The Use Of Tevagrastim (Biosimilar Filgrastim XMO2) For Hematopoietic Stem Cell Mobilization In HLA Matched Sibling Donors For Allogeneic Stem Cell Transplantation To AML/MDS Patients

Human recombinant G-CSF Filgrastim (Neupogen) has been widely used for the mobilization of CD34⁺ hematopoietic stem cells (HSC) from healthy donors. The experience with biosimilar G-CSF agents is limited and the only publication, to our knowledge, is the recent study by Schmitt M and co-authors (BMT 2013; 48, 922–925). This study involved 11donors and pts with various disease categories. The Biosimilar G-CSF was found to be comparable in efficacy and safety to Neupogen. Developing new cost effective mobilizing reagents if important.

We, therefore, initiated a prospective study assessing Tevagrastim (biosimilar Filgrastim XMO2) for mobilization of CD34⁺ PB HSC in healthy sibling donors (MRD) for transplantation in pts with AML/MDS (NCT01542944).

24 pts with AML or high-risk MDS undergoing allo-SCT from MRD were investigated. The study was approved by the National Regulatory Authorities and both patients and donors signed an informed consent. The donors, median age 46 years (range, 25–64), F- 14; M- 10 received Tevagrastim in a standard dose of 10 μg/kg BW s.c. BID for 4 days. On the morning of the 5th day they underwent conventional leukapheresis. The target yields of CD 34 cell was 5 × 10⁶ CD34⁺ cells/kg BW of the recipient. If one leukapheresis was insufficient a second was performed and, the last dose of Tevagrastim was administered on the evening of the 5th day. The conditioning was myeloablative Bu/Cy (n=10), reduced toxicity Flu/Treo (n=7), Flu/Bu4 (n=3) or RIC Flu/Bu2 (n=4).

The study parameters were: a CD34⁺ cell count,both absolute numbers and the CD34⁺ cells per kg BW of the recipient, the number of leukapheresis procedures, the number of CD3⁺ T lymphocytes in the graft, post transplantation engraftment including the WBC, the neutrophils and the platelets, as well as side effects. Follow up was 100 days post allo-SCT.

77-1982 × 10⁶ (median 749 × 10⁶) CD34⁺ were collected. The number of CD34⁺ cell per kg BW of the pts was 0.93-35.4 × 10⁶ (median 10.2 × 10⁶). Collections contained 144-709 × 10⁸ (median 299 × 10⁸) CD3⁺ T-cells, 1.74-11.6 ×10⁸ (median 4.4 ×10⁸) per kg BW of the pts. The mean number of leukapheresis procedures was 1.3. Engraftment was: ANC >0.5× 10⁹/L and >1× 10⁹/L within a median of 13 days (range, 10–21) and 13.5 days (range, 10–22), respectively. PLT reached counts of >20× 10⁹/L and >50× 10⁹/L within a median of 16 days (range, 12–33) and 17 days (range, 12–33) from allo-SCT, respectively. The median days of isolation was 10 (range, 6-21). As for blood support, the median number of PC and PLT transfusions was 5 (range, 2-20) and 21 (range, 0-180), respectively. 18/22 (81.8%) pts achieved full donor chimerism at 1 month after transplantation (2 pts are too early to evaluate).

Overall Tevagrastim was found to be safe with minimal transient side effects. Neither allergic reactions nor severe adverse events were observed in the donors. 12/24 donors reported transient arthralgias and 2 developed flu-like syndrome while receiving Tevagrastim. As for transplantation related toxicity in the 24 pts transplanted with Tevagrastim mobilized HSC grafts, side effects were not different than those we observed in historical controls. The main side effects were mucositis (n-15, grade II -9, grade III-IV- 6), infection complications (n-20) and fluid retention (n-8). One pt suffered from VOD (Grade-I) that resolved with conventional therapy. Five pts developed acute GVHD (grade II-III) that responded to conventional therapy. In total TRM was 1/24 at d 100. 2 pts died from leukemia progression.

Our study with 24 AML/MDS pts, indicates that the G-CSF biosimilar XM02, Tevagrastim is safe and efficient for stem cells mobilization in HLA matched normal sibling donors. The CD34 yield and post transplantation engraftment are similar to those achieved with the human recombinant G-CSF Filgrastim (Neupogen). We have not seen significant differences in the graft CD34⁺ and CD3⁺ T lymphocytes cell count, the number of leukapheresis procedures and the regeneration of WBC, neutrophils and platelets in comparison with our historical controls. All patients promptly engrafted, and the donors developed only expected side effects like arthralgias and flu-like syndrome. Neither graft rejection nor side effects occurred more frequently than expected from the standard G-CSF.

Nagler:Teva : Consultancy, Honoraria, Research Funding.