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.
ADCC; KIR; FcR; neuroblastoma; immunocytokine; mAb; IL2
Response to immunocytokine (IC) therapy is dependent on natural killer (NK) cells in murine neuroblastoma (NBL) models. Furthermore, killer immunoglobulin-like receptor (KIR) / KIR-ligand mismatch is associated with improved outcome to autologous stem cell transplant for NBL. Additionally, clinical anti-tumor response to monoclonal antibodies has been associated with specific polymorphic-FcγR alleles. Relapsed/refractory NBL patients received the hu14.18-IL2 IC (humanized anti-GD2 monoclonal antibody linked to human IL2) in a Children’s Oncology Group (COG) Phase II trial. In this report, these patients were genotyped for KIR, HLA and FcR alleles to determine if KIR receptor-ligand mismatch or specific FcγR alleles were associated with anti-tumor response. Thirty-eight of 39 patients enrolled had DNA available for analysis; 24 were found to have autologous KIR/KIR -ligand mismatch; 14 were matched. Seven of 24 mismatched patients experienced either complete response or improvement of their disease after IC therapy. There was no response or comparable improvement of disease in patients who were matched. Thus KIR/KIR-ligand mismatch was associated with response/improvement to IC (p = 0.03). There was a trend towards patients with the FcγR2A 131-H/H genotype showing a higher response rate compared to other FcγR2A genotypes (p = 0.06). These analyses indicate that response or improvement of relapsed/refractory neuroblastoma patients after IC treatment is associated with autologous KIR/KIR-ligand mismatch, consistent with a role for NK cells in this clinical response.
Natural killer cells; Killer immunoglobulin-like receptor; Fragment c gamma-receptor; Neuroblastoma; Immunocytokine
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.
Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Autologous Transplantation
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.
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.
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.
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.
Multiple myeloma; Bortezomib; Melphalan
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.
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).
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.
Post-transplant D+14 BMPCp is a useful parameter for predicting the outcome for patients with MM receiving ASCT.
Multiple myeloma; Stem cell transplantation; Bone marrow; Plasma cell
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).
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.
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.
Hodgkin lymphoma; autologous haematopoietic stem cell transplantation; BEAM; second malignancy
To compare the outcomes of melphalan 200 mg/m2 (HDM200) and 8 Gy total marrow irradiation (TMI) delivered by helical tomotherapy plus melphalan 140 mg/m2 (HDM140 + TMI 8 Gy) in newly diagnosed symptomatic multiple myeloma (MM) Asian patients. Between 2007 and 2010, nine consecutive myeloma patients who were scheduled to undergo autologous stem cell transplantation (ASCT) were studied. The patients received three cycles of vincristine-adriamycin-dexamethasone (VAD) regimen as induction chemotherapy, and if they had a partial response, peripheral blood stem cells were collected by dexamethasone-etoposide-cyclophosphamide-cisplatin (DECP). In arm A, six patients received the HDM200. In arm B, three patients received HDM140 + TMI 8 Gy. In arm B, the neutropenic duration was slightly longer than in arm A (P = 0.048). However, hematologic recovery (except for neutrophils), transfusion requirement, median duration of hospitalization, and the dose of G-CSF were similar in both arms. The median duration of overall survival and event-free survival was similar in the two arms (P = 0.387). As a conditioning regiment, HDM140 + TMI 8 Gy provide another chance for MM Asian patients who were not feasible for HDM200.
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.
Hematopoietic Stem Cell Transplantation; Follicular lymphoma; Mantle cell lymphoma; Peripheral T cell lymphoma
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.
Autologous transplant; Ewing sarcoma; Progression-free survival
High-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) have been used for the treatment of clinically aggressive non-Hodgkin's lymphoma (NHL). However, the superiority of specific conditioning regimens has not yet been established. The present study evaluated the efficacy and toxicity of a conditioning regimen involving fractionated total body irradiation (TBI), and the use of Ara-C and melphalan (TAM) for clinically aggressive NHL.
Materials and Methods
Between March 2002 and December 2004, 31 patients with aggressive NHL received fractionated TBI with a dose of 12 Gy over 3 days, and were administered 9 g/m2 Ara-C and 100 mg/m2 melphalan followed by autologous peripheral blood stem Cell Transplantation at the Catholic Hematopoietic Stem cell transplantation Center Korea. Patients that responded to first line chemotherapy and achieved complete remission (CR), or were in a first sensitive relapse were defined as having less advanced disease, while the other patients were defined as having more advanced disease.
Objective responses were obtained in 24 of 31 patients (77.4%), comprising complete remission in 19 patients (61.3%) and partial remission in 5 (16.1%) patients. The median follow-up time was 28 months (range 1~62 months). At 3 years, the overall survival and event-free survival (EFS) rates were 62.3% and 47.3%, respectively. Patients with less advanced disease and more advanced disease showed 3-year EFS rates of 73.3% and 22.5 %, respectively (p=0.006). Early (within the first 100 days) treatment-related mortality occurred in 3 (9.7%) patients. Of the 31 total patients, 15 (48.4%) developed grade 3 mucositis, 22 (70.9%) developed neutropenic fever, and two (6.5%) developed interstitial pneumonia syndrome>grade 3.
The modified TAM conditioning regimen and ASCT appear to be a feasible treatment regimen for clinically aggressive NHL, particularly for patients with less advanced disease.
TAM conditioning; High dose therapy; Autologous stem cell transplantation; Non-Hodgkin's lymphoma
Autologous stem cell transplantation (ASCT) is considered the standard therapy for younger patients with newly diagnosed symptomatic multiple myeloma (MM). The introduction into clinical practice of novel agents, such as the proteasome inhibitor bortezomib and the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide, has significantly contributed to major advances in MM therapy and prognosis. These novel agents are incorporated into induction regimens to enhance the depth of response before ASCT and further improve post-ASCT outcomes. Between January 2000 and November 2011, 65 patients with MM were transplanted in the Department of Biomedical Science and Clinical Oncology at the University of Bari. According to Durie-Salmon, 60 patients had stage III of disease and 5 stage II. Only 7 patients were in stage B (renal failure). Induction regimens that were administered in two or more cycles were VAD (vincristine, adriamycin, and dexamethasone), Thal-Dex (thalidomide, dexamethasone), Len-Dex (lenalidomide, dexamethasone), Vel-Dex (bortezomib, dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone), and PAD (bortezomib, pegylated liposomal doxorubicin, and dexamethasone). In mobilization procedure, the patients received cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). The number of cells collected through two or more leukapheresess, response after induction, and toxicity were evaluated to define the more adequate up-front induction regimen in transplantation-eligible MM patients.
The infused stem cell autograft in autologous stem cell transplantation (ASCT) has been viewed mainly as hematologic rescue from the myelosuppressive side effect of conditioning regimens. However, recent reports have shown that the immune effector cells collected at the same time as the stem cells can produce an autologous graft-versus-tumor effect, similar to the graft-versus-tumor effect seen in allogeneic stem cell transplantation without the detrimental effects of graft-versus-host disease. In this article, we review the different immune effector cells collected and infused from the stem cell autograft and their association with clinical outcome post-ASCT, suggesting that ASCT can be viewed not only as a therapeutic maneuver to recover bone marrow function after deliver high-dose chemotherapy, but also as an adoptive immunotherapeutic intervention capable of eradicating residual tumor cells in patients with cancer.
Adoptive immunotherapy; Autologous graft versus tumor effect; Autograft
The benefit of high-dose chemotherapy (HDC) for metastatic breast cancer (MBC) is controversial. We evaluated the efficacy and safety of HDC with cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by autologous stem-cell transplantation (ASCT) for MBC patients.
Materials and Methods
From September 1994 to December 1999, 23 MBC patients were enrolled. All the patients received 2 to 10 cycles of induction chemotherapy. Before transplantation, 12 patients were in complete response (CR), nine were in partial response (PR), and two had progressive disease (PD). The HDC regimen consisted of cyclophosphamide 1,500 mg/m2/day, thiotepa 125 mg/m2/day and carboplatin 200 mg/m2/day intravenously for 4 consecutive days.
After ASCT, 13 patients (56%) had a CR, five (22%) had a PR, three (13%) had no change, while two (9%) showed a PD. Seventeen patients relapsed or progressed during the median follow-up of 78 months. The median progression-free survival (PFS) time was 11 months and the median overall survival (OS) time was 23 months. The 5-year PFS and OS rates were 22% and 25%, respectively. On the multivariate analyses, less than 4 involved lymph nodes was predictive of a better PFS and OS.
HDC with CTCb for MBC has acceptable toxicity; however, this treatment does not show a survival benefit.
Metastatic breast neoplasms; High-dose chemotherapy; Cyclophosphamide; Thiotepa; Carboplatin
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.
Conventional chemotherapy; high dose stem cell therapy; multiple myeloma
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.
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).
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.
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.
We retrospectively analyzed 106 consecutive patients with MM who underwent ASCT within 1 year of diagnosis as first-line therapy.
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.
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.
Multiple myeloma; Novel agents; Autologous stem cell transplantation; Induction and maintenance treatment
Lymphoma remains a leading cause of mortality in HIV infected patients. In the HIV negative setting high dose therapy with autologous stem cell rescue (ASCT) has been a long accepted treatment for certain malignancies such as lymphoma and leukemia. Early transplant trials excluded older patients, and patients with comorbidities such as HIV infection. However, the procedural related mortality of transplantation has decreased both due to the use of peripheral blood stem cells instead of bone marrow and due to the use of new reduced intensity conditioning regimens. During this same era, the treatment of HIV infection has also become more effective. Patients are no longer dying of opportunistic infections and in addition, their hematologic function has improved.
With these advances in HIV therapy it is possible for HIV infected patients to mobilize adequate numbers of stem cells for an autologous transplant. In addition, with appropriate antiretroviral therapy and infection prophylaxis, the HIV infected patient can tolerate intensive doses of chemotherapy. This review will summarize clinical trials of ASCT in HIV positive patients. Furthermore, the field of solid organ transplantation has grown to also include HIV positive patients. The challenges in solid organ transplantation are similar to allogeneic stem cell transplantation, namely that patients require chronic immunosuppression. This article will also review some of the approaches to allogeneic stem cell transplantation in the HIV positive patient and provide a rationale for the broader use of stem cell transplantation for appropriate HIV related hematologic malignancies.
Autologous transplant; Allogeneic Transplant; Lymphoma
Diffuse large B-cell lymphoma (DLBCL) in Koreans is frequently accompanied by extranodal (EN) disease at the time of autologous stem cell transplantation (ASCT). We sought to determine whether high EN involvement affected survival following ASCT in Koreans.
We reviewed 27 patients who had DLBCL with residual disease at ASCT: 13 with residual disease at nodal site(s) only and 14 with nodal and EN disease.
Univariate analysis showed that disease status, lactate dehydrogenase (LDH), and performance status at ASCT were predictors of survival following ASCT. The number of EN sites, as categorized by the International Prognostic Index system, had no prognostic significance. When EN involvement at ASCT was classified as negative or positive, the 2-year overall survival for the negative group was 64%, significantly better than the 14% for the positive group (p=0.021), and the event-free survival for the negative group was 62%, significantly better than the 14% for the positive group (p=0.02).
Patients who had DLBCL with residual EN involvement at ASCT showed worse outcomes following ASCT compared to those without EN disease.
Diffuse large B-cell lymphoma; Autologous stem cell transplantation; Extranodal involvement; Residual disease
Radioimmunotherapy (RIT) combines the mechanism of action and targeting capability of monoclonal antibodies with the tumoricidal effect of radiation and has shown promising results in the treatment of various hematologic malignancies. Based on RIT’s efficacy and safety profile, many investigators have evaluated its use in transplant conditioning regimens with the goal of improving long-term disease control with limited toxicity. In lymphoma, two basic transplant approaches targeting CD20 have emerged: 1. Myeloablative doses of RIT with or without chemotherapy, and 2. Standard non-myeloablative doses of RIT combined with high-dose chemotherapy. Myeloablative RIT has been shown to be feasible and efficacious using escalated doses of I-131-Tositumomab (Bexxar), Y-90-ibritumomab tiuxetan (Zevalin), and I-131-rituximab with or without chemotherapy followed by autologous stem cell transplant (ASCT). The second approach predominantly has used standard doses of Y-90-ibritumomab tiuxetan or I-131 Tositumomab plus BEAM chemotherapy followed ASCT. RIT targeting CD-45, CD-33 and CD-66 prior to allogeneic transplantation has also been evaluated for the treatment of acute leukemia. Overall RIT-based transplant conditioning for lymphoma and leukemia has been shown to be safe, effective, and feasible with ongoing randomized trials currently underway to definitively establish its place in the treatment of hematologic malignancies.
Radioimmunotherapy; stem cell transplantation; CD20; CD45; I-131; Y-90
We have reported promising outcomes using a staged approach, in which bortezomib/thalidomide/dexamethasone was used only in 14 patients with suboptimal response to VAD (vincristine/adriamycin/dexamethasone) before autologous stem cell transplantation (ASCT). Here we compared the outcomes of the staged approach with frontline PAD (bortezomib/doxorubicin/dexamethasone) or VTD (bortezomib/thalidomide/dexamethasone) induction, and analysed prognostic factors for outcome.
Patients and methods
Ninety-one transplant-eligible Chinese patients received three induction regimens prior to ASCT [staged approach (N = 25), PAD (N = 31), VTD (N = 35)]. and received thalidomide maintenance for 2 years post-ASCT.
43 (47.3%) patients had International Staging System (ISS) III disease. By an intention-to-treat analysis, the overall CR/nCR rate were 37.4% post-induction, and 62.6% post-ASCT. Five-year overall (OS) and event-free (EFS) survivals were 66% and 45.1%. There was no difference of the post-induction CR/nCR rate, EFS or OS between patients induced by these three regimens. Moreover, ISS III disease did not affect CR/nCR rates. Multivariate analysis showed that ISS and post-ASCT CR/nCR impacted OS while ISS and post-induction CR/nCR impacted EFS.
These three induction regimens produced comparable and favorable outcomes in myeloma. The unfavorable outcome of ISS stage III persisted despite upfront/early use of bortezomib. CR/nCR predicted favorable survivals.
Myeloma; Staged approach; PAD; VTD; Prognostic factors; Deep vein thrombosis
AL amyloidosis is caused by clonal plasma cells that produce immunoglobulin light chains which misfold and get deposited as amyloid fibrils. Therapy directed against the plasma cell clone leads to clinical benefit. Melphalan and corticosteroids have been the mainstay of treatment for a number of years and the recent availability of other effective agents (IMiDs and proteasome inhibitors) has increased treatment options. Autologous stem cell transplant (ASCT) has been used in the treatment of AL amyloidosis for many years. It is associated with high rates of hematologic response and improvement in organ function. However, transplant carries considerable risks. Careful patient selection is important to minimize transplant related morbidity and mortality and ensure optimal patient outcomes. As newer more affective therapies become available the role and timing of ASCT in the overall treatment strategy of AL amyloidosis will need to be continually reassessed.
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.
Mantle cell lymphoma; Autologous stem cell transplantation; HyperCVAD; CHOP; Non-Hodgkin lymphoma
Melphalan 200 mg/m2 is the standard conditioning regimen for patients with multiple myeloma (MM) with normal renal function (NRF) undergoing autologous stem cell transplant (ASCT). In an effort to escalate the dose of melphalan and to improve the efficacy, we designed a dose-escalation study of melphalan in conjunction with palifermin in patients with NRF, with the hope that a higher dose of melphalan can be administered with an acceptable degree of oral mucositis (OM). We enrolled 19 patients (18 evaluable) with NRF. Dose-escalation of melphalan administered on day –2 began at 200 mg/m2 with palifermin administered at a fixed dose of 60 mcg/kg/day. Palifermin was given as an i.v. bolus on day −5, −4, and −3, and then on day +1, +2, and +3. Subsequent dose escalations of melphalan were done at 20 mg/m2 increments up to a maximum dose of 280 mg/m2. Of 18 evaluable patients, there were no treatment-related deaths by day 100. The median age was 48.5 years (range, 33-65 years). The most common adverse events related to palifermin included rash (18 events, no ≥grade 3 events), elevation of amylase (10 events, 4 were grade 3 but asymptomatic), and lipase (5 events, 2 were grade 3 but asymptomatic), edema (11 events, no ≥grade 3). The overall incidence of OM grade 3 was 44% (8/18) with a median duration of severe mucositis of 5 days (range, 3-6 days). Eleven patients (61%) required opioid analgesics. None of the patients received total parenteral nutrition (TPN)/nasogastric feeding. Two of 6 patients who were given melphalan 280 mg/m2 did not develop OM. Cardiac dose-limiting toxicity (DLT) in the form of atrial fibrillation did occur in 1 of 6 patients treated with melphalan 280 mg/m2. Palifermin has permitted safe dose escalation of melphalan up to 280 mg/m2, thus reaching the cumulative dosage of melphalan administered in tandem ASCT. This higher dose of melphalan has the potential to improve the efficacy and, hopefully, outcomes of patients with MM with a single ASCT. A phase 2 trial is necessary to better delineate the antimyeloma efficacy of this regimen.
Palifermin; Oral mucositis; High-dose melphalan
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.
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.
Multiple Myeloma; Transplantation; Bortezomib; Lenalidomide