Optimal Timing of Peripheral Blood Stem Cell Mobilisation in Patients with Hematological Malignancies Treated with the Hyper-CVAD Chemotherapy Regimen.
Authors: Mills Anthony K. , Gibbs Simon , Keane Colm , Mollee Peter , Grimmett Karen , Van Kuilenburg Rosita , Saal Russell , Gill Devinder , Prince H. Miles , Seymour John F. , Marlton Paula 
Published: October 2019

The Hyper-CVAD chemotherapy regimen (JCO2000;18:547) is being increasingly applied to a number of haematological malignancies. We have previously demonstrated Hyper-CVAD to be a highly stem cell toxic regimen which adversely affects peripheral blood stem cell (PBSC) mobilisation and that mobilising efficiency can be significantly improved by collecting PBSC earlier in the treatment course. We now examine the optimal timing of PBSC collection when using this regimen. A retrospective analysis was performed at two centres of consecutive patients (pts) treated with Hyper-CVAD in whom an attempt was made to collect PBSC. The regimen consists of alternating cycles of: (A) cyclophosphamide 300mg/m2 q12hrs for 6 doses d1-3, vincristine 2mg d4&11, doxorubicin 50mg/m2 d4 and dexamethasone 40mg daily d1-4 and d11-14; and (B) methotrexate 1g/m2 over 24 hours d1 and ara-C 1–3g/m2 q12hrs for 4 doses d2&3. PBSCs were collected on recovery from chemotherapy using G-CSF in a daily dose of 10mcg/kg. Target cell number for optimum engraftment was defined as CD34 ≥5 x106/kg, while the minimum threshold for proceeding to ASCT was CD34 ≥2 x106/kg. Pts were analysed according to the timing of mobilisation. 74 pts were identified: median age 44yrs; 69% male; 53% with initial marrow involvement; diagnoses (ALL n=14, lymphoblastic lymphoma n=7, Burkitt’s/Burkitt-like lymphoma n=8, aggressive NHL n=34, mantle cell lymphoma n=11). 28 pts were mobilized off the back of cycle A, 32 pts off the back of cycle B, and 14pts after other mobilising regimens. Overall 66% and 42% of pts obtained a minimum and optimal PBSC collection, respectively. Only 3 of 17 patients (18%) collected beyond cycle 3B successfully mobilised. Two patients mobilised prior to 3B but receiving alternate mobilising chemotherapy were not analysed. The results of stem cell collection on the 55 remaining patients are shown below.

Stem cell collection results following hyper-CVAD chemotherapy

Timing of stem cell mobilisation Cycle 1B 2A 2B 3A N 13 21 14 7 Total CD34+ (range) 21.36 (4.2–69.1) 3.41 (0–11.18) 5.1 (0–22.3) 4.6 (1.9–8.6) Day of 1st apheresis 12 (11–13) 13.5 (11–16) 13.5 (12–19) 15 (13–19) % with CD34+≥2 x106/kg All patients 100% 81% 64% 86% Obtained in 1 apheresis 92% 19% 36% 14% % with CD34+≥5 x106/kg All patients 92% 38% 50% 39% Obtained in 1 apheresis 77% 0% 21% 0%

Cycle 1B compared to 2A was not significantly better in obtaining a minimum graft (100% vs. 81%, p=0.14), but was superior in terms of total CD34+ yield (21.4 vs. 3.4x106/kg, p<0.001) and in achieving both a minimum (92% vs. 19%, p<0.001) and optimal (77% vs. 0%, p<0.001) PBSC collection with a single apheresis. There were no significant differences in PBSC yields following cycles 2A, 2B and 3A. The dose of ara-C used in cycle B had no effect on the subsequent stem cell yield. Hyper-CVAD is a highly stem cell toxic regimen. The mobilizing efficiency can be significantly improved by collecting PBSC earlier in the treatment course with cycle B appearing to be the superior mobilising arm. Mobilisation following cycle 1B allows the most predictable timing of PBSC collection and provides a significantly better PBSC graft and should be considered in those in whom marrow involvement has cleared.