Intravenous Compared to Oral Busulfan with Cyclophosphamide for Autologous Hematopoietic Progenitor Cell Transplant Conditioning for Plasma Cell Myeloma

Busulfan (Bu) is commonly used with cyclophosphamide (Cy) as a conditioning regimen for HPCT.  We previously reported that substituting IV for oral Bu was associated with less relapses and superior relapse free (RFS) and overall survivals (OS) for relapsed or refractory NHL pts undergoing AHPCT (Br J Haematol 2010;148:226-34).  It is unknown whether such a benefit exists for IV Bu when used with Cy for AHPCT for plasma cell myeloma.  We performed a prospective study with this regimen without Bu dose adjustment in order to compare outcomes with historical controls who received oral Bu at our institution.  55 pts were transplanted with IV Bu from 7/29/09-8/23/12 and 117 oral Bu pts were transplanted from 3/22/94-4/6/06.  IV Bu pts were older (p<0.001), more often had lower Karnofsky PS at HPCT (p<0.001), more prior therapies (p<0.001), more advanced disease status at HPCT (p=0.002) and a longer median time from diagnosis to HPCT (14 vs 8 mos, p<0.001).  More oral Bu pts received G-CSF alone for mobilization therapy (90 vs 46%, p<0.001), had more days of apheresis (median 3 vs 2, p<0.001) and higher median CD34+ and TNC doses (7.22 vs 4.68 x 10⁶/kg, respectively, p<0.001; 12.60 vs. 8.52 x 10⁸/kg, respectively, p<0.001).  There were no differences in time to neutrophil engraftment, but platelet engraftment was more rapid for oral Bu pts (median 11 vs 15 d, p<0.001).  Oral Bu pts had significantly more and worse mucositis by the modified OMAS (66% vs. 0%, p<0.001; median scores 0.2 vs. 0, p<0.001).  IV Bu pts had more infections (p=0.034), but there were no differences between the groups regarding CMV infection, GI or pulmonary toxicity, relapse, relapse free survival RFS or OS.  At this time 46 (84%) of the IV Bu and 39 (33%) of the oral Bu pts are alive, however, the median follow up was longer for the oral Bu pts (118 vs 13 mos, p<0.001).   The median RFS and OS have not yet been observed in the IV Bu group, but were 26 and 63 months, respectively for the oral Bu pts.  Disease relapse was the most common cause of death for both the IV and oral Bu pts (67% and 77% of deaths).  1 and 2 year relapse mortality rates were 7% and 19% for IV Bu pts and 7% and 22% for oral Bu pts.  1 and 2 year non-relapse mortality rates were 5% and 12% for IV Bu and 4% and 4% for oral Bu.  Death due to pulmonary toxicity occurred in 4 oral Bu pts and 0 IV Bu pts.  Based upon these preliminary results using IV instead of oral Bu decreases toxicity and potentially improves safety as suggested from our finding of significantly less oral mucositis and no pulmonary deaths with IV Bu.  Further follow up of the IV Bu pts is required to adequately assess for a survival benefit. Investigation of PK based Bu dosing strategies in this transplant setting may be appropriate to help elucidate whether outcomes may be further improved.