High Dose Thiotepa, Busulfan, Cyclophosphamide (TBC) and Autologous Hematopoietic Stem Cell Transplantation (ASCT) without Whole Brain Radiotherapy (WBRT) for Primary Central Nervous System Lymphoma (PCNSL).

Introduction: Treatment of PCNSL with high dose methotrexate (HD-MTX)-based chemotherapy and WBRT is associated with severe neurotoxicity, but high relapse rates are associated with the use of either modality alone.

Patients and Methods: In an attempt to improve upon these dismal results, we treated eleven PCNSL pts aged 40–68 years (median=55) with TBC/ASCT without WBRT. These pts all received prior induction therapy with HD-MTX 3.5 or 5g/m² q14d x 4-5 cycles +/− procarbazine 100mg/m² po d1-7 q28d x 2 cycles concurrently with HD-MTX, and then underwent stem cell mobilization with Ara-C 3g/m² IV d1 and 2, G-CSF d7-14, and apheresis d15 or 16. The TBC regimen consisted of thiotepa 300mg/m² d-8 and -7, busulfan 3.2mg/kg IV daily d-6 to -4, and cyclophosphamide 2g/m² d-3 and -2. Poor prognostic features included relapsed/progressive disease (n=2), immune-deficiency (SLE, Imuran/Prednisone = 1), ECOG 2-4 (n=9), age >60 yrs (n=4), deep brain involvement (n=8), elevated LDH (n=2), elevated CSF protein (n=2).

Results:Stem Cell Collection and Engraftment: A median of 24 (5–45) x 10⁶ CD34+ cells/kg were collected with a median 14.1L (8.5-30L) apheresis. Engraftment to ANC>0.5 and platelet>20 both occurred at a median of day +9 (7–12). TBC Toxicity: Two early treatment-related deaths occurred in pts 65 and 66 years of age, who both originally presented with ECOG of 4. In addition, a 68 yr old man developed Bearman grade 3 regimen-related toxicity (RRT) requiring ICU admission for encephalopathy and respiratory failure. He survived and returned home to function independently. The remaining pts experienced significant Bearman grade 1–2 RRT including generalized skin rash, peripheral edema, mucositis, delirium and asthenia. All surviving pts experienced improvement in neurological function and ECOG. Six pts returned to work including a 62 yr old pianist. Only one pt developed late neurotoxicity with symptoms of mild dementia. Survival: One patient relapsed 30 months post-TBC and died 1 month post-cranial radiotherapy. Eight pts (73%) are currently alive and relapse-free at 9, 15, 17, 18, 25, 43, 52, and 55 months post-TBC/ASCT. Two pts received TBC/ASCT as the only treatment after rapid disease progression following initial chemotherapy. One of these pts relapsed 7 mo after prior HD-MTX/Ara-C and BEAM/ASCT, and the other progressed within 1 mo of completing induction HD-MTX/Ara-C. Both these 2 pts remain relapse-free 43 and 52 months post-TBC/ASCT.

Conclusion: TBC/ASCT is capable of inducing prolonged remissions in pts with poor prognosis PCNSL, but is poorly tolerated in pts over 65 years. High dose chemotherapy for PCNSL should include drugs that penetrate the CNS well such as busulfan and thiotepa rather than standard lymphoma regimens such as BEAM.