Persistent Overall Response on Early PET/CT Scans during Salvage Therapy for Relapsed or Refractory DLBCL Predicts for Disease Specific Survival
Authors: Cherng Hua-Jay J , Steiner Raphael E , Fayad Luis , Strati Paolo , Nair Ranjit , Hagemeister F. B. B. , Nastoupil Loretta J. , Lee Hun Ju , Neelapu Sattva S. , Flowers Christopher , Samaniego Felipe , Rodriguez Maria Alma , Feng Lei , Chuang Hubert , Westin Jason R. 
Published: February 2021

Background
Patients (pts) with relapsed or refractory (R/R) diffuse large b-cell lymphoma (DLBCL) can achieve cure with platinum-containing chemotherapy (PCC) and autologous stem cell transplant (autoSCT). Only half of pts respond to PCC based on a positron emission tomography/computed tomography (PET/CT) scan after 2 cycles, but most experience significant toxicity. Minimizing exposure to PCC for non-responders in favor of other treatments such as anti-CD19 CAR T-cell therapy (CART19) is important. We hypothesized that PET/CTs performed earlier during salvage therapy could predict end-of-treatment (EOT) response and survival. We conducted an investigator initiated single-institution pilot study (NCT02405078) where 2 early PET/CTs were obtained during cycle 1 (C1) of salvage PCC.
Methods
Adult R/R DLBCL pts eligible for PCC with a pre-therapy PET/CT were eligible for enrollment. The PCC regimen was selected by the treating physician. The primary endpoint was EOT response. PET/CTs were obtained on D4 and D21 of C1 of PCC, and at EOT after 2-3 cycles. Treating physicians were not blinded to early PET/CT results. Disease-specific survival (DSS) was defined as time from D1 of C1 of salvage PCC to death from DLBCL.
Results
A total of 25 pts with a median age of 61 years (range 25-82) at relapse treated with PCC between 2/5/2016 and 10/30/2018 were included in the analysis, with data cutoff as of 2/29/2020. Selected baseline pt characteristics are as follows: 68% were GCB cell-of-origin by Hans algorithm, 60% were stage III/IV, 88% had an ECOG PS &lt; 2, 44% an international prognostic index (IPI) ≥3, and 32% double-hit lymphoma. Median time from initial diagnosis to first progression was 5.8 months. Therapies received were R-DHAP (44%), R-ICE (36%), and other regimens (20%). Ten (40%) pts had a therapy change after C1 and before EOT evaluation due to early treatment failure or progression based on early PET/CT result as interpreted by the treating physician. Twelve (48%) continued with a second cycle of the same regimen, and 3 discontinued therapy. Sixteen (64%) pts were evaluable for EOT response by PET/CT, while 7 (28%) pts were missing an EOT PET/CT due to early progression and 2 for other reasons. The only baseline characteristic different between EOT responders, non-responders, and pts missing EOT evaluation due to early progression was time from initial diagnosis to progression (8.6 vs. 5.3 vs. 4.5 months, p=0.035). Overall response (OR; complete or partial response) by Lugano criteria or decrease in maximum standardized uptake value (ΔSUVmax) ≥50% at D4 or D21 was not associated with EOT response. Median follow up was 19.7 months (range 0.7-40.9) from start of PCC. Median progression free survival was 2.7 months. Eleven pts died, 9 (36%) from progressive DLBCL and 2 from transplant complications. DSS was 61% at 24 months. DSS was worse for pts with an ECOG PS &gt; 1 (p=0.002), IPI ≥3 (p=0.046), and who did not receive R-ICE or R-DHAP (p=0.006). There was no difference in DSS based on the D4 or D21 PET/CT individually, by OR or ΔSUVmax. DSS was better for pts who had a persistent OR on both D4 and D21 vs. pts without a persistent OR (p=0.042) and was 100 vs. 47% at 24 months (Fig). Of the 6 pts with a persistent OR, 4 had a late first relapse (range 23.1-78.9 months after diagnosis) and 2 had an early first relapse (1.9-9.0 months). A total of 28% of pts had autoSCT and 8% allogeneic SCT, and 28% eventually had CART19 if not responsive to salvage treatment. Of the 10 pts who changed therapy after C1, 2/3 of the CART19 recipients were alive at data censoring compared to 1/7 of the pts who did not receive CART19.
Discussion
This pilot study is the first of its kind to investigate early PET/CT during salvage therapy for R/R DLBCL. Early PET/CT result did not predict the primary endpoint of EOT response, confounded as therapy was changed for some pts before final response evaluation due to early progression. Persistent OR on early PET/CTs during C1 predicted excellent DSS, even if pts were refractory to frontline treatment. Early therapy change after C1 based on unsatisfactory early PET/CTs to spare pts from ineffective therapy was feasible, with possible benefit to switching to CART19, but numbers were low and CART19 was not uniformly available during the study period. Risk for chemotherapy failure can be predicted early during salvage therapy, which may be important to change therapy to non-chemotherapy treatments such as CART19.
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Disclosures
Nastoupil: Genentech, Inc.: Honoraria, Research Funding; Gamida Cell: Honoraria; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Bayer: Honoraria; Gilead/KITE: Honoraria; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Lee:Seattle Genetics: Research Funding; Takeda: Research Funding; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy; Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau. Neelapu:Incyte: Other: personal fees; N/A: Other; Unum Therapeutics: Other, Research Funding; Calibr: Other; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Poseida: Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Cell Medica/Kuur: Other: personal fees; Celgene: Other: personal fees, Research Funding; Cellectis: Research Funding; Pfizer: Other: personal fees; Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Adicet Bio: Other; Takeda Pharmaceuticals: Patents & Royalties; Novartis: Other: personal fees. Flowers:Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; OptumRx: Consultancy; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Spectrum: Consultancy; Acerta: Research Funding; Millennium/Takeda: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Kite: Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding. Chuang:Sage-Evidence=Based Medicine & Practice: Consultancy. Westin:47 Inc: Consultancy; Curis: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Juno: Consultancy; Kite: Consultancy; MorphoSys: Consultancy; Unum: Consultancy.