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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

Michael Scordo, Valkal Bhatt, Meier Hsu, Antonio M. Omuro, Matthew J. Matasar, Lisa DeAngelis, Parastoo B. Dahi, Craig H. Moskowitz, Sergio A. Giralt and Craig S. Sauter

Abstract

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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.

Number of Clinically Significant Grade 3-5 Toxicities
Pre-ASCT VariablesAll (N=34)Fewer than 4 (N=21)4 or more (N=13)p-value
Age0.71
<6023 (68%)15 (71%)8 (62%)
≥6011 (32%)6 (29%)5 (38%)
Gender0.72
Female13 (38%)9 (43%)4 (31%)
Male21 (62%)12 (57%)9 (69%)
Disease0.30
PCNSL19 (56%)10 (48%)9 (69%)
SCNSL15 (44%)11 (52%)4 (31%)
KPS0.99
≥8032 (94%)20 (95%)12 (92%)
<802 (6%)1 (5%)1 (8%)
BMT HCT CI0.99
≤217 (50%)11 (52%)6 (46%)
>217 (50%)10 (48%)7 (54%)
Number of Prior Regimens0.04
≤221 (62%)16 (76%)5 (38%)
>213 (38%)5 (24%)8 (62%)
WBRT0.17
No28 (82%)19 (90%)9 (69%)
Yes6 (18%)2 (10%)4 (31%)
Disease state prior0.99
CR/CRu29 (85%)18 (86%)11 (85%)
PR5 (15%)3 (14%)2 (15%)
Table 1.

Association of Pre-ASCT Variables & Grade 3-5 Non-hematologic Toxicities

Figure 1.

Analysis of Grade 3-5 Non-Hematologic Toxicities

Figure 2.

Kaplan-Meier Curve for PFS

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.

  • * Asterisk with author names denotes non-ASH members.

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