Mobilization with etoposide and granulocyte colony-stimulating factor can replace bone marrow harvesting in patients with malignant lymphoma who previously failed to mobilize sufficient stem cells with cyclophosphamide and G-CSF.
Scheid C,Reiser M,Draube A,Josting A,Fuchs M,Chemnitz J,Winter S,Schultz A,Engert A,Diehl V,Söhngen D
Journal of hematotherapy & stem cell research
Chemomobilization with Etoposide is Highly Effective in Patients with Multiple Myeloma and Overcomes the Effects of Age and Prior Therapy.
Wood William A,Whitley Julia,Moore Dominic,Sharf Andrew,Irons Robert,Rao Kamakshi,Serody Jonathan,Coghill Jay,Gabriel Donald,Shea Thomas
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
The optimal mobilization strategy prior to autologous stem cell transplantation for patients with multiple myeloma remains unclear. Mobilization with cytokines alone appears to yield suboptimal results in older patients as well as patients who have received prior lenalidomide. To avoid the marked cytopenias and risks of hemorrhagic cystitis associated with the administration of cyclophosphamide, we investigated the efficacy and safety of chemomobilization with an intermediate dose etoposide (VP-16; 375 mg/m(2) on days +1 and +2) and granulocyte-colony stimulating factor (G-CSF) (5 μg/kg twice daily from day +3 through the final day of collection). We reviewed our institutional experience with 152 myeloma patients mobilized with this regimen. The addition of VP-16 to G-CSF resulted in successful mobilization in 100% of patients, including 143 (94%) who collected successfully in a single day. A total of 99% of patients, including those with prior XRT and/or prior lenalidomide or thalidomide therapy, collected at least 5 × 10(6) cells/kg in 1 or 2 days of apheresis, and the median total number of CD34(+) cells collected in the entire population was 12 × 10(6) cells/kg. Collection was predictable, with 61% of patients collecting on day +11, and the rest between days +7 and +13. There were no variables, including age, prior imid exposure, radiation therapy, or total amount of prior therapy that were associated with suboptimal mobilization. Adverse effects of the regimen included supportive transfusions required in 31 (20%) patients, and fevers requiring hospitalization or intravenous antibiotics in 26 (17%) patients. VP-16 and G-CSF appears to be a safe and effective mobilization regimen for patients with multiple myeloma undergoing autologous stem cell transplantation, producing excellent stem cell yield with the majority of patients requiring 1 day of apheresis.
Successful peripheral blood stem cell mobilization with etoposide (VP-16) in patients with relapsed or resistant lymphoma who failed cyclophosphamide mobilization.
Reiser M,Josting A,Draube A,Mapara M Y,Scheid C,Chemnitz J,Tesch H,Wolf J,Diehl V,Söhngen D,Engert A
Bone marrow transplantation
High-dose chemotherapy (HDCT) followed by autologous blood stem cell transplantation is considered the treatment of choice for patients with relapsed or resistant aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). However, several authors report failure of standard mobilization regimens in 29% to 56% of these patients making the completion of HDCT impossible and as a result, negatively influencing long-term outcome. Thus, effective new regimens for patients failing initial mobilization are needed. Here we report the results of using etoposide as a mobilizing agent in 16 patients with primary resistant or relapsed malignant lymphoma who had failed prior mobilization of peripheral blood stem cells (PBSC) with cyclophosphamide (4 g/m2) followed by G-CSF. The use of etoposide 500 mg/m2 (days 1-4) + G-CSF resulted in the successful collection of adequate numbers of PBSC with a median harvest of 3.6 x 10(6)/kg (range 2.2-12.6) CD34+ cells in all 16 patients. In 7/16 (44%) patients, the target yield of at least 2.0 x 10(6) CD34+ cells was harvested by a single apheresis and the maximum number of separations for all patients was two. No excessive toxicities appeared, allowing all patients to proceed to myeloablative chemotherapy. In addition, median peak values of circulating CD34+ cells were significantly higher after etoposide as compared to cyclophosphamide (49.2/microl vs 4.7/microl; P = 0.0004). These results indicate that etoposide + G-CSF is a highly effective mobilization regimen in patients who have failed cyclophosphamide mobilization.
Intermediate dose etoposide plus G-CSF 16 g/kg is more effective than cyclophosphamide 4 g/m(2) plus G-CSF 10 g/kg in PBSC mobilization of lymphoma patients.
Milone Giuseppe,Leotta Salvatore,Battiato Katia,Murgano Pamela,Mercurio Salvatore,Strano Aurora,Poidomani Massimo,Coppoletta Stefania,Mauro Elisa,Avola Giuseppe,Pinto Valeria,Camuglia Maria Grazia,Giustolisi Rosario
Leukemia & lymphoma
We designed intermediate dose etoposide + G-CSF 16 microg/kg as a Peripheral Blood Stem Cell (PBSC) mobilization schedule suitable for outpatient administration. Forty-one Lymphoma patients received intermediate dose etoposide (200 mg/m(2) i.v. day +1, +2, +3) +G-CSF 16 microg/kg/day. Results of PBSC mobilization in these patients were compared with those of a group of 37 lymphoma patients mobilized using cyclophosphamide (CTX) at dosage of 4 g/m(2) + G-CSF 10 microg/kg/die. Mean peak of CD34+ cells achieved in P.B. and total CD34+ cells harvested were higher in patients mobilized with intermediate dose etoposide (p = 0.003 and p = 0.004, respectively). After transplantation recovery of polymorphonucleate neutrophils (PMN) > 0.5 x 10(9)/L did not differ significantly between groups: 11.7 days in intermediate dose etoposide group and 11.5 days in CTX group (p = 0.7). Intermediate dose etoposide + G-CSF 16 microg/kg resulted in a maximum length of neutropenia (PMN < 0.5 x 10(9)/L) of 2 days and neutropenic fever was registered during only 3/41 courses (7.3%). Intermediate dose etoposide + G-CSF 16 microg/kg is a highly effective mobilizing therapy, further, it has the advantage of low hematologic toxicity and can be easily administered as outpatient treatment.
[Autologous peripheral blood stem cells mobilization with etoposide plus rhG-CSF versus cyclophosphamide plus rhG-CSF].
Shi Yuan-Kai,He Xiao-Hui,Han Xiao-Hong,Liu Peng,Yang Jian-Liang,Zhou Sheng-Yu,Zhou Ai-Ping,Zhang Chang-Gong,Ai Bin
Ai zheng = Aizheng = Chinese journal of cancer
BACKGROUND & OBJECTIVE:It is important to get high quality autologous peripheral blood stem cell (APBSC) for successful peripheral blood stem cell transplantation. Cyclophosphamide (CTX) plus recombined human granulocyte colony-stimulating factor (rhG-CSF) is standard regimen for APBSC mobilization. Etoposide plus rhG-CSF is another regimen for mobilization in recent years. The purpose of this study was to observe and compare the effects of these two regimens in APBSC mobilization for the patients with malignant lymphoma and germ cell tumors. METHODS:Fifty-two patients were divided into two groups according to the regimen of mobilization. In CTX group, 26 patients were injected CTX 3.5 g/m(2) intravenously. The other 26 patients in VP-16 group, VP-16 1000 mg/m(2) or 1500 mg/m(2) were given intravenously at random. All patients received rhG-CSF once daily as subcutaneous injection at the dose of 5 microg x kg(-1) x day(-1) from the day of the nadir of white blood cell (WBC) till the day before the last APBSC harvest in both groups. APBSC harvest was performed daily when WBC recovered more than 2.5x10(9)/L in CTX group and 5.0x10(9)/L in VP-16 group. APBSC harvest finished when accumulated mononuclear cells (MNCs) were more than 5x10(8)/kg or CD34(+) cells were more than 2x10(6)/kg. Collected APBSC was infused following condition regimen. Blood parameters, account of harvested cells, the time of hematopoietic reconstitute, and adverse effects were compared between two groups. RESULTS:Following administration of CTX or VP-16, the nadirs of WBC and PLT in CTX group appeared significantly earlier than that in VP-16 group. The doses and times of rhG-CSF administration were not significantly different between the two groups. The start was later and the times of APBSC apheresis were less significantly in VP-16 group. The processed blood volume in single apheresis was more in VP-16 group. Speed and duration of single apheresis were similar in the two groups. Total MNCs were similar in the two groups, but the numbers of MNCs and CD34(+) cells collected in the first harvest and total number of CD34(+) cells collected were significantly more in VP-16 group. With equal quantity infusion of MNCs and CD34(+) cells infusion, hematopoietic reconstitution was achieved in both groups and the time of reconstitution was similar. Nausea and vomiting were more frequent in CTX group. Obvious PLT decrease was observed in VP-16 group. Other adverse effects were similar. CONCLUSION:CTX or VP-16 plus rhG-CSF both were safe and effective regimens for APBSC mobilization. More CD34(+) cells can be harvested by mobilization with VP-16 plus rhG-CSF than mobilization with CTX plus rhG-CSF. And the APBSC mobilized with VP-16 plus rhG-CSF can assure successful hematopoietic reconstitution.
Effective mobilization with etoposide and cyclophosphamide for collection of peripheral blood stem cell in patients with multiple myeloma.
Wang Xiaoning,Zhang Ying,Fan Ting,Liu Haibo,Wang Mengchang,Liu Huasheng,Zhang Mei,He Pengcheng
Clinical and investigative medicine. Medecine clinique et experimentale
PURPOSE:To evaluate the efficacy and toxicity of etoposide and cyclophosphamide for mobilization peripheral stem cells in multiple myeloma patients. METHODS:We retrospectively analyzed 46 patients with multiple myeloma who underwent peripheral blood stem cell collection for upfront autologous hematopoietic stem cell transplantation in the First Affiliated Hospital of Xi'an Jiaotong University between January 2010 and July 2019. The mobilization protocols included cyclophosphamide 2.0 g/m2 with G-CSF (CTX group) before January 2015, and two-days of 5 mg/kg.d etoposide and 1.0 g/m2.d cyclophosphamide with G-CSF (EC group) after January 2015. RESULTS:The success rate of harvest (≥2×106 cells/kg) during the first mobilization attempt was 82.1% in the EC group and 50.0% in the CTX group, and the rate of adequate harvest (≥4×106 cells/kg) was 57.1% in the EC group and 15.8% in the CTX group. After the second mobilization, a sufficient number of CD34+/kg cells for an auto-HSCT was obtained for all patients in the EC group and the majority (68.4%) of patients in CTX group. There was no significant difference of non-hematological adverse events between two groups. The mean neutrophil engraftment time was 11.22±1.56 days and 9.89±2.81days for the CTX and EC groups, respectively (P>0.05). Platelet engraftments were significantly faster in the EC group than the CTX group (P0.05). CONCLUSION:The etoposide and cyclophosphamide regimen could be an effective and safe method for mobilization in patients with multiple myeloma.
Single-dose etoposide is an effective and safe protocol for stem cell mobilization in patients with multiple myeloma.
Park Yong,Kim Dae Sik,Jeon Min Ji,Lee Byung-Hyun,Yu Eun Sang,Kang Ka-Won,Lee Se Ryeon,Sung Hwa Jung,Nam Myung-Hyun,Yoon Soo-Young,Choi Chul Won,Kang Eun-Suk,Cho Duck,Kim Kihyun,Kim Byung Soo,Kim Dae-Won,Kim Seok Jin
Journal of clinical apheresis
BACKGROUND:Single-dose etoposide was used an outpatient-based protocol for mobilization in patients with multiple myeloma (MM) for autologous stem cell transplantation (ASCT). Thus, we retrospectively analyzed the efficacy and safety of our one-day protocol in comparison with that of previous methods. METHODS:We retrospectively analyzed 168 patients with MM who underwent peripheral blood stem cell collection for upfront ASCT between 2008 and 2018. The mobilization protocols included G-CSF alone (G-mobilization), one-day 375 mg/m of etoposide (E375), two-days of 375 mg/m of etoposide (E750), or one-day high-dose (3.5 g/m ) cyclophosphamide (HD CY). For comparison of efficacy of each protocol, collected CD34+ cells over 4 × 10 /kg and under 2 × 10 /kg were defined as "adequate harvest" and "harvest failure," respectively. RESULTS:The median number of collected CD34+ cells was 5.58 × 10 /kg in patients receiving single-dose etoposide, and the percentage of uncomplicated optimal harvest of E375 (65.6%, 21/32) was significantly higher than that of E750 (41.9%, 13/31) and HD CY (31.3%, 15/48). The E375 showed the highest rate of adequate harvest (96.9%, 31/32) compared to that of E750 (87.1%), HD CY (75.0%), and G-mobilization (59.6%). Most E375 patients achieved adequate harvest without complication (29/32, 90.6%), the CD34+ cell collection yield on apheresis days one and two of E375 was not significantly different from that of E750, and no harvest failures occurred for E375. Neutrophil and platelet engraftments were significantly faster in E375 than other groups (P < .001). CONCLUSIONS:The use of single-dose etoposide could be an effective and safe method for mobilization in patients with MM.
Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization.
Kang Ka-Won,Lee Seung-Jin,Kim Ji Hye,Lee Byung-Hyun,Kim Seok Jin,Park Yong,Kim Byung Soo
BACKGROUND:We assessed the mechanism of hematopoietic stem cell (HSC) mobilization using etoposide with granulocyte-colony stimulating factor (G-CSF), and determined how this mechanism differs from that induced by cyclophosphamide with G-CSF or G-CSF alone. METHODS:We compared the clinical features of 173 non-Hodgkin's lymphoma patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT). Additionally, we performed in vitro experiments to assess the changes in human bone marrow stromal cells (hBMSCs), which support the HSCs in the bone marrow (BM) niche, following cyclophosphamide or etoposide exposure. We also performed animal studies under standardized conditions to ensure the following: exclude confounding factors, mimic the conditions in clinical practice, and identify the changes in the BM niche caused by etoposide-induced chemo-mobilization or other mobilization methods. RESULTS:Retrospective analysis of the clinical data revealed that the etoposide with G-CSF mobilization group showed the highest yield of CD34+ cells and the lowest change in white blood cell counts during mobilization. In in vitro experiments, etoposide triggered interleukin (IL)-8 secretion from the BMSCs and caused long-term BMSC toxicity. To investigate the manner in which the hBMSC-released IL-8 affects hHSCs in the BM niche, we cultured hHSCs with or without IL-8, and found that the number of total, CD34+, and CD34+/CD45- cells in IL-8-treated cells was significantly higher than the respective number in hHSCs cultured without IL-8 (p = 0.014, 0.020, and 0.039, respectively). Additionally, the relative expression of CXCR2 (an IL-8 receptor), and mTOR and c-MYC (components of IL-8-related signaling pathways) increased 1 h after IL-8 treatment. In animal studies, the etoposide with G-CSF mobilization group presented higher IL-8-related cytokine and MMP9 expression and lower SDF-1 expression in the BM, compared to the groups not treated with etoposide. CONCLUSION:Collectively, the unique mechanism of etoposide with G-CSF-induced mobilization is associated with IL-8 secretion from the BMSCs, which is responsible for the enhanced proliferation and mobilization of HSCs in the bone marrow; this was not observed with mobilization using cyclophosphamide with G-CSF or G-CSF alone. However, the long-term toxicity of etoposide toward BMSCs emphasizes the need for the development of more efficient and safe chemo-mobilization strategies.
High-dose etoposide phosphate and G-CSF mobilizes peripheral blood stem cells in patients that previously failed to mobilize.
Junghanss C,Leithäuser M,Wilhelm S,Kleine H D,Knopp A,Decker S,Alscher A,Casper J,Köhne C H,Freund M
Annals of hematology
Ten consecutive patients in our unit who had failed to mobilize a sufficient stem cell yield after either an initial or several mobilization regimens received high-dose etoposide phosphate (1500-2000 mg/m2) followed by granulocyte colony-stimulating factor (G-CSF; 10 micrograms/kg per day) to stimulate mobilization. Eight of the ten patients were apheresed. A median of 2.1 x 10(6) CD34+/kg (range 0-5.2) was collected. The number of CD34+ cells/microliter peripheral blood (pB) was significantly increased compared to the first-line mobilization [median 13.0 (range 2.68-29) versus median 4.76 (range 1.36-12); P < 0.05]. Besides hematotoxicity and four cases of infection (WHO grade 3), no major side effects were seen. The median duration of neutropenia was short (5 days, range 0-10), which is important in heavily pretreated patients. These results indicate that high-dose etoposide phosphate with G-CSF is safe, well tolerated, and may be effective in peripheral blood stem cell (PBSC) mobilization in patients who had previously failed to mobilize.