High-dose therapy in patients with Hodgkin's disease: the use of selected CD34(+) cells is as safe as unmanipulated peripheral blood progenitor cells.

Register data suggest that patients with Hodgkin's disease (HD) given high-dose therapy (HDT) with peripheral blood progenitor cells (PBPC) have a less favourable prognosis as compared to those given bone marrow as stem cell support. Since this can be due to infusion of tumour cells contaminating the PBPC grafts, we initiated a feasibility study in which PBPC grafts from HD patients were purged by CD34(+) cell enrichment. Controversy exists about whether the use of CD34(+) enriched stem cells leads to a delayed haematological and immune reconstitution. We compared these parameters, including risk of infections and clinical outcome after HDT, in patients with HD given either selected CD34(+) cells or unmanipulated PBPC as stem cell support. From October 1994 to May 2000, 40 HD patients with primary refractory disease or relapse were treated with HDT and supported with either selected CD34(+) cells (n = 21) or unmanipulated PBPC (n = 19) as stem cell support. All patients had chemosensitive disease at the time of transplantation. A median of 5.8 (range 2.7-20.0) vs 4.5 (range 2.3-17.6) x 10(6) CD34(+) cells per kilo were reinfused in the CD34(+) group and PBPC group, respectively. No difference was observed between the two groups with regard to time to haematological engraftment, reconstitution of B cells, CD56(+) cells and T cells at 3 and 12 months and infectious episodes after HDT. Two (5%) treatment-related deaths, one in each group, were observed. The overall survival at 4 years was 86% for the CD34(+)group and 74% for the PBPC group with a median follow-up of 37 months (range 1-61) and 46 months (range 4-82), respectively (P = 0.9). The results of this study demonstrate that the use of CD34(+) cells is safe and has no adverse effects either with respect to haematological, immune reconstitution or to infections after HDT.     

Multiple cycles of PBPC-supported high-dose carboplatin and paclitaxel following mobilization with epirubicin and cisplatin are feasible but ineffective in treating patients with advanced non-small cell lung cancer

We verified the feasibility of a multi-cycle peripheral blood progenitor cell (PBPC)-supported high-dose chemotherapy (HDC) regimen in patients with non-small cell lung cancer (NSCLC). The HDC regimen consisted of a single course of high-dose epirubicin given in combination with cisplatin plus filgrastim, followed by three courses of high doses of carboplatin and paclitaxel with PBPC reinfusion and filgrastim. Of the 16 enrolled patients, 13 provided an adequate number of PBPCs by a single leukapheresis, while in the three needed two procedures, with a median number of CD34+, CD34+/CD33- and CD34+/CD38- cells collected per patient was 13.5 x 10(6), 10.9 x 10(6) and 0.9 x 10(6)/kg, respectively. No toxic death occurred, and the collected PBPCs supported a rapid hematopoietic reconstitution after HDC; however, seven patients early interrupted the treatment early due to early progressive disease (n=4) or prolonged grade 3 peripheral neurotoxicity (n=3). Despite an overall response rate of 42%, the median survival for stage IV patients has been 5 months (range: 1-25+). Of two patients with stage IIIB NSCLC, one is continuously disease-free at 71+ months, while of 14 with stage IV disease, one is currently alive with disease at 25+ months. In conclusion, the combination of high-dose epirubicin with cisplatin plus filgrastim is an effective regimen in releasing large amounts of PBPCs, which can then be safely employed to support multiple courses of HDC. Multiple cycles of PBPC-supported high-dose carboplatin and paclitaxel are ineffective in treating patients with advanced NSCLC.     

Bone Marrow Transplantation: Prognostic Factors of Peripheral Blood Stem Cell Mobilization with Cyclophosphamide and Filgrastim (r-metHuG-CSF): The CD34+ Cell Dose Positively Affects the Time to Hematopoietic Recovery and Supportive Requirements after High-Dose Chemotherapy

To prospectively analyze factors that influence peripheral blood stem cell (PBSC) collection and hematopoietic recovery after high-dose chemotherapy (HDC), 39 patients received cyclophosphamide 4 g/m(2) and rHuG-CSF (Filgrastim) 5 &mgr;g/kg/day. Leukapheresis was started when CD34(+) cells/mL were > 5 x 10(3). A minimum of 2 x 10(6) CD34(+) cells/kg was collected. Median steady-state bone marrow CD34(+) cell percentage was 0.8% (range, 0.1 to 6). Thirty-two patients received HDC with autologous PBSC transplantation plus Filgrastim. A median of 2 (range, 0 to 6) leukapheresis per patient were performed and a median of 6.3 x 10(6) CD34(+) cells/kg (range, 0 to 44.4) collected; four patients failed to mobilize CD34(+) cells. The number of cycles of prior chemotherapy had an inverse correlation with the number CD34(+) cells/kg collected (r = -0.38; p < 0.005). Patients with <7 cycles had a higher predictability for onset of leukapheresis than patients with (3) 7 (93% versus 50%; p < 0.005). The four patients who failed to mobilize had received >/=7 cycles. The number of CD34(+) cells/kg infused after HDC had an inverse correlation with days to recovery to 0.5 x 10(9) neutrophils/L and 20 x 10(9) platelets/L (r = -0.68 and -0.56; p < 0.005). The effect of these factors on mobilization and hematopoietic recovery were confirmed by multivariate analysis. Requirements for supportive measures were significantly lower in patients given a higher dose of CD34(+) cells/kg. Therefore, PBSC collection should be planned early in the course of chemotherapy. Larger number of CD34(+) cells/kg determined a more rapid hematopoietic recovery and a decrease of required supportive measures.     

An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy

The CD34 antigen is expressed by committed and uncommitted hematopoietic progenitor cells and is increasingly used to assess stem cell content of peripheral blood progenitor cell (PBPC) collections. Quantitative CD34 expression in PBPC collections has been suggested to correlate with engraftment kinetics of PBPCs infused after myeloablative therapy. We analyzed the engraftment kinetics as a function of CD34 content in 692 patients treated with high-dose chemotherapy (HDC). Patients had PBPCs collected after cyclophosphamide based mobilization chemotherapy with or without recombinant human granulocyte colony-stimulating factor (rhG-CSF) until > or = 2.5 x 10(6) CD34+ cells/kg were harvested. Measurement of the CD34 content of PBPC collections was performed daily by a central reference laboratory using a single technique of CD34 analysis. Forty-five patients required a second mobilization procedure to achieve > or = 2.5 x 10(6) CD34+ cells/kg and 15 patients with less than 2.5 x 10(6) CD34+ cells/kg available for infusion received HDC. A median of 9.94 x 10(6) CD34+ cells/kg (range, 0.5 to 112.6 x 10(6) CD34+ cells/kg) contained in the PBPC collections was subsequently infused into patients after the administration of HDC. Engraftment was rapid with patients requiring a median of 9 days (range, 5 to 38 days) to achieve a neutrophil count of 0.5 x 10(9)/L and a median of 9 days (range, 4 to 53+ days) to achieve a platelet count of > or = 20 x 10(9)/L. A clear dose-response relationship was evident between the number of CD34+ cells per kilogram infused between the number of CD34+ cells per kilogram infused and neutrophil and platelet engraftment kinetics. Factors potentially influencing the engraftment kinetics of neutrophil and platelet recovery were examined using a Cox regression model. The single most powerful mediator of both platelet (P = .0001) and neutrophil (P = .0001) recovery was the CD34 content of the PBPC product. Administration of a post-PBPC infusion myeloid growth factor was also highly correlated with neutrophil recovery (P = .0001). Patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin had more rapid platelet recovery than patients receiving other regimens (P = .006), and patients requiring 2 mobilization procedures versus 1 mobilization procedure to achieve > or = 2.5 x 10(6) CD34+ cells/kg experienced slower platelet recovery (P = .005). Although a minimal threshold CD34 dose could not be defined, > or = 5.0 x 10(6) CD34+ cells/kg appears to be optimal for ensuring rapid neutrophil and platelet recovery.     

A randomized multicenter comparison of CD34(+)-selected progenitor cells from blood vs from bone marrow in recipients of HLA-identical allogeneic transplants for hematological malignancies

OBJECTIVE: Peripheral blood progenitor cells (PBPC) have been established as an alternative source of hematopoietic stem cells for allogeneic transplantation, but an increased incidence of both acute and chronic graft-vs-host disease (GVHD) has become apparent. We performed a prospective randomized trial comparing bone marrow transplantation (BMT) vs PBPC transplantation (PBPCT) using CD34(+) selection for T-cell depletion (TCD) in both study arms. PATIENTS AND METHODS: Between January 1996 and October 2000, 120 patients with a diagnosis of acute leukemia, myelodysplasia, multiple myeloma, or lymphoma were randomized to receive either filgrastim-mobilized PBPC or BM from HLA-identical sibling donors after standard high-dose chemoradiotherapy. Patient characteristics did not differ between study arms. RESULTS: Recipients of PBPC received more CD3(+) T cells (median: 3.0 vs 2.0 x 10(5)/kg, p<0.0001) and more CD34(+) cells (median: 3.6 vs 0.9 x 10(6)/kg, p<0.0001). Neutrophil and platelet recoveries occurred significantly faster after PBPCT. The cumulative incidence of acute GVHD grades II-IV was 37% after BMT vs 52% after PBPCT and was most significantly (p=0.007) affected by the number of CD3(+) T cells in the graft. Acute GVHD appeared strongly associated with increased treatment-related mortality (TRM) in a time-dependent analysis. Higher numbers of CD34(+) cells were associated with less TRM. With a median follow-up of 37 months (range: 12-75), overall survival at 4 years from transplantation was 60% after BMT and 34% for recipients of PBPCT (p=0.04), which difference was largely due to increased GVHD and TRM in PBPC recipients receiving T-cell dosages greater than 2 x 10(5)/kg. CONCLUSION: Outcome following T cell-depleted PBPCT critically depends on the number of CD3(+) T cells, whereby high T-cell numbers may blunt a favorable effect of higher CD34(+) cell numbers.     

Dose-intensive melphalan with stem cell support (CM regimen) is effective and well tolerated in elderly myeloma patients

BACKGROUND AND OBJECTIVE: Multiple myeloma (MM) typically afflicts elderly patients. High-dose therapy has recently been shown to lead to a better outcome than standard treatment, mainly in younger patients. The extent to which older subjects can benefit from intensified approaches without excessive toxicity is examined in this study. DESIGN AND METHODS: Between December 1994 and May 1997, 12 Italian Multiple Myeloma Study Group institutions entered 68 patients at diagnosis (median age 65) into an intensified chemotherapy regimen: cyclophosphamide (CY) 3 g/m(2) plus melphalan 60 mg/m(2) followed by peripheral blood progenitor cells (PBPC) and G-CSF (CM regimen). CY (day 0) and G-CSF were used to mobilize PBPC harvested by a single leukapheresis on day 10. Melphalan was infused on day 11. PBPC were kept unprocessed at 4 degrees C for 48 hours and reinfused on day 12. Three CM regimens were delivered at 6-month intervals. RESULTS: Sufficient PBPC to support the first CM cycle were available (median CD34(+) harvest: 4.9x10(6)/kg), but dropped significantly after the second (median CD34(+) harvest: 2x10(6)/kg) and the third (median CD34(+) harvest: 0.9x10(6)/kg). The median durations of severe neutropenia (absolute neutrophil count < 500 microL) were 3, 4, and 3 days, and those of severe thrombocytopenia (platelets < 25,000/microL) were 2.5, 2, and 1 days, after the first, second and third courses, respectively. The frequency of extramedullary toxicities was low. Treatment-related mortality (TRM) was 3% after the first CM, only. Complete remission (CR) was 14% after the first, 16% after the second and 27% after the third CM. After a median follow-up of 34 months (range 19-49 months), median event-free survival was 35.6 months. INTERPRETATION AND CONCLUSIONS: These results indicate that dose-intensity of melphalan can be increased by reinfusing PBPC with acceptable low toxicity. The combination of CY and melphalan followed by PBPC is an effective chemotherapy for elderly myeloma patients. Repeated melphalan infusion hampered subsequent CD34(+) harvests.     

High-dose ara-C with autologous peripheral blood progenitor cell support induces a marked progenitor cell mobilization: an indication for patients at risk for low mobilization

A high-dose (HD) chemotherapy scheme was designed for the collection of large numbers of peripheral blood progenitor cells (PBPC) in lymphoma patients who were candidates for myeloablative therapy with autograft. The scheme included the sequential administration of HD cyclophosphamide (CY) (7 g/m(2)) and HD ara-C (2 g/m(2) twice a day for 6 consecutive days), followed by final consolidation with PBPC autograft. PBPC harvests were scheduled following both HD CY and HD ara-C. To minimize hematologic toxicity, small aliquots of PBPC (20 circulating CD34(+) cells/microl, whereas the remaining 19 'low-mobilizer' patients did not reach this cut-off value. In spite of poor mobilization after HD CY, 16 out of 19 low mobilizers provided good harvests following HD ara-C; overall, median collected CD34(+) cells x 10(6)/kg were 1.4 (0-3.1) and 10.2 (0-37) after HD CY and HD ara-C, respectively (P = 0.00007). Similar patterns were observed when PBPC were evaluated by CFU-GM/kg. Complete and durable hemopoietic reconstitution followed autograft with post HD ara-C PBPC. Within the high-mobilizer group, 88 patients received HD ara-C and 79 (90%) still showed high mobilization; overall, median collected CD34(+)cells x 10(6)/kg were 17.8 (range 3-94) and 19 (range 0-107) after HD CY and HD ara-C respectively (P = NS). Thus, the scheme allowed sufficient PBPC collections for autografting in low mobilizer patients; in addition, the scheme could be considered whenever extensive chemotherapy debulking is needed prior to PBPC collection.     

Consolidation treatment with autologous peripheral blood progenitor cell transplantation in acute myeloid leukemia: a single center experience

Several trials have suggested that intensive post-remission therapy may prolong the duration of complete remission (CR) in acute myeloid leukemia (AML). The purpose of this study was to evaluate the feasibility and the efficacy of high-dose cytarabine (HiDAC) consolidation chemotherapy followed by high-dose therapy and autologous infusion of peripheral blood progenitor cells (PBPC) mobilized by G-CSF in adult patients with AML in first CR. Fifteen consecutive AML patients underwent HiDAC consolidation chemotherapy, used as a method of in vivo purging, followed by G-CSF for the purpose of autologous PBPC collection. Eleven patients collected a median of 6.9x10(8)/kg peripheral blood mononuclear cells (MNC) (range 2.9-23) and a median of 6.67x10(6)/kg CD34+ cells (range 1.8-33.5) with a median of two aphereses (range 1-3). Two patients did not mobilize and two obtained an inadequate number of progenitor cells. The 11 patients with adequate collections received myeloablative chemotherapy followed by the infusion of PBPC. The median number of days to recover neutrophils and platelets was 12 and 13, respectively. After a median follow-up of 28.7 months (range 17.2-43.4), five out of 11 patients who underwent PBPC transplantation are still in CR, five have died in first relapse and one is alive in CR after relapse treated with salvage therapy and second PBPC infusion. These results demonstrate that HiDAC consolidation chemotherapy followed by autologous PBPC transplantation is a feasible procedure with minimal toxicity. Randomized studies should be performed to evaluate whether this form of consolidation may produce a significant improvement in leukemia-free survival.     

Hemopoietic Recovery and Infectious Complications in Breast Cancer and Multiple Myeloma after Autologous CD34<Superscript>+</Superscript> Cell-Selected Peripheral Blood Progenitor Cell Transplantation

Autografting with CD34+ cell-selected peripheral blood progenitor cells (PBPC) is often associated with a prolonged recovery time and a higher incidence of infections. The aim of our study was to evaluate whether underlying disease influences hemopoietic recovery and the infectious complications occurring after transplantation. We studied 19 breast cancer (BC) patients and 17 multiple myeloma (MM) patients entered in a high-dose chemotherapy (HDC) program of tandem autografting with CD34+ cell-selected PBPC. PBPC were collected after mobilizing chemotherapy plus granulocyte colony-stimulating factor and were processed for selection of CD34+ cells. After selection, a median of 53% CD34+ cells was recovered with a median final purity of 92% with no significant differences between the MM (52% and 92%, respectively) and BC (53% and 89%, respectively) patients. Medians of 4.5 x 10(6)/kg CD34+ cells (BC, 4.4 x 10(6)/kg; MM, 5.4 x 10(6)/kg) and 18 x 10(4)/kg colony-forming units-granulocyte-macrophage (BC, 21 x 10(4)/kg: MM, 16 x 10(4)/kg) were reinfused after each HDC. Twenty-six patients (10 MM and 16 BC) underwent tandem autografting, and 10 patients received only 1 autograft because of inadequate collection (5 patients), clinical condition (3 patients), and refusal (2 patients). In the BC patients, the HDC regimen included a high-dose melphalan course followed by an ICE (ifosfamide, carboplatin, and etoposide) course. In the MM patients, the regimen consisted of a course of high-dose melphalan therapy and a course of ICBV (idarubicin, cyclophosphamide [Cytoxan], BCNU, and etoposide) or total body irradiation, etoposide, and Cytoxan. We found a significantly prolonged time for neutrophil recovery to > 500/microL in the MM patients (13 days versus 10 days; P < .002), whereas the times for platelet recovery to > 20,000/microL in the two groups were not different (13 days versus 12 days; not significant). No late engraftment failures and no toxic deaths were observed. The incidences of extrahematologic toxicity were similar for the two patient groups. All patients received similar anti-infection prophylaxis for 3 months after transplantation. After 12 months of observation, we found a statistically significant higher incidence of bacterial infections in MM patients in both the early (77.8% versus 48.6%; P < .034) and the late (41.1% versus 0%; P < .014) posttransplantation periods, whereas the incidences of fungal infections were similar in the two groups. Viral infections consisted of herpes zoster virus infection in 2 patients of each group, and cytomegalovirus infection was observed in 3 MM patients and no BC patients. Our experience demonstrates a prolonged neutrophil recovery time and higher incidences of bacterial and viral infections in MM patients compared with BC patients. These observations, although limited by the small sample size, suggest that the underlying disease may influence the incidence of infections after CD34- cell-selected transplantation and should be considered in the planning of appropriate antimicrobial prophylaxis in the autologous transplantation setting.     

A comparison of toxicity following two different doses of cyclophosphamide for mobilization of peripheral blood progenitor cells in 116 multiple myeloma patients

High-dose cyclophosphamide (HDC) has been shown to be an effective regimen for collecting PBPC in multiple myeloma (MM) patients, but the optimal dose to be used remains controversial. Two historical cohorts of MM patients who received G- or GM-CSF and HDC at the dose of either 7 g/m(2) (HDC7, n = 74) or 4 g/m (HDC4, n = 42) were compared. As patients in the HDC4 group were more likely to have received G-CSF than GM-CSF (P < 10(-3)) and fewer previous alkylating agents (P = 0.004), multivariate logistic regression analysis was performed. In the HDC4 group, patients had a shorter median duration of neutropenia (P < 10(-4)), fewer RBC (P < 10(-3)) and platelet transfusions (P < 10(-3)) with fewer patients with platelets <20 x 10(9)/l (P = 0.004). Moreover, fewer febrile episodes (P < 10(-3)) and less need of intravenous antibiotics (P < 10(-3)) were found in the HDC4 group. No statistical difference was observed with regard to CD34(+) cell collection efficiency. Thus, the use of HDC at the dose of 4 g/m(2) for the collection of PBPC in MM patients decreases hematological and extrahematological toxicity with an equivalent CD34(+) cell collection efficiency.     

CD34+ selection of hematopoietic blood cell collections and autotransplantation in lymphoma: overnight storage of cells at 4 degrees C does not affect outcome

The purpose of this study was to investigate whether storing mobilized peripheral blood progenitor cell (PBPC) collections overnight before CD34+ selection may delay platelet count recovery after high-dose chemotherapy and CD34+-enriched PBPC re-infusion. Lymphoma patients underwent PBPC mobilization with cyclophosphamide 4 g/m2 i.v. and G-CSF 10 microg/kg/day subcutaneously. Patients were prospectively randomized to have each PBPC collection enriched for CD34+ cells with the CellPro CEPRATE SC System either immediately or after overnight storage at 4 degrees C. Thirty-four patients were randomized to overnight storage and 34 to immediate processing of PBPC; 15 were excluded from analysis due to tumor progression or inadequate CD34+ cell mobilization. PBPC from 23 patients were stored overnight, while 30 subjects underwent immediate CD34+ selection and cryopreservation. Median yield of CD34+ enrichment was 43.6% in the immediate processing group compared to 39.1% in the overnight storage group (P = 0.339). Neutrophil recovery >500 x 10(9)/l occurred a median of 11 days (range 9-16 days) in the overnight storage group compared to 10.5 days (range 9-21 days) in the immediate processing group (P = 0.421). Median day to platelet transfusion independence was 13 (range 7-43) days in the overnight storage group vs 13.5 (range 8-35) days in those assigned to immediate processing (P = 0.933). We conclude that storage of PBPC overnight at 4 degrees C allows pooling of consecutive-day collections resulting in decreased costs and processing time without compromising neutrophil and platelet engraftment after infusion of CD34+-selected progenitor cells. Bone Marrow Transplantation(2000) 25, 559-566.     

Safety and efficacy of a continuous infusion, patient controlled anti-emetic pump to facilitate outpatient administration of high-dose chemotherapy.

We evaluated the combination of diphenhydramine, lorazepam, and dexamethasone delivered as a continuous i.v. infusion via an ambulatory infusion pump with patient-activated intermittent dosing (BAD pump) for prevention of acute and delayed nausea/vomiting in patients receiving high-dose chemotherapy (HDC) for peripheral blood progenitor cell (PBPC) mobilization (MOB) or prior to autologous PBPC rescue. The BAD pump was titrated to patient response and tolerance, and continued until the patient could tolerate oral anti-emetics. Forty-four patients utilized the BAD pump during 66 chemotherapy courses, 34 (52%) for MOB and 32 (48%) for HDC with autologous PBPC rescue. The median number of days on the BAD pump during MOB and HDC was 3 (1-6) and 9 (2-19) days, respectively. Complete overall or complete emesis control occurred on 94% of MOB and 89% of HDC treatment days during chemotherapy administration and 72% and 43%, respectively, following chemotherapy administration. Eighty-three percent of MOB and 55% of HDC treatment days were associated with no nausea. While on the BAD pump, no patient experienced severe toxicity or required hospitalization for management of nausea/vomiting. The BAD pump was safe and effective in minimizing nausea and vomiting associated with HDC, and thus, eliminated the need for hospitalization for management of chemotherapy-induced nausea and vomiting.     

Ifosfamide in combination with paclitaxel or doxorubicin: regimens which effectively mobilize peripheral blood progenitor cells while demonstrating anti-tumor activity in patients with metastatic breast cancer

For patients with metastatic breast cancer (MBC) who undergo high-dose therapy with autologous peripheral blood progenitor cell (PBPC) transplantation, an important prerequisite is a mobilization regimen that efficiently mobilizes PBPCs while producing an effective anti-tumor effect. We prospectively evaluated ifosfamide-based chemotherapy for mobilization efficiency, toxicity and disease response in 37 patients. Patients received two cycles of the ifosfamide-based regimen; ifosfamide (5 g/m2 with conventional-dose cycle and 6 g/m2 with mobilization cycle) with either 50 mg/m2 doxorubicin (if limited prior anthracycline and/or progression more than 12 months after an anthracycline-based regimen) or 175 mg/m2 paclitaxel. For the mobilization cycle, all patients received additional G-CSF (10 microg/kg SC, daily) commencing 24 h after completion of chemotherapy. The target yield was >6x10(6) CD34+ cells/kg, sufficient to support the subsequent three cycles of high-dose therapy. The mobilization therapy was well tolerated and the peak days for peripheral blood (PB) CD34+ cells were days 10-13 with no significant differences in the PB CD34+ cells mobilization kinetics between the ifosfamide-doxorubicin vs. ifosfamide-paclitaxel regimens. The median PBPC CD34+ cell content ranged from 2.9 to 4.0x10(6)/kg per day during days 9-14. After a median of 3 (range 1-5) collection days, the median total CD34+ cell, CFU-GM and MNC for all 44 individual sets of collections was 9.2x10(6)/kg (range 0.16-54.9), 37x10(4)/kg (range 5.7-247) and 7.3x10(8)/kg (range 2.1-26.1), respectively. The PBPC target yield was achieved in 35 of the 37 patients. The overall response rate for the 31 evaluable patients was 68% with 10% having progressive disease. Thirty-three patients have subsequently received high-dose therapy consisting of three planned cycles of high-dose ifosfamide, thiotepa and paclitaxel with each cycle supported with PBPCs. Rapid neutrophil and platelet recovery has been observed. Ifosfamide with G-CSF in combination with doxorubicin or paclitaxel achieves effective mobilization of PBPC and anti-tumor activity with minimal toxicity.     

Fixed-dose single agent pegfilgrastim for peripheral blood progenitor cell mobilisation in patients with multiple myeloma

High-dose chemotherapy and autologous peripheral blood progenitor cell transplantation is an effective treatment for multiple myeloma. Progenitor cells are generally mobilised into the peripheral blood by administration of filgrastim. Pegfilgrastim is a covalent conjugate of filgrastim with a longer half-life. The results of a phase II study of pegfilgrastim, administered as a single injection to mobilise autologous peripheral blood progenitor cells in patients with multiple myeloma, is reported. All patients (n = 19) received 12 mg of pegfilgrastim. Leukaphaeresis was started when the peripheral blood CD34(+) count was >0.015 x 10(9)/l. Daily, leukaphaeresis was performed until the target progenitor cell dose was obtained. The median number of leukaphaeresis procedures required to collect the target CD34(+) cell dose was 2 (range 1-5). A median of 8.4 x 10(6) CD34(+) cells/kg (range 4.1-15.8) was collected. The most common toxicity was bone pain/myalgia. Sustained haematological recovery occurred in all the patients who underwent high-dose chemotherapy followed by autologous peripheral blood progenitor cell transplantation with pegfilgrastim-mobilised cells. A single fixed dose of pegfilgrastim was effective in mobilising adequate peripheral blood progenitor cells in patients with multiple myeloma. The efficacy and toxicity profile was similar to that described with filgrastim treatment.     

Ex vivo expanded unselected peripheral blood: progenitor cells reduce posttransplantation neutropenia, thrombocytopenia, and anemia in patients with breast cancer

The safety and efficacy of administering ex vivo expanded peripheral blood progenitor cells (PBPC) to patients with breast cancer who undergo high-dose chemotherapy and PBPC transplantation was investigated. Unselected PBPC were cultured in gas-permeable bags containing 1-L serum-free media, granulocyte colony-stimulating factor, stem cell factor, and pegylated megakaryocyte growth and development factor for 9 days. Cell dose cohorts were assigned to have between 2 and 24 x 10(9) PBPC cultured at 1, 2, or 3 x 10(6) cells/mL. Twenty-four patients received high-dose chemotherapy followed by infusion of the cultured PBPC and at least 5 x 10(6) CD34(+) uncultured cryopreserved PBPC per kilogram. No toxicities resulted from infusions of the ex vivo expanded PBPC. The study patients had shorter times to neutrophil (P =.0001) and platelet (P =.01) recovery and fewer red cell transfusions (P =.02) than 48 historical controls who received the same conditioning regimen and posttransplantation care and at least 5 x 10(6) CD34(+) PBPC per kilogram. Improvements in all these endpoints were significantly correlated with the expanded cell dose. Nine of 24 (38%) patients recovered neutrophil counts above 500/microL by day 5 or 6 after transplantation, whereas none of the controls had neutrophil recovery before the eighth day. Seven (29%) patients had neutropenia for 3 or fewer days, and 9 (38%) patients did not experience neutropenic fevers or require broad-spectrum antibiotics. Therefore, ex vivo expanded PBPC are capable of ameliorating posttransplantation neutropenia, thrombocytopenia, and anemia in patients receiving high-dose chemotherapy.     

CD34+-enriched peripheral blood progenitor cells from unrelated donors for allografting of adult patients: high risk of graft failure,infection and relapse despite donor lymphocyte add-back

Fifty-one adults with haematological malignancies were transplanted with CD34+-selected peripheral blood progenitor cells (PBPC) from unrelated donors. The conditioning protocol contained total body irradiation (n = 17) or combinations of busulphan and other alkylating agents (n = 34). Antithymocyte globulin was infused in all patients. The median number of CD3+ T cells infused with the graft after purification with the Isolex 300 system in the first cohort of 18 patients was 2.1 x 10(5)/kg. Prophylactic donor lymphocyte infusion (DLI) containing 1 x 10(5) CD3+ T cells was performed on d 21 in the following 33 patients who had received PBPC purified by the CliniMACS system. Early graft failure occurred in 8/51 patients (16%). After a median follow-up of 31 months (range 8-60), the probability of disease-free survival (DFS) was 36% for the whole group. Reasons for death were opportunistic infections (n = 15), graft-versus-host disease (GvHD, n = 7) and relapse (n = 4). Pre-transplant factors with significant impact on DFS were cytomegalovirus status and risk category of underlying disease. The occurrence of graft failure or GvHD was associated with poor outcome. Recipients of CD34+-selected PBPC from unrelated donors are at high risk of infectious complications, relapse and graft failure which cannot be prevented by early reinfusion of unmodified donor lymphocytes.     

Prolonged CD4 depletion after sequential autologous peripheral blood progenitor cell infusions in children and young adults

Administration of mobilized peripheral blood progenitor cells (PBPCs) after high-dose chemotherapy rapidly restores multilineage hematopoiesis, but the ability of such products to restore lymphocyte populations remains unclear. In this report, we evaluated immune reconstitution in a series of patients treated with sequential cycles of high-dose chemotherapy, followed by autologous PBPC infusions (median CD34(+) cell dose 7.2 x 10(6) cells/kg [range 2-29.3]). Although patients experienced rapid reconstitution of B cells and CD8(+) T cells, we observed CD4 depletion and diminished immune responsiveness in all patients for several months after completion of therapy. Mature CD4(+) T cells contained within the grafts did not appear to contribute substantially to immune reconstitution because CD4 counts did not differ between recipients of unmanipulated T-cell replete infusions versus CD34 selected, T-cell-depleted infusions. Rather, at 12 months after therapy, total CD4 count was inversely proportional to age (rho = -0.78, P =.04), but showed no relationship to CD34 cell dose (rho = -0.42, P =.26), suggesting that age-related changes within the host are largely responsible for the limited immune reconstitution observed. These results demonstrate that in the autologous setting, the infusion of large numbers of PBPCs is not sufficient to restore T-cell immune competence and emphasize that specific approaches to enhance immune reconstitution are necessary if immune-based therapy is to be used to eradicate minimal residual disease after autologous PBPC transplantation. (Blood. 2000;96:754-762)     

High-dose chemotherapy with peripheral blood stem cell support for stage IIIB inflammatory carcinoma of the breast

The purpose of this study was to determine outcomes for 56 patients with inflammatory breast cancer (IBC) receiving high-dose chemotherapy (HDC) with cyclophosphamide, thiotepa and carboplatin (CTCb) with peripheral blood stem cell (PBSC) support. All patients received the same total amount of chemotherapy but there were differences in the sequence of therapy: 15 received induction chemotherapy, chemotherapy mobilization of PBSC and CTCb after surgery (adjuvant group) while 41 received induction chemotherapy with (n = 17) or without (n = 24) chemotherapy for mobilization of PBSC prior to surgery and CTCb after surgery (neoadjuvant group). Median time from diagnosis to HDC was 5.5 months (range 3.5-12.5). Fifty-one patients (91%) required admission to the hospital following HDC for a median of 11 days (range 5-25). There were two (4%) infectious deaths after HDC. Twenty-four patients (43%) have relapsed at a median of 18 months (range 8-50) from diagnosis resulting in death in 34%. The probabilities of overall (OS) and event-free survival (EFS) at 3 years for all 56 patients were 0.72 and 0.53, respectively, with a median follow-up of 44 months (range 15-76) from diagnosis. There were no differences in OS, EFS or patterns of relapse between patients in the adjuvant or neoadjuvant groups. These sequences of combined modality therapy incorporating HDC are comparable or superior to other intensive approaches for the treatment of IBC. Further improvements will be necessary to decrease systemic recurrences.     

Infused CD34 cell dose, but not tumour cell content of peripheral blood progenitor cell grafts, predicts clinical outcome in patients with diffuse large B-cell lymphoma and follicular lymphoma grade 3 treated with high-dose therapy

Previously, we have shown that patients with diffuse large B-cell lymphoma (DLBCL) transplanted with contaminated bone marrow (BM) generally have a poor outcome. Whether this is also the case when peripheral blood progenitor cell (PBPC) grafts are used is not known. Forty-three patients with chemosensitive DLBCL or follicular lymphoma grade 3 (FLgr3) were treated with high-dose therapy (HDT) and autologous stem cell support. Nine patients received purged grafts. Quantitative real-time polymerase chain reaction (QRT-PCR) for either the BCL2/IgH translocation or allele specific oligonucleotide (ASO) QRT-PCR for the immunoglobulin heavy chain (IgH) complementarity-determining region 3 were used. Nine of 25 (36%) PBPC grafts contained tumour cells as tested by QRT-PCR, including two grafts purged by CD34(+) cell enrichment combined with B-cell depletion. The level of contamination of the PBPC/CD34(+) cells ranged from 0 to 8.28%. No relationship could be shown between the total number of tumour cells infused and relapse. Patients receiving PCR-positive or PCR-negative PBPC grafts had similar progression-free survival (PFS) (P = 0.49). However, a significant difference was seen in PFS and overall survival (OS) for the patients given >/=6.1 x 10(6) CD34(+) cells/kg compared with those given <6.1 x 10(6) CD34(+) cells/kg (P = 0.01 and P < 0.05 respectively).     

Preparation and successful engraftment of purified CD34+ bone marrow progenitor cells in patients with non-Hodgkin's lymphoma

From September 1992 to January 1994, we evaluated the use of the CEPRATE SC stem cell concentrator (CellPro, Inc, Bothell, WA) to select CD34+ cells from the bone marrow (BM) of 25 patients with non-Hodgkin's lymphoma in complete remission. This system uses the biotinylated 12.8 IgM MoAb to select CD34+ cells. Cells are retained on an avidin column and detached by agitation. Fifteen patients have been transplanted with the CD34+ purified fraction. The CD34+ purified fraction of the 25 processed BMs contained a median of 0.54% of the original nucleated cells in a volume of 5 to 10 mL. The median concentration of CD34+ cells was 49% (range, 12% to 80%), and the median enrichment of CD34+ cells was 33-fold (range, 9- to 85-fold). This selected CD34+ fraction retained 60% (range, 15% to 95%) of late granulocyte-macrophage colony- forming units (CFU-GM), 55% (range, 12% to 99%) of early CFU-GM, and 31% (range, 2% to 100%) erythroid burst-forming units (BFU-E) corresponding to median enrichments of 22-fold (range, 1- to 71-fold), 19-fold (range, 2- to 58-fold), and 14-fold (range, 2- to 200-fold), respectively. There was a correlation between immune phenotypes and progenitor cells. In the initial buffy-coat fractions, the percentage of CD34+ cells was correlated to the cloning efficiency of both late CFU-GM (P < .05) and early CFU-GM (P < .001). In the final selected fraction, there was a correlation between the percentage of CD34+/CD33- and the cloning efficiency of early CFU-GM (P < .05) and between the percentage of CD34+/CD33+ and the cloning efficiency of late CFU-GM (P < .05). Lymphoma cells positive for t(14; 18) were found by polymerase chain reaction in 9 of 14 buffy coats tested before CD34+ cell purification. In 8 cases, the CD34(+)-selected fraction was found to be negative, and the CD34- fraction was found to be positive. After cryopreservation, the recoveries of progenitor cells in the CD34(+)- purified fraction were 79% for late CFU-GM, 71% for early CFU-GM, and 73% for BFU-E. The 15 patients transplanted with the concentrated CD34+ fraction received a median dose of 1 x 10(6) CD34+ cells/kg (range, 0.3 to 2.96) and 10.62 x 10(4) early CFU-GM/kg (range, 0.92 to 25.55). Median days to recovery to 0.5 x 10(9)/L neutrophils and 50 x 10(9)/L platelets were days 15 (range, 10 to 33) and 23 (range, 11 to 68), respectively.(ABSTRACT TRUNCATED AT 400 WORDS)