13 Patients with AML1/ETO (+) acute myeloid leukemia, and to evaluate the role of quantitative detecting the AML1/ETO gene in treatment of AML patients. A total of 13 patients with AML1/ETO (+) acute myeloid leukemia treated with APBSCT from August 2007 to November 2012 were retrospectively analyzed. The median follow-up time was 26 (7.8-75.8)months. Kaplan-Meier analysis was used to calculate the overall survival (OS), leukemia-free survival (LFS) and cumulative relapse rate (RR). Log rank method was used to perform univariate analysis. The results showed that the 3 year-OS, LFS, and RR were (70.5 ± 15.3)%, (51.3 ± 16.7)%, 48.7%, respectively. The AML1/ETO expression level in 4 cases out of 5 relapsed patients was quantified during and after therapy, and the result showed that AML1/ETO expression level significantly increased before morphological relapse. In univariate analysis, there was no statistic significance in terms of age, sex, count of white blood cells at diagnosis, interval from diagnosis to transplantation, count of MNC for infusion. It is concluded that APBSCT has good therapeutic effect on AML1/ETO (+) AML, and regular quantitative monitoring of AML1/ETO expression level can predict early recurrence. Allogeneic hematopoietic stem cell transplantation after relapse may contribute to obtain opportunity to achieve the long-term survival for intermediate and high risk patients.

Safety and efficacy of high-dose cyclophosphamide, etoposide and ranimustine regimen followed by autologous peripheral blood stem cell transplant for patients with diffuse large B-cell lymphoma

We retrospectively evaluated the safety and efficacy of high-dose chemotherapy consisting of cyclophosphamide, etoposide and ranimustine (CEM) with autologous peripheral blood stem cell transplant (PBSCT) in 55 adult patients with relapsed or high-risk de novo diffuse large B-cell lymphoma (DLBCL) or DLBCL associated with follicular lymphoma. This included 36 patients in the upfront setting in their first complete remission. The median follow-up of 42 patients surviving at the time of the analysis was 52 months (range 1–159). Relapse or disease progression after PBSCT was a frequent cause of death, but no therapy-related mortality associated with PBSCT was observed. The 5-year overall survival and progression-free survival were 70.6% (95% confidence interval [CI], 54.0–82.1) and 57.0% (95% CI, 39.5–71.2), respectively. Chronic renal impairment, therapy-related myelodysplastic syndrome and prostate cancer were the major late complications. The CEM regimen is a tolerable, effective conditioning regimen for autologous PBSCT for DLBCL, with no therapy-related mortality observed.

Lenalidomide consolidation and maintenance therapy after autologous stem cell transplant for multiple myeloma induces persistent changes in T-cell homeostasis

Whether the efficacy of lenalidomide in the treatment of multiple myeloma (MM) is due to direct tumor toxicity only or to additional immunomodulatory effects is unclear. We studied the effect of lenalidomide treatment on T-cell immune reconstitution in patients with MM who had undergone autologous peripheral blood stem cell transplant (ASCT). Twenty-nine newly diagnosed patients with MM received induction therapy followed by high-dose melphalan and ASCT. After ASCT, 11 patients received lenalidomide consolidation therapy for 2 months followed by maintenance therapy until disease progression. The remaining 18 patients received no treatment. Serial analysis of thymic output, as given by numbers of T-cell receptor excision circles (sjTRECs), and T-cell phenotyping was performed until 18 months post-ASCT. Lenalidomide impaired long-term thymic T-cell reconstitution, decreased CD4 + and CD8 + CD45RA + CCR7 − effector-terminal T-cell absolute counts and increased CD4 + CD25 + CD127 − /low regulatory T-cells. Lenalidomide consolidation and long-term maintenance therapy, administered post-ASCT, may have a potentially negative impact on immune surveillance.

Novel and rapid enumeration method of peripheral blood stem cells using automated hematology analyzer

The number of infused CD34(+) cells is crucial to the success of peripheral blood stem cell transplantation (PBSCT). Here, we present, for the first time, a new method of enumerating hematopoietic progenitor cells (HPCs) for PBSCT. This novel method is based on hemolysis and chemical staining, followed by flow cytometry-based optical detection, conducted using an automated hematology analyzer (XN series, Sysmex). CD34(+) cells and HPCs were compared in 76 granulocyte colony-stimulating factor (G-CSF)-mobilized blood or apheresis samples taken from healthy donors (n=18) or patients undergoing autologous PBSCT (n=6). There was a strong correlation between the numbers of HPCs and CD34(+) cells (R(2) =0.958). The expected total number of HPCs in the final products, which was estimated from HPCs in pre-apheresis PB or mid-apheresis products, also correlated well with the total number of CD34(+) cells in the final products. The change in HPCs in PB closely resembled that of CD34(+) cells during mobilization. Experiments using immunomagnetic beads suggested that the majority of CD34(+) cells existed in HPCs, and vice versa. Hematopoietic progenitor cells may serve as surrogates for CD34(+) cells in PBSCT. However, further investigations are required to verify this.

Clinical efficacy and prognosis with advanced Wilms' tumor in children

Objective To analyze the clinical data of 12 children with advanced Wlims' tumor in children from Feb. 2009 to Jun. 2012. All cases were diagnosed by pathology and to analysis the clinic efficacy and treatment experience were analyzed. Methods Of 12 patients, 10 cases were male and 2 cases were female. The medium age of 12 patients was 2.54 years old(9 months-15 years old). According to pathological stage and clinical stage of The Natio-nal Wilms' Tumor Study Group(NWTSG), 5 cases belonged to stage Ⅲ, and 7 cases stage Ⅳ. Six cases were well-diffe-rentiated tissue type, and 6 cases were poorly differentiated tissue type according to NWTSG. In all patients, different ways of chemotherapy and radiotherapy were selected according to clinical stage and tissue type differentiation. If a patient had repeated recurrence after common surgery and chemotherapy, would treated by autologous peripheral blood stem cell transplantation(APBSCT). Statistic analysis was used to analyze the clinical characters and efficacy and prognosis for 12 patients. Results 1. Initial symptoms: in 12 cases, 8 cases presented abdominal mass(66.6%), 2 cases with abdominal pain and fever(12.7%), and 2 cases with hematuria(12.7%).2. Eleven cases followed up to Jan. 2013, the medium time was 31.5 months(8-131 months). Of 12 cases, 1 case give up therapy and follow-up and 11 cases were followed up. Of those 11 cases followed-up, 4 cases had complete remission(CR), and 1 case had remission in part(PR), the conditions of 5 cases were progressively worse, 1 case replapsed, and 4 patients died. Total survival rate was 63.63%(7/11 cases), and mortality was 36.37%(4/11 cases), and free survival rate was 36.37%(4/11 cases), of that, 1 patient of stage Ⅳ, relapsed 3 times after common radiotherapy and chemotherapy, achieved complete remission after high dose chemotherapy(Melphalan+Carboplatin+Etoposide, CEM) and APBSCT. The estimated 3-year-survival rate was 51.4%. Conclusions The prognosis of advanced Wilms' tumor is poor, and the mortality is still high. High dose chemotherapy with APBSCT may be a valuable method for advanced cases. Key words: Wilms'tumor; Chemotherapy; Autologous peripheral blood stem cell; Transplantation; Child

Early application of percutaneous vertebroplasty reduces pain without affecting peripheral blood stem cell (PBSC) collection and transplant in newly diagnosed multiple myeloma (MM) patients

Vertebral fractures occur in over 60% of newly diagnosed multiple myeloma (MM) patients and can cause pain, disability and poor quality of life. Antimyeloma therapy can lead to symptoms improvement, but these effects can take time to be perceived. Application of radiotherapy prior to peripheral blood stem cells (PBSC) mobilisation can impair stem cell collection. Percutaneous vertebroplasty has been proposed as a suitable option to rapidly relieve bone pain from vertebral fractures in MM patients, but, little is known about the effects of this procedure on subsequent PBSC mobilisation, collection and transplant. Eighteen patients (10M/8F, median age 64.5 years) with untreated MM and painful vertebral lesions underwent vertebroplasty prior to proceed to the planned transplant program at our Institution. Forty-one procedures were performed at C2-L5 levels, eight patients were treated at ≥2 levels. Ninety-five per cent of the cases obtained a complete or optimal pain control. All the patients successfully mobilised PBSC (median CD34+ cells = 10.8 × 10(6) /kg) and underwent autologous PBSC transplant; both polymorphonucleates and platelets recovery averaged 11 days. Our data seem to suggest that percutaneous vertebroplasty is useful in newly diagnosed MM patients with painful vertebral fractures as it allows rapid and durable achievement of pain control, without interfering with further treatment.

Curative efficacy for nasal type extranodal NK/T-cell lymphoma by autologous peripheral blood stem cell transplantation after sequencing chemotherapy and radiotherapy

The purpose of this study was to explore the curative efficacy for nasal type extranodal NK/T-cell lymphoma by autologous peripheral blood stem cell transplantation (APBSCT) after sequencing chemotherapy and radiotherapy. A total 65 cases diagnosed as nasal type extranodal NK/T-cell lymphoma by pathology and immuno-histochemistry were treated with chemotherapy and radiotherapy in our hospital from January of 2000 to December of 2009. They were divided into observation group (34 cases) and transplantation group (31 cases). The 34 cases of observation group were ceased from treatment, the 31 cases in transplantation group received APBSCT after conditioning regimen with TBI combined VEMAC. Autologous peripheral blood stem cells were mobilized with chemotherapy combined rhG-CSF. The patients were followed up for 3-5 years. The results showed that some side-effects such as bone marrow suppression and injure of oral cavity mucosa were found in patients after sequencing chemotherapy and radiotherapy. All patients in transplantation group obtained hematopoietic reconstruction, and there were no any special side effect such as VOD. In transplantation group, the median time of ANC ≥ 0.5×10(9)/L was 14 (11-17) days, median time of WBC count ≥ 4.0×10(9)/L was 17 (16-20) days, median time of Plt count ≥ 50×10(8)/L were 25 (23-28) days. After chemotherapy and radiotherapy, effective rate of treatment was 91.2% in observation group, whereas was 90.3% in transplantation group, there were no obvious difference between two groups (P > 0.05). After following up about 1 year, effective rate of treatment was 76.5% in observation group, whereas was 96.8% in transplantation group, there were obvious difference between two groups (P < 0.05). After following up about 3 years and 5 years the disease-free survival (DFS) was 61.3%, 43.5% and 87.1%, 81.5% in observation group and transplantation group, there was significant difference between two groups (P < 0.05). It is concluded that treatment with APBSCT after sequencing chemotherapy and radiotherapy for nasal type extranodal NK/T-cell lymphoma may increase DFS efficiently.

Prognostic Significance Of S-Phase Kinase-Associated Protein 2 (Skp2) In DLBCL Patients Treated With Upfront Autologous Peripheral Blood Stem Cell Transplantation

We have reported that S-phase kinase-associated protein 2 (Skp2) expression in tumor cells is an unfavorable prognostic factor in diffuse large B cell lymphoma (DLBCL) with CHOP-R. Therapeutic strategies other than CHOP-R should be needed for DLBCL patients exhibiting a high Skp2 expression at the time of diagnosis. High dose chemotherapy followed by autologous peripheral blood stem cell transplantation (APBSCT) is mainly adapted for DLBCL patients in high and high intermediate risk groups in IPI. However, the definite beneficial evidence for APBSCT in DLBCL remains unclear.In the present study, we investigated the clinical significance of Skp2 expression in the patients with DLBCL treated with CHOP-R plus high-dose chemotherapy followed by APBSCT. We retrospectively analyzed the outcomes of 93 patients (age range: 14-65). The patients were newly diagnosed as having DLBCL from 2002 to 2012, and were treated with either CHOP-R plus upfront APBSCT (n=31) or CHOP-R (n=62) in the19 hospitals in Kyushu, Japan. All patients had high and high intermediate risk in IPI. All biopsy specimens were immunohistopathologically reconfirmed by one pathologist with expertise before entering into this study. The median follow-up time was 2.3 y. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional Hazard model with inverse probability of treatment weight (IPTW).In background of the patients, age was younger in transplant group (mean age 52) than in non-transplant group (mean age 59). CR rate was higher in non-transplant (30.7%) than in transplant (12.9%). Sex, stage, PS, LDH extranodal lesion and IPI showed no difference in both group.Overall survival (OS) for 3 years were 77.0% and 59% in transplant group and in non-transplant group (P=0.077), respectively. Progression-free survival (PFS) for 3 years, 65.7% and 53.2% in transplant and non-transplant group (P=0.233), respectively. In Skp2 high expression (positive rate >40%) group (n=37), 3y-OS was 44.9% and 16.4% in transplant (n=13) and non-transplant (n=24) group (P=0.065), respectively. 3y-PFS was 40.3% and 7.5% in transplant and non-transplant (P=0.032), respectively (Fig A). However, in low Skp2 expression group (n=56), OS was 100% and 92.7% (P=0.254), PFS was 83.6% and 82.6% (P=0.945)(Fig B)in transplant (n=18) and non-transplant (n=38) group, respectively. In propensity score analysis using center effect, age, extranodal lesion, IPI and CR rate as logistic regression model, transplant group showed the excellent benefit in OS ( OR= 0.469, 95%CI =0.266-0.825, P=0.009) and PFS (OR=0.456, 95%CI=0.255-0.815, P=0.008) in Skp2 high expression group (n=37).P value for transplant x Skp2 interaction was P=0.643 in OS and P=0.020 in PFS.In conclusion, Skp2 was a good biomarker for indication of ABSCT for high risk DLBCL patients. In low expression of Skp2, patients should not be treated with high dose chemotherapy followed by APBSCT, even though in patients with high risk in IPI. However, ABSCT have some advantage in DLBCL patients with high expression of Skp2. Disclosures:No relevant conflicts of interest to declare.

Recovery Of Natural Killer Cells and Monocyte Subsets Following Autologous Peripheral Blood Stem Cell Transplantation Predicts Longer Progression Free Survival Among Multiple Myeloma Patients

Prior research has shown that a timely immune recovery following peripheral blood stem cell transplantation (PBSCT) may improve progression free and overall survival for lymphoma and leukemia patients (pts). However, this has not been studied in multiple myeloma (MM) pts. We conducted an exploratory investigation of the extent to which the recovery of Natural Killer (NK) cell and monocyte (Mo) subsets predicted progression free survival (PFS) among MM pts following autologous PBSCT. Patients (N = 37) were treated with 200mg/m2 of melphalan, followed by infusion of >2 x106 CD34 cells/kg, and were followed prospectively for 3 to 36 months. Immunophenotyping and multicolor flow cytometry were used to identify NK and Mo subsets at Day 100 post-PBSCT. Disease progression or relapse was defined using IMWG criteria. Cox proportional hazard regression models were used to examine relationships between cell subpopulation counts and time from PBSCT to MM progression. All models were adjusted for ISS stage and risk (high, defined as plasma cell leukemia; loss of p53, myc rearrangement, t(14;16), t(14:20) by FISH; minus 13 by cytogenetics; versus standard) at diagnosis, and hazard ratios were standardized to correspond to a 2 standard deviation difference in the logarithm of NK or Mo cell counts. Compared to a healthy reference sample, MM patients showed good recovery of all Mo subsets with normal counts by Day 100, but CD56+CD3- NK cell numbers remained low, with the subset of NK cells expressing high CD16 particularly suppressed. During the follow-up period, 25 patients (67.6%) progressed or relapsed. Pts with higher Day 100 CD56+CD16hi NK cell counts had a longer PFS (hazard ratio = .351, p = .033). A similar effect was seen for CD56+CD16lo NK cells (hazard ratio = .321, p = .079). Higher CD14+ Mo counts were also associated with longer PFS (hazard ratio = .230, p = .007). An examination of Mo subpopulations showed that higher numbers of Mo expressing low or no CD16 predicted a longer time to disease progression (hazard ratio = .207, p = .011), but the inflammatory subsets with moderate or high CD16 expression were not significantly associated with PFS. Results suggest that MM patients who have lower NK cell and CD14+ Mo counts may be at risk for a poorer outcome following autologous PBSCT, with these subsets adding prognostic significance above and beyond cytogenetic risk and ISS stage. Subpopulations with greater regulatory and less inflammatory function had the most salient effects. These NK cell and Mo subsets may inhibit residual MM growth and progression and could serve as novel markers of the clinical outcome following PBSCT for MM. Disclosures:No relevant conflicts of interest to declare.

Enumeration of Peripheral Blood Hematopoietic Stem Cells Using Automated Hematology Analyzer, Sysmex-XN: A Multicenter Prospective Study

▪ BackgroundA rapid enumeration of CD34+ cells is expected to facilitate a safe and efficient PBSC collection for a successful transplantation. We previously reported a novel enumeration method of hematopoietic progenitor cells (designated as HPC) using an automated hematology analyzer, XN-series model (Sysmex Corporation, Japan), which does not require monoclonal antibody. This method seemed very promising in a pilot study in a single institute (ASH meeting #1922, 2011). Hence, we conducted a multicenter study to confirm the results in a larger number of subjects in various situations. In this study, we used an up-graded analyzer which had been installed with a revised analytical program. This new program employs an automatically-adjusted gating to fit the individual variety, whereas the former used a fixed gating for detecting HPC. We planned to divide the study into 2 parts; the first is to confirm the outcome of the previous single-institute study and to develop a model to predict CD34+ cell counts from HPC, and the second is to validate the model. Here we show the results of the first part of the study. Patients and MethodPB or PBSC samples were taken from G-CSF- and/or chemo-mobilized subjects (25 patients undergoing PBSCT and 25 healthy donors) in 5 institutes. Samples were divided into 2 tubes; one is for in-house assay in which HPC and CD34+ cells were counted in each institute within a few hours without any manipulation, and another was shipped to the central laboratory (SRL, Inc., Japan) where CD34+ cell count was examined. HPC and central labo-assayed CD34+ cell counts were compared with each other and used in a correlation analysis. HPC and in-house CD34+ cells were used in the analysis of kinetics. This study was approved by IRB, and an informed consent was obtained from each participant before apheresis. ResultsFive PBSC samples (2.3%) were estimated to be invalid for HPC assay because of difficulty in identifying HPC, and were excluded from the analysis. There were good correlations between HPC and CD34+ cell counts in all samples (n=211; R2 0.9576, slope 1.0678, Fig.1), in PB (n=87; R2 0.7631, slope 0.8878) and PBSC (n=124; R2 0.9501, slope 1.0689), in autologous PBSCT patients (n=116; R2 0.9759, slope 1.0596) and donors (n=95; R2 0.7914, slope 1.1381). However, HPC and CD34+ cell counts differ more than 3 times around the critical concentrations for making decision in some samples. Concerning their kinetics in PB during mobilization, which was observed in 2 donors and 9 patients, HPC showed a very similar trend as CD34+ cells, and the timing of appearance and increase in PB was almost concordant in most cases (Fig. 2). [Display omitted] [Display omitted] ConclusionsIn this multicenter study, we confirmed not only there was a good correlation between HPC and CD34+ cell counts, but also both HPC and CD34+ cell counts in PB showed a very similar trend during mobilization, as was observed in our previous single-institute study. However, a few samples were estimated as invalid for HPC assay, and there were a few more samples in which HPC and CD34+ cell counts differ significantly. Therefore, it remains to be elucidated how much HPC could be helpful in the clinical setting for determining the optimal timing of collection, for predicting the number of CD34+ cells in the apheresis product, and for determining the optimal blood volume to be apheresed. We are currently underway of the later validation part of this study to evaluate these issues. Disclosures:Tanosaki:Sysmex Corporation: Automated hematology instruments were provided on loan and the cost for CD34+ cell counts were owed to Sysmex Corporation, Kobe, Japan in this study. Other.

Brentuximab vedotin (SGN-35) in Hodgkin lymphoma patients with relapsed after autologous peripheral blood stem-cell transplantation

Background: Approximately 15 to 30% of patients with Hodgkin's lymphoma (HL) do not have a long-term remission with conventional therapy. Autologous peripheral blood stem-cell transplantation (APBSCT) represents a potentially curative treatment for some patients with recurrent or progressive HL after failure of initial combination chemotherapy. Unfortunately, APBSCT is only effective in approximately 50% of such patients. Brentuximab vedotin comprises an anti-CD30 antibody conjugated by a plasma-stable linker to the potential microtubule agent, monomethyl auristatin.

Multidisciplinary Collaborative Therapy for 30 Children with Orbital Rhabdomyosarcoma

To explore clinical experience and propose new ideas for treating children diagnosed with orbital rhabdomyosarcoma (RMS). We retrospectively analyzed the clinical data for30 patients (16 males and 14 females, with a median age of 6.2 years) with primary orbital RMS who were enrolled in the Department of Eye Oncology and Pediatrics of our hospital from November 2004 to December 2012. International Rhabdomyosarcoma Organization Staging Standards indicated that among the 30 patients, 4 cases were in phase II, 20 were in phase III, and 6 were in phase IV. All patients underwent a multidisciplinary collaborative model of comprehensive treatment (surgery, chemotherapy, external radiotherapy, 125I radioactive particle implantation, and autologous peripheral blood stem-cell transplantation). Follow-up was conducted until March 2013, with a median follow-up time of 47.2 months (5 to 95 months), and 7 deaths occurred. The 2-year estimated survival rate reached 86.1%, the ≥3-year estimated survival rate was 77%, and the 5-year estimated survival rate was 70.6%. The multidisciplinary collaborative model can be a safe and effective approach to the comprehensive treatment of children with orbital RMS. It has clinical significance in improving the tumor remission rate.

Advanced neuroblastoma with intracranial metastasis in 14 children

Objective To explore the clinical features and outcome of advanced neuroblastoma(NB) with intracranial metastasis in children. Methods Retrospective review was performed on 14 cases(8 boys, 6 girls) with advanced NB who suffered from intracranial metastasis from Aug.2005 to Feb.2013 in Pediatrics of Beijing Tongren Hospital.The average age was 5.5 years old.Their primary sites of NB, metastatic sites, symptoms, therapy and survival time were analyzed, to investigate the relationship between the treatment of autologous peripheral blood stem cell transplantation(APBSCT) and intracranial metastasis. Results (1) In main clinical features of the children, 10 cases with headache, 10 cases with hyperspasmia, 9 cases with nausea or vomiting, 6 cases with many of the block in head, 6 cases with exophthalmos.(2)In the majority of primary tumors, 11 cases arise in sympathetic nervous system of the abdomen and pelvic cavity, 11 cases of these arising in posterior mediastinum, 1 case arising in cavum nasi.The intracranial metastasis expression of these children with NB were: the brain parenchymal metastasis tumor 11/14 cases, meningeal metastasis 4/14 cases, visible tumor cells in cerebrospinal fluid 2/14 cases, 9 cases with bone marrow metastasis, 12 cases with multiple bone metastasis, 9 cases with multiple skull metastasis, 6 cases with the orbital transfer.(3) Eight cases were treated with APBSCT, including 3 cases of complete remission, partial remission in 2 cases, 3 cases of advanced, 4 cases of focal radiotherapy, 3 cases of 131I-metaiodobenzylguanidine(131I-MIBG) therapy.Intracranial metastasis from time of APBST, the 3 cases of complete remission was 22.0 months, 12.0 months, 4.3 months, respectively; the 2 cases of partial remission was 41.0 months, 36.8 months, respectively; the 3 cases of advanced was 1.2, 2.3, 2.2 months, respectively.The occurrence of intracranial metastasis time was statistically significant(χ2=6.25, P=0.044) after APBSCT in total and partial remission compared with the advanced cases.One case was lost in follow up.(4) The average follow-up time was(30.74±19.67) months and until Feb.2013.Nine cases died(64.3%) who had NB with intracranial metastasis, while 7 cases who took the APBSCT treatment died of intracranial metastasis, and the average time from intracranial metastasis to death was 7.3 months so it was statistically significant(χ2=5.0, P=0.025) in cases with remission NB before transplantation compared with 1.1 months in cases with advanced NB before transplantation; but the average time was not statistically significant(χ2=5.4, P=0.067) compared with the APBSCT patients.The survival time of NB children from tumor onset to death of intracranial metastasis was: the average time was 43.4 months in cases with remission NB before transplantation compared with 15.2 months in cases with advanced NB before transplantation, which had statistical significance(χ2=5.0, P=0.025). Two cases who hadn't APBSCT died of intracranial metastasis, in which the survival time was 60 months, 38 months, respectively.The remaining 3 cases continued to receive treatment, now the survival time was 14 months, 42 months and 13 months.One case was lost in follow up. Conclusions The prognosis is poor in cases of children with advanced NB combined intracranial metastasis.APBSCT should be carried on during remission period, as it could delay the occurrence of intracranial metastases.To prevent the occurrence of intracranial metastasis, various methods of treatment should be combined in NB. Key words: Neuroblastoma; Intracranial metastases; Child

Divergent Effects of Novel Immunomodulatory Agents and Cyclophosphamide on the Risk of Engraftment Syndrome after Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma

Engraftment syndrome (ES) is an increasingly observed and occasionally fatal complication after autologous peripheral blood stem cell transplantation (PBSCT). In this study, we demonstrate that the incidence of ES is significantly increased in patients undergoing autologous PBSCT for multiple myeloma in comparison to patients with non-Hodgkin lymphoma or Hodgkin lymphoma. Multivariate analysis revealed that age > 60 (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.12 to 2.62; P = .013) and transplantation for multiple myeloma (HR, 2.80; 95% CI, 1.60 to 4.90; P = .0003) were associated with an increased risk of this complication. When stratified for myeloma patients only, age > 60 (HR, 1.80; 95% CI, 1.13 to 2.87; P = .013) and prior treatment with both lenalidomide and bortezomib (HR, 1.83; 95% CI, 1.11 to 3.04; P = .0001) were associated with an increased incidence of ES. Conversely, lack of exposure to cyclophosphamide from either chemomobilization or as a component of the pretransplantation therapeutic regimen increased the risk of this complication (HR, 3.05; 95% CI, 1.91 to 4.87; P <.0001). These studies demonstrate that the pretransplantation exposure of multiple myeloma patients to novel immunomodulatory agents and cyclophosphamide significantly affects the subsequent risk of developing ES.

Autologous peripheral blood stem cell transplantation with granulocyte colony-stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission

We retrospectively analyzed the outcomes of 81 patients with non-M3 acute myelogenous leukemia (AML) in first complete remission (CR1) who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (Auto-PBSCT) by the Fukuoka Blood and Marrow Transplantation Group between 1989 and 2005. Cytogenetically, 16 patients were defined as good risk, 56 as intermediate risk, and nine as poor risk, following the Southwest Oncology Group criteria. The pre-transplant conditioning regimen consisted of high-dose busulfan, etoposide, and cytarabine (BEA regimen), combined with priming by granulocyte colony-stimulating factor (G-CSF). Disease-free survival (DFS) and overall survival at 5years were 64.0% (95% CI 52.5-73.4) and 66.4% (95% CI 54.9-75.6) after Auto-PBSCT at a median follow-up time of 103months (range 3-240months), respectively. Two patients died of transplant-related pulmonary complications 6months after Auto-PBSCT without relapse. The 5-year DFS rates of patients in the genetically good-, intermediate-, and poor-risk groups were 80.8, 64.3, and 33.3%, respectively, but there was no significant difference statistically among the risk groups (log-rank p=0.0579). These observations suggest that HDCT supported by Auto-PBSCT with the BEA regimen combined with G-CSF priming is a therapeutic option for postremission therapy of AML in CR1.

Detection of minimal residual disease in patients with multiple myeloma using clonotype-specific PCR primers designed from DNA extracted from archival bone marrow slides

Polymerase chain reaction (PCR)-negative molecular complete remission (mCR) can be induced by stem cell transplantation in some patients with multiple myeloma (MM) and is associated with long-term progression-free survival (PFS). The detection of molecular minimal residual disease (MRD), however, requires fresh or frozen materials for designing clone-specific primers, which are not always readily available. In this study, we used DNA extracted from archival bone marrow (BM) slides for PCR to detect MRD in 50 patients with MM who received various induction therapies and autologous peripheral blood stem cell transplantation (ASCT). Clonotype-specific immunoglobulin (Ig) H PCR primers were prepared for 32 of 50 cases (64%) using BM slides, and for 9 of 14 cases (64%) using fresh BM cells. DNA in peripheral blood stem cell autografts of the 22 patients who achieved at least a partial response after ASCT was subjected to PCR to amplify clonotype-specific rearranged IgH gene sequences. The median PFS of the eight patients with MRD-positive autografts was 18 months, whereas that of 14 patients with MRD-negative autografts was not reached at a median follow-up of 27 months (p = 0.012). Post-ASCT PFS of the four patients who achieved mCR was 100% at a median follow-up of 47 months. These results indicate that archival BM slides can serve as a source of DNA for preparing clonotype-specific primers for MRD monitoring in patients with MM whose cryopreserved myeloma cells are not available for DNA preparation. Our results also suggest that patients with MM who received MRD-negative autografts and achieved mCR have a long PFS.

A comparison between next-generation sequencing and ASO-qPCR for minimal residual disease detection in multiple myeloma.

8601 Background: Although molecular CR in multiple myeloma (MM) can be assessed by allele-specific oligonucleotide (ASO)-PCR, this technique requires preparation of clonotype-specific primers for each individual which is laborious and time-consuming. The usage of the LymphoSIGHT method, a next-generation sequencing (NGS)-based platform, may overcome these challenges and increase sensitivity and specificity. We compared the LymphoSIGHT approach with ASO-qPCR for minimal residual disease (MRD) detection in autografts in the autologous peripheral blood stem cell transplantation (ASCT) setting. Methods: Seventeen Japanese patients with newly diagnosed MM who received various induction regimens prior to ASCT were retrospectively analyzed. All patients had achieved a PR or CR after ASCT. Bone marrow (BM) slides from 13 MM patients and fresh BM cells from 4 MM patients at diagnosis as well as autografts were obtained for DNA extraction. Using universal primer sets, we amplified IGH variable (V), diversity (D), and joining (J) gene segments, IGH-DJ, and IGK from genomic DNA. Amplified products were subjected to deep sequencing using NGS. Reads were analyzed using standardized algorithms for clonotype determination. Myeloma-specific clonotypes were identified for each patient based on their high frequency in BM samples. The presence of the myeloma clonotype was then assessed in follow-up samples. Results: MRD in autografts was detected in 6 of 17 (35%) by ASO-qPCR and 13 of 17 (76%) by NGS. When MRD was assessed by NGS, 6 MRD (+) cases received post-ASCT therapy while 4 MRD (-) cases and 7 MRD (+) cases were followed without post-ASCT therapy. The MRD (-) cases tended to show a better PFS than the MRD (+) cases with post-ASCT therapy (P = 0.26) and those without post-ASCT therapy (P = 0.09) although overall survival rates were comparable among the three groups. There was no difference in PFS between MRD (-) and MRD (+) cases when MRD was assessed by ASO-qPCR (P = 0.6). These studies will be extended in 30 additional MM patients, and results will be presented. Conclusions: MRD-negativity in autografts revealed by NGS may be more closely associated with durable remission of MM than that revealed by ASO-qPCR.

Molecular Monitoring of Minimal Residual Disease in the Peripheral Blood of Patients with Multiple Myeloma

The prognostic relevance of minimal residual disease (MRD) in patients with multiple myeloma is still an open question. In bone marrow, the level of residual myeloma cells is associated with treatment outcome, but the role of clonotypic cells in the peripheral blood (PB) for the prognosis of patients is not identified yet. In this study, we retrospectively analyzed MRD by quantitative real-time IgH-PCR (IgH-qPCR) in the PB of 42 patients undergoing high-dose therapy followed by autologous PB stem cell transplantation as first-line therapy for multiple myeloma. The MRD level of PB samples was in median 40-fold lower than in bone marrow samples, collected on the same day, with a wide intra- and interindividual variation (range, .4- to 4628-fold). The presence or absence of detectable MRD levels in PB did not correlate with the serological remission status. Still, patients with negative PCR results in PB 3 months after high-dose therapy and PB stem cell transplantation had lower International Staging System stage (P = .01), lower levels of β2-microglobulin (P = .02), higher hemoglobin levels (P = .01), and a prolonged event-free (median, 15 versus 4 months; P = .004) and overall (median, 52 versus 17 months; P = .03) survival. Importantly, by sequential monitoring of clonotypic cells in PB, in 19 of 29 patients (66%) with progressive disease, an increase of the 2IgH/β-actin ratio of at least 1 log step could be detected in median 4 months (range, .8 to 13 months) before the relapse was diagnosed on the basis of the European Group for Blood and Marrow Transplantation criteria. These patients with a molecular relapse in PB before a serological relapse had a significantly shorter overall survival than other patients (median, 17 months versus median not reached, P = .02). In conclusion, IgH-qPCR is a sensitive technique for the detection of clonotypic cells in PB, which precede clinical relapse. Future studies are needed to evaluate whether these circulating tumor cells play a role in promoting disease recurrence.

What Is the Role of Stem-Cell Transplantation for Follicular Non-Hodgkin Lymphoma in the Rituximab Era?

Defining the best treatment for follicular lymphoma (FL) is still a challenge, partly because the available treatment options are often associated with prolonged overall survival (OS) as a result of the long natural history of this disease. Many clinical studies have used progression-free survival (PFS) as their end point but suffer from insufficient follow-up or lack of statistical power to assess OS, which is the indisputably best end point. Until the introduction of rituximab, standard chemotherapy (varying from low-dose oral chlorambucil to intensive multidrug schedules) was effective in producing responses but did not result in a survival benefit. The introduction of autologous peripheral-blood stem-cell transplantation with its inherent low morbidity and mortality in comparison with autologous bone marrow transplantation resulted in three trials applying high-dose therapy as first-line treatment for FL. All these studies showed an improvement of antitumor efficacy, but none had a significant impact on OS. This is most likely the result of the inability to select patients who might benefit most from this procedure or, again, insufficient follow-up. Patients who experience relapse, especially early relapse, have shown that they have a lymphoma with a clinically less benign behavior. In this patient population, several phase II studies suggested an improved survival, which was confirmed by the only randomized study in relapsed FL that showed a significantly improved OS in patients who underwent transplantation as compared with standard chemotherapy. Several authors have described a relatively high incidence of myelodysplasia, attributed to the high-dose therapy. However, this may also be the result of extensive pretreatment, suggesting that high-dose therapy might be of greater benefit earlier in the treatment course, as opposed to after multiple relapses. After the introduction of rituximab, several groups chose to investigate whether OS was improved with the incorporation of rituximab in standard-dose, first-line treatment of FL. The general conclusion is that PFS was improved in all, but OS was prolonged in only some, of these trials. Likewise, incorporating rituximab into highdose chemotherapy as part of first-line therapy resulted in better PFS but an OS benefit was observed in only one such trial. In the article that accompanies this editorial, Pettengel et al describe the results of the randomized European Group for Blood and Marrow Transplantation (EBMT) LYM-1 study. Rituximab-naive patients with relapsed chemosensitive FL were randomly assigned to analyze the efficacy of in vivo purging and maintenance therapy with rituximab in combination with high-dose therapy and autologous stem-cell transplantation. In 7 years, 280 patients were included. The authors conclude that in vivo purging did not improve outcome; however, maintenance therapy did improve PFS, but not OS at the time of this report. This study was not designed to assess the value of high-dose therapy because all patients received this treatment, which the authors considered standard therapy in relapsed FL. Although an important observation, it is important to realize that the patients in the EBMT LYM-1 study all were rituximab naive, which limits conclusions on current applicability. In addition, from the French Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) study, we have learned that the results of high-dose therapy in patients with diffuse large B-cell lymphoma who experience relapse after first-line rituximab-containing therapy are significantly inferior, especially in the situation of an early relapse. Whether this is also the case in FL is an open question, but data from another French study in FL may be reassuring that this is not necessarily the case in FL. We can conclude that high-dose therapy changes the natural behavior of FL in relapsed disease and, probably, also in first-line therapy if PFS is a convincing end point. However, it is not clear that PFS is the best end point in FL. How can we improve the outlook for patients with FL? One approach is to wait for the current studies to mature and report OS data. Alternative options are new and more effective monoclonal antibodies or monoclonals conjugated to either radionuclides or toxins. Currently, there are no randomized data in support of these expensive options. Is allogeneic transplantation the panacea? Although complicated by a high treatment-related mortality (TRM), myeloablative transplants resulted in convincing evidence of cure in patients for whom other intensive therapies had failed. With the introduction of nonmyeloablative transplants, the decreased TRM resulted in better outcomes, even in patients who had previously undergone autograft. The high TRM after allografting in comparison with autografting limits its role in first-line salvage. It remains to be seen whether tandem transplantation combining the efficacy of highdose therapy with the immunological graft versus lymphoma effect will lead to the desired more favorable outcome. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 13 MAY 1 2013

Efficacy of Autologous Peripheral Blood Stem Cell Transplantation (Auto-PBSCT) on the Neuropathic Manifestations in POEMS Syndrome (P01.147)

Efficacy of Autologous Peripheral Blood Stem Cell Transplantation (Auto-PBSCT) on the Neuropathic Manifestations in POEMS Syndrome (P01.147)