Influence of Different Dosages of Cyclophosphamide on Stem Cell Mobilization and Engraftment In Newly Diagnosed Multiple Myeloma Patients Treated with a Thalidomide Containing Regimen.

Treatment of multiple myeloma (MM) patients (<65 yrs) consists of induction chemotherapy for 3–6 months followed by peripheral blood stem cell collection and transplantation. Both high dose cyclophosphamide (HD-C, 2 gr/m²/day, on days 1–2) and lower dosage of cyclophosphamide (1 gr/m²/i.v.on day 1) combined with doxorubicin (15 mg/m²/day, on days 1–4) and dexamethason 40 mg orally, days 1–4 (LD-C) are used, in combination with G-CSF, to mobilize hematopoietic stem/progenitor cells. A great variability was observed in the engraftment of different hematopoietic lineages post-ASCT. Therefore we questioned whether the dose of cyclofosfamide as mobilizing agent might affect the neutrophil and platelet recovery post-ASCT. The studied MM patients were treated with VAD or TAD (Blood 2010;11:115). Peripheral blood stem cells were collected after LD-C and HD-C with the Cobe Spectra; in each collection, 10 – 12 L of blood was processed in 3 – 4 hours. The target yield was 10 × 10⁶/kg CD34⁺ cells.

92 patients were treated according to VAD and 41 patients with TAD. In the VAD arm 89% of the patients reached the target yield of CD34⁺ cells after 1 collection compared to 61% in patients treated with TAD (p = 0.0003). The number of CD34⁺ cells collected at the first day and the total CD34 yield after HD-C or LD-C was significantly higher in patients treated with VAD compared with TAD: 16.6 ± 11.6 × 10⁶/kg vs. 10.4 ± 9.3 × 10⁶/kg (p=0.003), and 16.9 ± 11.1 × 10⁶/kg vs 12.3 ± 8.6 × 10⁶/kg (p=0.02). No significant difference was observed in the total yield of collected CD34⁺ cells in the VAD arm or TAD arm between HD-C vs. LD-C.

In all patients high dose melphalan (200 mg/m²) was used as conditioning regimen followed by reinfusion of peripheral blood stem cells. In the VAD arm no difference in neutrophil and platelet engraftment (absolute neutrophil count > 0.5 × 10⁹/L and platelet count > 20 × 10⁹/L without platelet transfusions) was noticed between patients mobilized with LD-C (22 ±12 days and 23 ±13 days) or HD-C (18 ± 5 (p=0.1) and 21 ±11 days (p=0.5)); in contrast a significant difference was demonstrated in neutrophil and platelet engraftment between patients treated according the TAD arm and mobilized with LD-C (20 ± 8 days and 20 ±19 days) or HD-C (34 ± 11 days (p<0.0001) and 43 ±22 days (p=0.001)). These differences could not be ascribed to differences in the number of infused CD34⁺ cells: VAD arm: LD-C: 5.7 ± 2.6 × 10⁶/kg, HD-C: 5.7 ± 2.5 × 10⁶/kg: TAD arm: LD-C: 5.2 ± 2.5 × 10⁶/kg and TAD-HD-C 6.4 ± 2 × 10⁶/kg. It might be assumed that the higher dosage of cyclophosphamide had a positive effect on tumor response. However the impaired engraftment was not associated with differences in relapse free survival between the different arms (p = 0.2). In summary these data demonstrate that thalidomide containing regimen in MM patients impair mobilization of stem/progenitor cells and that a mobilization with high dose cyclophosphamide and not low dose cyclophosphamide after treatment with thalidomide prolong the engraftment post-transplantation.

No relevant conflicts of interest to declare.