Leona Holmberg

High-dose therapy followed by autologous hematopoietic stem-cell infusion for patients with multiple myeloma.

PURPOSE To evaluate the outcome of patients with multiple myeloma (MM) who received high-dose therapy followed by autologous bone marrow (BM) or peripheral-blood stem-cell (PBSC) infusion. PATIENTS AND METHODS Sixty-three consecutive patients with MM received autologous BM (n = 13) or PBSC with or without BM (n = 50) following regimens that contained busulfan (Bu) and cyclophosphamide (Cy) (n = 18), modified total-body irradiation (TBI) followed by Bu and Cy (n = 36), or Bu, melphalan, and thiotepa (n = 9). Two thirds of the patients had resistant disease and 69% had received more than 6 months of previous chemotherapy. RESULTS AND CONCLUSION Recovery of peripheral-blood cell counts was more rapid in patients who received PBSC with or without BM than in patients who received BM alone. Sixteen of 63 patients (25%) died of complications of treatment within 100 days. Nineteen (40%) of 48 assessable patients achieved a complete response (CR), 23 (48%) had a partial response (PR), and six (12%) had no response. The probabilities of survival and survival without relapse or progression for all 63 patients at 3.0 years were .43 and .21, respectively. The probability of relapse or progression at 3 years was .69, and 17 patients (27%) have died of progressive MM. The probabilities of survival and relapse-free survival at 3 years for the 19 patients who achieved a CR were .42 and .17, respectively. In the multivariate analysis, beta2-microglobulin levels more than 2.5 micrograms/mL, more than two regimens of prior therapy and eight cycles of treatment, time to transplant longer than 3 years from diagnosis, and prior radiation were associated with adverse outcomes. Additional strategies, such as intervention earlier in the disease course, improved treatment regimens, sequential high-dose treatments, and posttransplant therapies may improve outcome of selected patients with MM.

Evidence of a cellular immune response against sialyl-Tn in breast and ovarian cancer patients after high-dose chemotherapy, stem cell rescue, and immunization with Theratope STn-KLH cancer vaccine

Seven ovarian and 33 breast high-risk stage II/III and stage IV cancer patients received high-dose chemotherapy followed by stem cell rescue. Thirty to 151 days after stem cell transplantation, the patients received their first immunotherapy treatment with Theratope STn-KLH cancer vaccine. Most patients developed increasing IgG anti-STn titers to a sustained peak after the fourth or fifth immunizations. Only one patient had elevated CA27.29 (MUC1 mucin) serum levels at trial entry. Five of the seven patients with preimmunotherapy elevated serum CA125 levels demonstrated decreasing CA125 levels during immunotherapy, consistent with an antitumor response. Evidence of STn antigen-specific T-cell proliferation was obtained from 17 of the 27 evaluable patients who received at least three immunotherapy treatments. Eleven of the 26 patients tested had evidence of an anti-STn TH1 antigen-specific T-cell response as determined by interferon-gamma, but not interleukin (IL)-4, production. After immunization, lytic activity of peripheral blood lymphocytes (PBLs) tested against a lymphokine activated killer (LAK)-sensitive cell line, a natural killer (NK)-sensitive cell line, and an STn-expressing cancer cell line (OVCAR) increased significantly. In vitro IL-2 treatment of the PBLs after vaccination greatly enhanced killing of the STn+ cancer cell line. Evidence of the development of OVCAR specific killing activity, over and above that seen due to LAK or NK killing, is presented. These studies provide the strongest evidence in humans of the development of an antitumor T-cell response after immunization with a cancer-associated carbohydrate antigen.

The predictive value of white cell or CD34+ cell count in the peripheral blood for timing apheresis and maximizing yield

BACKGROUND: The collection of peripheral blood stem and progenitor cells (PBPCs) for transplantation can be time‐consuming and expensive. Thus, the utility of counting CD34+ cells and white cells (WBCs) in the peripheral blood was evaluated as a predictor of CD34+ cell yield in the apheresis component.

Hematopoietic Cell Transplantation for Systemic Mature T-Cell Non-Hodgkin Lymphoma

PURPOSE To analyze outcomes of hematopoietic cell transplantation (HCT) in T-cell non-Hodgkin lymphoma. PATIENTS AND METHODS Outcomes of 241 patients (112 anaplastic large-cell lymphoma, 102 peripheral T-cell lymphoma not otherwise specified, 27 angioimmunoblastic T-cell lymphoma) undergoing autologous HCT (autoHCT; n = 115; median age, 43 years) or allogeneic HCT (alloHCT; n = 126; median age, 38 years) were analyzed. Primary outcomes were nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Patient, disease, and HCT-related variables were analyzed in multivariate Cox proportional hazard models to determine association with outcomes. RESULTS AutoHCT recipients were more likely in first complete remission (CR1; 35% v 14%; P = .001) and with chemotherapy-sensitive disease (86% v 60%; P < .001), anaplastic large-cell histology (53% v 40%; P = .04), and two or fewer lines of prior therapy (65% v 44%; P < .001) compared with alloHCT recipients. Three-year PFS and OS of autoHCT recipients beyond CR1 were 42% and 53%, respectively. Among alloHCT recipients who received transplantations beyond CR1, 31% remained progression-free at 3 years, despite being more heavily pretreated and with more refractory disease. NRM was 3.5-fold higher (95% CI, 1.80 to 6.99; P < .001) for alloHCT. In multivariate analysis, chemotherapy sensitivity (hazard ratio [HR], 1.8; 95% CI, 1.16 to 2.87) and two or fewer lines of pretransplantation therapy (HR, 5.02; 95% CI, 2.15 to 11.72) were prognostic of survival. CONCLUSION These data describe the roles of autoHCT and alloHCT in T-cell non-Hodgkin lymphoma and suggest greater effectiveness earlier in the disease course, and limited utility in multiply relapsed disease. Notably, autoHCT at relapse may be a potential option for select patients, particularly those with anaplastic large-cell lymphoma histology.

Vaccination with Theratope® (STn-KLH) as treatment for breast cancer

Cancer vaccines have demonstrated that they can stimulate antibody and cell-mediated immune responses against tumor-associated antigens in the laboratory [1-9]. However, few clinical studies with cancer vaccines have demonstrated convincing clinical responses. Sialyl-Tn is a carbohydrate associated with MUC1. It is a unique tumor-associated antigen, present on many adenocarcinomas including breast, ovarian, colorectal, gastric and pancreatic. Consequently, Sialyl-TN is an ideal candidate for boosting the patient’s immune system specifically against a unique tumor-associated antigen. The cancer vaccine Theratope® was developed by Biomira, Inc. using a synthetic Sialyl-Tn antigen that emulates the unique carbohydrate on human cancer. Clinical trials have predominately been carried out in breast cancer patients and these trials are outlined in this profile.

Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study.

Blockade of tumor necrosis factor (TNF)α by a soluble TNF receptor fusion protein (etanercept; Enbrel) improved in vitro hemopoiesis from the marrow of patients with myelodysplastic syndrome (MDS). Therefore, we enrolled 14 MDS patients (4 RA, 2 RARS, 6 RAEB, 2 CMML), 44–80 (median 60) years old, in a pilot trial. Etanercept, 25 mg, was given twice a week s.c. for 16 weeks (increased to three times a week if no response at 8 weeks). Among 12 evaluable patients, four had rises in hemoglobin by 1–1.5 gm/dl (three) or decreased transfusion requirements (one). Two patients had increased platelet counts (54% and 73%), and two increased neutrophils (63% and 120%). Baseline TNFα levels, determined in all patients, did not correlate with responses. Among eight marrows available for sequential in vitro assays, four showed increases in CFU-GM of 1.5- to 5-fold at 8 weeks, whereas three showed 3- to 10-fold decrements relative to baseline. Thus, etanercept treatment resulted in moderate improvements of cytopenias in some patients, while cell counts declined in others. Additional trials are needed to evaluate its clinical efficacy in MDS.

Clinical outcome of breast and ovarian cancer patients treated with high-dose chemotherapy, autologous stem cell rescue and THERATOPE ® STn-KLH cancer vaccine

The purpose of this study was to evaluate the toxicity and potential efficacy of administering the THERATOPE® STn-KLH cancer vaccine to ovarian and breast cancer patients after an autologous stem cell transplant. Forty patients (11 high-risk stage II/III breast cancer, 22 stage IV breast cancer, and seven stage III/IV ovarian cancer patients) were treated with high-dose chemotherapy followed by autologous/syngeneic stem cell rescue and vaccination with THERATOPE STn-KLH (Sialyl-Tn-KLH with Detox-B Stable Emulsion). Each patient was scheduled to receive a total of five vaccinations beginning on days 30–151 after stem cell infusion. The vaccine was well tolerated. Induration and erythema at the site of injection were the most common side-effects. When one compares the outcome of patients vaccinated with 66 breast and ovarian cancer patients who were not, following risk-adjustment analysis, vaccinated patients appeared more likely to survive (P = 0.07) and less likely to relapse (P = 0.10). Vaccinated patients with the greatest specific lytic activity against STn+OVCAR tumor cells relative to nonspecific killing of Daudi cells tended to remain in remission longer than patients who displayed less specific immune activity (P = 0.057). We conclude that the THERATOPE STn-KLH cancer vaccine is well tolerated in breast and ovarian cancer patients after autologous transplant and, while not statistically significant, the trends in data support the concept that THERATOPE vaccine may decrease the risk for relapse and death and thus warrants further study. Bone Marrow Transplantation (2000) 25, 1233–1241.

A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation.

Forty patients with multiple myeloma scheduled to receive melphalan 200 mg/m2 followed by autologous stem cell transplantation were randomly assigned to receive oral cryotherapy or room temperature normal saline rinses 30 min before and for 6 h after high-dose therapy. Patients were evaluated for the development of mucositis using the National Cancer Institute grading system as well as evaluation of secondary measures such as days of total parenteral nutrition (TPN), narcotic use, hospitalization, weight loss and resumption of oral caloric intake for 28 days after transplant. Patients self-scored their pain, swallowing, drinking, eating, sleeping and taste alterations for 28 days. The primary end point of this trial was the incidence of grades 3–4 mucositis. Compared to the normal saline group, patients using cryotherapy experienced less grade 3–4 mucositis, 14 vs 74%, P=0.0005. Patients receiving cryotherapy also had statistically lower uses of narcotics and TPN, although there were no differences in length of hospitalization or weight loss. Patient-reported pain was significantly lower and activities were significantly better in the cryotherapy group.

Epstein-Barr Virus–Associated Posttransplantation Lymphoproliferative Disorder after High-Dose Immunosuppressive Therapy and Autologous CD34-Selected Hematopoietic Stem Cell Transplantation for Severe Autoimmune Diseases

High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated for the control of severe autoimmune diseases. The addition of antithymocyte globulin (ATG) to high-dose chemoradiotherapy in the high-dose immunosuppressive therapy regimen and CD34 selection of the autologous graft may induce a higher degree of immunosuppression compared with conventional autologous HSCT for malignant diseases. Patients may be at higher risk of transplant-related complications secondary to the immunosuppressed state, including Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD), but this is an unusual complication after autologous HSCT. Fifty-six patients (median age, 42 years; range, 23-61 years) with either multiple sclerosis (n = 26) or systemic sclerosis (n = 30) have been treated. The median follow-up has been 24 months (range, 2-60 months). Two patients (multiple sclerosis, n = 1; systemic sclerosis, n = 1) had significant reactivations of herpesvirus infections early after HSCT and then developed aggressive EBV-PTLD and died on days +53 and +64. Multiorgan clonal B-cell infiltrates that were EBV positive by molecular studies or immunohistology were identified at both autopsies. Both patients had positive screening skin tests for equine ATG (Atgam) and had been converted to rabbit ATG (Thymoglobulin) from the first dose. Of the other 54 patients, 2 of whom had partial courses of rabbit ATG because of a reaction to the intravenous infusion of equine ATG, only 1 patient had a significant clinical reactivation of a herpesvirus infection (herpes simplex virus 2) early after HSCT, and none developed EBV-PTLD. The T-cell count in the peripheral blood on day 28 was 0/microL in all 4 patients who received rabbit ATG; this was significantly less than in patients who received equine ATG (median, 174/microL; P =.001; Mann-Whitney ranked sum test). Although the numbers are limited, the time course and similarity of the 2 cases of EBV-PTLD and the effect on day 28 T-cell counts support a relationship between the development of EBV-PTLD and the administration of rabbit ATG. The differences between equine and rabbit ATG are not yet clearly defined, and they should not be considered interchangeable in this regimen without further study.

A randomized phase III clinical trial of autologous blood stem cell transplantation comparing cryopreservation using dimethylsulfoxide vs dimethylsulfoxide with hydroxyethylstarch

Summary:Hematopoietic stem cells intended for autologous transplantation are usually cryopreserved in solutions containing 10% dimethylsulfoxide (DMSO, v/v) or 5% DMSO in combination with 6% hydroxyethylstarch (HES, w/v). We performed a single-blinded, randomized study comparing these cryoprotectant solutions for patients undergoing autologous peripheral blood stem cell (PBSC) transplantation. A total of 294 patients were evaluable; 148 received cells frozen with 10% DMSO and 146 received cells frozen in 5% DMSO/6% HES. Patients who received cells frozen with the combination cryoprotectant recovered their white blood cell count ⩾1.0 × 109/l at a median of 10 days, one day faster than those who received PBSC frozen with DMSO alone (P=0.04). Time to achieve neutrophil counts of ⩾0.5 × 109 and ⩾1.0 × 109/l were similarly faster for the recipients of the cells frozen in the combination solution. This effect was more pronounced for patients who received quantities of CD34+ cells higher than the median for the population. Median time to discontinuation of antibiotic use was also one day faster for the recipients of cells cryopreserved with DMSO/HES (P=0.04). In contrast, median times to recovery of platelet count ⩾20 × 109/l were equivalent for each group (10 days; P=0.99) and the median numbers of red cell and platelet transfusions did not differ.