Vinorelbine-Cyclophosphamide Compared to Cyclophosphamide in Peripheral Blood Stem Cell Mobilization for Multiple Myeloma

Hematol Oncol Stem Cell Ther (2018) 11, 225– 232

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ORIGINAL RESEARCH REPORT Vinorelbine-Cyclophosphamide compared to cyclophosphamide in peripheral blood stem cell mobilization for multiple myeloma

Sanjay de Mel a,*, Yunxin Chen b, Adeline Lin a, Teck Guan Soh c, Melissa Ooi a, Eng Soo Yap a, Lara Kristina Sioco Donato b, Nurul Aidah Abdul Halim b, Joanna Mah c, Karen Lim c, Li Mei Poon a, Belinda Tan a, Yelly a, Hui Li Lim a, Liang Piu Koh a, Bee Choo Tai d,e, Zhaojin Chen e, Wee Joo Chng a, Satish Kumar Gopalakrishnan b, Lip Kun Tan a,c a Department of Haematology-Oncology National University Cancer Institute, National University Health System, Singapore b Department of Haematology, Singapore General Hospital, Singapore c Department of Laboratory Medicine, National University Health System, Singapore d Saw Swee Hock School of Public Health, National University of Singapore, Singapore e Investigational Medicine Unit, National University Health System, Singapore

Received 18 December 2017; received in revised form 19 March 2018; accepted 9 April 2018 Available online 23 April 2018

KEYWORDS Abstract Stem cells; Background: High dose Cyclophosphamide (Cy) and Vinorelbine Cyclophosphamide (Vino-Cy) Autologous transplantation; are stem cell (SC) mobilisation options for patients with multiple myeloma (MM). We present Chemotherapy a comparison of mobilisation outcomes using these regimens. Patients and methods: Vino-Cy patients received Vinorelbine 25 mg/m2 on day 1, cyclophosphamide 1500 mg/m2 on day 2, and pegylated GCSF on day 4 or GCSF 10 mcg/kg/day from day 4 onwards. Cy patients were given cyclophosphamide 4000 mg/m2 on day 1 and GCSF10 mcg/kg/day from day 5 onwards. The target CD34 + SC collection was 5 Â 106 per kg/BW. Results: 149 patients were included. SC collection was lower in the Vino-Cy group (8.20 Â 106/ Kg BW) compared to the Cy group (11.43 Â 106/Kg BW), with adjusted geometric mean ratio of

* Corresponding author at: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, 1E Kent Ridge Road, NUHS Tower Block, Level 7, Singapore 119228, Singapore. E-mail address: [email protected] (S. de Mel). https://doi.org/10.1016/j.hemonc.2018.04.001 1658-3876/Ó 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 226 S. de Mel et al.

0.59 (95% CI 0.41 to 0.86, p = 0.006). Time taken to achieve an adequate PB SC count was shorter for Vino-Cy (9 ± 1 day compared to 12 ± 2 days for Cy, adjusted absolute mean difference À3.95, 95% CI À4.85 to À3.06, P < .001). Mobilisation related toxicities (in particular, neu- tropaenic fever) were greater for Cy. Conclusion: Vino-Cy is a potential alternative to Cy given the need for effective mobilisation protocols with acceptable toxicity. Ó 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/).

Introduction review board approval, medical records for patients with MM who underwent SC mobilization between 2004 and High dose therapy (HDT) followed by autologous stem cell 2014 at NUH and SGH were analysed. transplant (ASCT) has been shown to prolong survival in patients with multiple myeloma (MM) [1–3]. HDT followed Patients by ASCT is therefore the standard of care for transplant eligible patients with MM [4]. Cyclophosphamide (Cy) at low, Patients who underwent CD34 + SC mobilization with Vino- intermediate or high dose (1.5–7 g/m2) with daily gr4anulo- Cy and Cy were included in the analysis. Two patients were cyte colony stimulating factor (GCSF) until CD34 + Stem Cell mobilized using the DT-PACE (Dexamethasone, Thalido- (SC) collection has been used successfully for SC mobiliza- mide, Cisplatin, Doxorubicin, Cyclophosphamide, Etopo- tion [5–8]. This regimen resulted in effective mobilization side) regimen during this period, and were excluded from in more than 80% of patients but was associated with a sig- the analysis. We retrieved data on patient demographics, nificant incidence of febrile neutropaenia (5.8%) and hospi- disease and treatment characteristics, SC mobilization, talization (10.2%) [5]. timing of SC collection, mobilization related complications, As older patients with more co-morbidities are being time to count recovery, transfusion requirements, considered for HDT, mobilization regimens with equal effi- unplanned admissions between mobilization and SC collec- cacy but less toxicity are required. The chemokine receptor tion and post ASCT outcomes. 4 antagonist Plerixafor has recently been shown to be an effective mobilization therapy but is costly and in most cen- Stem cell mobilization ters is therefore only used for patients who fail mobilization using conventional therapy [9]. At NUH, the mobilization regimen of choice before 2007 was Vinorelbine based SC mobilization for MM was first pro- 2 posed by Bargetzi and colleagues who demonstrated the cyclophosphamide 4000 mg/m followed by GCSF. After efficacy and safety of vinorelbine and GCSF in a series of 2007, the mobilisation regimen has been modified to the 19 patients [10]. A similar protocol was proposed by Sama- Vino-Cy regimen as described by Annunziata et al. [12].At ras et al who used Vinorelbine 35 mg/m2 and filgrastim 5 SGH, Cy remains the standard mobilization regimen of mg/kg daily with a successful SC collection in 99% of patients choice. Patients mobilized with Vino-Cy received Vinorel- bine 25 mg/m2 on day 1 followed by cyclophosphamide with only 1 of 221 patients developing febrile neutropaenia 2 [11]. In a phase II study Annunziata et al used vinorelbine 25 1500 mg/m on day 2. GCSF 10 mcg/kg/day was started on mg/m2 on day 1 followed by cyclophosphamide 1500 mg/m2 day 4 and continued until completion of harvest. Alterna- tively, pegylated GCSF 6 mg was given on day 4. Patients on day 2 and filgrastim from day 3 until SC collection as a 2 mobilization regimen. This was compared with cyclophos- mobilized with Cy were given cyclophosphamide 4000 mg/m phamide 4000 mg/m2 followed by filgrastim which was used on day 1 and GCSF 10 mcg/kg/day from day 5 onwards. At to mobilize a historical control cohort. They showed that NUH, conventional GCSF was the growth factor of choice Vinorelbine-Cyclophosphamide (Vino-Cy) was associated prior to 2007, after which pegylated GCSF was adopted as with a superior SC collection with a more predictable day the new standard. Conventional GCSF has been preferred of collection and less toxicity. The majority of patients in at SGH throughout the study period. Apheresis (using the this study were however treated in the pre novel agent Cobe spectra or Optia system at NUH and the Haemonetics era [12]. We present a retrospective comparison of mobi- MCS + system at SGH) was commenced once a peripheral Â 6 lization efficacy and safety of Vino-Cy and Cy regimens in blood CD34 + SC count of >/=10 10 /l was achieved. The the novel agent era. Spectra and Haemonetics MCS + systems have been shown to have equivalent efficacy in HPC mobilization [13].At NUH, the Cobe Spectra system was used prior to 2011 and Patients and methods the Optia system was used from 2012 onwards. These two systems have also been shown to have a comparable effi- Study design cacy in terms of SC collection [14]. The number of total blood volume exchanges per apheresis was 3 at NUH and 4 The National University Hospital (NUH) and the Singapore at SGH. Apheresis was continued until a minimum target General Hospital (SGH) are the two tertiary hematopoietic CD34 + SC collection of 5 Â 106 per kg body weight (BW) stem cell transplant centres in Singapore. With institutional was achieved. An CD34 + SC collection of 2.5 Â 106/Kg BW Vinorelbine Cyclophosphamide for Stem Cell Mobilisation in Myeloma 227 was considered adequate for one ASCT and mobilisation Results failure was defined as a CD34 + SC collection of <2 Â 106 per kg/BW [15]. Patient demographics and treatment characteristics HDT and ASCT A total of 149 patients underwent CD34 + SC mobilization Patients who proceeded to HDT after successful CD34 + SC between 2004 and 2014. Their demographic and disease collection received melphalan 200 mg/m2 on Day minus 2 characteristics are described in Table 1. Disease status at (D-2) or 100 mg/m2 on D-3 and D-2. Patients with a poor per- mobilisation, induction regimen used, growth factor used formance status or compromised organ function were given and type of apheresis system used were found to be signif- melphalan 100 mg/m2 on D-2. SC infusion was performed on icantly different between the groups. D0 with a minimum CD34 + SC dose of 2 Â 106 per Kg BW. The majority of patients underwent bortezomib or GCSF was administered at 10 mcg/kg BW/day from thalidomide based induction therapy and the mean number D + 1 until ANC engraftment which was defined as an of treatment cycles was not significantly different between ANC > 0.5 Â 109/l sustained for at least 3 days. the groups. However, a significantly higher proportion of patients in the Vino-Cy cohort received bortezomib based Statistical analysis induction. Twelve patients in the Cy group (25.0%) and one patient in the Vino-Cy group (1.0%) received a second line The demographic and clinical characteristics of patients of induction therapy prior to CD34 + SC collection. All the were summarised by mean ± SD for continuous variables, second line regimens were bortezomib based regimens in and count (percentage) for categorical variables. The dif- patients which did not include melphalan. No patient had ference between the two mobilisation regimens (Vino-Cy more than two lines of therapy prior to CD34 + SC collection. versus Cy) was compared using the independent two- The majority of Vino-Cy patients (64.2%) received Pegylated sample t test for continuous variables, and Fisher’s exact GCSF while Cy patients were given exclusively conventional test for categorical variables. GCSF. A minority of Vin-Cy patients (6.3%) received conven- Among harvest related outcomes, day 1 and total CD34 + tional GCSF in addition to pegylated GCSF due to slow count SC collection were log-transformed before analysis. The recovery. Two Cy patients and one Vino-Cy patient had efficacy of mobilisation regimen on each outcome was first radiotherapy prior to mobilization. All the patients were evaluated using an independent two-sample t test. Its undergoing their first ASCT except one Vino-Cy patient for effect was quantified based on the ratio of geometric means whom it was their second ASCT. In view of the institutional and its associated 95% confidence interval (CI) for day 1 and differences in usage apheresis systems, the majority of Cy total CD34 + SC collection. Absolute mean difference and its patients (85.4%) were mobilized using the Haemonetics 95% CI were adopted for outcomes of day when harvest took MCS + system while the Cobe spectra or Optia system was place and number of apheresis sessions. Multiple linear utilized for most of the Vino-Cy patients (89.1%). The SC regression was subsequently performed to account for dose infused was significantly greater in the Cy cohort. potential confounders and important predictors. A con- founder was selected if it demonstrated a strong association (P < .05) with both the mobilisation regimens and the out- Efficacy of stem cell mobilisation come concerned. Toxicities of mobilisation regimens between the start of mobilisation chemotherapy and CD34 A total of 131 patients achieved a CD34 + SC collection of + SC collection were compared using the Fisher’s exact test. greater or equal to 5 Â 106/Kg BW which was considered ASCT outcomes including days from CD34 + SC infusion to adequate for two ASCT. The median SC collection on day recovery of absolute neutrophil and platelet counts were 1 of apheresis was comparable between the groups (3.86 analysed in a similar manner as the harvest related Â 106/Kg BW for Vino–Cy compared to 4.76 Â 106/Kg BW outcomes. for Cy), adjusted geometric mean ratio of 0.58 (95% CI Disease relapse (as defined by IMWG criteria) [16] was 0.32 to 1.05, P = .073). The total CD34 + SC collection was first depicted by the nonparametric cumulative incidence also lower in the Vino-Cy group with a median of curves, and was subsequently analysed using the Fine and 8.20 Â 106/Kg BW compared to 11.43 Â 106/Kg BW in the Gray’s competing risks method by regarding death as a com- Cy group. The adjusted geometric mean ratio was 0.59 peting event. The association between the mobilisation reg- (95% CI 0.41 to 0.86, P = .006). In the above models, the imen and relapse was measured by the subdistribution confounders and important predictors adjusted for were hazard ratio. A time-varying covariate model was further gender, disease status at mobilisation, induction regimen, constructed to test potentially time-varying effect of the growth factor used and type of apheresis system. mobilisation regimen. The Kaplan-Meier survival curves Eighteen patients achieved a suboptimal collection (less were plotted for overall survival and compared using the than 5 Â 106/Kg BW), 16 patients from the Vino-Cy cohort Log-rank test. The effect of mobilisation regimen was sum- (15.8%) and two from the Cy cohort (4.2%). The data for marised by the hazard ratio and its 95% CI. the patients with suboptimal mobilization are summarized All statistical analyses were performed using Stata/ in supplementary Table 1. They were all treated with a SE14.0 (StataCorp LP, College Station TX, USA) assuming a novel agent based protocol and had achieved at least a two-sided test with a significance level of 5%. partial remission at the time of harvest. None required addi- 228 S. de Mel et al.

Table 1 Baseline demographic, disease and treatment characteristics of the Vino-Cy and Cy cohorts. Mobilisation Regimen Overall Cy Vino-Cy P value (n = 149) (n = 48) (n = 101) Demographics Age (year), mean ± SD 56 ± 7 54 ± 7 56 ± 7 .136 Gender, n (%) 1.000 Male 87 (58.4) 28 (58.3) 59 (58.4) Female 62 (41.6) 20 (41.7) 42 (41.6) BMI, mean ± SD 25 ± 4 24 ± 5 25 ± 4 .415

Disease characteristics ISS stage, n (%) .082 I 27 (19.9) 14 (31.1) 13 (14.2) II 54 (39.7) 15 (33.3) 39 (42.9) III 55 (40.4) 16 (35.6) 39 (42.9)

Disease status at mobilisation, n (%) <.001 Complete remission 44 (31.2) 26 (56.5) 18 (18.9) Very good partial remission 47 (33.3) 13 (28.3) 34 (35.8) Partial remission 50 (35.5) 7 (15.2) 43 (45.3)

Treatment characteristics Induction regimen, n (%) <.001 Thalidomide based 37 (25.0) 15 (31.9) 22 (21.8) Bortezomib based 101 (68.2) 23 (48.9) 78 (77.2) Others* 10 (6.8) 9 (19.2) 1 (1.0) Number of cycles of chemo before harvest, mean ± SD 5 ± 2 5 ± 2 5 ± 1 .639

Growth factor used, n (%) <.001 Conventional GCSF 74 (52.5) 46 (100.0) 28 (29.5) Pegylated GCSF 61 (43.3) 0 (0.0) 61 (64.2) Pegylated GCSF followed by conventional GCSF 6 (4.2) 0 (0.0) 6 (6.3) Radiotherapy prior to mobilisation, n (%) 3 (2.0) 2 (4.4) 1 (1.1) .254

Type of Apheresis system, n (%) <.001 Haemonetics MCS + system 52 (34.9) 41 (85.4) 11 (10.9) Cobe spectra/Optia system 97 (65.1) 7 (14.6) 90 (89.1) CD34 + stem cells infused (Â106 cells/kg BW), mean ± SD 6.73 ± 4.20 9.07 ± 5.75 5.66 ± 2.69 <.001 P values of < 0.05 were considered significant. * Other induction regimens: One Vino Cy patient received melphalan, prednisolone, thalidomide. Among the Cy patients, two patients received melphalan, prednisolone and three patients received vincristine, adriamycin, dexamethasone and four received the Dexam- ethasone, Thalidomide, Cisplatin, Doxorubicin, Cyclophosphamide, Etoposide (DTPACE) regimen. tional therapy prior to harvest or had alkylator based treat- Mobilisation and harvest related toxicity ment. There were three mobilization failures in the Vino-Cy group and two in the Cy group. Among the Vino-Cy mobiliza- Complications occurring during and after CD34 + SC collection failures, one patient was previously treated with mel- tion were more common in the Cy group. The incidence of phalan (at an overseas centre) and another required neutropenic fever (FN) was greater in the Cy cohort with radiotherapy for a plasmacytoma causing spinal cord com- eight episodes (three of these cases did not require hospital pression during induction therapy. These two patients failed admission) of FN compared to two episodes in the Vino-Cy SC mobilization despite using plerixafor. The other three group. Unplanned hospital admissions between the start of patients were mobilized successfully using plerixafor. mobilization chemotherapy and SC harvest were greater in The time taken to achieve an adequate peripheral blood the Cy cohort with a total of six admissions compared to CD34 + SC count to enable CD34 + SC collection was signifi- three in the Vino-Cy group. There was one case of catheter cantly shorter in the Vino-Cy group compared to the Cy related thrombosis in the Cy cohort and one case of fluid À À cohort (adjusted mean difference 3.95, 95% CI 4.85 to overload in the Vino-Cy group. There was no grade 3–4 nau- À 3.06, P < .001). The number of apheresis sessions required sea or vomiting in either group and no significant neuropa- to complete an adequate SC collection was comparable thy in the Vino-Cy cohort. There were no cases of between the groups. A summary of the data on mobilization mortality related to mobilization chemotherapy or harvest efficacy is presented in Table 2. in either group. Vinorelbine Cyclophosphamide for Stem Cell Mobilisation in Myeloma 229

Transfusion requirements between the start of mobilization chemotherapy and CD34 + SC collection were used as an

value indicator of the haematologic toxicity of the regimens. Both P institutions use a transfusion threshold of 7 g/dl for Hae- moglobin (Hb) in the absence of symptoms and 10 Â 109/l for platelet count in the absence of bleeding or sepsis. In the Cy cohort, eight patients (16.7%) required red blood cell 3.06) <.001

À (RBC) transfusion compared to 12 patients (11.9%) in the b Vino-Cy cohort (P = .447). Platelet transfusion was required by 15 patients (31.3%) in the Cy cohort compared to 5 4.85 to a

À patients (5%) in the Vino-Cy group (P < .001). Data on trans- ion. fusion requirements are summarized in Table 3. 3.95 ( effect measure (95% CI) À Autologous stem cell transplant outcomes

The mean time from CD34 + SC infusion to achieving an absolute neutrophil count (ANC) of > 0.5 Â 109/l was value Adjusted

P 10 ± 1 days in both Vino-Cy and Cy groups. The absolute mean difference was À0.27 (95% CI À0.87 to 0.32, P = .363) after adjusting for confounders, including disease status, growth factor used, type of apheresis and SC dose

2.82) <.001 infused. The median time to platelet count >50 Â 109/l À

b was 18 days in the Vino-Cy group and 14 days in the Cy cohort, with unadjusted geometric mean ratio 1.38 (95%

4.03 to CI 1.25 to 1.53, P < .001) and adjusted geometric mean ratio À 0.30 to 0.33) .927 0.56 (0.001 to 1.12)1.12 .050 (95% CI 0.95 to 1.31, P = .181). ASCT outcome data are À summarized in Table 4. 3.43 ( The median follow up for the entire study sample was 38 (95% CI) À Unadjusted effect measure months. The median time to relapse was 41 and 56 months for the Vino-Cy and Cy cohorts respectively. Median overall survival (OS) was 88 and 113 months for the Vino-Cy and Cy cohorts. These were not statistically signiﬁcant differences between the cohorts in terms of incidence of relapse (unadjusted SHR = 1.03, 95% CI 0.61–1.77, p = 0.901) and OS (unadjusted HR = 1.82, 95% CI 0.92–3.59, p = 0.078). The = 101) analysis of incidence of relapse and OS are presented in n Vino-Cy ( Fig. 1A.

Discussion

Annunziata et al demonstrated that the median CD34 + SC collection was not significantly different between the Vino-Cy arm and the Cy historical control [12]. Within the = 48) limitations of a retrospective analysis, our data suggest that n 2 (1) 2 (1) 0.01 ( 4.76 (2.37–11.76)11.43 (7.49–20.10) 3.86 (2.18–6.00) 8.20 (5.77–13.20) 0.76 (0.51 to 1.14) 0.68 (0.55 to 0.85) .177 .001 0.58 (0.32 to 1.05) 0.59 (0.41 to 0.86) .073 .006 12 (2) 9 (1) ( the Cy cohort had a superior CD34 + SC collection. As different apheresis systems were used at the two institutions, we have considered the adjustment of potential confounders in this analysis. The difference in CD34 + SC collection remained significant after the adjustment via multiple linear regression. To further address this issue, we compared the CD34 + SC collection on day one of harvest which is less dependent on the apheresis equipment used. The CD34 + SC collection on day one of harvest was comparable between the two groups, in keeping with the data that the two apheresis systems are of equivalent efficacy. Our data are

cells/Kg BW), median (IQR) cells/Kg BW), median (IQR) similar to that reported by Annunziata et al. in terms of 6 6

Effect of mobilisation regimen (Vino-Cy vs. Cy) on mobilisation efﬁcacy. the shorter time to harvest for the Vino-Cy cohort. One 10 10 Â Â caveat in our study is that GCSF was started for the Cy group ( mean ± SD ( mean ± SD on day 5 while it was given on day 4 for the Vino Cy group, Gender, disease status atThe mobilisation, effect induction measure regimen, was growth the factor ratio used of and geometric type means of for apheresis outcomes were 1 adjusted and for 2, in and the absolute multiple mean linear difference regress for outcomes 3 and 4. a b we propose that this would not signiﬁcantly affect the time Table 2 1 Stem cell collection on day1 4 Number of apheresis sessions, 2 Total3 stem cell collection Day when harvest took place, Outcome Cy to achieve an adequate CD34 + SC count. Our studies are 230 S. de Mel et al.

Table 3 Toxicities of mobilisation regimens between the start of mobilisation chemotherapy and CD34 + stem cell harvest. Toxicity Overall Mobilisation Regimen Cy (n = 48) Vino-Cy P value (n = 101) Neutropenic fever (%) 10 (6.8) 8 (17.4) 2 (2.0) .002 Thrombosis (%) 1(0.7) 1(2.2) 0(0.0) .313 Fluid overload (%) 1 (0.7) 0 (0.0) 1 (1.0) 1.000 Total hospital admissions (%) 9 (6.1) 6 (12.8) 3 (3.0) .029 Number requiring RBC transfusion (%) 20 (13.4) 8 (16.7) 12 (11.9) .447 Number requiring platelet transfusion (%) 20 (13.4) 15 (31.3) 5 (5.0) <.001 Number requiring more than one RBC transfusion (%) 7 (4.7) 3 (6.3) 4 (4.0) .681 Number requiring more than one platelet transfusion (%) 6 (4.0) 6 (12.5) 0 (0.0) .001

Table 4 Effect of mobilisation regimen (Vino-Cy vs. Cy) on Autologous stem cell transplant outcomes. Outcome Cy Vino-Cy Unadjusted p-value Adjusteda P value (n = 48) (n = 101) effect measureb effect measureb (95% CI) (95% CI) 1 Days from stem cell infusion 10 ± 1 10 ± 1 À0.01 (À0.47 to 0.44) .952 À0.27 (À0.87 to 0.32) .363 to recovery of absolute neutrophil count, mean ± SD 2 Days from stem cell infusion 14 (12–15) 18 (14–22) 1.38 (1.25 to 1.53) <.001 1.12 (0.95 to 1.31) .181 to recovery of platelet count, median (IQR) a Disease status, growth factor used, type of apheresis and CD34 + stem cells infused were adjusted for in the multiple linear regression. b The effect measure was the absolute mean difference for outcome 1, and ratio of geometric means for outcome 2.

Fig. 1A Comparison of the cumulative incidence of relapse Fig. 1B Comparison of the overall survival probability between Vino-Cy = (Vinorelbine-Cyclophosphamide) and Cy between Vino-Cy = (Vinorelbine-Cyclophosphamide) and Cy (Cyclophosphamide) cohorts based on five year follow up data. (Cyclophosphamide) cohorts based on five year follow up data. also similar in that the toxicity profile of Vino-Cy was supe- our Vino-Cy patients used pegylated GCSF. Our study con- rior to Cy. One of the advantages of Vino-Cy proposed by firms that the results reported by Annunziata et al. are Annunziata et al. is the ability to deliver this regimen in applicable in the era of novel agent based induction the outpatient setting. Our mobilization protocols are therapy. administered in the inpatient setting although we are mov- The vinorelbine/GCSF (Vino-GCSF) mobilization protocol ing towards establishing this as an outpatient service. reported by Samaras et al was associated with a mobiliza- Another difference in the data sets is that the majority of tion failure rate of 5% which is comparable to our study Vinorelbine Cyclophosphamide for Stem Cell Mobilisation in Myeloma 231

(3% for Vino-Cy and 4% in the Cy cohort) [11]. The Vino-GCSF References protocol had an excellent toxicity profile with only three hospital admissions (1.5%) after mobilization. The favour- [1] Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi able toxicity profile of Vino-Cy compared to Cy in our study JF, et al. A prospective, randomized trial of autologous bone also suggests that high dose Cy is responsible for the bulk of marrow transplantation and chemotherapy in multiple mye- the toxicity and vinorelbine is relatively well tolerated. loma. Intergroupe Francais du Myelome. New England J Med Samaras et al also concluded that lenalidomide based induc- 1996;335(2):91–7. tion was a risk factor for poor mobilization. As we have not [2] Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, been using lenalidomide based therapy as standard upfront et al. High-dose chemotherapy with hematopoietic stem-cell treatment in transplant eligible patients our study does not rescue for multiple myeloma. New England J Med 2003;348 (19):1875–83. address this question. [3] Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Although more patients in the Cy group received two Mohty M, et al. Bortezomib plus dexamethasone is superior to lines of therapy before CD34 + SC collection, this is unlikely vincristine plus doxorubicin plus dexamethasone as induction to have a significant bearing on the efficacy of collection treatment prior to autologous stem-cell transplantation in since all the second line regimens were bortezomib based newly diagnosed multiple myeloma: results of the IFM 2005–01 protocols which did not contain melphalan and the mean phase III trial. J Clin Oncol: Off J Am Soc Clin Oncol 2010;28 number of treatment cycles was similar between the groups (30):4621–9. overall. The majority of our Vino-Cy patients were given [4] Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Blade pegylated GCSF while all of the Cy patients were adminis- J, et al. International Myeloma Working Group consensus tered conventional GCSF. A limitation of our data is that approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood 14 patients in the Cy group did not have data available on 2011;117(23):6063–73. the type of growth factor used. We also performed multiple [5] Hamadani M, Kochuparambil ST, Osman S, Cumpston A, linear regression to adjust for the discrepancy in growth fac- Leadmon S, Bunner P, et al. Intermediate-dose versus low- tor usage, as well as other differences in baseline character- dose cyclophosphamide and granulocyte colony-stimulating istics such as induction regimen and disease status at factor for peripheral blood stem cell mobilization in patients mobilisation, however, the results were not materially with multiple myeloma treated with novel induction therapies. altered with or without adjustment. Biol Blood Marrow Transplant : J Am Soc Blood Marrow The mean CD34 + SC dose infused was greater in the Cy Transplant 2012;18(7):1128–35. cohort. After adjustment for this and other confounders [6] Petrucci MT, Avvisati G, La Verde G, De Fabritiis P, Ribersani using multiple linear regression we found no significant dif- M, Palumbo G, et al. Intermediate-dose cyclophosphamide and granulocyte colony-stimulating factor is a valid alternative to ference in the time to count recovery after ASCT between high-dose cyclophosphamide for mobilizing peripheral blood the two regimens. CD34+ cells in patients with multiple myeloma. Acta Haematol We did not see a difference in the incidence of relapse or 2003;109(4):184–8. OS post SCT between the groups. (Fig. 1B) Within the limita- [7] Lerro KA, Medoff E, Wu Y, Seropian SE, Snyder E, Krause D, tions of a retrospective analysis, this suggests that the cyto- et al. A simplified approach to stem cell mobilization in toxic effect of high dose cyclophosphamide on the plasma multiple myeloma patients not previously treated with alky- cell clone is matched by the Vino Cy regimen. Our findings lating agents. Bone Marrow Transplant 2003;32(12):1113–7. are supported by recent data showing that the addition of [8] Olivieri A, Capelli D, Montanari M, Brunori M, Massidda D, high dose chemotherapy to the mobilization protocol did Poloni A, et al. Very low toxicity and good quality of life in 48 not influence progression free or overall survival [17]. elderly patients autotransplanted for hematological malignan- cies: a single center experience. Bone Marrow Transplant In conclusion, Vino-Cy and Cy are comparable mobiliza- 2001;27(11):1189–95. tion regimens with their respective strengths and weak- [9] DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff nesses. Our data suggests that the Cy regimen is superior PJ, Kaufman JL, et al. Plerixafor and G-CSF versus placebo and in terms of the efficacy of SC mobilization while Vino-Cy G-CSF to mobilize hematopoietic stem cells for autologous results in a shorter time to harvest with a more acceptable stem cell transplantation in patients with multiple myeloma. toxicity profile. Prospective studies comparing vinorelbine Blood 2009;113(23):5720–6. based protocols with other chemo mobilization and growth [10] Bargetzi MJ, Passweg J, Baertschi E, Schoenenberger A, factor based mobilization regimens are called for to estab- Gwerder C, Tichelli A, et al. Mobilization of peripheral blood lish the standard of care for SC mobilization in myeloma. progenitor cells with vinorelbine and granulocyte colony- stimulating factor in multiple myeloma patients is reliable and cost effective. Bone Marrow Transplant 2003;31 Statement of conflict of interest (2):99–103. [11] Samaras P, Pfrommer S, Seifert B, Petrausch U, Mischo A, The authors have no conflict of interest to disclose. Schmidt A, et al. Efficacy of vinorelbine plus granulocyte colony-stimulation factor for CD34+ hematopoietic progenitor cell mobilization in patients with multiple myeloma. Biol Blood Marrow Transplant : J Am Soc Blood Marrow Transplant Appendix A. Supplementary material 2015;21(1):74–80. [12] Annunziata M, Celentano M, Pocali B, D’Amico MR, Palmieri S, Viola A, et al. Vinorelbine plus intermediate dose cyclophos- Supplementary data associated with this article can be phamide is an effective and safe regimen for the mobilization found, in the online version, at https://doi.org/10.1016/j. of peripheral blood stem cells in patients with multiple hemonc.2018.04.001. myeloma. Ann Hematol 2006;85(6):394–9. 232 S. de Mel et al.

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