A Detailed Evaluation of Transplant-Related Toxicities and Outcome for Patients with CNS Lymphoma (CNSL) Consolidated with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT) Using Thiotepa, Busulfan (Bu), Cyclophosphamide (TBC) Conditioning
Authors: Scordo Michael , Bhatt Valkal , Hsu Meier , Omuro Antonio M. , Matasar Matthew J. , DeAngelis Lisa , Dahi Parastoo B. , Moskowitz Craig H. , Giralt Sergio A. , Sauter Craig S. 
Published: October 2019

Background: HDT-ASCT with TBC conditioning has emerged as a common consolidation strategy for patients (pts) with relapsed/refractory (rel/ref) primary (PCNSL) or secondary (SCNSL) (Welch et al, Leuk & Lymph 2014). In a prospective study, chemosensitive PCNSL pts in first remission after induction with R-MPV (rituximab, MTX, procarbazine and vincristine) proceeding to HDT-ASCT with TBC conditioning, experienced an encouraging 2-year PFS and OS of 75% and 81%, respectively (Omuro et al, Blood, 2015). Three of these patients experienced transplant-related mortality (TRM, 11.5%), which appears greater than HDT-ASCT for other lymphomas. The purpose of this report is to correlate characteristic toxicities of TBC conditioning for CNSL to pre-HDT-ASCT clinical variables.

Methods: The MSKCC IRB approved this retrospective chart review. Eligible pts (n=34) were ≥ 18 years of age with PCNSL or SCNSL that was chemosensitive to induction therapy after which they proceeded to HDT-ASCT conditioned with TBC between December 2006 and April 2015. All pts included were treated outside of prospective clinical trials. Clinically significant grade 3-5 non-hematologic toxicities per CTCAE 4.0 occurring in >20% of pts were recorded from the initiation of conditioning until 6 months post ASCT (Figure 1). Pre-HDT-ASCT variables for analysis include: age, gender, disease (PCNSL or SCNSL), Karnofsky performance status (KPS), hematopoietic cell transplant comorbidity index (HCT-CI), number of prior regimens, prior use of whole-brain radiotherapy (WBRT), and disease status prior to HDT-ASCT (CR/CRu or PR). We evaluated the association of these pre-HDT-ASCT characteristics with the number of clinically significant grade 3-5 non-hematologic toxicities (≥4 vs. <4) using FisherÕs exact test. We further estimated progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods.

Results: Thirty-three patients (97%) experienced ≥ 1 grade 3-5 non-hematologic toxicity. Febrile neutropenia (grade 3) occurred in 32 pts (94%). Of all pre-HDT-ASCT variables, only the number of prior regimens (>2) was significantly associated with incurring more grade 3-5 non-hematologic toxicities, p=0.04 (Table 1). With a median follow-up for survivors of 12 months (range, 1.5-86.2 months), PFS was 79% (95% CI, 65-96) and OS was 82% (95% CI, 68-98) at 1 year (Figures 2 and 3). During the follow-up period, there were 7 pt deaths: 4 died of disease, 2 died secondary to TRM (5.9%), and one died of a secondary malignancy (squamous cell carcinoma) 86.2 months after HDT-ASCT. There were no progression events beyond 12 months. In a limited subset analysis wherein n=22 had first dose bu pharmacokinetics evaluated, pre-HDT-ASCT variables were not associated with higher bu AUC levels, though 64% of these pts required a dose reduction.

Conclusions: We reaffirmed that HDT-ASCT with TBC conditioning is effective consolidation for CNSL, but it is associated with more grade 3-5 non-hematologic toxicity in pts having had >2 prior regimens. Risk-adapted dose attenuation of TBC conditioning for this group of pts may mitigate observed toxicity.

Table 1. Association of Pre-ASCT Variables & Grade 3-5 Non-hematologic Toxicities Number of Clinically Significant Grade 3-5 Toxicities Pre-ASCT Variables All (N=34) Fewer than 4 (N=21) 4 or more (N=13) p-value Age 0.71 <60 23 (68%) 15 (71%) 8 (62%) ≥60 11 (32%) 6 (29%) 5 (38%) Gender 0.72 Female 13 (38%) 9 (43%) 4 (31%) Male 21 (62%) 12 (57%) 9 (69%) Disease 0.30 PCNSL 19 (56%) 10 (48%) 9 (69%) SCNSL 15 (44%) 11 (52%) 4 (31%) KPS 0.99 ≥80 32 (94%) 20 (95%) 12 (92%) <80 2 (6%) 1 (5%) 1 (8%) BMT HCT CI 0.99 ≤2 17 (50%) 11 (52%) 6 (46%) >2 17 (50%) 10 (48%) 7 (54%) Number of Prior Regimens 0.04 ≤2 21 (62%) 16 (76%) 5 (38%) >2 13 (38%) 5 (24%) 8 (62%) WBRT 0.17 No 28 (82%) 19 (90%) 9 (69%) Yes 6 (18%) 2 (10%) 4 (31%) Disease state prior 0.99 CR/CRu 29 (85%) 18 (86%) 11 (85%) PR 5 (15%) 3 (14%) 2 (15%)

Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 2. Kaplan-Meier Curve for PFS Figure 2. Kaplan-Meier Curve for PFS Figure 3. Kaplan-Meier Curve for OS Figure 3. Kaplan-Meier Curve for OS

Disclosures

Bhatt: Spectrum: Consultancy. Moskowitz:GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.