High OS and low NRM achieved with high-dose chemotherapy and ASCT in patients with PCNSL treated in first complete remission

On 15th August, in the journal Cancer, Zachariah DeFilipp, MD, from Massachusetts General Hospital, Boston, Massachusetts, USA, et al. reported findings from a retrospective analysis of patients with Primary Central Nervous System Lymphoma (PCNSL) in First Complete Remission (CR1) who underwent Autologous Stem Cell Transplantation (ASCT) using a thiotepa, busulfan, and cyclophosphamide (TBC)-based conditioning regimen.

Adult patients (aged 18 years or older) with PCNSL, treated from 2008 to 2016 with High-Dose Chemotherapy (HDC)-ASCT in CR1 using a TBC-based conditioning regimen at the cancer center of Massachusetts General Hospital and Dana-Farber/Brigham and Women’s Cancer Center, were included in this analysis.

Key Highlights:
Patients and treatment:
  • Pts identified = 46; all with CD20+ diffuse large B-cell histology
  • Median age at diagnosis = 58 years (range, 27–68)
  • Before chemotherapy was initiated, 7 pts (15%) had undergone surgical resection of CNS mass
  • None of the pts had received Whole Brain Radiotherapy (WBRT)
  • Methotrexate (MTX), temozolomide, and rituximab was the most common induction regimen (59%)
  • All pts were administered systemic high-dose IV MTX as part of induction therapy; 87% were administered rituximab IV
  • Before ASCT, 87% of pts (n=40) received cytarabine as induction intensification, early consolidation, or mobilization
  • Consolidation/stem cell mobilization for 36 pts consisted of cytarabine and filgrastim (R-HiDAC) and in 10 pts was filgrastim alone
  • Median time from diagnosis to transplantation = 6 months (range, 4–15)
Transplantation outcomes:
  • Median age at time of transplantation = 59 years (range, 27–69)
  • Median number of CD34-positive cells/kg infused = 16x106 (range, 2.09–36.6x106)
  • TBC-conditioning in 37 pts; TBC plus rituximab conditioning in 9 pts
  • Median time to neutrophil engraftment = 9 days (range, 2–7); median time to platelet recovery = 12 days (range, 9–22)
  • Median length of hospital admission = 22 days (range, 18–67)
  • Median follow-up of survivors after ASCT = 2.7 years (range, 0.5–7.5)
  • Recurrent disease developed in 4 pts at a median of 1.5 years (range, 0.5–3.6) after ASCT
  • At time of last follow-up, 3 pts had died (one due to recurrent disease, one due to sepsis from pneumonia, and one from progressive neurologic decline with multi-organ failure)
  • Estimated 2-year Non-Recurrent Mortality (NRM) = 2.9% (95% CI, 0.2–13.4%)
  • Estimated 2-year OS = 95% (95% CI, 80–99%)
  • Estimated 2-year PFS = 92% (95% CI, 77–97%)
Transplantation toxicities:
  • Within 100 days of ASCT, 16 pts (35%) developed infections; the most common bacterial infection was Clostridium difficile colitis in 13 pts
  • The most common non-infectious toxicity = severe mucositis (35%)
  • Engraftment syndrome occurred in 17% of pts (n=8); managed with a short course of corticosteroids
  • Only one case of suspected busulfan-associated pulmonary toxicity was observed
  • Transient neurotoxicity occurred in 7 pts (15%) designated delirium in 5 pts and vertigo in 2 pts
  • Persistent or late clinical neurotoxicity occurred in 7 pts (15%) designated as memory loss in 2 pts, cognitive defects in one patient, and progressive neurologic decline in 4 pts
  • Three of the late neurotoxicity cases occurred after disease recurrence

The authors concluded by stating that they found favorable outcomes with HDC-ASCT with TBC-based conditioning in patients with PCNSL treated in CR1. They go on to emphasize that the high OS and low NRM rates support the use of this therapeutic strategy. Finally, the group greatly anticipate the final results of other ongoing randomized clinical trials investigating HDC-ASCT consolidation therapy for PCNSL (NCT01011920, NCT00863460, NCT01511562, NCT02531841). The final results of these studies will help to “better clarify the role of HDC-ASCT in the management of patients with PCNSL.”

Abstract:

BACKGROUND: High-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) is a therapeutic option for patients with primary central nervous system lymphoma (PCNSL). To the authors' knowledge, data are limited regarding its use among patients in first complete remission (CR1) with the CNS-directed conditioning regimen of thiotepa, busulfan, and cyclophosphamide (TBC).

METHODS: A retrospective analysis of patients with PCNSL in CR1 who underwent transplantation using a TBC-based conditioning regimen at 2 academic institutions was performed.

RESULTS: Forty-six consecutive patients who underwent HDC-ASCT while in CR1 were identified. The most common induction regimen was high-dose methotrexate plus temozolomide and rituximab (59%). No patients received whole-brain radiotherapy. A total of 40 patients (87%) received cytarabine before undergoing ASCT as either induction intensification, early consolidation therapy, or mobilization. The median time from diagnosis to transplantation was 6 months (range, 4-15 months). The median age of the patients at the time of transplantation was 59 years (range, 27-69 years). With a median follow-up of 2.7 years after ASCT (range, 6 months-7.5 years), the Kaplan-Meier estimates of 2-year overall survival and progression-free survival were 95% (95% confidence interval [95% CI], 80%-99%) and 92% (95% CI, 77%-97%), respectively. The most common toxicities were severe mucositis (35%) and bacterial infections occurring within 100 days of transplantation (35%). The estimated 2-year nonrecurrence mortality rate was 2.9% (95% CI, 0.2%-13.4%).

CONCLUSIONS: HDC-ASCT with a CNS-directed conditioning regimen such as TBC should be considered for patients with PCNSL who are in CR1 because this approach is associated with encouraging disease control and survival in this select patient population. Cancer 2017;123:3073-79. © 2017 American Cancer Society.

References
  1. DeFilipp Z. et al. High-dose chemotherapy with thiotepa, busulfan, and cyclophosphamide and autologous stem cell transplantation for patients with primary central nervous system lymphoma in first complete remission. Cancer. 2017 Aug 15;123(16):3073-3079. DOI: 10.1002/cncr.30695. Epub 2017 Apr 3.