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Variable Success Rates of Haplo-Cord Transplants in High Risk Patients: A Minimum Serotherapy Exposure Is a Prerequisite for Sustainable Engrafting
Combining a CD34+ selected haplo-graft with a full graft cord blood (CB) unit is a cell support procedure that can make single CB available as a donor source to a larger proportion of patients. Early haplo-donor cell engraftment may serve as a myeloid bridge until sustainable CB-engraftment. In addition it has been hypothesized that haplo-derived innate anti-tumor activity (e.g. NK- / γd-Tcells through other cell selection techniques) plus CB could be a platform for multi-modal anti-tumor activity in high-risk malignancies. The latter in the context of omitting serotherapy. The impact of serotherapy-exposure on the success of "haplo-myeloid bridge to CB engraftment" is however unknown.
Methods: Since 2009 in the UMC Utrecht 2 haplo-CB protocols were open; 1) active infection and/or known difficult engraftment without a conventional donor available: CB + CD34+selected Haplo-id donor (5milj CD34+/kg), 2) Poor risk malignancies, not eligible to other treatment protocols: CB + CD19/αβTCR depleted haplo-id donor (5milj CD34+/kg). Conditioning regimens: 1st HCT busulfan (targeted cum.exposure of 90mg*h/L)+ Fludarabine (Flu)+ Thymoglobulin (ATG) in protocol 1 or Flu/Cyclophosphamide (Cy)/TBI as RIC-alternative; 2nd HCT Treosulfan, Flu+Campath (TreoFluCamp: protocol 1). G-CSF was given from day +7. Patients received GvHD-profylaxis with CsA and pred 1 mg/kg. Active-ATG levels and Campath levels were measured as described previously (Jol et al. BMT 2012). The association of serotherapy-exposure for the endpoints overall survival (OS), non-relapse mortality (NRM), neutrophil recovery and graft failure (GF) was analyzed. GF was defined as either "early loss of Haplo and no engraftment of the CB" or secondary loss of both grafts. Logrank testing was used in statistical analyses.
Results: 22 patients were included (18 protocol 1; 4 protocol 2): 20 patients received FluBu (15 ATG, 1 Campath), 1 TreoFluCamp and 1 FluCyTBI. Median nucleated cell dose was 4.1 x 10e7/kg (2.0-20.0). There was a cumulative incidence (CI) of neutrophil recovery of 81% with a median of 13 days. The CI of GF was however 43 ±11%. The median "active ATG-AUC" (area under the curve) was 17 IU*day/L (1 pat no Campath AUC, 1 very high AUC: 150 IU*day/L). Patients were grouped to having no serotherapy (n=5), a low exposure (AUC<median: n=8), or high exposure (AUC³ median: n=9). GF were significantly higher in the no serotherapy/low AUC group (p=0.032: Fig 1) vs. the high AUC group. 3-yr prob. of OS was 48 ±12% (32± 17% for the no/low AUC vs. 65 ± 17% for high AUC, p=0.18 ). NRM in the no/low AUC group was 56±16% versus 22±14% for high-AUC (Fig.2. p=0.21).
In conclusion, a minimum of serotherapy exposure is required for a successful "haplo-myeloid bridge to CB engraftment". It is doubtful whether omitting serotherapy will have a place in haplo-CB HCT. With sufficient serotherapy exposure good OS (low NRM) was noted in a high-risk group of HCT patients.
