To improve disease control without increasing the toxicity of a reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM), a phase I trial was performed using an ...antibody-radionuclide conjugate targeting CD45 (.sup.90Y-DOTA-BC8) as conditioning. .sup.90Y-DOTA-BC8 was combined with fludarabine and low-dose TBI followed by allogeneic HCT in patients with MM and greater than or equal to1 adverse risk characteristic at diagnosis, relapse after autologous transplant, or plasma cell leukemia (PCL). The primary objective was to estimate the maximum tolerated radiation absorbed dose. Fourteen patients were treated (one with PCL, nine failed prior autologous HCT, and nine with greater than or equal to1 adverse cytogenetics). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Non-hematologic toxicities were manageable and included primarily gastrointestinal (43%) and metabolic/electrolyte disturbances (36%). Treatment-related mortality at 100 days was 0%. At a median follow-up of 5 years, the overall survival was 71% (median not reached) and the progression-free survival was 41% (median 40.9 months). The incorporation of CD45-targeted radioimmunotherapy (RIT) into a reduced-intensity allogeneic HCT is well-tolerated and may induce long-term remissions among patients with poor-risk MM, supporting further development of RIT-augmented conditioning regimens for HCT.
•Circulating plasma cells (CPCs) are a well-described risk factor in multiple myeloma.•The impact of CPCs at time of collection of autologous stem cells was examined.•CPCs are still an adverse ...prognostic factor in the era of modern therapy.•Maintenance therapy did not overcome the negative impact of CPCs.
Circulating plasma cells (CPCs) have been detected in patients with multiple myeloma (MM) at various stages of disease and associated with worse outcomes. Little data exist regarding the impact of CPCs at the time of autologous peripheral blood stem cell (PBSC) collection on outcomes, and the impact of maintenance therapy after autologous stem cell transplantation (ASCT) on prognosis in patients with CPC-containing collections. All patients with MM who underwent first ASCT at Fred Hutchinson Cancer Research Center from 2012 to 2015 and had evaluation for CPCs at the time of PBSC collection were included in our analysis. Seven-color flow cytometry was used to detect the presence of CPCs. Kaplan-Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS) rates from the time of ASCT. A multivariate analysis, including receipt of maintenance therapy post-ASCT, high-risk cytogenetics, and international staging system (ISS) stage, was included in a Cox proportional hazards regression model for associations with OS and PFS. We identified 227 patients with MM who underwent ASCT; of these, 144 (63.4%) patients had routine assessment of CPCs at the time of PBSC collection. One hundred seventeen (81.3%) patients did not have CPCs and 27 (18.8%) did have CPCs. The presence of CPCs was highly associated with poorer PFS (P = .031 by log-rank analysis), but did not affect OS. The median PFS for those patients without CPCs was 39.4 months (95% confidence interval CI, 31.1 to not reached), while the median PFS for those patients with CPCs was 16.5 months (95% CI, 13.7 to not reached). A subgroup analysis of patients achieving very good partial response (VGPR) or better at time of collection, showed the median PFS for patients without CPCs was 38.3 months (95% CI, 29 to not reached), as compared with those patients with CPCs, where it was only 16.5 months (95% CI, 12 months to not reached; P = .02). There was no statistically significant difference in PFS or OS among those patients achieving partial response at the time of collection. In a Cox proportional hazards model, adjusting for post-ASCT maintenance therapy, high-risk cytogenetics, and ISS stage at time of initial diagnosis, there was a 43% higher risk of progression or death among the patients with CPCs (P = .04). The presence of CPCs at the time of autologous PBSC collection is a negative prognostic factor for risk of early relapse or death despite the advent of novel agents and maintenance strategies. The impact of CPCs was most significant among patients achieving a VGPR or better at time of collection. The presence of CPCs denotes a unique group of high-risk MM patients for whom alternative treatment strategies are needed to overcome resistance to current standard therapies.
Myelodysplastic syndrome (MDS) comprises a spectrum of heterogeneous diseases. Most patients present with ineffective hematopoiesis. The pathophysiology involves immune-mediated effects, cytokine ...dysregulation, and apoptosis, among others. We treated 14 transfusion-requiring patients with MDS, 10 with refractory anemia (RA) and four with RA with excess blasts (RAEB) with a 4-day course of antithymocyte globulin (ATG) followed by intermittent etanercept for 4 months. Among 13 evaluable patients, five are red blood cell and platelet transfusion independent for intervals extending beyond 2 years, and two have normalized their peripheral blood parameters. One additional patient showed a transient rise of platelet and neutrophil counts, for an overall response rate of 46%. Responding patients showed striking improvements in marrow cell abnormalities as characterized by flow cytometry. These data show that a combination of ATG plus etanercept offers effective palliative therapy for unselected patients with MDS. Further trials incorporating these two agents are warranted.
Abstract Objective To determine the nature and degree of toxicity, response rate, quality of life (QOL), and progression-free interval in women with platinum-resistant refractory ovarian or ...peritoneal cancer receiving weekly topotecan and gemcitabine. Methods A Phase II trial of gemcitabine 800 mg/m2 and topotecan 3.0 or 2.5 mg/m2 administered on days 1 and 8 of a 21-day cycle was conducted. Response was assessed by RECIST criteria. Quality of life was assessed with FACT-O. Results Twenty-three patients were enrolled in the study and all were evaluable. One patient was later found to be ineligible due to a concurrent endometrial malignancy, but remains part of the analysis. Sixteen patients (70%) had measurable disease at baseline and 7 (30%) had elevated CA125 only. The median number of prior regimens was 1, range 1–4 and median number of prior cycles was 8, range 3–39. The first 6 patients received topotecan at a dose of 3.0 mg/m2 , but because of dose delays and need for GCSF the dose of topotecan was lowered to 2.5 mg/m2 . There were 4 (17%) partial responses, but only two (9%) were confirmed prior to progression; and 8 (35%) had stable disease. Toxicity was acceptable with only 8 of the 107 cycles given requiring a dose reduction. Four patients (17%) were taken off the study for toxicity, two at the higher dose and two at the lower dose. Median time to recurrence was 3.0 months and median overall survival was 12.6 months. QOL did not differ with subsequent cycles as compared to baseline. Conclusion The combination of weekly topotecan and gemcitabine is well tolerated, but best response rate is 17%, and confirmed response is only 9%, which is not significantly better than single agent gemcitabine or topotecan. These results do not provide compelling evidence for the combination of weekly gemcitabine and topotecan as a promising therapy.
Theratope® vaccine (STn-KLH) Holmberg, Leona A; Sandmaier, Brenda M
Expert opinion on biological therapy,
09/2001, Letnik:
1, Številka:
5
Journal Article
Recenzirano
Active specific immunotherapy (ASI) is a promising approach to treating cancer. Numerous studies in the laboratory have demonstrated that various cancer vaccines can stimulate antibody and cell ...mediated immune responses against tumour-associated antigens 1-9. Yet few studies have demonstrated convincing clinical responses. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on a number of human cancer cells and is associated with more aggressive disease. Consequently, STn is an ideal candidate for ASI therapy. Theratope® vaccine is a cancer vaccine that was designed by Biomira, Inc. (Edmonton, Alberta, Canada) by incorporating a synthetic STn antigen that emulates the carbohydrate seen on human tumours. The clinical trials conducted to date with Theratope® vaccine are outlined in this report. Overall, Theratope® vaccine has been well-tolerated with minimal toxicity. The most common side effects have been induration and erythema at the site of injections. Both in a non-transplant setting following low dose iv. cyclophosphamide and high dose autologous transplant setting, there has been a trend toward Theratope® vaccine decreasing the risk for relapse, prolonging the time to relapse and thus impacting on overall survival. The definitive Phase III trial comparing the outcome of patients with metastatic breast cancer receiving vaccinations with Theratope® vaccine versus vaccination with the nonspecific immune stimulants Keyhole Limpet Hemocyanin (KLH) and Detox™-B stable emulsion (Detox-B) (now called Enhanzyn™ Immunostimulant) was closed to enrolment on March 30, 2001. Over 1000 women with distant metastatic breast cancer were enrolled into the program.
To estimate the maximum tolerated dose of hyperfractionated total marrow irradiation (TMI) as a second consolidation after high-dose chemotherapy with autologous or syngeneic blood stem cell ...transfusion for patients with bone/bone marrow-based malignant disease.
Fifty-seven patients aged 3-65 years (median, 45 years), including 21 with multiple myeloma, 24 with breast cancer, 10 with sarcoma, and 2 with lymphoma, were treated with 1.5 Gy administered twice daily to a total dose of 12 Gy (n = 27), 13.5 Gy (n = 12), and 15 Gy (n = 18). Median time between the 2 transplants was 105 days (range, 63-162 days).
All patients engrafted neutrophils (median, Day 11; range, Day 9-23) and became platelet independent (median, Day 9; range, Day 7-36). There were 5 cases of Grade 3-4 regimen-related pulmonary toxicity, 1 at 12 Gy, and 4 at 15 Gy. Complete responses, partial responses, and stabilizations were achieved in 33%, 26%, and 41% of patients, respectively. Kaplan-Meier estimates of 5-year progression-free survival and overall survival for 56 evaluable patients are 24% and 36%, respectively. Median time of follow-up among survivors was 96 months (range, 77-136 months).
Total marrow irradiation as a second myeloablative therapy is feasible. The estimated maximum tolerated dose for TMI in a tandem transplant setting was 13.5 Gy. Because 20% of patients are surviving at 8 years free of disease, further studies of TMI are warranted.
Abstract Autologous stem cell transplantation (ASCT) is standard therapy for mantle cell lymphoma (MCL) in remission after induction chemotherapy, with the best results for patients in complete ...remission (CR). We hypothesized that evaluation of minimal residual disease (MRD) before ASCT could further stratify outcomes for these patients. Patients with MCL who underwent ASCT in clinical CR between 1996 and 2011 with pretransplantation MRD testing were eligible. Presence of a clonal IgH rearrangement, t(11; 14) by PCR or positive flow cytometry from blood or bone marrow, was considered positive. An adjusted proportional hazards model for associations with progression-free (PFS) and overall survival (OS) was performed. Of 75 MCL patients in CR, 8 (11%) were MRD positive. MRD positivity was associated with shorter OS and PFS. The median OS for MRD-negative patients was not reached, with 82% survival at 5 years, whereas for the MRD-positive patients, median OS was 3.01 years (hazard ratio HR, 4.04; P = .009), with a median follow-up of 5.1 years. The median PFS for MRD-negative patients was not reached with 75% PFS at 5 years, whereas for MRD-positive patients, it was 2.38 years (HR, 3.69; P = .002). MRD positivity is independently associated with poor outcomes after ASCT for MCL patients in CR.
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