Cell-Freezing Devices Are Not Strictly Needed to Start an Autologous Hematopoietic Transplantation Program: Non-Cryopreserved Peripheral Blood Stem Cells Can be Used to Restore Hematopoiesis after High Dose Chemotherapy: A Multicenter Experience in 268 Autografts in Patients with Multiple Myeloma or Lymphoma. Study on Behalf of the Latin-American Bone Marrow Transplantation Group (LABMT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 849-849 ◽  
Author(s):  
Amado J Karduss-Urueta ◽  
Guillermo J. Ruiz-Arguelles ◽  
Rosendo Perez ◽  
Guillermo J Ruiz-Delgado ◽  
Angelica Maria Cardona ◽  
...  

Abstract Storage of peripheral blood stem cells (PBSC) at 4ºC is a simple and inexpensive alternative to cryopreservation for preserving the clonogenic capacity of progenitors cells in the autologous transplant setting, however it has been perceived as unsafe and has deserved little attention. We present the experience of two Latin-American centers using refrigerated, non-cryopreserved stem cells after conditioning with high dose melphalan, CBV or BEAM in a large group of lymphoma and myeloma patients Materials and Methods PBSC were mobilized with filgrastim 5 mg/kg/BID for three to six days.One to three apheresis procedure were employed; the cells were stored at 4ºC for 5 to 6 days in patients who received BEAM or CBV and for 3 days in those given melphalan. All of the conditioning regimens were administered preserving the full intensity of dose (Table 1). After the autograft all patients received filgrastim or pegfilgrastim Table 1 BEAM D-5 D-4 D-3 D-2 D-1 BiCNU 300 mgs/m2 X Etoposide 200-400 mgs/m2 X X X X Citarabine 300-400 mgs/m2 X X X Melphalan 140 mgs/m2 X CBV BiCNU 300 mgs/m2 13 patients received carboplatin 900 mgs/m2 instead BiCNU X Etoposide 300 mgs/m2 X X X Ciclophosphamide 2.000 mgs/m2 X X X Melphalan Melphalan 200 mgs/m2 X Melphalan 100 mgs/m2 X X Results 102 lymphoma patients: 48 Hodgkin`s lymphoma (HL) and 54 non-Hodgkin´s lymphoma (NHL) received BEAM (71) or CBV (31). A median of 3.3 millions/kg of CD34 was infused; the median viability of the cells after 5-6 days of refrigeration (trypan blue exclusion) was 82%. 101 out of 102 patients engrafted, median time to achieve 500/ul neutrophil or more was 12 days, 100 were evaluable for thrombopoiesis, 99 of them had a self- sustained platelet count of 20.000 or more at a median of 17 days. The OS at 5 years was 59% and 42% for patients with Hodgkin and lymphoma respectively 151 patients with multiple myeloma received melphalan 200 mgs/m2. After 72 hours of refrigeration, a median of 2.6 millions/kg of CD34 cells were infused, the viability in all cases being > 90%. Three patients were not evaluable because early death. Median time to achieve 500 neutrophil or more and 20.000 platelets was 12 (9-50) and 15 (7-50) days. The OS at 5 years was 50% 21 patients with NHL and HL received as conditioning regimen melphalan 200 mgs/m2. After 72 hours of storage, a median of 1.75 millions/kg of CD34 cells were transplanted, 100% of them engrafted, median time to 500 neutrophils and 20.000 platelets was 11.9 and 15 days respectively There were no cases of secondary engraftment failure in any of the three groups Conclusion In this series of 268 patients, we have shown that autologous PBSC can be kept at 4ºC in a conventional blood bank refrigerator for up to six days and use them to rescue high-dose chemotherapy in both multiple myeloma and lymphoma patients. Avoiding freezing procedures results in substantial cost savings. The availability of freezing devices for hematopoietic stem cells is not anymore an obstacle to start a an autologous transplantation program This observation is critical in areas of underprivileged economic circumstances, where more than 50% of the inhabitants of the world live. Disclosures No relevant conflicts of interest to declare.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 502-502 ◽  
Author(s):  
Noel-Jean Milpied ◽  
Gerald Marit ◽  
Bernard Dazey ◽  
Jean-Michel Boiron ◽  
Zoran Ivanovic ◽  
...  

Abstract Abstract 502 Autologous stem cell transplantation with PBSC after high-dose chemotherapy remains standard therapy for patients with symptomatic Multiple Myeloma (MM). Strategies to minimize complications could significantly reduce the morbidity of that procedure. One possibility could be to shorten the duration of induced neutropenia through the injection of an ex-vivo expanded graft. Nineteen patients (pts) received EVEC after high-dose Melphalan (HDM) (200 mg/m2) as the only graft. The ex-vivo expanded procedure has been described elsewhere (Boiron et al. Transfusion 2006 and Ivanovic et al. Transfusion 2006). Briefly, thawed peripheral blood CD 34+ cells collected after G-CSF mobilisation and selected with immunomagnetic devices were incubated for 10 days in a serum free medium (Maco Biotech HP01) with Stem Cell Factor (Amgen), G-CSF (Amgen) and TPO (Amgen: 7 pts; Cellgenix:12 pts). The expanded cells were then thoroughly washed and injected 48h after the HDM injection. The ex-vivo expansion lead to a median fold of 5,4 for CD34+ cells (1,3-11,8); 118 for CD33+ (1-703880); 3386 for CD14+ (4-101075); 28,5 for CD13+ (10-703880) and 13 for CFUs (6-21). The median N° of CD34+ cells injected was 14×10e6/kg (5,3-48). The results of these transplants were compared to those achieved in 38 pts who received unmanipulated PBSC after HDM. Pts and controls were matched for age, sex, stage of the disease, first line chemotherapy ( VAD or VD) status of the disease at time of transplant, year of transplant, time between diagnosis and transplant, CD34+ mobilisation technique (HD cytoxan + G-CSF or G-CSF alone) and the median N° of total nucleated cells and of CD34+ collected. The results are summarized on the table: There was no secondary neutropenia in the patients who received EVEC. With a median FU of the entire cohort of 30 m, the median OS for pts who received their first transplant with EVEC and with PBSC is 69 m and not reached respectively (p=NS), the median PFS is 18 m and 27 m (p = NS) and the median time to progression is 14 m and 15 m (p=NS). Conclusion: EVEC is feasible, safe and reduce significantly the morbidity of autologous stem cell transplantation after HDM for multiple myeloma. Disclosures: Milpied: Amgen France: Honoraria.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4213-4213 ◽  
Author(s):  
Carole Soussain ◽  
Laure Marec ◽  
Wajed Abarah ◽  
Christian Allard ◽  
Hassina Mallek ◽  
...  

Abstract The efficacy of Pegfilgrastim (PF) in decreasing the duration of neutropenia has been proved after standard dose of chemotherapy. Results of PF after high dose chemotherapy (HDC) and autologous peripheral blood stem cells transplantation ASCT) are lacking. We studied the efficacy of PG in patients receiving HDC and ASCT for lymphoproliferative disease. Fifteen consecutive patients (8 males; 7 females) were onrolled in the study from September 2003 through March 2004. Median age of the patients was 56 years. Diseases were multiple myeloma in 5 patients, diffuse large cell non-Hodgkin’s lymphoma (NHL) in 3 patients, follicular lymphoma in 4 patients, mantle cell lymphoma in one patient, and primary central nervous system lymphoma PCNSL) in 2 patients. All patients were eligible for HDC and ASCT per institutional criteria. Stem cells were collected with peripheral blood pheresis after high dose cyclophosphamide (7 cases); high dose Ara-c (5 cases); ifosfamide (1 case); CHOP-like chemotherapy (1 case); or in steady state (1 case). All the patients received daily G-CSF (5 to 10 mcg/kg). Three different conditioning regimens were used. Patients with multiple myeloma received high dose melphalan (200 mg/m²), patients with PCNSL received a combination of high dose Thiotepa (750 mg/m²), Busulfan (12 mg/kg), and Cyclophosphamide (120 mg/kg), and patients with NHL received a BEAM chemotherapy. PF was administered as a single subcutaneous injection of 6 mg at day +3 after stem cell infusion, except for one patient whose injection was done on day 4. No adverse event attributable to PF was observed. There were no toxic death on study. All patients engrafted neutrophils and platelets. The median time to neutrophils engraftment (> 500/mm3) was 7 days (range, 4–12). Febrile neutropenia was almost constant (14/15) but never exceed OMS grade 2. Median number of days with IV antibiotics was 7 days (range 5–22). These preliminary data show that a fixed dose of 6 mg of PF given subcutaneously at day +3 after HDC and ASCT is safe and effective. A cost efficacy study is warranted to compare PF and daily dose of standard G-CSF after ASCT.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3494-3494
Author(s):  
Joost TM De Wolf ◽  
Gustaaf Van Imhoff ◽  
Gerwin A Huls ◽  
Edo Vellenga

Abstract Abstract 3494 Introduction: Treatment of multiple myeloma (MM) patients (<65 yrs) consists of induction chemotherapy for 3–6 months followed by peripheral blood stem cell collection and transplantation. Both high dose cyclophosphamide (HD-C, 2 gr/m2/day, on days 1–2) and lower dosage of cyclophosphamide (1 gr/m2/i.v.on day 1) combined with doxorubicin (15 mg/m2/day, on days 1–4) and dexamethason 40 mg orally, days 1–4 (LD-C) are used, in combination with G-CSF, to mobilize hematopoietic stem/progenitor cells. A great variability was observed in the engraftment of different hematopoietic lineages post-ASCT. Therefore we questioned whether the dose of cyclofosfamide as mobilizing agent might affect the neutrophil and platelet recovery post-ASCT. The studied MM patients were treated with VAD or TAD (Blood 2010;11:115). Peripheral blood stem cells were collected after LD-C and HD-C with the Cobe Spectra; in each collection, 10 – 12 L of blood was processed in 3 – 4 hours. The target yield was 10 × 106/kg CD34+ cells. Results: 92 patients were treated according to VAD and 41 patients with TAD. In the VAD arm 89% of the patients reached the target yield of CD34+ cells after 1 collection compared to 61% in patients treated with TAD (p = 0.0003). The number of CD34+ cells collected at the first day and the total CD34 yield after HD-C or LD-C was significantly higher in patients treated with VAD compared with TAD: 16.6 ± 11.6 × 106/kg vs. 10.4 ± 9.3 × 106/kg (p=0.003), and 16.9 ± 11.1 × 106/kg vs 12.3 ± 8.6 × 106/kg (p=0.02). No significant difference was observed in the total yield of collected CD34+ cells in the VAD arm or TAD arm between HD-C vs. LD-C. In all patients high dose melphalan (200 mg/m2) was used as conditioning regimen followed by reinfusion of peripheral blood stem cells. In the VAD arm no difference in neutrophil and platelet engraftment (absolute neutrophil count > 0.5 × 109/L and platelet count > 20 × 109/L without platelet transfusions) was noticed between patients mobilized with LD-C (22 ±12 days and 23 ±13 days) or HD-C (18 ± 5 (p=0.1) and 21 ±11 days (p=0.5)); in contrast a significant difference was demonstrated in neutrophil and platelet engraftment between patients treated according the TAD arm and mobilized with LD-C (20 ± 8 days and 20 ±19 days) or HD-C (34 ± 11 days (p<0.0001) and 43 ±22 days (p=0.001)). These differences could not be ascribed to differences in the number of infused CD34+ cells: VAD arm: LD-C: 5.7 ± 2.6 × 106/kg, HD-C: 5.7 ± 2.5 × 106/kg: TAD arm: LD-C: 5.2 ± 2.5 × 106/kg and TAD-HD-C 6.4 ± 2 × 106/kg. It might be assumed that the higher dosage of cyclophosphamide had a positive effect on tumor response. However the impaired engraftment was not associated with differences in relapse free survival between the different arms (p = 0.2). In summary these data demonstrate that thalidomide containing regimen in MM patients impair mobilization of stem/progenitor cells and that a mobilization with high dose cyclophosphamide and not low dose cyclophosphamide after treatment with thalidomide prolong the engraftment post-transplantation. Disclosures: No relevant conflicts of interest to declare.


2000 ◽  
Vol 18 (1) ◽  
pp. 43-43 ◽  
Author(s):  
Charles H. Weaver ◽  
Kevin A. Schulman ◽  
Barbara Wilson-Relyea ◽  
Robert Birch ◽  
William West ◽  
...  

PURPOSE: The purpose of this study was to compare the effects of filgrastim, sargramostim, or sequential sargramostim and filgrastim on CD34+ cell yields and morbidity after myelosuppressive mobilization chemotherapy (MC). PATIENTS AND METHODS: One hundred fifty-six patients were randomized to receive filgrastim (n = 51), sargramostim (n = 52), or sargramostim for 5 days followed by filgrastim (n = 53) after MC with either cyclophosphamide and etoposide (n = 75) or paclitaxel and cyclophosphamide (n = 81). RESULTS: Compared with those who received sargramostim, patients who received filgrastim had faster recovery of an absolute neutrophil count of 0.5 × 109/L or greater (a median of 11 v 14 days; P = .0001), with fewer patients requiring RBC transfusions (P = .008), fewer patients with fever (18% v 52%; P = 0.001), fewer hospital admissions (20% v 42%; P = .013), and less intravenous antibiotic therapy (24% v 69%; P = .001). Patients who received filgrastim yielded more CD34+ cells (median, 7.1 v 2.0 × 106/kg/apheresis; P = .0001), and a higher fraction achieved 2.5 × 106 (94% v 78%; P = .021) and 5 × 106 (88% v 53%; P = .001) or more CD34+ cells/kg with fewer aphereses (median, 2 v 3; P = .002) and fewer days of growth-factor treatment (median, 12 v 14; P = .0001). There were no major differences in outcomes between the filgrastim alone and the sequential regimens. After high-dose chemotherapy, patients who had peripheral-blood stem cells (PBSCs) mobilized with filgrastim or the sequential regimen received higher numbers of CD34+ cells and had faster platelet recovery (P = .015), with fewer patients (P = .014) receiving fewer platelet transfusions (P = .001) than patients receiving sargramostim-mobilized PBSCs. CONCLUSION: It was concluded that filgrastim alone or sequential sargramostim and filgrastim were superior to sargramostim alone for the mobilization of CD34+ cells and reduction of toxicities after MC.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2868-2868 ◽  
Author(s):  
Ingmar Bruns ◽  
Ulrich Steidl ◽  
Christof Scheid ◽  
Kai Hübel ◽  
Roland Fenk ◽  
...  

Abstract To date the most effective treatment for patients (pts) with multiple myeloma consists of conventional induction chemotherapy followed by either single or tandem high-dose chemotherapy and autologous blood stem cell transplantation. Collection of sufficient numbers of hematopoietic stem cells is essential for high-dose chemotherapy. Current regimens for stem cell mobilization are based on daily subcutaneous injections of human recombinant G-CSF starting shortly after cytotoxic therapy. Here we examined the use of polyethyenglycole (PEG)-conjugated G-CSF (pegfilgrastim) at two different doses in patients with stage II or III multiple myeloma. Patients received induction therapy with 2–4 cycles ID or VAD. Following cytotoxic therapy with cyclophosphamide (4g/m2) we administered either a single dose of 6 mg pegfilgrastim (n=10 pts; median age: 55 years), 12 mg pegfilgrastim (n=12 pts; median age: 51 years) or daily doses of 8,5 μg/kg unconjugated G-CSF (filgrastim) (n=12 pts; median age: 51 years). The growth factor was given on day 4 (range 2–5 days) in the “6 mg pegfilgrastim group”, on day 5 (range 2–7 days) in the “12 mg pegfilgrastim group” and on day 4 (range 3–6 days) in the “filgrastim group” after cyclophosphamide. Numbers of CD34+ cells were determined during leukocyte recovery and harvested by large volume apheresis using a cobe spectra blood cell separator. Pegfilgratim was associated with an earlier leukocyte recovery both at the 6mg dose (median 12 days, range 8–16 days) and the 12mg dose (median 12 days, range 7–16 days) as compared to filgrastim (median 14 days, range 11–15 days, p=0.04). Similarily, the peripheral blood CD34+ cell peak occurred earlier in patients who received pegfilgrastim (median 12 days, range 11–18 days versus median 15 days, range 12–18). On the other hand the peripheral blood CD 34+ peak did not differ significantly between the three groups (median 129/μl with 6 mg pegfilgrastim, range 30–433, median 78/μl with 12 mg pegfilgrastim, range 20– 1055 and median 111/μl with filgrastim, range 28–760, p=0.95). With a median of 1.0x10E7 CD34+ cells per kg (range 5.8x10E6-1.9x10E7) in the “6 mg pegfilgrastim group”, 7.4x10E6 CD34+ cells per kg (median, range 4.9x10E6- 3.8x10E7) in the “12 mg pegfilgrastim group” and 10.8x10E6 CD34+ cells per kg (median, range 5.0x10E6-8.7x10E7) in the “filgrastim group” there were no significant differences in the total number of harvested CD34+ cells. Following high-dose therapy with melphalan (200 mg/m2) and autografting leukocyte and platelet reconstitution was similar within all groups. In summary, a single dose of pegfilgrastim after high dose cyclophosphamide is capable of mobilizing a sufficient number of CD 34+ cells for succesful autografting and sustained hematological reconstitution in patients with multiple myeloma. No difference could be observed between 6 mg and 12 mg of pegfilgrastim. Our data provide the basis for randomized studies evaluating the optimal dose and timing of pegfilgrastim as well as long-term outcome in larger cohorts of patients.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 902-902 ◽  
Author(s):  
Noel-Jean Milpied ◽  
Thierry Lamy ◽  
Philippe Casassus ◽  
Eric Deconninck ◽  
Remy Gressin ◽  
...  

Abstract Background: The beneficial effect of adding rituximab to CHOP has been shown for elderly patients with DLBCL (Coiffier et al, N.E.J.M 2002). We have shown that HDT with autologous stem cell transplantation is superior to CHOP in young adults with DLCL ( Milpied et al GOELAMS 072 trial, N.E.J.M 2004). The feasibility of adding rituximab to front-line HDT remains to be established. Methods: A prospective pilot trial was proposed to patients with DLBCL, with intermediate-high or high adjusted IPI, up to the age of 60 y.o. This program consisted of 2 courses of high-dose CHOP-like regimen, 15 days apart, with rituximab (375/mg/m2) on day 1 of each course, followed by rituximab on d 22, harvest of G-CSF mobilised peripheral blood stem cells on d 28,29, then rituximab on d 36 followed by a course of high-dose methotrexate with cytarabin. For patients who achieved at least a PR after these 3 courses, a BEAM regimen started on d 66 to 80 followed by the infusion of stem cells. Results: Between 04/2002 and 05/2003, 42 pts gave their informed consent and were included in that trial. Median age was 50 y.o (18–60 y.o), 23 had WHO PS ≥ 2, the LDH level was >N in 41 pts and 38 had stage III or IV disease. The age-adjusted IPI was intermediate-high in 23 and high in 19 pts. The program was completed in 30 pts (71%), 3 pts died of toxicity before the BEAM regimen, 8 pts failed to achieve at least a PR after the first 3 courses and 1 refused the autologous transplant. On an intent-to-treat basis, the response rate at the end of the treatment was CR/Cru=64%, PR=7%, less than PR or progression= 22% and toxic death=7%. No toxic death was directly attributable to the addition of rituximab. With a median FU of 19 m, the KM 2y probability of OS and EFS are 79% and 59% respectively, these figures compare to those achieved without rituximab in the previous trial as shown on the table: Conclusion : The addition of 4 doses of rituximab to this HDT program is feasible with no unexpected toxicity, allows the harvesting of sufficient numbers of stem cells to support an autologous transplant with a BEAM regimen in responding patients. This treatment is now being randomly prospectively compared with CHOP-14-rituximab in youg adults with DLBCL (Goelams 075 trial).Supported in part by Roche which kindly provided rituximab for that trial and by DRC Nantes programme N°:02/2N 2002. GOELAMS 072 (IPI 2 only) GOELAMS 074 (IPI 2–3) 2y OS 80% 79% 2y EFS 60% 59%


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5107-5107
Author(s):  
Yi Xiao ◽  
Hanyin Sun ◽  
Jianfeng Zhou ◽  
Wenli Liu ◽  
Yicheng Zhang

Abstract The prognosis for patients with severe refractory systemic lupus erythematosus (SLE) is poor; High dose chemotherapy with hematopoietic stem cell support is a salvage treatment under investigation for these patients. In our center, 17 patients with severe refractory SLE received autologous peripheral blood stem cells transplantation (PBSCT); Peripheral blood stem cells were mobilized with cyclophosphamide 4g/m2 and granulocyte colony-stimulating factor (G-CSF) 5 μg/kg/day. Enough PBSC were collected in all patients. There’s no mobilization-related mortality, while 3 patients developed active lupus after mobilization which was controlled by slightly increasing the dosage of steroids. Following conditioning with cyclophosphamide 6g/m2 plus anti-thymocyte globulin (ATG, 20mg/kg/d, 5 days), cryopreserved PBSC (mean MNC 4.28×108/kg and CD34(+) cell 2.48×106/kg) were infused. Median ANC and platelet engraftment time were days +11 and +12 after transplantation, respectively. Treatment related complications include mucositis (14/17), infection (12/17), liver malfuction (10/17), edema or/and heart failure (3/17), renal failure (2/17), bleeding (5/17); One patient died from cerebral hemorrhage. Median follow-up is 22 months (9–28 months); All the patients improved with the SLEDAI score reduced from 25.2±6.6 before to 9.7±1.2 3 months after transplantation; Steroids were stopped or maintained at very low dose (equal to 5 to 7.5 mg/d predinisone). One patient had overt lupus relapse 8 months following transplant Conclusions Mobilization, harvesting and transplantation of peripheral blood stem cells in patients with severe refractory systemic lupus erythematosus is safe; The short-term result of the approach is effective in this group of patients; More patients needed to enroll a control study to validate the role of high-dose chemotherapy/PBSCT as the salvage treatment for severe SLE.


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