Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant

Abstract

IMPORTANCE Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens.OBJECTIVE To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). DESIGN, SETTING, AND PARTICIPANTSThis observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. INTERVENTIONS Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). MAIN OUTCOMES AND MEASURESThe primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. RESULTSOf 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. CONCLUSIONS AND RELEVANCEIn this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.

Advances in treatment of elderly primary central nervous system lymphoma

“…64 A recent retrospective bone marrow transplant study which included 603 patients demonstrated superiority of thiotepa-based conditioning associated with better threeyear PFS [75% vs 58% with carmustine, etoposide, cytarabine and melphalan (BEAM)]; notably, the upper limit of age for HDT-ASCT was 77 years. 69 Within a large UK retrospective study of patients >65 years, only 22% of patients received consolidation treatment with thiotepa/carmustine HDT-ASCT. Interestingly, this selected subgroup showed two-year PFS and OS rates of 62% and 73%, respectively, 47 which is in line with benchmark trials in younger patients.…”

“…Various single‐arm 11,54,64–67 and two randomized trials 10,15,63,68 provide a robust body of evidence for the use of thiotepa‐based HDT–ASCT in younger PCNSL patients <65–70 years with 3–5‐year survival ranging between 69% 15 and 87% 64 . A recent retrospective bone marrow transplant study which included 603 patients demonstrated superiority of thiotepa‐based conditioning associated with better three‐year PFS [75% vs 58% with carmustine, etoposide, cytarabine and melphalan (BEAM)]; notably, the upper limit of age for HDT–ASCT was 77 years 69 …”

Recent Progress on Primary Central Nervous System Lymphoma—From Bench to Bedside

“…In contrast to BEAM or BUCYE, thiotepa has an excellent penetration ability through the central nervous system, with CSF levels greater than 80%, and has been adopted in combination with busulfan, cyclophosphamide, and carmustine in different conditioning regimens (82). Recently, an observational cohort study reported by the Center for International Blood and Marrow Transplant Research (CIBMTR) gave 603 adult PCNSL patients ASCT as either initial or subsequent consolidation therapy (83).…”

Relapsed and refractory primary CNS lymphoma: treatment approaches in routine practice

“…In this phase 2 study, 56% of patients achieved CR after ASCT with an encouraging 2-year PFS of 46%, after a median follow up of 45 months ( 60 ). Inclusion of thiotepa in the conditioning regimen appears to be key; independently associated with improved outcomes ( 61 , 62 ). Although younger patients are more likely to be considered for HDT-ASCT approaches, a multicenter retrospective study supports this approach in appropriately selected older patients with rrPCNSL (median age: 67 yrs, range: 65−77 yrs) ( 63 ).…”