ABSTRACT
Whole blood cytokine release assays (CRA) assessing cellular immunity to gluten could simplify the diagnosis and monitoring of coeliac disease (CD). We aimed to determine the effectiveness of electrochemiluminescence CRA to detect responses to immunodominant gliadin peptides. HLA-DQ2·5+ CD adults (cohort 1, n = 6; cohort 2, n = 12) and unaffected controls (cohort 3, n = 9) were enrolled. Cohort 1 had 3-day gluten challenge (GC). Blood was collected at baseline, and for cohort 1 also at 3 h, 6 h and 6 days after commencing 3-day GC. Gliadin peptide-stimulated proliferation, interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and 14- and 3-plex electrochemiluminescence CRA were performed. Poisson distribution analysis was used to estimate responding cell frequencies. In cohort 1, interleukin (IL)-2 dominated the gliadin peptide-stimulated cytokine release profile in whole blood. GC caused systemic IL-2 release acutely and increased gliadin peptide-stimulated IFN-γ ELISPOT and whole blood CRA responses. Whole blood CRA after GC was dominated by IL-2, but also included IFN-γ, C-X-C motif chemokine ligand 10/IFN-γ-induced protein 10 (CXCL10/IP-10), CXCL9/monokine induced by IFN-γ (MIG), IL-10, chemokine (C-C motif) ligand 3/macrophage inflammatory protein 1-alpha (CCL3/MIP-1α), TNF-α and IL-8/CXCL8. In cohorts 2 and 3, gliadin peptide-stimulated whole blood IL-2 release was 100% specific and 92% sensitive for CD patients on a gluten-free diet; the estimated frequency of cells in CD blood secreting IL-2 to α-gliadin peptide was 0·5 to 11 per ml. Whole blood IL-2 release successfully mapped human leucocyte antigen (HLA)-DQ2·5-restricted epitopes in an α-gliadin peptide library using CD blood before and after GC. Whole blood IL-2 release assay using electrochemiluminescence is a sensitive test for rare gliadin-specific T cells in CD, and could aid in monitoring and diagnosis. Larger studies and validation with tetramer-based assays are warranted.
Subject(s)
Celiac Disease/immunology , Glutens/immunology , Interleukin-2/immunology , T-Lymphocytes/immunology , Adult , Aged , Chemokine CXCL10/immunology , Cytokines/immunology , Epitopes, T-Lymphocyte/immunology , Female , Gliadin/immunology , HLA-DQ Antigens/immunology , Humans , Immunity, Cellular/immunology , Interferon-gamma/immunology , Interleukin-8/immunology , Male , Middle Aged , Peptide Fragments/immunology , Peptides/immunology , Young AdultABSTRACT
High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Boronic Acids , Multiple Myeloma , Pyrazines , Stem Cell Transplantation , Transplantation Conditioning , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Autografts , Boronic Acids/administration & dosage , Boronic Acids/adverse effects , Bortezomib , Carmustine/administration & dosage , Carmustine/adverse effects , Cytarabine/administration & dosage , Cytarabine/adverse effects , Female , Follow-Up Studies , Humans , Male , Melphalan/administration & dosage , Melphalan/adverse effects , Middle Aged , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Podophyllotoxin/administration & dosage , Podophyllotoxin/adverse effects , Pyrazines/administration & dosage , Pyrazines/adverse effects , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methodsABSTRACT
BACKGROUND: Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). This pilot prospective randomized clinical trial compares valganciclovir (VGV) to ganciclovir (GCV) as pre-emptive therapy for CMV viremia in the post-allogeneic HSCT population. METHODS: Patients undergoing allogeneic HSCT who were at risk for CMV viremia were monitored post HSCT by weekly quantitative whole blood polymerase chain reaction. Pre-emptive therapy was delayed until the viral load (VL) was >10,000 copies/mL once, or >5000 copies/mL twice. Patients were randomized to either GCV 5 mg/kg twice a day (b.i.d.) for 7 days followed by daily GCV 5 mg/kg for up to 21 days, or VGV 900 mg b.i.d. for 7 days followed by 900 mg daily for up to 21 days. The primary endpoint was clearance of viremia (VL <5000 copies/mL) within 28 days of initiation of therapy. RESULT: In total, 37 patients were enrolled; 19 patients received treatment with VGV and 18 patients received treatment with GCV. The VGV was not inferior in efficacy to GCV as pre-emptive therapy, with rates of viral clearance at 28 days of 89.5% and 83%, respectively (P-value for non-inferiority = 0.030). Toxicities were similar between the 2 arms. No patients developed CMV disease. CONCLUSIONS: In this trial, the rates of clearance of viremia appear to be similar with VGV and GCV.
Subject(s)
Antiviral Agents/therapeutic use , Cytomegalovirus Infections/prevention & control , Ganciclovir/analogs & derivatives , Ganciclovir/therapeutic use , Hematopoietic Stem Cell Transplantation , Viremia/prevention & control , Administration, Oral , Adolescent , Adult , Antiviral Agents/administration & dosage , Cytomegalovirus/drug effects , Cytomegalovirus Infections/virology , Dose-Response Relationship, Drug , Female , Ganciclovir/administration & dosage , Humans , Male , Middle Aged , Pilot Projects , Polymerase Chain Reaction , Prospective Studies , Transplantation, Homologous , Valganciclovir , Viral Load/drug effects , Viremia/virology , Young AdultABSTRACT
Germ cell tumors carry an excellent prognosis with platinum-based therapy upfront. The patients who either relapse or demonstrate refractoriness to platinum pose a challenge. There exist many reports in the literature on the use of high-dose chemotherapy and stem cell rescue improving the outcome in patients with relapsed germ cell tumors. However, the reports have great variability in the patient selection, prior treatments, the choice of the conditioning regimen and variability of the doses within the same regimen. In this report, we present 37 patients who underwent a uniform protocol of high-dose chemotherapy with stem cell rescue. Stem cell mobilization was performed with high-dose CY (4 g per m(2)) and we were able to collect adequate cells for marrow rescue in all patients. Patients received a high-dose regimen with etoposide (800 mg/m(2) per day) days -6, -5 and -4 as a continuous infusion, carboplatin (667 mg/m(2) per day) on days -6, -5 and -4 as a 1 h infusion, and CY (60 mg/kg per day) on days -3 and -2. In this high-risk group of patients, high-dose chemotherapy with autologous stem cell rescue led to a 3-year overall survival of 57% and a 3-year event-free survival of 49%. The results are reflective of a single procedure. No tandem transplants were performed. The treatment-related mortality was low at 3% in this heavily pretreated group.
Subject(s)
Hematopoietic Stem Cell Transplantation , Neoplasms, Germ Cell and Embryonal/therapy , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carboplatin/administration & dosage , Child , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Etoposide/administration & dosage , Female , Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cells/pathology , Humans , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/drug therapySubject(s)
Hematopoietic Stem Cell Transplantation/methods , Transplantation, Homologous/methods , Anemia/therapy , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Leukemia/therapy , Lymphoma/therapy , Transplantation, Homologous/adverse effectsABSTRACT
BACKGROUND: Acute graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Preclinical studies have suggested that a T-cell subset with a CD4-/CD8- double-negative (DN) T-cell phenotype is capable of suppressing GVHD. Double-negative T cells can be mobilized into the peripheral blood with granulocyte colony-stimulating factor (G-CSF) and enriched by density centrifugation. The current study was performed to study the feasibility and safety of applying a density gradient separation technique for enrichment of CD34+ and DN T cells, while depleting CD4+ and CD8+ single-positive (SP) T cells from peripheral blood progenitor cells (PBPCs) for the purpose of allogeneic transplantation. METHODS: Twenty-five patients with advanced hematologic malignancies were treated with a myeloablative preparative regimen consisting of fractionated total body irradiation, etoposide, and cyclophosphamide. Human leukocyte antigen identical donors were mobilized with G-CSF PBPC collected by apheresis. The apheresis product was applied to a single-step density gradient, and the low-density cell population was collected. The low-density cell population was infused as the sole source of allogeneic cells after myeloablative therapy. Graft versus host disease prophylaxis consisted of cyclosporine with or without prednisone. RESULTS: CD34 cell recovery was efficient with a median 72% yield, providing for a median CD34+ cell dose of 6.5 x 10(6)/kg (range,1.0- 13.9 x 10(6)/kg). CD3+CD4+ or CD3+CD8+ SP T cells were depleted by a median of 94.4% (range, 58.8- 99.2%), and the ratio of CD34+:SP T cells increased 10-fold. Double-negative T cells were depleted by 92% (range, 18.8- 99.4%), thus the ratio of DN:SP T cells increased less than 2-fold in 71% of apheresis samples tested. Hematopoietic engraftment was rapid, and there was no occurrence of graft failure in examinable patients. Median time to absolute neutrophil count greater than 0.5 x 10(9)/L and platelet count greater than 20 x 10(9)/L was 10.5 and 12 days, respectively. The incidence of Grade 2-4 acute GVHD was 26% (95% confidence interval [CI], 6-45%), although not all patients were examinable due to an unexpectedly high nonrecurrence mortality that at Day 180 was 62% (95% CI, 40-83%). CONCLUSIONS: These data suggest that T-cell subset manipulation via density gradient separation is a safe procedure and allowed rapid hematopoietic recovery. Selective enrichment of a donor DN T-cell subset was observed in only a few and was not associated with a reduced incidence of GVHD. However, the low-density selected cells still resulted in GVHD, and there was a high treatment-related mortality.
Subject(s)
Antigens, CD34/analysis , Cell Separation/methods , Hematopoietic Stem Cell Transplantation , Leukemia/therapy , Lymphoma/therapy , T-Lymphocytes/immunology , Adult , Centrifugation, Density Gradient , Female , Flow Cytometry , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Mobilization/methods , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Leukemia, Myeloid, Acute/therapy , Lymphoma, Non-Hodgkin/therapy , Male , Middle Aged , Multiple Myeloma/therapy , Myelodysplastic Syndromes/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transplantation, Homologous , Treatment OutcomeABSTRACT
A retrospective analysis was performed to investigate the outcome of high-dose therapy (HDT) and autologous hematopoietic cell transplantation in patients with follicular lymphomas beyond first remission. Ninety-two patients with primary induction failure or relapsed follicular low-grade lymphoma (FLGL), follicular large cell lymphoma (FLCL), and transformed follicular lymphoma (TFL) were treated with myeloablative therapy consisting of etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and either carmustine (BCNU;15 mg/kg) or fractionated total body irradiation (FTBI; 1200 cGy) followed by transplantation of purged autologous bone marrow or peripheral blood hematopoietic cells. For the 49 patients with relapsed FLGL, the median age was 49 years and the median interval from diagnosis to HDT was 30 months. The 4-year estimate of overall survival (OS) was 60% (95% confidence interval [CI], 45%-75%) and of disease-free survival (DFS) was 44% (95% CI, 29%-59%). Treatment with the FTBI-containing HDT regimen was associated with significantly longer DFS (P = .04) and OS (P = .04) in our multivariate analysis. OS was also significantly longer among those treated with 3 or fewer chemotherapy regimens. For the 26 FLCL patients, the median age was 51 years and in 31% the indication for HDT was primary induction failure. For FLCL patients, the 4-year estimate of OS was 58% (95% CI, 37%-79%) and of DFS was 51% (95% CI, 30%-72%). Among the 17 patients with TFL, 13 (76%) transformed at first relapse, and only 6 patients (35%) achieved complete remission with salvage therapy prior to HDT. For TFL patients, the 4-year estimate of OS was 50% (95% CI, 24%-76%) and of DFS 49% (95% CI, 20%-78%). There were 3 occurrences of myelodysplasia (1 after treatment with TBI, 2 after BCNU treatment), yielding an estimated incidence of 7% (95% CI, 0%-16%) at 56 months. This analysis shows that relapsed FLGL patients treated with 3 or fewer different chemotherapy regimens show inferior survival. The HDT regimen containing FTBI appears to be superior to the BCNU-based regimen for relapsed FLGL, although longer follow-up is needed to evaluate late effects. Lastly, patients with TFL or induction failure and relapsed FLCL can achieve survival outcome comparable to those observed with the indolent follicular lymphomas.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Hematopoietic Stem Cell Transplantation , Lymphoma, Follicular/therapy , Adult , Aged , Carmustine/administration & dosage , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Etoposide/administration & dosage , Female , Humans , Lymphoma, Follicular/classification , Lymphoma, Follicular/complications , Male , Middle Aged , Neural Tube Defects/etiology , Prognosis , Recurrence , Remission Induction , Retrospective Studies , Survival Analysis , Transplantation, Autologous , Treatment Outcome , Whole-Body IrradiationABSTRACT
High-dose CBV (cyclophosphamide, carmustine, and etoposide) in combination with autologous HCT achieves survival rates of approximately 50% at 5 years in recurrent or refractory Hodgkin's disease (HD). However, carmustine (BCNU) dose-dependent pulmonary toxicity occurs in 20% to 30% of patients. A decreased incidence of interstitial pneumonitis as well as a possible benefit in efficacy has been reported with lomustine (CCNU) compared to BCNU in the standard dose setting. In a dose-escalation study, we substituted CCNU for BCNU in the CBV regimen for 16 patients with HD (n = 12) or non-Hodgkin's lymphoma (n = 4). Based on the promising results, an additional 47 consecutive patients with HD were treated with the following regimen: CCNU (15 mg/kg) orally on day -6, etoposide (60 mg/kg) intravenously on day -4, and cyclophosphamide (100 mg/kg) intravenously on day -2. Peripheral blood progenitor cells and/or bone marrow were infused on day 0. With a median follow-up for the surviving patients of 3.2 years (range, 0.8-9.9 years), the 3-year overall survival rate was 57% (CI, +/-15%), event-free survival was 52% (CI, +/-14%), and freedom from progression was 68% (CI, +/-14%). There were 21 deaths, 10 due to HD. Six patients died due to respiratory failure. Interstitial pneumonitis occurred in 63% of patients and could not be correlated with prior chest radiotherapy. This regimen demonstrated survival rates similar to those of historical studies that used the CBV regimen. However, the incidence of interstitial pneumonitis was in excess of expected.
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Hodgkin Disease/therapy , Lomustine/administration & dosage , Stem Cell Transplantation/methods , Adolescent , Adult , Aged , Antineoplastic Agents, Alkylating/toxicity , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carmustine/administration & dosage , Carmustine/toxicity , Child , Cyclophosphamide/administration & dosage , Dose-Response Relationship, Drug , Etoposide/administration & dosage , Female , Hodgkin Disease/complications , Humans , Lomustine/toxicity , Lung Diseases, Interstitial/chemically induced , Lymphoma, Non-Hodgkin/complications , Lymphoma, Non-Hodgkin/therapy , Male , Maximum Tolerated Dose , Middle Aged , Salvage Therapy/adverse effects , Salvage Therapy/methods , Salvage Therapy/mortality , Stem Cell Transplantation/adverse effects , Stem Cell Transplantation/mortality , Survival Rate , Therapeutic Equivalency , Transplantation, AutologousABSTRACT
The idiotype (Id) determinants on the multiple myeloma immunoglobulin can serve as tumor-specific antigens. An anti-Id immune response may stem the growth of the malignant clone. We report on 26 patients treated at our institution with high-dose chemotherapy and peripheral blood progenitor cell transplantation (PBPCT) and vaccinated with the Id protein. The patients received chemotherapy and PBPCT to establish a minimal residual disease state. After high-dose therapy, the patients received a series of monthly immunizations consisting of 2 intravenous infusions of dendritic cells (DCs) pulsed with either Id protein or Id coupled with keyhole limpet hemocyanin (KLH) as an immunogenic carrier protein, followed by subcutaneous boosts of Id-KLH conjugates. DCs were obtained in all patients from a leukapheresis product 3 to 9 months after PBPCT. Patients were observed for toxicity, immune responses, and tumor status. The DC infusions and the administration of Id-KLH boosts were well tolerated, with patients experiencing only minor and transient side effects. Of the patients, 24 of 26 generated a KLH-specific cellular proliferative immune response. Only 4 patients developed an Id-specific proliferative immune response. Three of these immune responders were in complete remission at the time of vaccination. A total of 17 patients are alive at a median follow-up of 30 months after transplantation. Id vaccination with autologous DCs is feasible for myeloma patients after transplantation. Id-specific cellular responses can be induced in patients who are in complete remission. Further studies are needed to increase the rate of anti-Id immune responses in patients who do not achieve complete remission.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Dendritic Cells/transplantation , Hematopoietic Stem Cell Transplantation , Multiple Myeloma/therapy , Adult , Combined Modality Therapy , Dendritic Cells/immunology , Female , Humans , Immunoglobulin Idiotypes/administration & dosage , Immunoglobulin Idiotypes/immunology , Immunotherapy , Male , Middle Aged , Multiple Myeloma/immunology , Transplantation, Autologous , VaccinationABSTRACT
We conducted a pilot study in 20 patients with high-risk or recurrent/refractory non-Hodgkin's lymphoma (NHL) using high-dose sequential chemotherapy (HDSC) and autologous hematopoietic cell transplantation (AHCT). After cytoreduction with standard salvage therapy, HDSC/AHCT was administered in 4 phases at 2- to 4-week intervals. Phase 1 consisted of cyclophosphamide 7 g/m2 followed by granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg per day and leukapheresis upon recovery from white blood cell nadir. The hematopoietic cell product was enriched by Percoll gradient separation and purged with a B-cell or T-cell monoclonal antibody panel and complement. Phase 2 consisted of methotrexate 8 g/m2 with leucovorin rescue and vincristine 1.4 mg/m2. Phase 3 was etoposide 2 g/m2 with G-CSF 5 microg/kg per day. In phase 4, the preparative regimen of mitoxantrone 60 mg/m2 and melphalan 180 mg/m2 was administered followed by AHCT. The NHL histologies were diffuse large cell, follicular/diffuse mixed, small noncleaved cell, T-cell-rich B-cell, lymphoblastic, and peripheral T cell. The remission status was first partial remission (PR1; n = 1) or beyond first complete remission (post-CR1; n = 19). Of the 20 patients enrolled, 11 proceeded through all 4 phases. Nine were removed from the study after the first or second phase because of progressive disease (n = 5), poor hematopoietic cell mobilization (n = 1), excessive toxicity (n = 2), and chronic active hepatitis C (n = 1). Treatment-related toxicities in the remaining 11 transplant recipients were cardiomyopathy, hemorrhagic cystitis, persistent cytopenias, acute renal failure, abnormal liver function test results, and infectious complications. There were no treatment-related deaths. Eight of the 11 transplant recipients were alive, 6 without disease, at a median follow-up of 2.7 years. The estimated median 2-year event-free survival was 55%, and overall survival was 70%. We conclude that HDSC/AHCT in refractory/recurrent NHL is associated with considerable acute and chronic toxicities. Given the toxicity profile, efficacy data were not sufficiently promising to warrant further study.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bone Marrow Purging , Hematopoietic Stem Cell Mobilization/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , Lymphoma, Non-Hodgkin/drug therapy , Transplantation Conditioning/adverse effects , Acute Kidney Injury/chemically induced , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Diseases/chemically induced , Cardiomyopathies/chemically induced , Chemical and Drug Induced Liver Injury/etiology , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Cystitis/chemically induced , Disease Progression , Disease-Free Survival , Drug Administration Schedule , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Follow-Up Studies , Granulocyte Colony-Stimulating Factor/therapeutic use , Hemorrhage/chemically induced , Humans , Infections , Leucovorin/administration & dosage , Life Tables , Lymphoma, Non-Hodgkin/mortality , Lymphoma, Non-Hodgkin/therapy , Male , Melphalan/administration & dosage , Melphalan/adverse effects , Methotrexate/administration & dosage , Methotrexate/adverse effects , Middle Aged , Mitoxantrone/administration & dosage , Mitoxantrone/adverse effects , Pilot Projects , Salvage Therapy , Survival Analysis , Survival Rate , Transplantation, Autologous , Treatment Outcome , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
The role of high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell rescue in breast cancer is still controversial. We analyzed the outcomes of 1111 consecutive patients with histologically proven breast cancer who underwent HDCT at 5 major California medical centers. The overall treatment-related mortality (TRM) was 2.3%. TRM was not influenced by disease stage or the HDCT regimen delivered, but it was influenced by hematopoietic graft source. The TRM was 6.1% when bone marrow with or without blood stem cells was used, but only 1.4% when blood stem cells alone were used (P < .001). With a median follow-up of 2.8 years (range, 0.1-8.2 years) after HDCT and autologous hematopoietic stem cell rescue, the estimated 5-year event-free survival (EFS) and overall survival (OS) for stage II/IIIA patients with > or =10 involved axillary lymph nodes were 67% and 76%, respectively. Patients with metastatic breast cancer (MBC) (median follow-up, 1.9 years [range, 0.03-8.3 years]) achieving a complete response (CR) to conventional-dose chemotherapy or rendered to a "no evidence of disease" status before HDCT had significantly better estimated 5-year EFS and OS (28% and 57%, respectively) than those achieving a partial response before HDCT (19% and 27%, respectively; P < or = .0001). Our data suggest that HDCT with hematopoietic stem cell rescue is safe and can be beneficial to patients with high-risk primary breast cancer and for those with MBC achieving CR/no evidence of disease.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Hematopoietic Stem Cell Transplantation , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation , Breast Neoplasms/mortality , Breast Neoplasms/therapy , California/epidemiology , Carboplatin/administration & dosage , Carmustine/administration & dosage , Cisplatin/administration & dosage , Clinical Trials, Phase II as Topic , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Female , Follow-Up Studies , Humans , Life Tables , Lymphatic Metastasis , Mastectomy , Mitoxantrone/administration & dosage , Multicenter Studies as Topic , Radiotherapy, Adjuvant , Retrospective Studies , Survival Analysis , Thiotepa/administration & dosage , Treatment OutcomeABSTRACT
Our purpose was to evaluate the outcome and costs of high-dose chemotherapy and autologous peripheral blood progenitor cell (PBPC) transplantation in patients with the inability to mobilize sufficient numbers of PBPCs to allow rapid engraftment after PBPC transplantation. We treated 172 consecutive non-Hodgkin's lymphoma (NHL) patients with cyclophosphamide and granulocyte colony-stimulating factor followed by apheresis to collect PBPCs. The cells were separated on a Percoll gradient and purged with monoclonal antibodies and complement. The patients were categorized as "good" mobilizers if a collection of > or =2 x 10(6) CD34+ cells/kg was obtained (n = 138, 80%) or "poor" mobilizers if <2 x 10(6) CD34+ cells/kg were obtained (n = 34, 20%). With a median follow-up of 3.5 years, there is no statistically significant difference in actuarial event-free survival, overall survival, or relapse for good mobilizers compared with poor mobilizers. However, there was a trend toward increasing nonrelapse, transplantation-related mortality of 11.8% for poor mobilizers versus 3.6% for good mobilizers (P = .08) and early death from all causes including relapse within 120 days (poor 20.6% versus good 8.7%, P = .06). The total cost for bone marrow transplantation-related care was significantly higher, at $140,264 for poor mobilizers versus $80,833 for good mobilizers (P = .0001). The population of patients with NHL who mobilize PBPCs poorly into the circulation have a higher cost for posttransplant support. However, there is no significant difference in relapse, event-free survival, or overall survival for such patients compared with those who mobilize PBPCs easily.
Subject(s)
Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cell Transplantation , Lymphoma, Non-Hodgkin/therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood Cell Count , California/epidemiology , Carmustine/administration & dosage , Costs and Cost Analysis , Cyclophosphamide/administration & dosage , Disease-Free Survival , Etoposide/administration & dosage , Female , Follow-Up Studies , Graft Survival , Health Care Costs , Hematopoietic Stem Cell Mobilization/economics , Hematopoietic Stem Cell Transplantation/economics , Hematopoietic Stem Cell Transplantation/mortality , Humans , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/economics , Lymphoma, Non-Hodgkin/mortality , Male , Middle Aged , Remission Induction , Treatment Outcome , Whole-Body IrradiationABSTRACT
We performed a retrospective review to investigate pulmonary toxicity syndrome (PTS) in a cohort of breast cancer patients undergoing BCNU-containing high-dose chemotherapy (HDC). Our aim was to characterize presentation, identify risk factors, determine outcome following therapy, and find any association with differences in survival. We reviewed the data of 152 patients with stage II or III or metastatic breast cancer treated with cyclophosphamide 5625 mg/m2, cisplatin 165 mg/m2, and BCNU 600 mg/m2 followed by autologous peripheral blood hematopoietic cell transplantation. During follow-up, PTS was diagnosed when the following criteria were met: (1) presentation with typical clinical symptoms of PTS, (2) an absolute carbon monoxide diffusion capacity (DLCO) decline of 10% compared with pre-HDC DLCO, and (3) no clinical evidence of active pulmonary infection. Patients were then treated with a course of corticosteroid therapy. The incidence of PTS for all 152 patients was 59%, with a median onset at 45 days (range, 21-149 days) post-HDC. The median absolute DLCO decrement was 26% (range, 10%-73%) at diagnosis of PTS. There was no significant correlation between patient age, stage of breast cancer, pre-HDC chemotherapy regimen, pre-HDC chest wall radiotherapy, tobacco use, prior lung disease, or baseline pulmonary function test results and the development of PTS. We did observe an interesting association between PTS and the development of a noncholestatic elevation of transaminases. Of PTS patients treated with prednisone therapy for a median of 105.5 days (range, 44-300 days), 91% achieved resolution of their PTS without pulmonary sequelae. At 3 years, the overall survival (OS) of stage II or III patients who developed PTS was 84% (95% confidence interval [CI], 73%-95%); of metastatic breast cancer patients with PTS, the OS was 58% (95% CI, 38%-78%). These values were not significantly different from those of patients who did not develop PTS (91% [95% confidence interval [CI], 81%-100%] and 53% [95% CI, 32%-74%], respectively). No significant differences in disease-free or event-free survival were observed between patients with and without PTS. The incidence of PTS in breast cancer patients treated with a BCNU-containing HDC regimen can be remarkably high. Treatment with a course of corticosteroid therapy is successful in the vast majority.
Subject(s)
Breast Neoplasms/drug therapy , Carmustine/toxicity , Hematopoietic Stem Cell Transplantation/adverse effects , Lung Diseases/chemically induced , Adult , Aged , Alanine Transaminase/blood , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/toxicity , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/toxicity , Breast Neoplasms/complications , Breast Neoplasms/therapy , Breast Neoplasms, Male/complications , Breast Neoplasms, Male/drug therapy , Carmustine/administration & dosage , Cohort Studies , Disease-Free Survival , Female , Humans , Liver Function Tests , Lung Diseases/drug therapy , Male , Middle Aged , Neoplasm Metastasis , Prednisone/administration & dosage , Radiotherapy, Adjuvant/adverse effects , Respiratory Function Tests , Retrospective Studies , Risk Factors , Survival Rate , Syndrome , Transplantation, Autologous/adverse effects , Treatment OutcomeABSTRACT
We report here the transplantation of extensively purified "mobilized" peripheral blood CD34Thy-1 hematopoietic stem cells from 22 patients with recurrent or metastatic breast cancer. Patients were mobilized with either high-dose granulocyte colony-stimulating factor (G-CSF) alone or cyclophosphamide plus G-CSE Median purity of the stem cell product at cryopreservation was 95.3% (range, 91.1%-98.3%), and viability was 98.6% (range, 96.5%-100%). After high-dose chemotherapy with carmustine, cisplatin, and cyclophosphamide, CD34+Thy-1 cells at a median dose of 11.3 x 10(5) per kilogram (range, 4.7-163 x 10(5) per kilogram) were infused. No infusion-related toxicity was observed. Neutrophil recovery was prompt, with median absolute neutrophil count >500/microL by day 10 (range, 8-15 days) and >1000/microL by day 11 (range, 8-17 days). Median platelet recovery (>20,000/microL) was observed by day 14 (range, 9-42 days) and >50,000/microL by day 17 (range, 11-49 days). Tumor cell depletion below the limits of detection of a sensitive immunofluorescence-based assay was accomplished in all patients who had detectable tumor cells in apheresis products before processing. Although CD4+ T-cell reconstitution was slow, no unusual infections were observed. Neither early nor late graft failure was observed, and no patient required infusion of unmanipulated backup cells. At a median follow-up of approximately 1.4 years and a maximum follow-up of 2.5 years, 16 of the 22 patients remain alive, with 9 free of disease progression, and have stable blood counts. In summary, highly purified CD34+Thy-1+ cells used as the sole source of the hematopoietic graft result in rapid and sustained hematopoietic engraftment.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Adult , Aged , Antigens, CD34 , Breast Neoplasms/pathology , Carmustine/administration & dosage , Cisplatin/administration & dosage , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Female , Hematopoietic Stem Cell Mobilization , Humans , Middle Aged , Neoplasm Metastasis , Transplantation, AutologousABSTRACT
We have previously demonstrated a decrease in the incidence of acute graft-versus-host disease (GVHD) with the addition of methotrexate (MTX) to cyclosporine (CSP) and prednisone (PSE) chemotherapy in patients with leukemia. We have now completed a prospective randomized trial comparing the 3-drug regimen (CSP/MTX/PSE, including 3 doses of MTX) to the standard 2-drug regimen (CSP/MTX, including 4 doses of MTX) to investigate the benefit of PSE used up front for the prevention of acute and chronic GVHD. In the trial, 193 patients were randomized and 186 were included in the final analysis. All patients received a bone marrow graft from a fully histocompatible sibling donor. The preparatory regimen consisted of fractionated total-body irradiation (fTBI) and etoposide in all but 13 patients, who received fTBI and cyclophosphamide. The patients were randomized to receive either CSP/MTX/PSE or CSP/MTX. The 2 groups were well balanced with respect to diagnosis, disease stage, age, donor-recipient sex, and parity. In an intent-to-treat analysis, the incidence of acute GVHD was 18% (95% confidence interval [CI] 12-28) for the CSP/MTX/PSE group compared with 20% (CI 10-26) for the CSP/,MTX group (P = .60), with a median follow up of 2.2 years. Overall survival was 65% for those receiving CSP/MTX/PSE and 72% for those receiving CSP/MTX (P = .10); the relapse rate was 15% for the CSP/MTX/PSE group and 12% for the CSP/MTX group (P = .83). The incidence of chronic GVHD was similar (46% versus 52%; P = .38), with a follow-up of 0.7 to 6.0 years. Of interest, 21 patients went off study due to GVHD (5 in the CSP/MTX/PSE group and 16 in the CSP/MITX group [P = .02]), and 11 patients went off study because of alveolar hemorrhage (3 in the CSP/MTX/PSE group and 8 in the CSP/MTX group [P = .22]). The addition of PSE did not result in a higher incidence of infectious complications, bacterial (66% versus 58%), viral (77% versus 66%), or fungal (20% versus 20%), in those receiving CSP/MTX/PSE versus CSP/MTX, respectively. These data suggest that the addition of PSE was associated with a somewhat lower incidence of early posttransplantation complications but did not have a positive impact on the incidence of acute or chronic GVHD or event-free or overall survival.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Bone Marrow Transplantation , Cyclosporine/administration & dosage , Graft vs Host Disease/prevention & control , Immunosuppressive Agents/administration & dosage , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Leukemia/therapy , Methotrexate/administration & dosage , Prednisone/administration & dosage , Acute Disease , Adolescent , Adult , Bone Marrow Transplantation/adverse effects , Child , Child, Preschool , Double-Blind Method , Graft vs Host Disease/etiology , Humans , Infant , Middle Aged , Prospective Studies , Survival Analysis , Transplantation, Homologous , Treatment OutcomeABSTRACT
BACKGROUND: Because all patients receiving bone marrow transplant (BMT) and peripheral blood progenitor cell transplant (PBPCT) experience gastrointestinal (GI) toxicity from the preparative regimen of chemotherapy, with or without radiation, oral glutamine was administered during the preparatory regimen and after transplant to maintain GI structure and function. METHODS: To evaluate effects of oral glutamine on nutritional status and overall outcome, a prospective, randomized, double-blinded study was performed on 58 autologous and allogeneic BMT patients. Patients received 30 g of oral glutamine or placebo daily. RESULTS: The trends of decreased median length of stay and the median number of days of total parenteral nutrition (TPN) were seen in the group supplemented with the >0.285-g/kg (the recommended dosage) dose of glutamine; however, there was no statistically significant difference in the nutritional status and overall patient outcome as assessed by days receiving TPN, number of days required until oral intake resumed, length of hospitalization, number of days and highest grade of mucositis, and quantity and number of days of diarrhea. CONCLUSIONS: This study does not support the hypothesis that oral glutamine may offer benefit. Further investigation is required regarding clinical tools for determining effectiveness, administration for tolerance and compliance, dosage, and potential of oral glutamine usage.
Subject(s)
Bone Marrow Transplantation , Glutamine/therapeutic use , Leukemia/therapy , Parenteral Nutrition, Total , Administration, Oral , Adolescent , Adult , Double-Blind Method , Female , Glutamine/administration & dosage , Humans , Length of Stay , Male , Middle Aged , Nutritional StatusABSTRACT
Dose-intensive chemotherapy appears to be important in the treatment of patients with recurrent solid tumors. Expanding upon our prior experience, we report the results of our most recent approach to administering dose-intensive therapy using four cycles of moderately high-dose chemotherapy with hematopoietic cell support for patients with metastatic breast cancer. This outpatient therapy includes high-dose melphalan, thiotepa, and paclitaxel for two cycles followed by mitoxantrone, thiotepa, and paclitaxel for two cycles, with each cycle supported with autologous peripheral blood progenitor cells (PBPCs). Between December 1994 and June 1996, 16 patients with recurrent or refractory breast cancer were enrolled in this prospective study. They had received a median of two previous chemotherapy regimens, with a median of nine prior cycles of chemotherapy. For mobilization of autologous PBPCs, patients received cyclophosphamide, 4 g/m2, followed by granulocyte colony-stimulating factor (G-CSF). PBPCs were collected by apheresis. Each day's collection was divided into four equal fractions, and each fraction was infused after each cycle of combination therapy. Cycles 1 and 2 consisted of melphalan, 80 mg/m2, thiotepa, 300 mg/m2, and paclitaxel, 200 mg/m2. Cycles 3 and 4 were comprised of mitoxantrone, 30 mg/m2, and thiotepa and paclitaxel at the same doses as in the first two cycles. The cyclophosphamide infusion was administered in the hospital, whereas all subsequent infusions of chemotherapy and PBPCs were performed on an outpatient basis. The first seven patients were randomized to receive alternate cycle G-CSF or placebo on day +1 of each cycle. Including the initial pulse of cyclophosphamide, 67 (84%) of a planned 80 total courses of chemotherapy were delivered. Of the planned 64 cycles of high-dose combination chemotherapy, 52 cycles (81%) were delivered. Treatment was discontinued for progressive disease (one patient) or morbidity (five patients). Twelve of 16 patients completed at least three cycles of therapy. Nine patients completed all four cycles. One death resulted from fungal sepsis. In 20 cycles delivered to the first seven patients, day +1 G-CSF versus placebo was administered, with a median WBC recovery of 10 versus 13 days, respectively (P = 0.048 in cycle 1). The median duration of response was almost 9 months, and the median survival was 18 months after therapy. With a median follow-up of 1.5 years and longest follow-up of 4.2 years, two patients continue to be without evidence of disease. The 3-year event-free survival, freedom from progression, and overall survival are 19%, 20%, and 31%, respectively. This four-cycle regimen of high-dose combination therapy supported with hematopoietic progenitor cells is feasible, but it is associated with a range of posttransplant complications. The efficacy of such a treatment would have to be substantially superior to that of other currently available therapies, including single autologous transplant procedures, to justify the prolonged period of treatment, multiple episodes of pancytopenia, and associated toxicities, including infectious risks. G-CSF administration after each PBPC infusion appears to accelerate time to neutrophil recovery but does not affect red cell or platelet engraftment.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Feasibility Studies , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Melphalan/administration & dosage , Middle Aged , Mitoxantrone/administration & dosage , Neoplasm Metastasis , Paclitaxel/administration & dosage , Recurrence , Thiotepa/administration & dosage , Transplantation, Autologous , Treatment OutcomeABSTRACT
We performed a retrospective analysis of 473 consecutive adult patients undergoing autologous bone marrow transplantation for hematologic malignancies between 1988 and 1995. The analysis examined whether significant deviation from ideal body mass index is associated with a decrease in event-free survival (EFS), an increase in nonrelapse mortality (NRM) including late toxicities and second malignancies, or relapse. Chemotherapy dosing in underweight and overweight patients is administered based on the relationship of admission body weight (ABW) to ideal body weight (IBW). Doses were adjusted for obesity; however, the adjustment did not obviate increased risk for NRM. Patients were categorized into five groups according to the relationship of ABW to age-adjusted body mass index (aBMI) as a percent of actual BMI, as follows: group I, 70-79%; group II, 80-99%; group III, 100-119%; group IV, 120-139%; and group V, 140-199% aBMI. When body weight was expressed as percent BMI adjusted for age, there was a significantly increased risk for NRM in groups I and IV (p = 0.03 and 0.02, respectively). A trend toward greater NRM in group V (p = 0.10) was also noted. Multivariate analysis confirmed that the risk of NRM for extremely underweight and overweight patients is almost three times that of patients close to ideal body weight. Age-adjusted BMI was an independent predictive factor for NRM but not associated with increased relapse. We determined that dose adjustment could be safely used without significant increase of relapse. In patients with significant deviation of BMI from aBMI, dose adjustment and possible weight normalization should be considered.
Subject(s)
Bone Marrow Transplantation , Hematologic Diseases/drug therapy , Hematologic Diseases/epidemiology , Obesity/complications , Adolescent , Adult , Aged , Body Mass Index , Bone Marrow Transplantation/mortality , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Male , Middle Aged , Recurrence , Retrospective Studies , Transplantation, Autologous/mortality , Treatment OutcomeABSTRACT
The idiotype (Id) determinant on the multiple myeloma (MM) protein can be regarded as a tumor-specific marker. Immunotherapy directed at the MM Id may stem the progression of this disease. We report here on the first 12 MM patients treated at our institution with high-dose therapy and peripheral blood stem cell transplantation (PBSCT) followed by Id immunizations. MM patients received PBSCT to eradicate the majority of the disease. PBSCT produced a complete response in 2 patients, a partial response in 9 patients and stable disease in 1 patient. Three to 7 months after high-dose therapy, patients received a series of monthly immunizations that consisted of two intravenous infusions of Id-pulsed autologous dendritic cells (DC) followed by five subcutaneous boosts of Id/keyhole limpet hemocyanin (KLH) administered with adjuvant. Between 1 and 11 x 10(6) DC were obtained by leukapheresis in all patients even after PBSCT. The administration of Id-pulsed DC and Id/KLH vaccines were well tolerated with patients experiencing only minor and transient side effects. Two of 12 patients developed an Id-specific, cellular proliferative immune response and one of three patients studied developed a transient but Id-specific cytotoxic T-cell (CTL) response. Eleven of the 12 patients generated strong KLH-specific cellular proliferative immune responses showing the patients' immunocompetence at the time of vaccination. The two patients who developed a cellular Id-specific immune response remain in complete remission. Of the 12 treated patients, 9 are currently alive after autologous transplantation with a minimum follow-up of 16 months, 2 patients died because of recurrent MM and 1 patient succumbed to acute leukemia. These studies show that patients make strong anti-KLH responses despite recent high-dose therapy and that DC-based Id vaccination is feasible after PBSCT and can induce Id-specific T-cell responses. Further vaccine development is necessary to increase the proportion of patients that make Id-specific immune responses. The clinical benefits of Id vaccination in MM remain to be determined.
Subject(s)
Biomarkers, Tumor/immunology , Cancer Vaccines/therapeutic use , Dendritic Cells/immunology , Hematopoietic Stem Cell Transplantation , Immunoglobulin Idiotypes/immunology , Immunotherapy, Active , Multiple Myeloma/therapy , Vaccination , Adjuvants, Immunologic , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Vaccines/immunology , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Dendritic Cells/transplantation , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Feasibility Studies , Female , Follow-Up Studies , Hemocyanins/immunology , Humans , Immunocompetence , Lymphocyte Activation , Male , Melphalan/administration & dosage , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/immunology , Prednisone/administration & dosage , Recurrence , Remission Induction , T-Lymphocytes, Cytotoxic/immunology , Transplantation, Autologous , Treatment Outcome , Vincristine/administration & dosageABSTRACT
With conventional therapy, multiple myeloma (MM) has a poor prognosis. During the last few years, it has become clear that high-dose chemotherapy with autologous stem cell support can increase overall survival of MM patients, but further improvement in outcome is desperately needed. The monoclonal immunoglobulin (Ig) produced by the MM cells called idiotypes (Id) is a tumor-specific antigen due to unique antigenic determinants that are localized in the variable regions of the Ig molecule. Conceivably, Id immunization of MM patients in complete remission could further increase survival. Here we review the scientific basis for such Id immunization.