Transfusion and Apheresis Science xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma Juan Montoro ⇑, Giovanna Andreola, Angelo Gardellini, Aleksandra Babic, Mara Negri, Niccolò Frungillo, Giovanni Martinelli, Daniele Laszlo Haematoncology Division, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy
a r t i c l e
i n f o
Article history: Received 5 December 2013 Accepted 24 March 2014 Available online xxxx Keywords: R-ESHAP Pegfilgrastim Stem cell mobilization CD34+ collection Diffuse large B-cell lymphoma
a b s t r a c t Stem cell (SC) mobilization is significantly influenced by the mobilization schedule in patients with lymphoma. We evaluated data from 30 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) undergoing SC mobilization. All received R-ESHAP plus a single dose of pegfilgrastim. All patients collected P2 106 CD34+ cells/kg, 80% of them at least 5 106 CD34+ cells/kg. Adverse effects of the regimen included myelosuppression and neutropenic fever. Herein, our results suggest that R-ESHAP plus pegfilgrastim is a highly effective mobilization strategy in patients affected by DLBCL associated with a low incidence of adverse events. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction High dose chemotherapy followed by autologous stem cell transplant (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) patients who are still chemotherapy-sensitive and are otherwise suitable for transplant [1], but the optimal strategy for mobilizing peripheral blood stem cell (PBSC) remains unclear. The most commonly used regimen for stem cell mobilization is granulocyte colony-stimulating factor (G-CSF) with or without chemotherapy [2]. Thus, R-ESHAP (rituximab in association with etoposide, methylprednisone, cytarabine and cisplatin) plus G-CSF has been shown to be effective for mobilizing PBSC in non-Hodgkin’s
⇑ Tel.: +39 0257489538; fax: +39 0294379219.
lymphoma patients [3–5] producing overall response rates of 73%, and complete remission around 35% in patients with DLBCL [6]. Nevertheless, previous studies suggested that pegylated G-CSF (pegfilgrastim, NeulastaÒ) and filgrastim are similar in terms of mobilization efficiency after chemotherapy [7–9]. Our group [10] and others [9,11–13] have demonstrated that chemotherapy followed by pegfilgrastim is able to mobilize an adequate number of PBSC in patients with lymphoma. These studies showed that the CD34+ cell target was achieved in most patients after mobilization with single-dose injection of pegfilgrastim administered one day after the end of treatment. Furthermore, different dosing schedules of pegfilgrastim with or without chemotherapy have been considered in PBSC mobilization with no correlation between the dosage of pegfilgrastim administered after chemotherapy and the peripheral blood CD34+ cell concentration [7,14,15].
E-mail address: [email protected] (J. Montoro). http://dx.doi.org/10.1016/j.transci.2014.03.006 1473-0502/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Montoro J et al. R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma. Transf Apheres Sci (2014), http:// dx.doi.org/10.1016/j.transci.2014.03.006
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J. Montoro et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
Here, we report our institutional experience in DLBCL patients who received R-ESHAP plus pegfilgrastim to mobilize PBSC, in order to confirm the safety and efficacy in terms of mobilization and clinical activity of this regimen.
2. Materials and methods We analyzed data from 30 consecutive patients affected by relapsed or refractory DLBCL who received R-ESHAP with a curative purpose and pegfilgrastim to mobilize PBSC for ASCT at our institution from January 2008 to December 2012. Patient’s characteristics are shown in Table 1. Median age was 61 years (range, 20–76 years), 17 were male and 13 female. Before PBSC mobilization, eight patients had received one prior treatment regimen and twenty-two, two or more prior chemotherapy regimens. 40 patients had localized disease (stage I or II). All patients received ESHAP regimen modified schedule as follows (Fig. 1): etoposide (100 mg/m2; days 1–3), cytarabine (2 gr/m2 2; days 1–2), cisplatin (80 mg/m2; day 1) and methylprednisolone (500 mg; days 1–3). Rituximab was administered in addition to chemotherapy at a standard dose (375 mg/m2) at day 0 before chemotherapy. Twenty-four hours after the end of treatment, a single subcutaneous injection of 6 mg of pegfilgrastim was
administered. Peripheral blood CD34+ were counted with a white blood cell (WBC) count of at least 1.0 109/L by flow cytometry using an activated fluorescence cell sorter (BD, Germany) as previously described [16]. PBSC collections was initiated with a peripheral blood CD34+ count of P20 l/L, with the intent of reaching at least P2 106 CD34+ cells/kg for each patient. All stem cell collections were performed using the Cobe Spectra separator (Cobe BCT Inc., Lakewood, Colorado, USA). At the end of each procedure, CD34+ cells collected were counted and then cryopreservated in 10% dimethyl sulfoxide (DMSO); the products were frozen until reinfusion. Patients who presented P20 lL CD34+ cell peak in peripheral blood following R-ESHAP were defined as ‘‘good mobilizers’’. Twenty-seven of the 30 patients received one additional cycle of R-ESHAP chemotherapy, with the same schedule, as salvage treatment and three patients received two additional cycle of R-ESHAP in order to improve the response. The regimen was administered every 3 week. Response assessment was performed after two cycles by conventional diagnosis methods, including computer tomography scans. Bone marrow biopsies were only repeated if abnormal before treatment. Response was defined according to the International Working Group criteria [17]. All patients were assessed for toxicity according to the National Cancer Institute Common Toxicity Criteria, version 3.0. Stem cell engraftment was defined as neutrophils count >0.5 109 L for three consecutive days and platelets P20 109/ L without transfusion support.
Table 1 Baseline characteristics of patients (n = 30). Characteristic
Number
Age Median (range)
Percent (%)
61 (20–76)
Sex Male Female
17 13
57 43
Stage I/II III IV
12 5 13
40 17 43
Number of prior chemotherapy regimens 1 2–4
8 22
27 73
3. Results All patients successfully collected P2 106 6 CD34+ cells/kg (median 9.45 10 , range 2.8–47.6) with only one leucoapheresis procedure, with no patients requiring a second attempt. Apheresis procedures were started on median day +9 after pegfilgrastim administration (range, 8–11) (Fig. 2). On the day of collection, median number of CD34+ at the peak in peripheral blood was 119 lL (range, 20–631). 93% of patients were considered as ‘‘good mobilizers’’. 18 patients (60%) presented a peak of CD34+ P100 lL. Median total blood volume processed was 9720 ml (range, 6124–16,010). None of the patients were regarded
Fig. 1. R-ESHAP plus pegfilgrastim regimen schedule.
Please cite this article in press as: Montoro J et al. R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma. Transf Apheres Sci (2014), http:// dx.doi.org/10.1016/j.transci.2014.03.006
J. Montoro et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
Fig. 2. Apheresis and peripheral blood CD34+ cell count. Apheresis was initiated when the peripheral blood CD34+ cell count was P20 l/L and all patients successfully collected stem cell between days +8 and +11 post treatment. Peripheral CD34+ cell count before collection was between 20 and 631 lL at peak.
as mobilization failures. Twenty-four (80%) patients achieved ‘‘optimal’’ PBSC collections (P5 106 CD34+ cells/kg) in one apheresis (Table 2). Seventeen (56.7%) of the patients required red blood cell transfusion and 70% required platelet support. Grade 4 neutropenia lasted for a median number of 4 (range, 1– 7) days and six patients (20%) required inpatient admission due to febrile neutropenia (>38 °C, blood neutrophil count 20 lL CD34+ cells/kg in one apheresis) (%)
9 (8–11) 9.45 (2.8–47.6) 119 (20–631) 30 (100) 24 (80) 28 (93.3)
3
consolidated with high dose chemotherapy and ASCT in patients who experienced a relapse after achieving complete remission (CR) and those who do not achieve CR but are still chemotherapy-sensitive [18,19]. Salvage strategies outcome are expressed as response rates and the ability to mobilize and collect stem cells for transplant. The requested amount of CD34+ cells is frequently achieved by means of diverse mobilization regimens, which may contain cytotoxic drugs and/or growth factors [20]. In the rituximab era, for patients who have experienced relapse, only one randomized trial has been done comparing two salvage regimens with rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) [18]. In this phase III multicenter randomized trial, no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival was observed. These regimens showed a similar response rate of 63% for the two regimens and similar mobilization failure rates of 10% after both regimens. Leucoapheresis were performed after the third or second course of salvage therapy to obtain a target of 2 106 CD34+ cells/kg hematopoietic stem cells for cryopreservation. Median number of CD34+ cells collected was 4.5 106/kg in patients treated with the R-ICE regimen, and 4.9 in the R-DHAP regimen but failed stem cell collections were observed 10% and 8% of the cases respectively. Only 50% of patients were able to undergo ASCT. Toxicities were similar in both arms, with grade 3–4 hematologic toxicities more severe in the R-DAP arm than the RICE arm, and four toxic deaths occurred. Previously, the Spanish group analyzed 163 patients diagnosed with relapsed or refractory DLBCL treated with R-ESHAP as salvage therapy with a curative purpose to investigate, among other things, the toxicity and efficacy of this regimen. The overall response rate (ORR) was 73% and myelosuppression was the most prominent adverse effect, with three deaths due to infectious complications [6]. Pegfilgrastim’s potential in PBSC mobilization has been investigated in several phase-II clinical studies in patients with myeloma and lymphoma [9,11–13]. Most patients, between 79% and 100%, achieved the required target of CD34+ cells after mobilization with a dose of pegfilgrastim varying between 6 and 18 mg, usually administered 1– 3 days after chemotherapy. We have previously demonstrated that patients affected by relapsed lymphoma (Hodgkin’s and non-Hodgkin’s lymphoma) receiving a mobilization regimen with ESHAP and a single dose (6 mg) of pegfilgrastim, achieved a significant better peak of peripheral blood CD34+ cells compared to a control group receiving daily filgrastim following the same chemotherapy regimen. Thus, 83% of patients collected P5 106/ kg CD34+ cell in only one apheresis [21]. Different doses of pegfilgrastim with or without chemotherapy have been explored in PBPC mobilization. Studies did not demonstrated a clear correlation between the amount of pegfilgrastim delivered and the peripheral blood CD34+ cell peak. A single dose of 6 mg pegfilgrastim was equally potent as 12 mg for mobilization and harvest of PBPCs after chemotherapy in patients with myeloma and lymphoma. The largest published study randomized 92 NHL patients
Please cite this article in press as: Montoro J et al. R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma. Transf Apheres Sci (2014), http:// dx.doi.org/10.1016/j.transci.2014.03.006
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J. Montoro et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
to receive single-dose of 6 vs. 12 mg pegfilgrastim vs. filgrastim 5 lg/kg/day following ICE chemotherapy. The maximum number of circulating CD34+ cells and total number collected showed no statistical differences among the groups. In addition, the use of pegfilgrastim for PBSC mobilization, may increase the compliance of patients and be cost-effective due to some advantages such as earlier start of apheresis, reduction in the number of apheresis procedures as well as reduced number of injections [22]. On the basis of previous data, we therefore administered R-ESHAP regimen plus pegfilgrastim as salvage therapy and in order to mobilize stem cell in a small number of patients with relapsed/refractory diffuse large B-cell lymphoma. Our results showed that R-ESHAP used as salvage treatment is an effective strategy, able to achieve similar response rates than those published in the literature. Notably and in contrast to what previously reported by others, we observed no mobilization failures. In fact, this regimen allowed successful collection of PBSC in all patients in only one apheresis procedure; all procedures could be scheduled within 4 days, between +8 and +11 from pegfilgrastim with no need to perform leucoapheresis on the weekends: most of the patients (93%) collected the optimal target of CD34+ cells with a single apheresis. The high percent of good mobilizers, may furthermore suggest the possibility to shorten the time of collection treating less peripheral blood volumes. Apart from myelosuppression requiring transfusion support, only 20% of the patients required inpatient hospitalization for febrile neutropenia. No treatment-related mortality was observed, addressing the safety of the regimen. In summary, although limited by the small numbers of the patients, our results support that R-ESHAP plus pegfilgrastim as mobilization regimen of patients with DLBCL undergoing ASCT, appears to result safe, tolerable and highly effective, producing excellent stem cell yield. Further studies for increasing the stem cell yield, improve the quality of graft content and the transplantation outcomes are required in the chemomobilization strategies. Acknowledgment Juan Montoro was supported by a Grant from the European Institute of Oncology Foundation (FIEO). References [1] Vose JM, Zhang MJ, Rowlings PA, Lazarus HM, Bolwell BJ, Freytes CO, et al. Autologous transplantation for diffuse aggressive nonHodgkin’s lymphoma in patients never achieving remission: a report from the autologous blood and marrow transplant registry. J Clin Oncol 2001;19(2):406–13. [2] Moskowitz CH, Glassman JR, Wuest D, Maslak P, Reich L, Gucciardo A, et al. Factors affecting mobilization of peripheral blood progenitor cells in patients with lymphoma. Clin Cancer Res 1998;4(2):311–6. [3] Lee JL, Kim S, Kim SW, Kim EK, Kim SB, Kang YK, et al. ESHAP plus GCSF as an effective peripheral blood progenitor cell mobilization regimen in pretreated non-Hodgkin’s lymphoma: comparison with high-dose cyclophosphamide plus G-CSF. Bone Marrow Transplant 2005;35(5):449–54. [4] Watts MJ, Ings SJ, Leverett D, MacMillan A, Devereux S, Goldstone AH, et al. ESHAP and G-CSF is a superior blood stem cell mobilizing regimen compared to cyclophosphamide 1.5 g/m2 and G-CSF for pre-treated lymphoma patients: a matched pairs analysis of 78 patients. Br J Cancer 2000;82(2):278–82.
[5] Petit J, Boque C, Cancelas JA, Sarrà J, Muñoz J, Garcia J, et al. Feasibility of ESHAP + G-CSF as peripheral blood hematopoietic progenitor cell mobilisation regimen in resistant and relapsed lymphoma: a single-center study of 22 patients. Leukemia Lymphoma 1999;34(1–2):119–27. [6] Martín A, Conde E, Arnan M, Canales MA, Deben G, Sancho JM, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica 2008; 93(12):1829–36. [7] Russell N, Mesters R, Schubert J, Boogaerts M, Johnsen HE, Canizo CD, et al. A phase 2 pilot study of pegfilgrastim and filgrastim for mobilizing peripheral blood progenitor cells in patients with nonHodgkin’s lymphoma receiving chemotherapy. Haematologica 2008;93(3):405–12. [8] Kroschinsky F, Hölig K, Platzbecker U, Poppe-Thiede K, Ordemann R, Blechschmidt M, et al. Efficacy of single-dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma. Transfusion 2006;46(8):1417–23. [9] Putkonen M, Rauhala A, Pelliniemi TT, Remes K. Single-dose pegfilgrastim is comparable to daily filgrastim in mobilizing peripheral blood stem cells: a case-matched study in patients with lymphoproliferative malignancies. Ann Hematol 2009;88(7): 673–80. [10] Simona B, Cristina R, Luca N, Sara S, Aleksandra B, Paola B, et al. A single dose of pegfilgrastim versus daily filgrastim to evaluate the mobilization and the engraftment of autologous peripheral hematopoietic progenitors in malignant lymphoma patients candidate for high-dose chemotherapy. Transfus Apheres Sci 2010; 43(3):321–6. [11] Steidl U, Fenk R, Bruns I, Neumann F, Kondakci M, Hoyer B, et al. Successful transplantation of peripheral blood stem cells mobilized by chemotherapy and a single dose of pegylated G-CSF in patients with multiple myeloma. Bone Marrow Transplant 2005;35(1): 33–6. [12] Fruehauf S, Klaus J, Huesing J, Veldwijk MR, Buss EC, Topaly J, et al. Efficient mobilization of peripheral blood stem cells following CAD chemotherapy and a single dose of pegylated G-CSF in patients with multiple myeloma. Bone Marrow Transplant 2007;39(12):743–50. [13] Isidori A, Tani M, Bonifazi F, Zinzani P, Curti A, Motta MR, et al. Phase II study of a single pegfilgrastim injection as an adjunct to chemotherapy to mobilize stem cells into the peripheral blood of pretreated lymphoma patients. Haematologica 2005;90(2):225–31. [14] Bruns I, Steidl U, Kronenwett R, Fenk R, Graef T, Rohr UP, et al. A single dose of 6 or 12 mg of pegfilgrastim for peripheral blood progenitor cell mobilization results in similar yields of CD34+ progenitors in patients with multiple myeloma. Transfusion 2006;46(2):180–5. [15] Tricot G, Barlogie B, Zangari M, van Rhee F, Hoering A, Szymonifka J, et al. Mobilization of peripheral blood stem cells in myeloma with either pegfilgrastim or filgrastim following chemotherapy. Haematologica 2008;93(11):1739–42. [16] Barnett D, Granger V, Storie I, Peel J, Pollitt R, Smart T, et al. Quality assessment of CD34+ stem cell enumeration: experience of the United Kingdom National External Quality Assessment Scheme (UK NEQAS) using a unique stable whole blood preparation. Br J Haematol 1998;102(2):553–65. [17] Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an International Workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 1999;17(4): 1244. [18] Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28(27):4184–90. [19] Gisselbrecht C. Use of rituximab in diffuse large B-cell lymphoma in the salvage setting. Br J Haematol 2008;143(5):607–21. [20] Olivieri A, Marchetti M, Lemoli R, Tarella C, Iacone A, Lanza F, et al. Proposed definition of ‘poor mobilizer’ in lymphoma and multiple myeloma: an analytic hierarchy process by ad hoc working group gruppo italianotrapianto di midollo osseo. Bone Marrow Transplant 2012;47(3):342–51. [21] Andreola G, Vanazzi A, Radice D, Babic A, Rabascio C, Negri M, et al. Who should be really considered as a poor mobilizer in the plerixafor era? Transfus Apheres Sci 2012;47(1):27–32. [22] Bakanay S ß M, Demirer T. Novel agents and approaches for stem cell mobilization in normal donors and patients. Bone Marrow Transplant 2012;47(9):1154–63.
Please cite this article in press as: Montoro J et al. R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma. Transf Apheres Sci (2014), http:// dx.doi.org/10.1016/j.transci.2014.03.006
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma Juan Montoro ⇑, Giovanna Andreola, Angelo Gardellini, Aleksandra Babic, Mara Negri, Niccolò Frungillo, Giovanni Martinelli, Daniele Laszlo Haematoncology Division, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy
a r t i c l e
i n f o
Article history: Received 5 December 2013 Accepted 24 March 2014 Available online xxxx Keywords: R-ESHAP Pegfilgrastim Stem cell mobilization CD34+ collection Diffuse large B-cell lymphoma
a b s t r a c t Stem cell (SC) mobilization is significantly influenced by the mobilization schedule in patients with lymphoma. We evaluated data from 30 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) undergoing SC mobilization. All received R-ESHAP plus a single dose of pegfilgrastim. All patients collected P2 106 CD34+ cells/kg, 80% of them at least 5 106 CD34+ cells/kg. Adverse effects of the regimen included myelosuppression and neutropenic fever. Herein, our results suggest that R-ESHAP plus pegfilgrastim is a highly effective mobilization strategy in patients affected by DLBCL associated with a low incidence of adverse events. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction High dose chemotherapy followed by autologous stem cell transplant (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) patients who are still chemotherapy-sensitive and are otherwise suitable for transplant [1], but the optimal strategy for mobilizing peripheral blood stem cell (PBSC) remains unclear. The most commonly used regimen for stem cell mobilization is granulocyte colony-stimulating factor (G-CSF) with or without chemotherapy [2]. Thus, R-ESHAP (rituximab in association with etoposide, methylprednisone, cytarabine and cisplatin) plus G-CSF has been shown to be effective for mobilizing PBSC in non-Hodgkin’s
⇑ Tel.: +39 0257489538; fax: +39 0294379219.
lymphoma patients [3–5] producing overall response rates of 73%, and complete remission around 35% in patients with DLBCL [6]. Nevertheless, previous studies suggested that pegylated G-CSF (pegfilgrastim, NeulastaÒ) and filgrastim are similar in terms of mobilization efficiency after chemotherapy [7–9]. Our group [10] and others [9,11–13] have demonstrated that chemotherapy followed by pegfilgrastim is able to mobilize an adequate number of PBSC in patients with lymphoma. These studies showed that the CD34+ cell target was achieved in most patients after mobilization with single-dose injection of pegfilgrastim administered one day after the end of treatment. Furthermore, different dosing schedules of pegfilgrastim with or without chemotherapy have been considered in PBSC mobilization with no correlation between the dosage of pegfilgrastim administered after chemotherapy and the peripheral blood CD34+ cell concentration [7,14,15].
E-mail address: [email protected] (J. Montoro). http://dx.doi.org/10.1016/j.transci.2014.03.006 1473-0502/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Montoro J et al. R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma. Transf Apheres Sci (2014), http:// dx.doi.org/10.1016/j.transci.2014.03.006
2
J. Montoro et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
Here, we report our institutional experience in DLBCL patients who received R-ESHAP plus pegfilgrastim to mobilize PBSC, in order to confirm the safety and efficacy in terms of mobilization and clinical activity of this regimen.
2. Materials and methods We analyzed data from 30 consecutive patients affected by relapsed or refractory DLBCL who received R-ESHAP with a curative purpose and pegfilgrastim to mobilize PBSC for ASCT at our institution from January 2008 to December 2012. Patient’s characteristics are shown in Table 1. Median age was 61 years (range, 20–76 years), 17 were male and 13 female. Before PBSC mobilization, eight patients had received one prior treatment regimen and twenty-two, two or more prior chemotherapy regimens. 40 patients had localized disease (stage I or II). All patients received ESHAP regimen modified schedule as follows (Fig. 1): etoposide (100 mg/m2; days 1–3), cytarabine (2 gr/m2 2; days 1–2), cisplatin (80 mg/m2; day 1) and methylprednisolone (500 mg; days 1–3). Rituximab was administered in addition to chemotherapy at a standard dose (375 mg/m2) at day 0 before chemotherapy. Twenty-four hours after the end of treatment, a single subcutaneous injection of 6 mg of pegfilgrastim was
administered. Peripheral blood CD34+ were counted with a white blood cell (WBC) count of at least 1.0 109/L by flow cytometry using an activated fluorescence cell sorter (BD, Germany) as previously described [16]. PBSC collections was initiated with a peripheral blood CD34+ count of P20 l/L, with the intent of reaching at least P2 106 CD34+ cells/kg for each patient. All stem cell collections were performed using the Cobe Spectra separator (Cobe BCT Inc., Lakewood, Colorado, USA). At the end of each procedure, CD34+ cells collected were counted and then cryopreservated in 10% dimethyl sulfoxide (DMSO); the products were frozen until reinfusion. Patients who presented P20 lL CD34+ cell peak in peripheral blood following R-ESHAP were defined as ‘‘good mobilizers’’. Twenty-seven of the 30 patients received one additional cycle of R-ESHAP chemotherapy, with the same schedule, as salvage treatment and three patients received two additional cycle of R-ESHAP in order to improve the response. The regimen was administered every 3 week. Response assessment was performed after two cycles by conventional diagnosis methods, including computer tomography scans. Bone marrow biopsies were only repeated if abnormal before treatment. Response was defined according to the International Working Group criteria [17]. All patients were assessed for toxicity according to the National Cancer Institute Common Toxicity Criteria, version 3.0. Stem cell engraftment was defined as neutrophils count >0.5 109 L for three consecutive days and platelets P20 109/ L without transfusion support.
Table 1 Baseline characteristics of patients (n = 30). Characteristic
Number
Age Median (range)
Percent (%)
61 (20–76)
Sex Male Female
17 13
57 43
Stage I/II III IV
12 5 13
40 17 43
Number of prior chemotherapy regimens 1 2–4
8 22
27 73
3. Results All patients successfully collected P2 106 6 CD34+ cells/kg (median 9.45 10 , range 2.8–47.6) with only one leucoapheresis procedure, with no patients requiring a second attempt. Apheresis procedures were started on median day +9 after pegfilgrastim administration (range, 8–11) (Fig. 2). On the day of collection, median number of CD34+ at the peak in peripheral blood was 119 lL (range, 20–631). 93% of patients were considered as ‘‘good mobilizers’’. 18 patients (60%) presented a peak of CD34+ P100 lL. Median total blood volume processed was 9720 ml (range, 6124–16,010). None of the patients were regarded
Fig. 1. R-ESHAP plus pegfilgrastim regimen schedule.
Please cite this article in press as: Montoro J et al. R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma. Transf Apheres Sci (2014), http:// dx.doi.org/10.1016/j.transci.2014.03.006
J. Montoro et al. / Transfusion and Apheresis Science xxx (2014) xxx–xxx
Fig. 2. Apheresis and peripheral blood CD34+ cell count. Apheresis was initiated when the peripheral blood CD34+ cell count was P20 l/L and all patients successfully collected stem cell between days +8 and +11 post treatment. Peripheral CD34+ cell count before collection was between 20 and 631 lL at peak.
as mobilization failures. Twenty-four (80%) patients achieved ‘‘optimal’’ PBSC collections (P5 106 CD34+ cells/kg) in one apheresis (Table 2). Seventeen (56.7%) of the patients required red blood cell transfusion and 70% required platelet support. Grade 4 neutropenia lasted for a median number of 4 (range, 1– 7) days and six patients (20%) required inpatient admission due to febrile neutropenia (>38 °C, blood neutrophil count 20 lL CD34+ cells/kg in one apheresis) (%)
9 (8–11) 9.45 (2.8–47.6) 119 (20–631) 30 (100) 24 (80) 28 (93.3)
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consolidated with high dose chemotherapy and ASCT in patients who experienced a relapse after achieving complete remission (CR) and those who do not achieve CR but are still chemotherapy-sensitive [18,19]. Salvage strategies outcome are expressed as response rates and the ability to mobilize and collect stem cells for transplant. The requested amount of CD34+ cells is frequently achieved by means of diverse mobilization regimens, which may contain cytotoxic drugs and/or growth factors [20]. In the rituximab era, for patients who have experienced relapse, only one randomized trial has been done comparing two salvage regimens with rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) [18]. In this phase III multicenter randomized trial, no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival was observed. These regimens showed a similar response rate of 63% for the two regimens and similar mobilization failure rates of 10% after both regimens. Leucoapheresis were performed after the third or second course of salvage therapy to obtain a target of 2 106 CD34+ cells/kg hematopoietic stem cells for cryopreservation. Median number of CD34+ cells collected was 4.5 106/kg in patients treated with the R-ICE regimen, and 4.9 in the R-DHAP regimen but failed stem cell collections were observed 10% and 8% of the cases respectively. Only 50% of patients were able to undergo ASCT. Toxicities were similar in both arms, with grade 3–4 hematologic toxicities more severe in the R-DAP arm than the RICE arm, and four toxic deaths occurred. Previously, the Spanish group analyzed 163 patients diagnosed with relapsed or refractory DLBCL treated with R-ESHAP as salvage therapy with a curative purpose to investigate, among other things, the toxicity and efficacy of this regimen. The overall response rate (ORR) was 73% and myelosuppression was the most prominent adverse effect, with three deaths due to infectious complications [6]. Pegfilgrastim’s potential in PBSC mobilization has been investigated in several phase-II clinical studies in patients with myeloma and lymphoma [9,11–13]. Most patients, between 79% and 100%, achieved the required target of CD34+ cells after mobilization with a dose of pegfilgrastim varying between 6 and 18 mg, usually administered 1– 3 days after chemotherapy. We have previously demonstrated that patients affected by relapsed lymphoma (Hodgkin’s and non-Hodgkin’s lymphoma) receiving a mobilization regimen with ESHAP and a single dose (6 mg) of pegfilgrastim, achieved a significant better peak of peripheral blood CD34+ cells compared to a control group receiving daily filgrastim following the same chemotherapy regimen. Thus, 83% of patients collected P5 106/ kg CD34+ cell in only one apheresis [21]. Different doses of pegfilgrastim with or without chemotherapy have been explored in PBPC mobilization. Studies did not demonstrated a clear correlation between the amount of pegfilgrastim delivered and the peripheral blood CD34+ cell peak. A single dose of 6 mg pegfilgrastim was equally potent as 12 mg for mobilization and harvest of PBPCs after chemotherapy in patients with myeloma and lymphoma. The largest published study randomized 92 NHL patients
Please cite this article in press as: Montoro J et al. R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma. Transf Apheres Sci (2014), http:// dx.doi.org/10.1016/j.transci.2014.03.006
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to receive single-dose of 6 vs. 12 mg pegfilgrastim vs. filgrastim 5 lg/kg/day following ICE chemotherapy. The maximum number of circulating CD34+ cells and total number collected showed no statistical differences among the groups. In addition, the use of pegfilgrastim for PBSC mobilization, may increase the compliance of patients and be cost-effective due to some advantages such as earlier start of apheresis, reduction in the number of apheresis procedures as well as reduced number of injections [22]. On the basis of previous data, we therefore administered R-ESHAP regimen plus pegfilgrastim as salvage therapy and in order to mobilize stem cell in a small number of patients with relapsed/refractory diffuse large B-cell lymphoma. Our results showed that R-ESHAP used as salvage treatment is an effective strategy, able to achieve similar response rates than those published in the literature. Notably and in contrast to what previously reported by others, we observed no mobilization failures. In fact, this regimen allowed successful collection of PBSC in all patients in only one apheresis procedure; all procedures could be scheduled within 4 days, between +8 and +11 from pegfilgrastim with no need to perform leucoapheresis on the weekends: most of the patients (93%) collected the optimal target of CD34+ cells with a single apheresis. The high percent of good mobilizers, may furthermore suggest the possibility to shorten the time of collection treating less peripheral blood volumes. Apart from myelosuppression requiring transfusion support, only 20% of the patients required inpatient hospitalization for febrile neutropenia. No treatment-related mortality was observed, addressing the safety of the regimen. In summary, although limited by the small numbers of the patients, our results support that R-ESHAP plus pegfilgrastim as mobilization regimen of patients with DLBCL undergoing ASCT, appears to result safe, tolerable and highly effective, producing excellent stem cell yield. Further studies for increasing the stem cell yield, improve the quality of graft content and the transplantation outcomes are required in the chemomobilization strategies. Acknowledgment Juan Montoro was supported by a Grant from the European Institute of Oncology Foundation (FIEO). References [1] Vose JM, Zhang MJ, Rowlings PA, Lazarus HM, Bolwell BJ, Freytes CO, et al. Autologous transplantation for diffuse aggressive nonHodgkin’s lymphoma in patients never achieving remission: a report from the autologous blood and marrow transplant registry. J Clin Oncol 2001;19(2):406–13. [2] Moskowitz CH, Glassman JR, Wuest D, Maslak P, Reich L, Gucciardo A, et al. Factors affecting mobilization of peripheral blood progenitor cells in patients with lymphoma. Clin Cancer Res 1998;4(2):311–6. [3] Lee JL, Kim S, Kim SW, Kim EK, Kim SB, Kang YK, et al. ESHAP plus GCSF as an effective peripheral blood progenitor cell mobilization regimen in pretreated non-Hodgkin’s lymphoma: comparison with high-dose cyclophosphamide plus G-CSF. Bone Marrow Transplant 2005;35(5):449–54. [4] Watts MJ, Ings SJ, Leverett D, MacMillan A, Devereux S, Goldstone AH, et al. ESHAP and G-CSF is a superior blood stem cell mobilizing regimen compared to cyclophosphamide 1.5 g/m2 and G-CSF for pre-treated lymphoma patients: a matched pairs analysis of 78 patients. Br J Cancer 2000;82(2):278–82.
[5] Petit J, Boque C, Cancelas JA, Sarrà J, Muñoz J, Garcia J, et al. Feasibility of ESHAP + G-CSF as peripheral blood hematopoietic progenitor cell mobilisation regimen in resistant and relapsed lymphoma: a single-center study of 22 patients. Leukemia Lymphoma 1999;34(1–2):119–27. [6] Martín A, Conde E, Arnan M, Canales MA, Deben G, Sancho JM, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica 2008; 93(12):1829–36. [7] Russell N, Mesters R, Schubert J, Boogaerts M, Johnsen HE, Canizo CD, et al. A phase 2 pilot study of pegfilgrastim and filgrastim for mobilizing peripheral blood progenitor cells in patients with nonHodgkin’s lymphoma receiving chemotherapy. Haematologica 2008;93(3):405–12. [8] Kroschinsky F, Hölig K, Platzbecker U, Poppe-Thiede K, Ordemann R, Blechschmidt M, et al. Efficacy of single-dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma. Transfusion 2006;46(8):1417–23. [9] Putkonen M, Rauhala A, Pelliniemi TT, Remes K. Single-dose pegfilgrastim is comparable to daily filgrastim in mobilizing peripheral blood stem cells: a case-matched study in patients with lymphoproliferative malignancies. Ann Hematol 2009;88(7): 673–80. [10] Simona B, Cristina R, Luca N, Sara S, Aleksandra B, Paola B, et al. A single dose of pegfilgrastim versus daily filgrastim to evaluate the mobilization and the engraftment of autologous peripheral hematopoietic progenitors in malignant lymphoma patients candidate for high-dose chemotherapy. Transfus Apheres Sci 2010; 43(3):321–6. [11] Steidl U, Fenk R, Bruns I, Neumann F, Kondakci M, Hoyer B, et al. Successful transplantation of peripheral blood stem cells mobilized by chemotherapy and a single dose of pegylated G-CSF in patients with multiple myeloma. Bone Marrow Transplant 2005;35(1): 33–6. [12] Fruehauf S, Klaus J, Huesing J, Veldwijk MR, Buss EC, Topaly J, et al. Efficient mobilization of peripheral blood stem cells following CAD chemotherapy and a single dose of pegylated G-CSF in patients with multiple myeloma. Bone Marrow Transplant 2007;39(12):743–50. [13] Isidori A, Tani M, Bonifazi F, Zinzani P, Curti A, Motta MR, et al. Phase II study of a single pegfilgrastim injection as an adjunct to chemotherapy to mobilize stem cells into the peripheral blood of pretreated lymphoma patients. Haematologica 2005;90(2):225–31. [14] Bruns I, Steidl U, Kronenwett R, Fenk R, Graef T, Rohr UP, et al. A single dose of 6 or 12 mg of pegfilgrastim for peripheral blood progenitor cell mobilization results in similar yields of CD34+ progenitors in patients with multiple myeloma. Transfusion 2006;46(2):180–5. [15] Tricot G, Barlogie B, Zangari M, van Rhee F, Hoering A, Szymonifka J, et al. Mobilization of peripheral blood stem cells in myeloma with either pegfilgrastim or filgrastim following chemotherapy. Haematologica 2008;93(11):1739–42. [16] Barnett D, Granger V, Storie I, Peel J, Pollitt R, Smart T, et al. Quality assessment of CD34+ stem cell enumeration: experience of the United Kingdom National External Quality Assessment Scheme (UK NEQAS) using a unique stable whole blood preparation. Br J Haematol 1998;102(2):553–65. [17] Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an International Workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 1999;17(4): 1244. [18] Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28(27):4184–90. [19] Gisselbrecht C. Use of rituximab in diffuse large B-cell lymphoma in the salvage setting. Br J Haematol 2008;143(5):607–21. [20] Olivieri A, Marchetti M, Lemoli R, Tarella C, Iacone A, Lanza F, et al. Proposed definition of ‘poor mobilizer’ in lymphoma and multiple myeloma: an analytic hierarchy process by ad hoc working group gruppo italianotrapianto di midollo osseo. Bone Marrow Transplant 2012;47(3):342–51. [21] Andreola G, Vanazzi A, Radice D, Babic A, Rabascio C, Negri M, et al. Who should be really considered as a poor mobilizer in the plerixafor era? Transfus Apheres Sci 2012;47(1):27–32. [22] Bakanay S ß M, Demirer T. Novel agents and approaches for stem cell mobilization in normal donors and patients. Bone Marrow Transplant 2012;47(9):1154–63.
Please cite this article in press as: Montoro J et al. R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma. Transf Apheres Sci (2014), http:// dx.doi.org/10.1016/j.transci.2014.03.006
