Annals of Hematology

, Volume 85, Issue 6, pp 394–399

Vinorelbine plus intermediate dose cyclophosphamide is an effective and safe regimen for the mobilization of peripheral blood stem cells in patients with multiple myeloma

Authors

  • Mario Annunziata
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
  • Maria Celentano
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
  • Barbara Pocali
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
  • Maria Rosaria D’Amico
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
  • Salvatore Palmieri
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
  • Assunta Viola
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
  • Carolina Copia
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
  • Claudio Falco
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
    • Service of Transfusion MedicineCardarelli Hospital
  • Luigi Del Vecchio
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
    • Service of Transfusion MedicineCardarelli Hospital
    • Division of Hematology and Stem Cell Transplantation UnitCardarelli Hospital
    • Via Nicolò Piccinni 6
Original Article

DOI: 10.1007/s00277-005-0058-0

Cite this article as:
Annunziata, M., Celentano, M., Pocali, B. et al. Ann Hematol (2006) 85: 394. doi:10.1007/s00277-005-0058-0

Abstract

High dose cyclophosphamide (HD-Cy) is commonly used to mobilize stem cells in multiple myeloma (MM). However, timing of collection is variable and incidence of side effects is substantial. We evaluated a combination of vinorelbine (VNB) (25 mg/m2 day 1) plus Cy (1.5 g/m2 day 2) and G-CSF as mobilizing regimen in 37 patients with MM. Results were compared to those achieved in 41 previously diagnosed patients mobilized with Cy at 4 g/m2. Overall, 36/37 patients receiving VNB–Cy (97%) mobilized, as opposed to 40/41 (97%) in the controls (p:0.51). Median CD34+ cells peak was 94/μl for VNB–Cy patients and 96 for controls, p=0.36; median number of CD34+ cells collected was 9.2×106/kg and 8.7×106/kg, respectively (p=0.85). Median number of days to the highest CD34 count was shorter for VNB–Cy patients (nine vs 11, p=0.001). No VNB–Cy patient experienced grade 3–4 neutropenia and thrombocytopenia, as opposed to 63 and 19% in the controls (p=0.001 and 0.01, respectively). Hospitalization from toxicity was never required in VNB–Cy patients as compared to 19% in control group (p=0.01). We conclude that an outpatient combination of VNB plus intermediate dose Cy plus G-CSF is a safe, predictable, and highly effective mobilization regimen for patients with newly-diagnosed MM.

Keywords

Stem cellMobilizationMultiple myelomaVinorelbineCyclophosphamide

Introduction

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently recognized as the standard therapeutic option for patients with multiple myeloma (MM) [13, 24, 28, 37]. Two recent large randomized trials have clearly demonstrated that ASCT results in higher remission rate and longer disease free and overall survival as compared to conventional therapy [3, 14]. The survival advantage of ASCT does mainly rely on its capacity of inducing complete remission (CR), which represents an important surrogate for long term survival [2, 29]. More than 95% of autografts are currently performed with the support of peripheral blood stem cells (PBSC), which has consistently reduced the toxicity of the procedure and extended the feasibility of ASCT to MM patients older than 65 years [5, 20, 35, 36]. In most cases, cyclophosphamide (Cy) at doses of 4–7 g/m2 and granulocyte colony stimulating factor (G-CSF) are successfully used to induce mobilization of stem cells into the peripheral blood [12, 15, 19, 27]. However, high dose Cy is associated with substantial haematologic toxicity, needs concomitant administration of the uroprotectant mesna, and often requires hospitalization. In addition, the day of CD34 positive (CD34+) cell peak is unpredictable and monitoring of CD34+ cells for several days is required [12, 19, 27]. Aiming at a reduction of toxicity and costs of mobilization, different authors have proposed alternative regimens based on lower dose Cy, ranging from 1.2 to 2 g/m2, with satisfying results in terms of CD34+ cells collection [25, 30, 33, 34]. On the other hand, vinorelbine (VNB), a semisynthetic vinca alkaloid active in solid tumors [1], has also been successfully used either as single agent or in combination with other cytotoxic agents for the mobilization of PBSC [6, 7, 31]. Furthermore, this drug has also been reported as effective in refractory patients with MM [21, 22]. In this study, we report the disease characteristics and treatment results from a series of 37 patients with MM in whom a combination of VNB and Cy (VNB–Cy) was given as mobilization therapy on an outpatient basis. Results from this group were compared with a historical cohort of patients managed with similar upfront therapy and mobilized with Cy at 4 g/m2. In both protocols, G-CSF was given at identical doses starting soon after the end of chemotherapy until last PBSC apheresis.

Materials and methods

Patients’ characteristics

Overall, 37 patients affected by MM were enrolled into this prospective phase-two study based on the combination of VNB plus Cy for the mobilization of PBSC in MM (Fig. 1). Written informed consent was obtained from all patients. Inclusion criteria included a diagnosis of MM in stage II or III according to the Durie and Salmon classification [16], age less than 75 years, and achievement of at least partial response after vincristine, adryamicin and desamethazone (VAD) chemotherapy [8]. Patients with renal insufficiency were included; however, no patients were on dialysis at the time of mobilization. Evaluation of response was assessed according to EBMT criteria [11]. Chemotherapy preceding mobilization consisted of three cycles of VAD in 31 patients and VAD plus thalidomide 100 mg/die in six patients. The median age of the whole patient population was 60 years (range 37–71). There were 25 males and 12 females. Twelve patients were in stage II-A, three in stage II-B, 18 in stage III-A, and four in stage III-B. Twenty patients had IgG myeloma, ten had IgA myeloma, five had light chain disease (three kappa and two lambda) and two had non-secretory MM. The main characteristics of patients are shown in Table 1.
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Fig. 1

Schedule of the VNB–Cy protocol

Table 1

Characteristics of the patients according to mobilization regimen

 

VNB–Cy

Cy 4 g/m2

p value

Total number

37

41

 

Sex (M/F)

25/12

22/19

0.25

Age, median (range)

60 (37–71)

56 (35–72)

0.03

Durie–Salmon stage

   

 IIa

12

12

 

 IIb

3

4

 

 IIIa

18

20

 

 IIIb

4

5

 

MM type

   

 IgG

20

22

 

 IgA

10

10

 

 Light chains

5

7

 

 Non secretory

2

2

 

 Creatinine >2 mg/dl

7/37

9/41

 

Treatment

   

 VAD

31

41

 

 VAD+thalidomide

6

  

Response to VAD

   

 CR

4

5

 

 nCR

10

12

 

 PR

23

24

 

PBSC mobilization

VNB was administered at a dose of 25 mg/m2 intravenously over 5–10 min in an outpatient setting on day 1; hydration or antiemetic drugs were not used. Cy was also given as outpatient at 1.5 g/m2 on day 2 after 500 ml of prehydration with normal saline over 2 h. Mesna uroprophylaxis was not administered. G-CSF, 10 μg/kg/day subcutaneously, divided into a morning and an evening dose was started on day 4 and was continued daily until apheresis.

PBSC collection

WBC and circulating CD34+ cells in peripheral blood were monitored to determine the timing of PBSC harvest. Apheresis was performed when the peripheral CD34+ cell count was >20×106/l using a Cobe Spectra cell separator processing 15 l of blood by continuous flow. Set as target by our protocol, no additional apheresis was planned if the number of CD34+ cells in the collected apheresis product exceeded 6×106/kg body weight of the patient.

Control group and comparison

Historical control group, treated at our Institution prior to this experimental protocol, consisted of 41 consecutive patients, pretreated with an average of three cycles of VAD and mobilized with high-dose cyclophosphamide (4 g/m2) and G-CSF, 10 μg/kg/day subcutaneously, divided in a morning and evening dose was started on day +2 and continued daily until apheresis.

Stem cell number in the blood and in the collected transplant product were compared between the VNB–Cy and the HD-Cy groups. In addition, haematologic toxicity, occurrence of infections or other extra-haematologic toxicity, and hospitalization were also compared. The antineoplastic activity was evaluated by measuring serum before and after mobilization therapy in both groups, while bone marrow plasma cells percentage pre- and post mobilization therapy was assessed only in the study group. The Mann–Whitney test was used to compare CD34+ cells per milliliter in the blood prior to stem cell collection and the number of CD34+ cells in the collected products in the study group and the historical controls. The Wilcoxon signed rank test was applied to compare the amount of M component before and after mobilization therapy for either patients in the study or the historical controls. Survival curves were calculated according to Kaplan and Meier method [26] and compared by the log-rank test. Main patient and disease characteristics of the population on study and controls are summarized in Table 1.

Results

The VNB–Cy and control groups were comparable with regard to age, sex, and Durie–Salmon stage at diagnosis. In addition, the proportion of PR and CR were not different after VAD therapy as shown in Table 1. On the contrary, patients mobilized with VNB–Cy had a significantly higher median age (60 vs 56, p=0.03). The median number of days of G-CSF administration was 10 days for the VNB–CY group (range 8–12) as opposed to 11 (range 7–17) in the HD-Cy group (range 7–17), p=0.16.

Efficacy of mobilization

Overall, 36 out of 37 patients receiving VNB–Cy (97%) achieved a successful mobilization and collection of CD34+ cells as opposed to 40 out of 41 (97%) in the control group (p:051). More in detail, the median value of CD34 peak was 94/μl (33–343) for VNB–Cy patients as compared to 96 (21–1,507) for controls, p=0.36; the median number of total stem cells collected was 9.2×106/kg (3.3–18.9) and 8.7 (2.5–43), respectively (p=0.85). Finally, both groups of patients needed a median of two apheresis (range 1–2 for VNB–Cy and 1–3 for HD-Cy), p=0.28. On the contrary, the median number of days from therapy to the highest CD34 count was significantly shorter for VNB–Cy patients (nine vs 11, p=0.001); in addition, in this group, collections of CD34+ cells were performed within a range of 5 days as opposed to 12 days for HD-Cy patients (p=0.001), as indicated in Fig. 2. Figure 3 shows the efficacy of mobilization with 78 and 33% of VNB–Cy patients achieving a peak CD34+ cell count of more than 50 and 100/μl, respectively; no statistically significant difference was found by comparing these results to those achieved in the HD-Cy group (p=0.17).
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Fig. 2

Day of first apheresis after mobilizing chemotherapy in VNB–Cy (panel A) and HD-Cy (panel B) groups

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Fig. 3

Maximum CD34 peak (μl) in peripheral blood according to mobilizing regimen

Either patients mobilized with VNB–Cy or those receiving HD-Cy achieved a slight reduction of M component, which accounted for a median of 10% (range 0–21) in the study group and 12% (range 0–24) in the controls, respectively. The difference was not statistically significant (p=0.25). Overall, no difference between the two groups was found when patients were reassessed for EBMT response criteria after mobilization (p=0.34) and, no patient changed response status after either VNB–Cy or HD-Cy.

Toxicity

No patient in the VNB–Cy experienced grade 3–4 haematologic toxicity, while grade 3–4 neutropenia and thrombocytopenia occurred in 26/41 and 8/41 HD-Cy patients, respectively. The difference is highly statistically significant as shown in Table 3. In addition, fever occurred in 44% of patients receiving HD-Cy as opposed to 0% in the study group (p<0.001). Finally, hospitalization due to febrile neutropenia was required in 19% of HD-Cy group, while it was never needed in VNB–Cy patients.

Autologous stem cell transplantation

All patients who were successfully mobilized proceeded to high dose therapy with stem cell rescue. Depending on age, i.e., less or more than 65 years, patients were conditioned with melphalan at 200 or 140 mg/m2, respectively. All patients received G-CSF after the progenitor cell infusion starting on day +5. All patients engrafted, and no death occurred in the cytopenic phase after stem cell infusion. Of note, a considerable number of patients were managed in an outpatient setting as previously reported [17]. No differences were observed between the two groups in terms of neutrophils and platelet recovery, as shown in Table 4. Finally, no difference was recorded in terms of progression free survival from ASCT as indicated in Fig. 4 (p=0.48). Obviously, patients mobilized with HD-Cy have a substantially longer follow up.
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Fig. 4

Progression free survival after ASCT in the VNB–Cy group compared to HD-Cy group (p=0.48)

Discussion

Autologous stem cell transplantation represents the first treatment resulting in a significant improvement of disease free and overall survival for patients with multiple myeloma in over 30 years [13, 24, 28, 37]. The strategy of double autograft may further improve the therapeutic results [4], but it needs a higher number of CD34+ cells after mobilization. Accordingly, the current initial approach in newly-diagnosed patients should include a less stem cell-toxic treatments such as pulse VAD or thalidomide/dexamethasone until stem cells have been collected. Such an approach makes stem cell collection easier and more productive than in patients who have been heavily pretreated with alkylating agent-based regimens. As mobilization therapy is concerned, an ideal regimen, apart from an effective mobilization, would also exert a significant antineoplastic effect in absence of relevant toxicity. Currently, cyclophosphamide at doses of 4–7 g/m2 and G-CSF is the most commonly used regimen to induce mobilization of stem cells into the peripheral blood [3, 13, 14, 24, 28, 29, 37]. However, such a treatment is associated with substantial haematologic toxicity, needs concomitant administration of the uroprotectant mesna, and can require hospitalization, in most cases due to febrile neutropenia [12, 15, 19, 27, 34]. Furthermore, the day of CD34+ cell peak is unpredictable and monitoring of CD34+ cells for several days is required. On this basis, different authors have successfully adopted less toxic regimens with comparable results in terms of CD34+ cell collection [7, 25, 30, 33, 34].

In this study, based on a mobilization regimen including VNB+Cy, 36 out of 37 patients (97%) did successfully mobilize with a median collection of 9.2×106/kg CD34+ cells. The rationale for adopting such a combination relies on the capability of both drugs in mobilizing stem cells and in exerting anti-myeloma activity. Results in terms of efficiency of mobilization and collection were comparable to those achieved in a control group consisting of 41 patients previously mobilized with Cy at 4 g/m2, although VNB–Cy patients had a significantly higher median age, which is per se an adverse parameter for mobilization [18]. While the median number of apheresis was similar, two major advantages did clearly emerge for the VNB–Cy patients. The first one does strictly concern the negligible toxicity associated with this mobilization regimen. No patient in the VNB–Cy group experienced either fever or relevant neutropenia which occurred in 44 and 63%, respectively, in the HD-Cy group. As a consequence, in the control group, hospitalization requiring intravenous antibiotics was more frequently needed (19 vs 0%, p=0.001), as detailed in Table 3. The second advantage of VNB–Cy regimen relies in the high predictability of the day of first apheresis. In our series, 34 out of 36 VNB–Cy patients (94%) underwent CD34+ cells collection in a range of 3 days, i.e., day 8 through 10, while a significantly wider range of 12 days was observed for the HD-Cy group, as indicated in Fig. 2. As a consequence, patients in the study group needed less frequent controls of peripheral blood CD34+ cells and in most of them, collection was highly predictable allowing the avoidance of apheresis on week-end days.

Until now, few studies have specifically addressed the potential antineoplastic activity of mobilization regimen in MM patients. HD-Cy provides a modest therapeutic effect after three cycles of VAD with an additional 21% of patients achieving a partial response [9]. As detailed in Table 2, we evaluated the decrease of M component before and after mobilization in both groups of patients with comparable results. These data suggest that the VNB–Cy regimen, apart from efficiency in mobilization, has also a modest effect in reducing myeloma burden, which, at least in the present series, was not inferior to that achieved with HD-Cy. All patients who were successfully mobilized were actually given ASCT, and no differences were found between the two groups in terms of haematopoietic recovery and transplant related toxicity. This is not surprising if we consider that a comparable number of CD34+ positive cells was given in the two groups.
Table 2

Mobilization results

 

VNB–CTX

Cy 4 g/m2

p value

Successful mobilization

36/37

40/41

0.51

Days from therapy to the highest CD34 count, median (range)

9 (8–11)

11 (6–17)

0.001

Number of apheresis, median (range)

2 (1–2)

2 (1–3)

0.28

Highest CD34 count measured (/μl), median (range)

94 (33–343)

96 (21–1507)

0.36

Total number of CD34+ cells collected (×106/kg), median (range)

9.2 (3.3–18.9)

8.7 (2.5–43)

0.85

Median reduction of M component before and after mobilization therapy

10% (0–21%)

12% (0–24%)

0.25

Table 3

Toxicity

 

VNB–CTX

Percentage

Cy 4 g/m2

Percentage

p value

Fever >38°C

0/37

(0)

18/41

(44)

<0.001

Need for RBC transfusion

1/37

(3)

10/41

(24)

0.008

Need for platelet transfusion

0/37

(0)

3/41

(7)

0.24

Grades 3–4 neutropenia

0/37

(0)

26/41

(63)

<0.001

Grades 3–4 thrombocytopenia

0/37

(0)

8/41

(19)

0.01

Need for hospitalization*

0/37

(0)

14/41

(19)

0.001

*Due to febrile neutropenia in all cases

Table 4

Stem cell transplantation and haematopoietic recovery

 

VNB–CTX

Cy 4 g/m2

p value

Total SCT performed

36

40

0.85

Melphalan 200

22

26

0.91

Melphalan 140

14

14

 

Stem cell dose

6.4

5.9

0.21

Days to neutrophils >0.5×109/l

12 (9–21)

12 (8–20)

0.43

Days to platelets >20×109/l

13 (8–22)

13 (8–25)

0.32

In summary, an outpatient combination of vinorelbine and low-dose cyclophosphamide plus G-CSF is a safe, predictable, and highly effective method for mobilizing stem cells in patients with newly diagnosed multiple myeloma. The adoption of higher doses of cyclophosphamide results in more frequent toxicity in absence of significant advantage on efficiency of mobilization and antineoplastic activity; this is particularly relevant in a disease with a median age at presentation of more than 60 years, in which the upper age limit for autologous transplantation is progressively increasing [10, 23, 32, 35].

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© Springer-Verlag 2006