Autologous Blood Stem Cell Collection Research Articles

Canadian Cancer Trials Group (CCTG) LY.17: A Randomized Phase II Study Evaluating Novel Salvage Therapy Pre-Autologous Stem Cell Transplant (ASCT) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR-DLBCL) - Outcome of Rituximab-Dose-Intensive Cyclophosphamide, Etoposide, Cisplatin (R-DICEP) Versus R-GDP

Introduction: The CCTG LY.12 trial established rituximab combined with gemcitabine, dexamethasone and cisplatin (R-GDP) as a standard salvage chemotherapy option prior to ASCT for patients (pts) with relapsed/refractory (RR) DLBCL (Crump JCO 2014). CCTG LY.17 is an ongoing multi-arm randomized phase II "pick a winner" trial evaluating novel salvage therapy compared with R-GDP in ASCT-eligible RR-DLBCL pts. Methods: The primary endpoint of the study is overall response rate (ORR) using CT imaging. According to the protocol futility rule, any treatment arm with an ORR lower than the R-GDP control arm at the first interim analysis (n = 16), or less than 10% higher at the second interim analysis (n=32) would not continue to full target accrual of 64 pts per treatment arm. Encouraging results could then be pursued in a larger phase III trial designed to detect differences in progression-free survival (PFS). This report involves the component of the trial that randomly allocated pts to either 1 cycle of inpatient R-DICEP (Rituximab 375mg/m2 IV or 1400mg sc days 1 and 5 plus dose-intensive Cyclophosphamide 5.25g/m2, Etoposide 1050mg/m2, Cisplatin 105mg/m2 divided over days 2-4, with daily filgrastim starting day 15 until apheresis of blood stem cells approximately between days 20-22) or to 3 cycles of outpatient R-GDP. This report is the result of the protocol-specified second interim analysis. Results: A total of 67 pts were randomized to R-DICEP (n=32) or to R-GDP (n=35) between April 2016 and April 2021. Table 1 lists baseline pt characteristics. Four pts (R-DICEP=2, R-GDP=2) were not evaluable for response. The ORR was 65.6% for R-DICEP (70.0% for evaluable pts), which was 17% greater than the ORR of 48.6% for R-GDP (51.5% for evaluable pts). Additionally, only 1 (3.1%) R-DICEP pts versus (vs) 11 (31.4%) R-GDP pts experienced progressive disease as best response to salvage therapy. Of interest, the ORR to salvage was 40% (14/35) for pts primary refractory to RCHOP (no response to RCHOP or progressive disease during or <3mo post RCHOP) vs 75% (24/32) for those who relapsed >3mo post RCHOP (p=0.006), with ORR to R-DICEP of 50% vs 81.3% and ORR to R-GDP of 31.6% vs 68.8% for primary refractory vs relapse >3mo, respectively. The ORR based on PET-CT scan was 50.0% vs 31.4% for the R-DICEP (n=26) vs R-GDP (n=25) arms, respectively. Overall, 23 (71.9%) R-DICEP pts and 19 (54.3%) R-GDP pts underwent ASCT. In total, 26 out of 27 (96.3%) R-DICEP, and 18 out of 20 (90%) R-GDP pts underwent successful autologous blood stem cell collection (requiring >1 attempt in 0 R-DICEP and 2 R-GDP pts). The median time to neutrophil engraftment post-ASCT was 13 (1-32) and 12 (1-22) days, and to platelet engraftment was 12 (1-50) and 16 (7-22) days for R-DICEP and R-GDP pts, respectively. Regarding adverse events (AEs) of salvage therapy and subsequent ASCT, R-DICEP pts had higher rates of culture positive infection (84% vs 40%), platelet (96.6% vs 60.0%) and red cell (75.0% vs 42.9%) transfusions, diarrhea (44% vs 14%), serious adverse events (50% vs 34.3%), and treatment-related mortality (3.1% vs 0%) but similar rates of other AEs including arrhythmia (6% vs 9%), bleeding (0 vs 0), fungal infections (0 vs 0) and pneumonitis (0 vs 0). At a median duration of follow-up of 26.9 months (R-DICEP 26.4 months and R-GDP 27.4 months), the 1-year PFS rate was 42% for R-DICEP and 32% for R-GDP (HR 0.59, 95%CI: 0.32-1.09, logrank p=0.09), and 1-year OS rate was 65% for R-DICEP and 55% for R-GDP (HR 0.675, 95%CI: 0.333-1.369, logrank p=0.27). Conclusions: Although the 17% improvement in ORR for R-DICEP vs R-GDP in the second interim analysis exceeded the pre-specified 10% threshold required proceed to full accrual of 64 pts in the R-DICEP arm, we decided to stop accrual to the R-DICEP arm of the LY.17 trial due to slow accrual, higher AE rates, and greater utilization of healthcare resources including hospitalization needed to administer treatment, which limits feasibility of R-DICEP at several Canadian centres. The LY.17 trial continues testing other salvage regimens. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim Restaging PET/CT-Guided High Dose Sequential Induction Therapy with Autologous Stem Cell Transplantation (ASCT) Does Not Improve Outcome for Poor Prognosis Diffuse Large B-Cell Lymphoma (DLBCL). ClinicalTrials.Gov Identifier: NCT00530179

Abstract 500 Purpose:Approximately 55% of patients (pts) with stage 3–4 DLBCL and elevated serum LDH achieve long-term progression-free survival (PFS) following R-CHOP chemotherapy. A prospective, multicentre, phase II clinical trial was designed to evaluate the use of high dose sequential therapy with RDICEP (Rituximab, Dose-Intensive Cyclophosphamide, Etoposide, Cisplatin) then RBEAM/ASCT (Rituximab, BCNU, Etoposide, Ara-C, Melphalan) for such pts who have unfavorable interim restaging FDG-PET/CT scans after 2 cycles of RCHOP. The trial was designed to minimize false positive interim restaging PET scans by only enrolling poor prognosis pts, and modifying response interpretation criteria such that unfavorable PET response required more than 1 site with uptake more intense than background liver. The use of RDICEP-RBEAM/ASCT built on our prior encouraging experience with DICEP-BEAM/ASCT for poor prognosis aggressive lymphoma (Blood 2006; 107: 4623–4627). The hypothesis was that interim PET response would stratify pts into good RCHOP responders who should avoid upfront ASCT, and poor RCHOP responders who may benefit from upfront ASCT, resulting in an overall PFS rate of 80%. Patients and Methods: Pts were eligible if they were HIV negative, 18–65 years of age, with stage 3–4 DLBCL and elevated serum LDH. An FDG-PET/CT scan was performed 10–15 days following the second cycle of R-CHOP. Pts with favorable interim PET response completed 4 further cycles of RCHOP, whereas pts with unfavorable PET response received one cycle of RDICEP (Rituximab 375mg/m2 day 1 and 8, C 1.75g/m2 d2-4, E 350mg/m2 d2-4 P 35mg/m2 d2-4, G-CSF d15-21 and autologous blood stem cell collection by apheresis d21or 22) followed by one cycle of RBEAM/ASCT (R 375mg/m2 day −6 and +14, B 300mg/m2 d-6, E 200mg/m2 d-5to-2, A 400mg/m2 d-5to-2, M 140mg/m2 d-1). Both groups could receive intrathecal (IT) chemotherapy or involved field radiation (IFRT) to a single site of disease at physician discretion. The sample size of 70–80pts assumed at least 33pts would be assigned to each of the favorable and unfavorable PET response groups, providing a lower limit of 66% for the 95% confidence interval around the expected 80% PFS rate. Results: Target accrual of 70 pts was achieved 5/2007–7/2011, and 67 pts have thus far undergone interim PET/CT restaging following 2 cycles RCHOP (favorable PET=32, unfavorable PET=35). The median IPI score was 3 (IPI 3–5=60pts) and median age was 54 years (range19–65) with 15 pts (21%) older than 60 years. Although there were no statistically significant differences in pt characteristics between PET response groups, the unfavorable PET response pts numerically had more ECOG 2–4 (51% vs 44%), stage IV (86% vs 69%), >1 extranodal site (60% vs 41%), bulk>10cm (54% vs 34%), B symptoms (63% vs 41%), involved marrow (40% vs 28%). IFRT was used for 8 and 5 pts, and IT chemo used for 0 and 3 pts in unfavorable and favorable PET response groups, respectively. At a median follow-up of 24mo, the 2 year OS and PFS rates for all 67 pts are 71% (95%CI 56%, 82%), and 60% (95%CI 46%, 72%), respectively (see figure). The PFS rates for the 35 unfavorable and 32 favorable PET pts were 66% (95%CI 46, 79) and 53% (95%CI 32, 71), respectively (logrank p=0.57). Of the 35 unfavorable PET pts, 3 refused assigned ASCT, 9 (25.7%) relapsed (1 in brain), and 3 (8.6%) experienced non-relapse mortality (NRM) (day+5 post-ASCT from sepsis, 12months post-ASCT from pneumonia, and 30months post-ASCT from recurrent pneumonia and heart failure). Of the 32 favorable PET pts, 12 (37.5%) relapsed (3 in brain); 9 relapses occurred in pts with completely negative PET scans, with no uptake above blood pool. Conclusions: 1) Favorable Interim PET/CT response as defined in this study does not identify good prognosis DLBCL following RCHOPx2, 2) RDICEP-RBEAM/ASCT may decrease relapse for poor prognosis DLBCL pts with unfavorable PET response, but is associated with risks of early and delayed NRM from infection, 3) a phase III trial evaluating this PET-guided RDICEP-RBEAM/ASCT approach compared to standard RCHOP alone is probably not warranted. [Display omitted] Disclosures:Stewart:Hoffmann La Roche: Honoraria, Research Funding. Off Label Use: Rituximab with High Dose Chemotherapy and Autologous Stem Cell Transplantation for DLBCL. Bence-Bruckler:Hoffmann La Roche: Honoraria, Research Funding.

Interim Restaging FDG-PET/CT to Guide Use of High Dose Sequential Induction Therapy with Rituximab-Dose-Intensive Cyclophosphamide, Etoposide, Cisplatin (RDICEP) and Rituximab-Carmustine, Etoposide, Cytarabine, Melphalan (RBEAM) and Autologous Stem Cell Transplantation (ASCT) for Poor Prognosis Diffuse Large B-Cell Lymphoma (DLBCL). ClinicalTrials. Gov Identifier: NCT00530179.

Abstract 3414Poster Board III-302 PurposeApproximately 50-55% of patients (pts) with stage 3-4 DLBCL and elevated serum LDH achieve long-term event-free survival (EFS) following R-CHOP chemotherapy. A prospective, multicentre, phase II clinical trial was designed to evaluate the use of high dose sequential therapy with RDICEP then RBEAM/ASCT for such pts who have positive interim restaging FDG-PET/CT scans after 2 cycles of RCHOP. Patients and MethodsPts were eligible if they were HIV-, 18-65 years of age, and had stage 3-4 DLBCL with elevated serum LDH. An FDG-PET/CT scan was performed 10-15 days following the second cycle of R-CHOP. Pts with negative interim restaging PET scans completed 4 further cycles of RCHOP, whereas pts with positive PET scans (more than 1 site with uptake more intense than background liver) received one cycle of RDICEP (Rituximab 375mg/m2 day 1 and 8, C 1.75g/m2 d2-4, E 350mg/m2 d2-4 P 35mg/m2 d2-4, G-CSF d15-21 and autologous blood stem cell collection by apheresis d21or 22) followed by one cycle of RBEAM/ASCT (Rituximab 375mg/m2 day -6 and +14, BCNU 300mg/m2 d-6, E 200mg/m2 d-5to-2, A 400mg/m2 d-5to-2, M 140mg/m2 d-1). ResultsOf the 36 pts who have been accrued from 5/2007-7/2009, 33 pts have undergone interim PET/CT restaging following 2 cycles RCHOP. All 33 pts had IPI scores 3-5, the median age was 55 years (range19-65) with 7 pts (21%) older than 60 years, 20 (61%) had ECOG status 2-4, 28 (85%) had stage 4, 22 (67%) >1 extranodal site. At a median follow-up of 12mo, the 1 year OS and EFS rates for all 33 pts are 82% (95%CI = 66-98%) and 76% (95%CI = 58-83%), respectively. Interim restaging PET/CT was positive for 16 pts and negative for 17 pts. The EFS rates for PET+ and PET- pts are 78% (95%CI = 57-100%) and 66% (95%CI = 36-99%), respectively (logrank p=0.97). To date, 4 pts have died, 3 from lymphoma at 6, 10, 11 months post-RCHOP1, and 1 from sepsis and necrotic bowel on day 5 post-ASCT. ConclusionsPreliminary results of this phase II study are encouraging, and suggest that high dose induction therapy with RDICEP and RBEAM/ASCT might improve EFS for poor prognosis DLBCL with positive interim restaging PET/CT. Accrual will continue to target ≥ 35 PET+ and ≥35 PET- pts. DisclosuresStewart:Hoffmann La Roche: Advisory Board, Honoraria, Research Funding. Off Label Use: Rituximab with High Dose Chemotherapy and Autologous Stem Cell Transplantation for DLBCL. Bence-Bruckler:Hoffmann La Roche: Honoraria, Research Funding.

A randomized comparison of peripheral blood hematopoietic progenitor cell level of 5/mm3 versus 50/mm3 as a surrogate marker to initiate efficient autologous blood stem cell collection

We previously showed that at least 5/mm(3) hematopoietic progenitor cells (HPCs) could be used as a marker for initiating autologous blood stem cell collection (ABSCC). However, the timing of efficient ABSCC following mobilization is still to be determined. We conducted a prospective, randomized comparison of 5/mm(3) versus 50/mm(3) peripheral blood (PB) HPCs as a surrogate marker to initiate efficient ABSCC. Forty-five consecutive patients, 26 with multiple myeloma (MM) and 19 with non-Hodgkin's lymphoma (NHL), were enrolled between October 2004 and October 2006. Chemotherapy was cyclophosphamide 4 g/m(2) for MM and ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), with or without Rituximab, for NHL. Circulating HPCs were monitored daily with the Sysmex SE9000 automated hematology analyzer, and harvested CD34+ cells were counted by flow cytometry. ABSCC was initiated when HPC levels reached at least 5/mm(3) (HPC5 group) or 50/mm(3) (HPC50 group). The median number of harvested CD34+ cells was 15.0 x 10(6)/kg and 21.0 x 10(6)/kg in the HPC5 and HPC50 groups, respectively (P = 0.23). Optimal collection (>5 x 10(6) CD34+ cells/kg) in a single session (day 1) was attained in 15 HPC5 patients (63%) and in 14 HPC50 patients (67%), and targeted collection of 5 x 10(6) CD34+ cells/kg was achieved in 100 and 95% of HPC5 and HPC50 patients, respectively (P = 0.47), with a median number of 1 apheresis in both groups (P = 0.58). There were no between group differences in optimal collection rate on day 1, median number of aphereses to achieve optimal collection, and overall optimal collection rate. HPC > or = 5/mm(3) and > or =50/mm(3) are both reliable indices for the timing of ABSCC.

Upfront double high-dose chemotherapy with DICEP followed by BEAM and autologous stem cell transplantation for poor-prognosis aggressive non-Hodgkin lymphoma

AbstractA single center, prospective clinical trial was conducted evaluating 2 cycles of induction high-dose chemotherapy for adults younger than 65 years of age with aggressive non-Hodgkin lymphoma (NHL) and 2 to 3 Age-Adjusted International Prognostic Index risk factors. Patients received one cycle of standard dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by one cycle of dose-intensive cyclophosphamide 5.25 g/m2, etoposide 1.05 g/m2, cisplatin 105 mg/m2 (DICEP), then underwent autologous blood stem cell collection, followed by one cycle of high-dose carmustine (BCNU) 300 mg/m2, etoposide 800 mg/m2, Ara-C 1600 mg/m2, melphalan 140 mg/m2 (BEAM), and autologous stem cell transplantation (ASCT) and radiotherapy to prior bulk. From June 1998 to August 2004, 55 patients aged 20 to 63 years (median 44 years) were accrued, 51 (92%) of whom had diffuse large B-cell NHL. Poor prognostic factors included stage 4 (n = 46), elevated lactate dehydrogenase (LDH; n = 47), Eastern Cooperative Oncology Group (ECOG) performance status 2 to 4 (n = 43), bulky mass more than 10 cm (n = 34), and marrow involvement (n = 16). Only one patient experienced nonrelapse mortality. With a median follow-up of 49 months, 4-year event-free survival (EFS) and overall survival (OS) rates for all 55 patients are 72% (95% confidence interval [CI] = 60%-84%) and 79% (95% CI = 69%-90%), respectively. In conclusion, CHOP-DICEP-BEAM is feasible and gave encouraging EFS and OS for patients with poor-prognosis aggressive NHL.

Occult tumor cells detected in autologous blood stem cell harvests have no impact on 5 year outcomes for breast cancer patients with 4-9 positive nodes treated with adjuvant high-dose therapy and stem cell transplantation.

Breast cancer cells have been detected in autologous blood stem cell collections of early stage breast cancer patients, but their clinical significance is undefined. From October 1993 to August 1998, 32 consecutive Stage II breast cancer patients with 4-9-positive nodes underwent stem cell apheresis. The patients were treated with cyclophosphamide 1.75 gm/m(2), etoposide 400 mg/m(2) and cisplatin 50 mg/m(2) daily for 3 days, followed by infusion of the autologous cells. Cytospins of cells from each apheresis collections and from an aliquot of three pooled collections were examined for cytokeratin expression using an immunocytochemical assay. The cells were considered positive for tumor if at least one cell with tumor morphology stained positively for cytokeratin. Negative aliquots were confirmed with RT-PCR. Six patients (19%) had positive collections. In total, 24 patients (75%) were disease free a median of 61 (30-86) months after transplant. Eight patients relapsed at a median of 17 (8-27) months after transplant. Four of the disease-free patients and two of the relapsed patients had positive apheresis collections. There was no significant correlation between the presence of detectable tumor cells in the graft product and outcome.

Autologous Blood Stem Cell Collection after Chemotherapy in Patients with Sensitive and Refractory Malignancies: A Multicenter Retrospective Study

A retrospective study was undertaken to assess the factors affecting the yield of peripheral blood stem cell (PBSC) collections after chemotherapy. Fifty-five patients with malignancies, observed in 4 Italian Institutions from January 1987 to June 1991 were eligible for evaluation. This series included 19 non-Hodgkin lymphoma, 11 multiple myeloma, 9 ovarian cancer, 7 Hodgkin disease, 7 acute non-lymphocytic leukemia, 1 acute lymphoblastic leukemia, 1 neuroblastoma. Five hundred and twenty two PBSC collections were performed on 55 patients after a median of 18 days after the start of chemotherapy. The yields of PBSC collections were related to the dose of cytoreductive chemotherapy exploited for PBSC mobilization and to the number of circulating white blood cells, colony forming unit granulocyte/macrophage (CFU-GM) and the percentage of monocytes at the time of collection. Forty-eight patients out of 55 transplanted (87%) had rapid, complete and sustained engraftment. Three patients (5%) died of transplant related complications.