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

Background

High dose therapy (HDT) followed by autologous stem cell rescue is the standard of care for transplant eligible patients with multiple myeloma (MM).  High dose cyclophosphamide (Cy) at 4-7g/m² with granulocyte colony stimulating factor (GCSF) has been shown to be effective for haematopoietic progenitor cell (HPC) mobilization despite associated haematologic toxicity. Vinorelbine 25mg/m² in combination with Cy 1500mg/m² (Vino-Cy) was shown to be comparable to Cy mobilization in a study using historical controls.

Vino-Cy is the mobilization regimen of choice at the National University Hospital Singapore (NUH) while Cy mobilization is preferred at the Singapore General Hospital (SGH). We present a retrospective comparison of HPC mobilisation outcomes using Vino- Cy and Cy at these institutions.

Methods

Medical records for patients undergoing HPC mobilization between 2004 and 2014 at NUH and SGH were analysed. Patients mobilized with Vino -cy received Vinorelbine 25mg/m2 on day 1 followed by cyclophosphamide 1500mg/m2 on day 2, GCSF 10mcg/kg/day was given from day 4 onwards. Alternatively, pegylated GCSF 6mg was given on day 4. Patients mobilized with Cy were given cyclophosphamide 1500mg/m2 on day 1 and 2 and GCSF 10mcg/kg/day from day 5 onwards. Apheresis (using the cobe spectra or optia system at NUH and the Haemonetics MCS+ system at SGH) was commenced once a peripheral blood CD 34+ count of >/= 10 x 10 ⁶ /l was achieved. The number of total blood volume exchanges per apheresis was 3 at NUH and 4 at SGH. Apheresis was continued until a minimum target CD 34 collection of 5 x 10 ⁶ per kg/BW was reached. Patients who were successfully mobilized proceeded to HDT with melphalan 200mg/m2.

Results

133 patients underwent HPC mobilization between 2004 and 2014. The median weight was 62 Kg for Vino Cy and 58Kg for the Cy patients (p=0.03). The groups were evenly matched in terms of age, presence of renal impairment, bone lesions, ISS stage and the use of novel agent based induction. Bortezomib based induction was used in 73% of Vino-Cy and 43% of Cy patients. A higher percentage of Cy patients were mobilized in complete remission (53%) compared to Vino-Cy (21%).

 Table 1 summarises the mobilization outcomes of the two groups. Although the total CD 34+ collection was greater in the Cy group, the difference in the percentage of patients achieving an adequate HPC collection was not statistically significant ,72/84 ( 85%) of Vino-Cy patients and 45/47 (95%) of Cy patients achieved a stem cell collection of greater than 5 x 10 ⁶ /Kg BW ( P=0.07). There were two mobilization failures in each group, one of whom (a Vino-Cy patient) was previously treated with melphalan.

The number of days taken to achieve an adequate peripheral blood HPC count was shorter in the Vino Cy group and the date of harvest was also more predictable for Vino Cy with a standard deviation of 0.95 compared to 1.95 for Cy. Grade 3- 4 harvest related complications were significantly more common in the Cy group (table 2). There was no significant drop in haemoglobin after harvest in either group.

Discussion

Our data suggest that HPC mobilization maybe more effective with Cy, differing from data published by Annunziata et al which showed a superior HPC mobilization with Vino-Cy compared to the historical Cy control. Vino-Cy appears superior in terms of the time taken for an adequate peripheral CD34+ count and predictability of the day of harvest. The incidence of harvest related complications is also greater for Cy. These findings are common to our cohort and that reported by Annunziata et al. Data on transfusion requirements, hospitalization rates and survival are being collected.  Prospective clinical trials are required to definitively determine which protocol is superior.

	Day of protocol when harvest took place		P value	Number of days taken to harvest		P value	CD34+/Kg Collected		P value
	Vino-Cy(n=84)	Cy(n=47)		Vino-Cy(n=84)	Cy(n=47)		Vino-Cy(n=84)	Cy(n=47)
Median	9	13	P=0.000	2	2	P=0.97	8.4	11.3	P=0.009
Mean	8.5	12		2	2		10.0	16.2
Maximum	11	16		5	5		32.5	73.9
Minimum	5	7		1	1		2.2	2.4
SD	0.95	1.9		0.94	0.93		5.7	14.5

Table1. Comparison of Mobilisation Outcomes with Vino-Cy and Cy.

		Mobilisation Chemotherapy		P value.
		Vino-Cy(84)	Cyclophosphamide (47)
Complications during and after harvest (grade3-4)		2(2.3)	9(19)	0.009
Fluid Overload		1	0
Neutropaenic Fever		1	8
Line related thrombosis		0	1

Table 2. Grade 3-4 Complications during and after stem cell collection, data presented as number (%).