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1.  Increasing the Clinical Efficacy of NK and Antibody-Mediated Cancer Immunotherapy: Potential Predictors of Successful Clinical Outcome Based on Observations in High-Risk Neuroblastoma 
Disease recurrence is frequent in high-risk neuroblastoma (NBL) patients even after multi-modality aggressive treatment [a combination of chemotherapy, surgical resection, local radiation therapy, autologous stem cell transplantation, and cis-retinoic acid (CRA)]. Recent clinical studies have explored the use of monoclonal antibodies (mAbs) that bind to disialoganglioside (GD2), highly expressed in NBL, as a means to enable immune effector cells to destroy NBL cells via antibody-dependent cell-mediated cytotoxicity (ADCC). Preclinical data indicate that ADCC can be more effective when appropriate effector cells are activated by cytokines. Clinical studies have pursued this by administering anti-GD2 mAb in combination with ADCC-enhancing cytokines (IL2 and GM-CSF), a regimen that has demonstrated improved cancer-free survival. More recently, early clinical studies have used a fusion protein that consists of the anti-GD2 mAb directly linked to IL2, and anti-tumor responses were seen in the Phase II setting. Analyses of genes that code for receptors that influence ADCC activity and natural killer (NK) cell function [Fc receptor (FcR), killer immunoglublin-like receptor (KIR), and KIR-ligand (KIR-L)] suggest patients with anti-tumor activity are more likely to have certain genotype profiles. Further analyses will need to be conducted to determine whether these genotypes can be used as predictive markers for favorable therapeutic outcome. In this review, we discuss factors that affect response to mAb-based tumor therapies such as hu14.18-IL2. Many of our observations have been made in the context of NBL; however, we will also include some observations made with mAbs targeting other tumor types that are consistent with results in NBL. Therefore, we hypothesize that the NBL observations discussed here may also be relevant to mAb therapy for other cancers, in which ADCC is known to play a role.
doi:10.3389/fphar.2012.00091
PMCID: PMC3353262  PMID: 22623917
ADCC; KIR; FcR; neuroblastoma; immunocytokine; mAb; IL2
2.  IgD multiple myeloma a descriptive report of 17 cases: survival and response to therapy 
Background
Immunoglobulin D multiple myeloma (MM) is rare and has a poorer prognosis than other MM isotypes.
Design and methods
Seventeen patients (pts) diagnosed from 1993 to 2009 with IgD MM were selected from six institutions of Multiple Myeloma Latium-Region GIMEMA Working Group.
Results
Median age was 55 years, 14 patients had bone lesions, eight had renal impairment with estimated glomerular filtration rate (eGFR) < 50 ml/min, one serum calcium ≥ 12 mg/dl, 11 had lambda light chains, five stage III of ISS, six with chromosomal abnormalities. Six pts received conventional chemotherapy (CT): five melphalan + steroids based regimens. Eleven underwent high-doses of chemotherapy with autologous stem cell transplantation (HDT/ASCT), five single and six tandem ASCT: six received bortezomib and/or thalidomide as induction therapy and five VAD. Thalidomide maintenance was used in two pts: one in HDT/ASCT and one in CT group; bortezomib was used in one patient after HDT/ASCT. At a median follow up of 38 (range 19-60) and 50 months (range 17-148) for pts treated with CT and HDT/ASCT, respectively, the overall response rate (ORR) was 83% and 90%. In the group of patients treated with CT, median overall survival (OS) was 34 months (95% CI 15- 54 months), median progression free survival (PFS) was 18 months (95% CI 3-33 months) and median duration of response (DOR) was 7 months (95% CI 5-9 months). Median OS, PFS and DOR were not reached at the time of this analysis in the HDT/ASCT group of patients. Death was observed in 27.3% of pts treated with HDT/ASCT and in 66.7% undergone CT.
Conclusions
Despite the retrospective analysis and the small number of pts our study showed that the use of HDT/ASCT seems to improve also the prognosis of IgD MM patients. Treatment options including new drugs, before and after stem cell transplantation, may further improve the outcomes of these patients.
doi:10.1186/1756-9966-31-17
PMCID: PMC3349499  PMID: 22381082
3.  Evolving role of high dose stem cell therapy in multiple myeloma 
Conventional chemotherapy has been used in the treatment of multiple myeloma. However the development of autologous stem cell transplant represented a major advance in its therapy. Complete response (CR) rates to the tune of 40-45% were seen and this translated into improvements in progression-free survival and also overall survival in some studies. As a result the autologous stem cell transplants (ASCT) is the standard of care in eligible patients and can be carried out with low treatment-related mortality. Allogenic transplant carries the potential for cure but the high mortality associated with the myeloablative transplant has made it unpopular. Reduced Intensity Stem Cell Transplants (RIST) have been tried with varying success but with a high degree of morbidity as compared to the ASCT. Introduction of newer agents like thalidomide, lenalidomide, bortezomib and liposomal doxorubicin into the induction regimens has resulted in higher CR and very good partial response rates (VGPR) as well as improvement in ease of administration. These drugs have also proved useful in patients with adverse cytogenetics. Recent trials suggest that this has translated into improvements in response rates post-ASCT. There is a suggestion that patients achieving CR/nCR or VGPR after induction therapy should be placed on maintenance and ASCT then could be used as a treatment strategy at relapse. All these trends however await confirmation from further trials. Tandem transplants have been used to augment the results obtained with ASCT and have demonstrated their utility in patients who achieved only a partial response or stable disease in response to the first transplant as well as patients with adverse cytogenetics. Incorporation of bortezomib along with melphalan into the conditioning regimen has also been tried. RIST following ASCT has been tried with varying success but does not offer any major advantage over ASCT and is associated with higher morbidity. It is hoped that recent advances in therapy will contribute greatly to improved survival.
doi:10.4103/0971-5851.81885
PMCID: PMC3124984  PMID: 21731211
Conventional chemotherapy; high dose stem cell therapy; multiple myeloma
4.  Predictive Value of Post-Transplant Bone Marrow Plasma Cell Percent in Multiple Myeloma Patients Undergone Autologous Transplantation 
Background/Aims
Autologous stem cell transplantation (ASCT) has become the treatment of choice for patients with multiple myeloma (MM). Studies have shown that maintenance treatment with interferon-alpha is associated with improved survival rates following ASCT. However, despite these recent advances in regimes, relapses are inevitable; thus, the prediction of relapse following ASCT requires assessment.
Methods
We retrospectively analyzed 39 patients who received ASCT between 2003 and 2008. All patients received chemotherapy with vincristine, adriamycin, and dexamethasone (VAD), and ASCT was performed following high-dose melphalan conditioning therapy. We evaluated the influence of the post-transplant day +14 (D+14) bone marrow plasma cell percent (BMPCp) (≥ 2 vs. < 2%), international scoring system (ISS) stage (II vs. III), response after 3 cycles of VAD therapy (complete response [CR] vs. non-CR), deletion of chromosome 13q (del[13q]) (presence of the abnormality vs. absence), and BMPCp at diagnosis (≥ 50 vs. < 50%) on progression-free survival (PFS) and overall survival (OS).
Results
During the median follow-up of 28.0 months, the median PFS and OS were 29.1 and 42.1 months, respectively. By univariate analysis, ISS stage III at diagnosis, BMPCp ≥ 50% at diagnosis, CR after 3 cycles of VAD therapy, del (13q) by fluorescence in situ hybridization, and BMPCp ≥ 2% at post-transplant D+14 were correlated with PFS and OS. A multivariate analysis revealed that a post-transplant D+14 BMPCp ≥ 2% (PFS, hazard ratio [HR] = 4.426, p = 0.008; OS, HR = 3.545, p = 0.038) and CR after 3 cycles of VAD therapy (PFS, HR = 0.072, p = 0.014; OS, HR = 0.055, p = 0.015) were independent prognostic parameters.
Conclusions
Post-transplant D+14 BMPCp is a useful parameter for predicting the outcome for patients with MM receiving ASCT.
doi:10.3904/kjim.2011.26.1.76
PMCID: PMC3056259  PMID: 21437166
Multiple myeloma; Stem cell transplantation; Bone marrow; Plasma cell
5.  The impact of novel therapeutic agents before and after frontline autologous stem cell transplantation in patients with multiple myeloma 
Blood research  2013;48(3):198-205.
Background
Novel agents (NAs) such as thalidomide and bortezomib have been administered in combination with autologous stem-cell transplantation (ASCT) to effectively treat multiple myeloma (MM). However, whether NAs perform better as induction treatments prior to transplantation, or as post-transplant maintenance therapies remains unclear.
Methods
We retrospectively analyzed 106 consecutive patients with MM who underwent ASCT within 1 year of diagnosis as first-line therapy.
Results
Eighty-seven (82.1%) patients received NAs before ASCT, whereas 68 (64.2%) received NAs after ASCT. NAs were administered to each patient as follows: before ASCT alone (N=29, 27.4%), after ASCT alone (N=10, 9.4%) or both before and after ASCT (N=58, 54.7%). High-quality rates before and after ASCT were significantly higher for patients who received NAs as induction treatment compared to those who did not receive pre-transplant NAs. At a median follow-up of 37.9 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 42.8% and 70.2%, respectively. The PFS and OS were significantly higher in patients with NAs as post-transplant maintenance treatment (P=0.03 and P=0.04, respectively), but not in those with NAs as pre-transplant induction treatment. The PFS of patients with NAs before and after ASCT was higher than that of the patients with NAs as induction therapy alone (P=0.05). Age, serum β2-microglobulin level, complete response after ASCT, and NA use post-ASCT independently predicted survival outcomes.
Conclusion
These findings suggest that integration of NAs post-ASCT could benefit patients with MM undergoing ASCT. Induction therapy using NAs also improves high-quality response rates before and after ASCT.
doi:10.5045/br.2013.48.3.198
PMCID: PMC3786280  PMID: 24086940
Multiple myeloma; Novel agents; Autologous stem cell transplantation; Induction and maintenance treatment
6.  MYELOABLATIVE THERAPY WITH AUTOLOGOUS STEM CELL RESCUE FOR PATIENTS WITH EWING SARCOMA 
Bone marrow transplantation  2008;41(10):867-872.
Summary
The aim of this study was to identify risk factors associated with progression-free survival in patients with Ewing sarcoma undergoing autologous stem cell transplantation (ASCT); 116 patients underwent ASCT in 1989-2000 and reported to the Center for International Blood and Marrow Transplant Research. Eighty patients (69%) received ASCT as first-line therapy and 36 (31%), for recurrent disease. Risk factors affecting ASCT were analyzed with use of the Cox regression method. Metastatic disease at diagnosis, recurrence prior to ASCT and performance score <90 were associated with higher rates of disease recurrence/progression. Five-year probabilities of progression-free survival in patients with localized and metastatic disease at diagnosis who received ASCT as first-line therapy were 49% (95% CI 30 – 69) and 34% (95% CI 22 – 47) respectively. The 5-year probability of progression-free survival in patients with localized disease at diagnosis, and received ASCT after recurrence was 14% (95% CI 3 – 30). Progression-free survival rates after ASCT are comparable to published rates in patients with similar disease characteristics treated with conventional chemotherapy, surgery and irradiation suggesting a limited role for ASCT in these patients. Therefore, ASCT if considered should be for high-risk patients in the setting of carefully controlled clinical trials.
doi:10.1038/bmt.2008.2
PMCID: PMC3164955  PMID: 18246113
Autologous transplant; Ewing sarcoma; Progression-free survival
7.  Second malignancies after autologous haematopoietic stem cell transplantation following modified BEAM conditioning regimen in patients with Hodgkin lymphoma – characteristics and risk factor analysis 
Contemporary Oncology  2013;17(2):200-204.
Aim of the study
The aim of the study was to determine the incidence of second malignancies among patients with Hodgkin lymphoma (HL) treated with autologous haematopoietic stem cell transplantation (ASCT) following a modified BEAM (BCNU, etoposide, cytarabine, melphalan, dexamethasone) regimen between 1992 and 2012 at our department. We also intended to define the risk factors for the occurrence of second neoplasm after ASCT.
Material and methods
The long-term outcomes after transplant were evaluated in 170 patients, median age 31 years (range 17–61), who received a median of two pre-transplant chemotherapy lines (range 1–5).
Results
MOPP (mechlorethamine, vincristine, procarbazine, prednisone) or MOPP-type regimens were given to 12% of patients prior to ASCT. The median follow-up of the survivors was 73 (12–242) months. The 7-year overall survival and progression-free survival were 75% and 64%, respectively. Second malignancies occurred in 7 of the 170 patients, including 5 haematological malignancies, and 2 solid tumors. They developed at a median of 8 years (range 0.4–13.5) from ASCT. The 10-year and 15-year cumulative incidence of developing a second malignancy were 7% and 13%, respectively. In multivariate analysis, age ≥ 40 years at transplant (HR = 8.8; p = 0.008) and pre-transplant MOPP-type chemotherapy (HR = 5.6; p = 0.030) were the only factors significant for developing a second malignancy.
Conclusions
Our results indicate that age of patient and the type of pre-transplant chemotherapy contribute to the risk of the development of a second neoplasm after ASCT in patients with HL. We believe that better characterization of second malignancies and associated risk factors may be useful for clinicians who care for these patients.
doi:10.5114/wo.2013.34626
PMCID: PMC3685379  PMID: 23788991
Hodgkin lymphoma; autologous haematopoietic stem cell transplantation; BEAM; second malignancy
8.  Double Autologous Stem Cell Transplantation for Multiple Myeloma: A Korean Single Center Study 
Background
Although high dose chemotherapy coupled with an autologous stem cell transplantation (ASCT) is widely accepted as effective therapy for multiple myeloma (MM), few reports are available in Korea, especially in the area of double ASCT. We present the results of an institutional retrospective study of 12 patients with MM treated by double ASCT.
Methods
Eligible patients received induction therapy using vincristine, adriamycin, dexamethasone (VAD), and mobilization was performed using cyclophosphamide plus lenograstim. High-dose melphalan (total 200 mg/m2) was used to condition the ASCT.
Results
The median interval from diagnosis to ASCT was 6 months (range, 1.8-15.3 months). The median interval between the 1st and 2nd ASCT was 4.4 months (range 2.1-48.7 months). The median follow up was 18.3 months (range 8.1-50.5 months) for the nine surviving patients. No therapy-related mortality occurred. Following induction chemotherapy, two patients experienced CR. Following double ASCT, eight patients experienced CR. The 5 year OS was 59%. The median duration of event free survival was 2.13 years (95% CI, 0.84-3.42).
Conclusion
Although the results of study did not demonstrate the advantage of double ASCT, this is the first report to outline the outcome of double ASCT for Korean MM patients.
doi:10.3904/kjim.2005.20.3.237
PMCID: PMC3891159  PMID: 16295783
Multiple myeloma; Autologous; Stem cell transplantation
9.  Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma 
Journal of Clinical Oncology  2012;30(36):4462-4469.
Purpose
The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known.
Patients and Methods
In total, 477 patients with CD20+ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation.
Results
After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01).
Conclusion
In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.
doi:10.1200/JCO.2012.41.9416
PMCID: PMC3646314  PMID: 23091101
10.  Determining the optimal time for bortezomib-based induction chemotherapy followed by autologous hematopoietic stem cell transplant in the treatment of multiple myeloma 
In our study, we determined the efficacy of bortezomib-based induction therapy followed by autologous stem cell transplant (ASCT) in newly diagnosed and relapsed/refractory (R/R) multiple myeloma (MM) patients and compared the advantages of early versus late transplant. We used a retrospective analysis to examine 62 patients, including 46 cases of newly diagnosed MM (early transplant group) and 16 cases of relapsed/refractory MM (late transplant group). All of these patients received bortezomib-based induction therapy followed by ASCT. The efficacy and side effects of the treatment regimen were analyzed. Patients’ overall survival (OS) and progression-free survival (PFS) times were determined. The ratio of complete remission to near-complete remission (CR/nCR) was 69.5% versus 56.2% (P=0.361), respectively, for the early transplant group versus the late transplant group, respectively, after receiving bortezomib-based induction therapy; the overall response rates of the two group were 91.3% and 81.2%, respectively (P=0.369). After receiving ASCT, the CR/nCR of the two groups increased to 84.8% and 81.3%, respectively. The median time required for neutrophil engraftment of the early transplant group and the late transplant group was 11 and 14.5 days, respectively (P=0.003); the median time required for platelet engraftment was 13 and 21.5 days (P=0.031), respectively. There were no significant differences in the toxic side effects observed during induction therapy and ASCT between the two groups. The OS of the two groups was not statistically different (P=0.058). The PFS of the early transplant group and the late transplant group was 41.6 and 26.5 months, respectively (P=0.008). Multivariate analysis demonstrated that the time of receiving ASCT, the types of M protein, and the International Staging System (ISS) stage were all independent factors that influenced PFS. In conclusion, patients in a suitable condition for ASCT should be recommended to have an early ASCT immediately after diagnosis.
doi:10.3978/j.issn.1000-9604.2013.02.02
PMCID: PMC3626983  PMID: 23592897
Multiple myeloma; autologous stem cell transplant; bortezomib; International Staging System stage
11.  Autologous stem cell transplantation for mantle cell lymphoma – single centre experience 
Contemporary Oncology  2013;17(5):456-459.
Aim of the study
Mantle cell lymphoma (MCL) is a B-cell neoplasm showing resistance to conventional chemotherapy. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) may result in higher progression-free (PFS) and overall survival (OS) when used as a consolidation for younger and fit patients.
Material and methods
We retrospectively evaluated the results of ASCT for MCL. Patients were transplanted after achieving first or subsequent complete or partial response after conventional chemotherapy.
Results
Twenty patients (7 male and 13 female) at median age of 59 years (range 41–68) were included. 90% of transplanted patients had stage III/IV disease at diagnosis and low, intermediate and high MIPI scores occurred in 5, 9 and 6 patients respectively. Induction chemotherapy consisted of the R-CHOP regimen in all patients except one who received R-CVAD. The disease status at transplant was as follows: first complete response (n = 13); second complete response (n = 4) and partial response (n = 3). The conditioning regimen prior to ASCT consisted of CBV and BEAM for 18 and 2 patients, respectively. The transplant-related mortality was 0% at day 100. Median OS and PFS were 48 and 29.8 months, respectively. The estimated 5-year OS and PFS were found to be 52% and 35%, respectively. After median follow-up after ASCT of 36 months (range 11–73), 10 patients were alive with 8 remaining in complete remission (CR) whereas 2 relapsed and received salvage chemotherapy. Ten patients died from disease recurrence and subsequent chemoresistance.
Conclusions
ASCT as a consolidation for MCL patients is found to be an effective and safe procedure.
doi:10.5114/wo.2013.37223
PMCID: PMC3934030  PMID: 24596536
mantle cell lymphoma; autologous stem cell transplantation; results
12.  Bortezomib and melphalan as a conditioning regimen for autologous stem cell transplantation in multiple myeloma 
The Korean Journal of Hematology  2010;45(3):183-187.
Background
High-dose melphalan (200 mg/m2) with autologous stem cell transplantation (ASCT) is the standard treatment for young patients with multiple myeloma (MM). However, the response rates after ASCT are often unsatisfactory. We performed a pilot study by using bortezomib-melphalan as conditioning regimen for ASCT in Korean patients with MM.
Methods
The conditioning regimen consisted of administration of intravenous infusion of bortezomib 1.0 mg/m2 on days -4 and -1 and melphalan 50 mg/m2 (day -4) and 150 mg/m2 (day -1). In this study, we enrolled 6 newly diagnosed patients and 2 patients with relapse.
Results
The disease status of the 6 newly diagnosed patients at ASCT was as follows: 1 complete remission (CR), 1 very good partial remission (VGPR), and 4 partial remissions (PRs). The disease status of the 2 relapsed patients at ASCT was PR. All patients except 1 showed adequate hematologic recovery after ASCT. The median time for the absolute neutrophil counts to increase over 500/mm3 was 13 days (range, 10-19 days). Six patients with VGPR or PR at the time of transplantation showed an improvement in response to CR after ASCT. The patients were followed up without any maintenance treatment after ASCT except 1 patient who died during ASCT. During the follow-up period, CR was maintained in 3 newly diagnosed patients, but the other 4 patients, including 2 newly diagnosed patients, relapsed.
Conclusion
Conditioning regimen consisting of bortezomib and melphalan may be effective for ASCT in MM; however, the feasibility of this regimen should be further evaluated in large study populations.
doi:10.5045/kjh.2010.45.3.183
PMCID: PMC2983035  PMID: 21120207
Multiple myeloma; Bortezomib; Melphalan
13.  Mantle Cell Lymphoma International Prognostic Index but Not Pretransplantation Induction Regimen Predicts Survival for Patients With Mantle-Cell Lymphoma Receiving High-Dose Therapy and Autologous Stem-Cell Transplantation 
Journal of Clinical Oncology  2011;29(22):3023-3029.
Purpose
High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) are frequently used in an attempt to improve outcome in patients with mantle-cell lymphoma (MCL); however, the importance of intensive induction regimens before transplantation is unknown.
Patients and Methods
To address this question, we evaluated baseline characteristics, time to treatment, induction regimen, disease status at the time of transplantation, and MIPI score at diagnosis and their associations with survival in 118 consecutive patients with MCL who received HDT and ASCT at our centers.
Results
The MIPI was independently associated with survival after transplantation in all 118 patients (hazard ratio [HR], 3.5; P < .001) and in the 85 patients who underwent ASCT as initial consolidation (HR, 7.2; P < .001). Overall survival rates were 93%, 60%, and 32% at 2.5 years from ASCT for all patients with low-, intermediate-, and high-risk MIPI, respectively. Low-risk MIPI scores were more common in the intensive induction group than the standard induction group in all patients (64% v 46%, respectively; P = .03) and in the initial consolidation group (66% v 45%, respectively; P = .03). After adjustment for the MIPI, an intensive induction regimen was not associated with improved survival after transplantation in all patients (HR, 0.5; P = .10), the initial consolidation group (HR, 1.1; P = .86), or patients ≤ 60 years old (HR, 0.6; P = .50). Observation of more than 3 months before initiating therapy did not yield inferior survival (HR, 2.1; P = .12) after adjustment for the MIPI in patients receiving ASCT.
Conclusion
An intensive induction regimen before HDT and ASCT was not associated with improved survival after adjusting for differences in MIPI scores at diagnosis.
doi:10.1200/JCO.2010.33.7055
PMCID: PMC3157964  PMID: 21730271
14.  Maintenance Therapy with Immunomodulatory Drugs after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2013;8(8):e72635.
Background
Although high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) has been confirmed to result in longer remission time than conventional chemotherapy, multiple myeloma (MM) remains incurable. Post-ASCT maintenance is considered as a strategy for obtaining durable remissions and preventing tumor progression. Randomized controlled trials (RCTs) studying maintenance therapy with immunomodulatory drugs (IMiDs) after ASCT have shown some valuable survival improvements. This meta-analysis of RCTs therefore assesses the effect of post-ASCT IMiDs maintenance on MM patients.
Methods
We performed a meta-analysis to evaluate the impact of IMiDs (thalidomide or lenalidomide) as post-ASCT maintenance therapy on the survival of newly diagnosed MM patients. The outcomes for this meta-analysis were progression-free survival (PFS) and overall survival (OS).
Results
Eight RCTs enrolling 3514 patients were included for analysis. An obvious improvement in Os (hazard ratio [HR] 0.75) and a significant PFS advantage (HR 0.58) with post-ASCT IMiDs maintenance was revealed. Thalidomide maintenance after ASCT can result in significant benefit in Os (HR 0.72), particularly combined with corticosteroids (HR 0.66).
Conclusions
MM patients after ASCT have a significant overall survival benefit with IMiDs maintenance. IMiDs maintenance was justified for MM patients who received HDT with ASCT.
doi:10.1371/journal.pone.0072635
PMCID: PMC3747129  PMID: 23977334
15.  Current Status of Autologous Stem Cell Transplantation in Relapsed and Refractory Hodgkin's Lymphoma 
The Oncologist  2011;17(1):80-90.
New developments in the treatment of patients with relapsed/refractory Hodgkin's lymphoma undergoing autologous stem cell transplantation are summarized including modern prognostic markers, the role of functional imaging, the role of newer drugs, different conditioning regimens, and maintenance therapy.
Despite the relatively high long-term disease-free survival (DFS) rate for patients with Hodgkin lymphoma (HL) with modern combination chemotherapy or combined modality regimens, ∼20% of patients die from progressive or relapsed disease. The standard treatment for relapsed and primary refractory HL is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), which has shown a 5-year progression-free survival rate of ∼50%–60%. Recent developments in a number of diagnostic and therapeutic modalities have begun to improve these results. Functional imaging, refinement of clinical prognostic factors, and development of novel biomarkers have improved the predictive algorithms, allowing better patient selection and timing for ASCT. In addition, these algorithms have begun to identify a group of patients who are candidates for more aggressive treatment beyond standard ASCT. Novel salvage regimens may potentially improve the rate of complete remission prior to ASCT, and the use of maintenance therapy after ASCT has become a subject of current investigation. We present a summary of developments in each of these areas.
doi:10.1634/theoncologist.2011-0177
PMCID: PMC3267827  PMID: 22210089
Autologous stem cell transplant; Hodgkin's lymphoma; High-dose chemotherapy
16.  Retrospective Analysis of Peripheral Blood Stem Cell Transplantation for the Treatment of High-Risk Neuroblastoma 
Journal of Korean Medical Science  2007;22(Suppl):S66-S72.
Disease relapse after autologous peripheral blood stem cell transplantation (APBSCT) is the main cause of treatment failure in high-risk neuroblastoma (NBL). To reduce relapse, various efforts have been made such as CD34+ selection and double APBSCT. Here the authors reviewed the clinical features and outcomes of high-risk NBL patients and analyzed their survival. The medical records of 36 patients with stage III or IV NBL who underwent APBSCT at Seoul National University Children's Hospital between May 1996 and May 2004 were reviewed. Total 46 APBSCTs were performed in 36 patients. Disease free survival (DFS) and overall survival of all patients were 47.7% and 68.8%, respectively. The patients were allocated to three groups according to the APBSCT type. The DFS of CD34+ non-selected single APBSCT patients (N=13), CD34+ selected single APBSCT patients (N=14), and CD34+ selected double APBSCT patients (N=9) were 55.6%, 40.6%, and 50.0%, respectively, which were not significantly different. Thus the survival was not found to be affected by CD34+ selection or transplantation number. To improve long-term survival, various efforts should be made such as chemotherapy dose intensification, more effective tumor purging, and control of minimal residual disease via the use of differentiating and immune-modulating agents.
doi:10.3346/jkms.2007.22.S.S66
PMCID: PMC2694391  PMID: 17923758
Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Autologous Transplantation
17.  Poor Outcomes for IgD Multiple Myeloma Patients Following High-Dose Melphalan and Autologous Stem Cell Transplantation: A Single Center Experience 
Journal of Korean Medical Science  2008;23(5):819-824.
Immunoglobulin (Ig) D multiple myeloma (MM) accounts for 2% of all MM cases and has been reported to be associated with poor prognosis compared with other MM subtypes. The aim of the present study was to compare the effects of high-dose melphalan treatment and autologous stem cell transplantation (ASCT) on the survival of patients with IgD MM and patients with other MM subtypes. Between November 1998 and January 2005, a total of 77 patients with MM who underwent ASCT at the Asan Medical Center were enrolled in this study. High-dose melphalan (total 200 mg/m2) was used as high-dose chemotherapy. The study population was divided into two groups based on MM subtype: those with IgD MM; and those with other MM subtypes. A total of 8 patients with IgD MM were identified, accounting for about 10% of the study population. Thirty-six patients (47%) had IgG MM, 17 patients (22%) had IgA MM, and 16 patients (20%) had free light-chain MM. The two groups were similar in baseline characteristics. The median follow-up was 17 months and the median overall survival (OS) was 39 months. In the IgD MM group, median event-free survival (EFS) and OS were 6.9 and 12 months, respectively. In the patients with other MM subtypes, median EFS and OS were 11.5 and 55.5 months (p=0.01, p<0.01), respectively. Multivariate analysis of all patients identified IgD subtype (p=0.002) and Southwest Oncology Group (SWOG) stage 2 or greater at the time of ASCT (p=0.01) as adverse prognostic factors for survival. In this small study at a single center in Korea, patients with IgD MM had poorer outcomes after ASCT than did patients with other MM subtypes.
doi:10.3346/jkms.2008.23.5.819
PMCID: PMC2580008  PMID: 18955788
Multiple Myeloma; Immunoglobulin D; Stem Cell Transplantation; Prognosis
18.  Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era 
Journal of Clinical Oncology  2010;28(27):4184-4190.
Purpose
Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown.
Patients and Methods
Patients with CD20+ DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT.
Results
The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001).
Conclusion
In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP.
doi:10.1200/JCO.2010.28.1618
PMCID: PMC3664033  PMID: 20660832
19.  Effect of Remission Status and Induction Chemotherapy Regimen on Outcome of Autologous Stem Cell Transplantation for Mantle Cell Lymphoma 
Leukemia & lymphoma  2008;49(6):1062-1073.
We analyzed the outcomes of autologous stem cell transplantation (ASCT) following high-dose therapy with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive patients with mantle cell lymphoma (MCL). Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (±R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (±R) followed by ASCT in CR1/PR1, and 20 received ASCT following disease progression. Estimates of overall and progression-free survival (PFS) at three years among patients transplanted in CR1/PR1 were 93% and 63% compared with 46% and 36% for patients transplanted with relapsed/refractory disease, respectively. The hazard of mortality among patients transplanted with relapsed/refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P=.006). Patients in the CHOP (±R) group had a higher risk of failure for PFS compared to patients in the HyperCVAD (±R) group, though the difference did not reach statistical significance (hazard ratio 3.67, P=.11). These results suggest that ASCT in CR1/PR1 leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed/refractory disease, and a HyperCVAD (±R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1.
doi:10.1080/10428190801923725
PMCID: PMC2769072  PMID: 18452065
Mantle cell lymphoma; Autologous stem cell transplantation; HyperCVAD; CHOP; Non-Hodgkin lymphoma
20.  Early versus delayed autologous stem cell transplantation in patients receiving novel therapies for Multiple Myeloma 
Leukemia & lymphoma  2012;54(8):1658-1664.
Autologous stem cell transplant (ASCT) is an effective treatment for multiple myeloma (MM). However the timing of ASCT in the era of novel agents (lenalidomide, thalidomide, bortezomib) is unknown. We retrospectively reviewed the outcome of MM patients who received novel agent based induction treatment and received first ASCT within 12 months of diagnosis (early ASCT, N = 102), or at a later date (late ASCT, N = 65). Median time to ASCT was 7.9 months vs. 17.7 months in the early vs. late ASCT. The 3 and 5 yr overall Survival (OS) from diagnosis was 90 and 63% versus 82 and 63% in early and late ASCT respectively (P=0.45). Forty-one and 36 patients in the early and late ASCT have relapsed or progressed with median time to relapse of 28 and 23 mos (p=0.055). On multivariable analysis, factors predictive of increased risk for progression were ISS stage III (p=0.007), and < VGPR post-ASCT (p<0.001). Factor predictive of worst outcomes for OS was being on hemodialysis (p=0.037). No superiority of one agent was seen. In summary, early or late ASCT is a viable option for MM patients receiving induction treatment with novel targeted therapies.
doi:10.3109/10428194.2012.751528
PMCID: PMC3769940  PMID: 23194056
Multiple Myeloma; Transplantation; Bortezomib; Lenalidomide
21.  Autologous Stem Cell Transplantation for Aggressive Lymphomas 
The role of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in the treatment armamentarium of aggressive B- and T-cell non-Hodgkin lymphoma (NHL) is still a matter of debate. In the pre-Rituximab era, the PARMA study demonstrated the superiority of HDT/ASCT over conventional salvage chemotherapy in chemosensitive, relapsed patients. Subsequently, HDT/ASCT has become a standard approach for relapsed NHL. With the advent of Rituximab in the landscape of NHL, transplantation as part of first-line therapy has been challenged. However, no benefit in terms of disease-free or overall survival of HDT/ASCT over standard therapy was shown when Rituximab was added to both arms. Moreover, the superiority of HDT/ASCT over conventional salvage therapy in patients relapsing from first-line therapy including Rituximab was not confirmed. From these disappointing results, novel strategies, which can enhance the anti-lymphoma effect, at the same time reducing toxicity have been developed, with the aim of improving the outcome of HDT/ASCT in aggressive NHL. In T-cell lymphoma, few publications demonstrated that consolidation of complete remission with HDT/ASCT is safe and feasible. However, up to one-third of patients may never receive transplant, mostly due to progressive disease, and relapse still remains a major concern even after transplant.
doi:10.4084/MJHID.2012.075
PMCID: PMC3507533  PMID: 23205263
22.  Immunochemotherapy and Autologous Stem-Cell Transplantation for Untreated Patients With Mantle-Cell Lymphoma: CALGB 59909 
Journal of Clinical Oncology  2009;27(36):6101-6108.
Purpose
Mantle-cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a poor prognosis. We explored the feasibility, safety, and effectiveness of an aggressive immunochemotherapy treatment program that included autologous stem-cell transplantation (ASCT) for patients up to age 69 years with newly diagnosed MCL.
Patients and Methods
The primary end point was 2-year progression-free survival (PFS). A successful trial would yield a 2-year PFS of at least 50% and an event rate (early progression plus nonrelapse mortality) less than 20% at day +100 following ASCT. Seventy-eight patients were treated with two or three cycles of rituximab combined with methotrexate and augmented CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This treatment was followed by intensification with high doses of cytarabine and etoposide combined with rituximab and filgrastim to mobilize autologous peripheral-blood stem cells. Patients then received high doses of carmustine, etoposide, and cyclophosphamide followed by ASCT and two doses of rituximab.
Results
There were two nonrelapse mortalities, neither during ASCT. With a median follow-up of 4.7 years, the 2-year PFS was 76% (95% CI, 64% to 85%), and the 5-year PFS was 56% (95% CI, 43% to 68%). The 5-year overall survival was 64% (95% CI, 50% to 75%). The event rate by day +100 of ASCT was 5.1%.
Conclusion
The Cancer and Leukemia Group B 59909 regimen is feasible, safe, and effective in patients with newly diagnosed MCL. The incorporation of rituximab with aggressive chemotherapy and ASCT may be responsible for the encouraging outcomes demonstrated in this study, which produced results comparable to similar treatment regimens.
doi:10.1200/JCO.2009.22.2554
PMCID: PMC2793032  PMID: 19917845
23.  Immunotherapy with low-dose recombinant interleukin 2 after high-dose chemotherapy and autologous stem cell transplantation in neuroblastoma. 
British Journal of Cancer  1998;78(4):528-533.
The purpose of this study was to evaluate in a phase I-II trial whether low doses of recombinant human interleukin 2 (rHuIL-2) over a prolonged period of time are safe and effective in eradicating or controlling minimal residual disease in children with neuroblastoma given high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). From January 1992 to July 1996, 17 consecutive patients, with either stage IV or relapsed neuroblastoma, were enrolled. Patients received rHuIL-2 after a median time interval (min-max) of 105 days (56-153) after HDCT and ASCT. The protocol consisted of 2 'priming' courses of rHuIL-2 at escalating doses administered intravenously at 72-h intervals, followed by 'maintenance' with 11 monthly and six bimonthly boosting 5-day courses administered subcutaneously on an outpatient basis. At April 1997, 7 out of the 17 patients had completed the treatment schedule, four had discontinued treatment because of toxicity and four because of relapse; the remaining two patients are still on treatment, having completed 15 courses. Expansion of T lymphocytes, together with an increase in both natural killer cells and in activated T lymphocytes was evidenced. After a median (min-max) follow-up time of 30 (16-64) months, 12 out of 17 patients are alive and well. Two patients relapsed and died 14 and 35 months after transplant. Three patients are alive after having relapsed at 41, 21 and 13 months. The actuarial 2-year event-free survival and overall survival are 67% and 92% respectively. Intermittent administration of low doses of rHuIL-2 given for a long period of time is well tolerated and seems capable of controlling minimal residual disease after HDCT and ASCT in children with high-risk neuroblastoma.
PMCID: PMC2063104  PMID: 9716039
24.  Controversies in the Treatment of Lymphoma with Autologous Transplantation 
The Oncologist  2009;14(9):921-929.
High dose therapy and autologous stem cell transplant (HDT-ASCT) is the standard of care for relapsed and refractory diffuse large B cell lymphoma and Hodgkin lymphoma, however the role for HDT-ASCT in the treatment of follicular lymphoma (FL), mantle cell lymphoma (MCL), and peripheral T cell lymphoma (PTCL) is controversial. In FL, phase II and randomized data support the use of HDT-ASCT in the relapsed setting and incorporation of rituximab into mobilization regimens and post transplant maintenance appears to prolong remission durations. Allogeneic stem cell transplant (SCT) remains the only curative treatment option and is appropriate for patients with high bone marrow disease burdens and refractory disease. In MCL, HDT-ASCT is most often administered upfront and phase II studies using intense immunochemotherapy followed by HDT-ASCT in first complete response (CR) have shown the most impressive outcomes. Complicating the situation, however, is data supporting upfront intensive immunochemotherapy without HDT-ASCT consolidation as well as a “watch and wait” strategy for selected patients. Finally, in PTCL, phase II data supports treatment with HDT-ASCT in first CR and it is rarely appropriate in the relapsed setting. Furthermore, disease status at the time of transplant likely impacts outcome, however this needs to be evaluated further. Overall, HDT-ASCT is an important element of the treatment of relapsed FL and untreated MCL and PTCL, however large prospective studies are needed to confirm its role and identify the most optimal induction, mobilization, and maintenance regimens for each disease.
doi:10.1634/theoncologist.2009-0162
PMCID: PMC3278670  PMID: 19737999
Hematopoietic Stem Cell Transplantation; Follicular lymphoma; Mantle cell lymphoma; Peripheral T cell lymphoma
25.  Outcomes for Patients Who Fail High Dose Chemoradiotherapy and Autologous Stem Cell Rescue for Relapsed and Primary Refractory Hodgkin Lymphoma 
British Journal of Haematology  2009;146(2):158-163.
Most patients with Hodgkin lymphoma (HL) are cured with first and second-line treatment; however for those who fail high dose chemoradiotherapy with autologous stem cell transplant (HDT-ASCT), outcome is unknown. This report is an analysis of patients with relapsed and primary refractory HL who were treated with HDT-ASCT and failed due to progression of disease (POD). Two hundred and two patients received HDT-ASCT at Memorial Sloan Kettering Cancer Center for relapsed or refractory HL between December 1994 and December 2005 and 71 failed due to POD. The median survival following HDT-ASCT failure was 25 months. Only 16 (23%) of the 71 patients are currently alive, 9 of whom are in remission. Multivariate analysis revealed two factors associated with poor outcome: relapse within 6 months of HDT-ASCT and primary refractory disease. The only factor associated with improved survival was the ability to receive a second transplant, in particular, reduced intensity allogeneic transplant (RIT). Novel therapies are needed for patients who fail HDT-ASCT, particularly those with primary refractory disease and those who relapse within 6 months of HDT-ASCT. Future studies should focus on prospectively evaluating RIT following HDT-ASCT failure in patients with remission duration from HDT-ASCT of greater than 6 months.
doi:10.1111/j.1365-2141.2009.07727.x
PMCID: PMC3278667  PMID: 19438504

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