bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-17. PHASE I STUDY OF THE SAFETY AND IMMUNOGENICITY OF PERSONALIZED NEOANTIGEN VACCINES AND TUMOR TREATING FIELDS IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Kodysh Julia , Rubinsteyn Alex , Blazquez Ana , Mandeli John , Bhardwaj Nina , Hormigo Adilia
Published: December 2020

BACKGROUND

Glioblastoma (GBM) generates mutation-derived tumor antigens, which arise from somatic variants that result in mutated protein fragments displayed to immune cells. These mutated proteins can provide targets for anti-tumor personalized neoantigen vaccine (PNV) therapy. Combining PNV with Tumor Treating Fields (TTFields), a modality that increases survival of GBM patients, is a viable option.

METHODS

In this phase I study (NCT03223103), PNV and TTFields are combined with the standard treatment for newly diagnosed GBM. Neoantigens are identified using the OpenVax computational pipeline, which identifies somatic variants in a patient’s DNA and ranks resulting neoantigens by their tumor RNA abundance and predicted HLA-I binding affinity. Each patient is vaccinated with up to 10 mutated peptides, receiving 14 doses of PNV administered subcutaneously with poly-ICLC as the adjuvant.

RESULTS

We report our preliminary results in the 8 patients with median age 59 (range 32–84) that have been vaccinated. Neoantigens were identified in each tumor sample in sufficient quantities for vaccination, with each vaccine comprising a median of 8.5 peptides (range 6–10). Patients received a median of 13 vaccines (range 8–14). Immune monitoring for one of the patients showed neoantigen-specific CD4 and CD8 T cell responses. There was radiological tumor progression in two while receiving PNV and in another, prior to PNV. The most common adverse events of the PNV were injection site reaction and flu-like symptoms. Combination with TTFields did not increase toxicity. The Kaplan-Meier estimated 12-month progression-free survival is 62.5% (s.e.= 17.1%) and the estimated 12-month survival from date of surgery is 83.3% (s.e.= 16.7%). The median survival has not been reached.

CONCLUSIONS

Despite a typically low mutational burden of GBM, selection of a sufficient number of neoantigens was successful for each patient’s vaccine. Treatment with PNV and TTFields is safe. The data is encouraging and updated results will be presented.
CTIM-19. MOLECULAR AND GENETIC DETERMINANTS OF RESPONSE TO PD-1 BLOCKADE IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Prins Robert , Galvez Mildred , Amouzgar Meelad , Campbell Katie , Wells Daniel , Bayless Nicholas , Everson Richard , Cloughesy Timothy
Published: December 2020

Despite immune checkpoint inhibitors having success in several other tumor types, many glioblastoma (GBM) patients fail to respond or maintain a sustained response. Work published by our group (Cloughesy et al, 2019) demonstrated that relative to adjuvant programmed cell death-1 (PD-1) blockade, neoadjuvant treatment doubled the median overall survival (OS) for recurrent GBM patients and resulted in an enhanced interferon-γ signature. This suggests that anti-PD-1 given in the neoadjuvant setting may improve outcomes for recurrent GBM patients. The challenge remains in identifying the molecular and genetic signatures associated with response to immune checkpoint blockade. To address this, we analyzed the tumor sample and clinical response data from the patients treated in this clinical trial (n=31). We stratified patients as stable disease (SD) versus progressive disease (PD) based on their response assessment in neuro-oncology criteria (RANO) scores from cycle 2 of treatment post-surgery. Among the SD patients, 77.8% received neoadjuvant treatment while 22.2% received adjuvant therapy. In this group, a median OS was not reached. Among the PD patients, 40.9% received neoadjuvant treatment and 59.1% received adjuvant therapy, with a median OS of 257 days. Next, we analyzed factors that impact response to immunotherapy, which includes somatic mutational burden and interferon-γ pathway induction. We calculated somatic mutational variants, copy number variants (CNVs), and differential gene expression from the bulk tumor exome and RNA-sequencing data. The total mutation counts were similar between groups and no association was identified with increased mutational burden. In addition, total CNV stability was similar between groups. However, when looking at genes involved in the JAK/STAT signaling pathway, there were notably more copy number losses of JAK2 in the PD group when compared to the SD group (85.0% versus 66.7%). These findings merit further exploration as the JAK/STAT pathway has been implicated in response to immune checkpoint blockade.
CTIM-28. PHASE 2 TRIAL OF CONTROLLED IL-12 IN COMBINATION WITH PD-1 INHIBITOR IN ADULT SUBJECTS WITH RECURRENT GLIOBLASTOMA (rGBM)
Authors: Lukas Rimas , Chiocca E Antonio , Bush Nancy Ann Oberheim , Landolfi Joseph , Cavaliere Robert , Yu John , Kurz Sylvia , Demars Nathan , Buck Jill , Hadar Nira , Miao John , Loewy John , Wang Yunxia , Gelb Arnold , Cooper Laurence
Published: December 2020

Ad-RTS-hIL-12 (Ad) is a gene therapy candidate for intratumoral (IT) delivery that conditionally expresses IL-12 (IL-12) under the transcriptional control of orally administered veledimex (V) acting via the RheoSwitch Therapeutic Systemâ gene switch. Increased PD-1 expression in samples of rGBM following Ad+V (ASCO 2020) supports combination immunotherapy with a PD-1 inhibitor. Phase 1 trials in rGBM of Ad+V as monotherapy and in combination with PD-1 inhibitor revealed encouraging safety and survival data. This phase 2 trial (NCT04006119) in adults with rGBM is evaluating safety and efficacy (overall survival) of Ad + V with pre/post-operative cemiplimab-rwlc (cemi) 350 mg IV, Days -7, 15, then Q3W; Ad single IT injection (2 x 1011 viral particles, day of resection (Day 0) /craniotomy); and V (20 mg PO, Days 0–14). Longitudinal sampling of serum assessed IL-12 and endogenous cytokines production. Anti-tumor effects were described upon preliminary review. Serial MRI evaluated tumor response. Follow-up described overall survival. Initial safety data (51 unique adverse reactions in 28 subjects) appeared similar to Ad+V and the cemi label, respectively, being manageable without synergistic toxicities and generally reversible. Of 35 SAEs reported in 18 subjects, 10 SAEs in 7 subjects were related to Ad+V. IL-12 and IFN-g levels increased after Ad+V administration peaking on Day 3 at 34 ± 11 pg/mL and 13 ± 5 pg/mL (mean ± SEM), respectively. Immune-mediated anti-tumor effects were noted, including a post-treatment biopsy to rule out progression which demonstrated an immune infiltrate consistent with pseudoprogression and loss of tumor cell heterogeneity suggesting immunoediting. Enrollment is anticipated to be completed in 2Q2020 with follow-up ongoing and initial survival data will be presented. V crossed the blood-brain barrier to produce functional IL-12. Controlled IL-12 therapy and cemi is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile.
CTIM-32. PHASE II AND BIOMARKER STUDY OF PEMBROLIZUMAB OR PEMBROLIZUMAB PLUS BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA PATIENTS
Authors: Reardon David , Molinaro Annette , Peters Katherine , Clarke Jennifer , Jordan Justin , de Groot John , Nghiemphu Phioanh , Kaley Thomas , Colman Howard , McCluskey Christine , Smith Timothy , Cote David , Severgnini Mariano , Yearley Jennifer , Zhao Qing , Blumenschein Wendy , Duda Gabriel , Muzikansky Alona , Jain Rakesh , Wen Patrick , Nayak Lakshmi
Published: December 2020

PURPOSE

Vascular endothelial growth factor (VEGF) is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase 2 study of pembrolizumab, a programmed death-1 (PD-1) blocking antibody alone or with the anti-VEGF antibody bevacizumab in recurrent glioblastoma with detailed analyses of biomarkers and patient neurologic function.

METHODS

Eighty bevacizumab-naive, recurrent glioblastoma patients were randomized to receive pembrolizumab with bevacizumab (cohort A, n=50) or pembrolizumab monotherapy (cohort B, n=30). The primary endpoint was six-month progression-free survival (PFS-6). Exploratory endpoints included evaluation of tumor PD-L1 expression, TIL density, immune activation gene expression signature and plasma cytokines with outcome. Changes in neurologic function were prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale.

RESULTS

Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% (95% CI: 16.3, 41.5), median OS was 8.8 months (95% CI: 7.7, 14.2), ORR was 20% and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI: 1.7, 25.4), median OS was 10.3 months (95% CI: 8.5, 12.5) and ORR was 0%. Factors associated with worsened OS included baseline dexamethasone use and increased post-therapy plasma VEGF (cohort A) and wild-type IDH1, unmethylated MGMT and increased baseline PlGF and sVEGFR1 levels (cohort B), but tumor immune markers were not informative. The NANO scale effectively predicted neurologic function.

CONCLUSIONS

Although well tolerated, pembrolizumab was ineffective both as monotherapy and with bevacizumab for recurrent glioblastoma. Nonetheless, radiographic responses to combinatorial therapy were durable. Baseline dexamethasone use and plasma cytokines but not tumor immunologic biomarkers were associated with outcome. Neurologic function evaluated by the NANO scale contributed to outcome assessment.
CTNI-01. EFFECT OF STEREOTACTIC RADIOSURGERY COMPARED TO WHOLE-BRAIN RADIOTHERAPY FOR LIMITED BRAIN METASTASIS ON LONG TERM COGNITION AND QUALITY OF LIFE: A POOLED ANALYSIS OF RANDOMIZED CLINICAL TRIALS
Authors: Palmer Joshua , Klamer Brett , Ballman Karla , Brown Paul , Cerhan Jane , Anderson S Keith , Whitton Anthony , Greenspoon Jeffrey , Chung Caroline , Burri Stuart , Parney Ian , Stieber Volker , Pollock Bruce , Laack Nadia , Ashman Jonathon , Bahary Jean-Paul , Barker Fred , Galanis Evanthia , Asher Anthony , Roberge David
Published: December 2020

PURPOSE

We investigated the long term impact of SRS and WBRT in two large prospective phase III trials.

METHODS

Patients with 1–4 BMs +/- resection were randomized to SRS or WBRT. Cognitive deterioration was a drop of >1 standard deviation from baseline in >2/6 cognitive measures (CM). Quality of life (QOL) scores were scored 0–100 point scale. CM and QOL scores were modeled using baseline adjusted Linear Mixed Models (LMM) with uncorrelated random intercept for subject and random slopes for time. Differences over time between groups and the effect of >2 cognitive scores with >2 SD change from baseline were assessed.

RESULTS

88 patients were included with median follow up of 24 months. We observed decreasing CM over time (SRS: 4/6; WBRT: 5/6). Mean CM was significantly higher in SRS for Total recall and Delayed Recall at 3, 6, 9, 12 months. More patients in WBRT arm declined 1 SD in >1 and >2 CM at the 3, 6, 9, and 12 months. A 1 SD decline in >3 CM at 1 year was 21% SRS vs 47% WBRT (p=0.02). SRS had fewer patients with a 2 SD decline in >1 CM at every time point. SRS had fewer patients with a 2 SD decline at >2 and >3 CM. WBRT had lower QOL at 3 months, but switched to SRS having lower QOL at 24 months for PWB, EWB, FWB, FactG, BR, and FactBR (p< 0.05). A 2 SD decline in cognition decreased mean FWB by 6.4 units (95% CI: -11, -1.75; p=0.007) and decreased QOL by 5.1 units (95% CI: -7.7, -2.5; p< 0.001).

CONCLUSIONS

We report the first pooled prospective study demonstrating the long term outcomes of patients with BMs after cranial radiation. WBRT was associated with worse cognitive outcomes. Impaired cognition is associated with worse QOL.
CTNI-09. A PHASE I HEALTHY VOLUNTEER STUDY ON THE RELATIVE BIOAVAILABILITY AND FOOD EFFECT OF CAPSULE AND GRANULE FORMULATIONS OF SELUMETINIB
Authors: Cohen-Rabbie Sarit , Mattinson Alexandra , So Karen , Wang Nan , McBride Eileen , Vishwanathan Karthick , Goldwater Ronald
Published: December 2020

Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective allosteric MEK 1/2 inhibitor approved by the FDA as a capsule formulation for treatment of pediatric patients ≥ 2 years old with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. A new granule formulation is being developed to support dose flexibility and for patients unable to swallow capsules. This Phase I, open-label, single-center, randomized crossover pharmacokinetics study (NCT03649165) investigated the new granule versus capsule formulation in both fasted and fed (low-fat) states. Twenty-four healthy adult male volunteers were randomized to receive single-dose selumetinib in one of four treatment sequences: 25 mg granule (fasted); 50 mg capsule (fasted); 25 mg granule (fed); and 50 mg capsule (fed). Primary endpoint: to compare pharmacokinetics of the formulations in fasted state. Secondary endpoints: pharmacokinetics of the formulations in fasted versus fed states, granule palatability, safety and tolerability. In fasted state, a slight delay in absorption of selumetinib by ~0.60 h, with geometric mean ratios (90% CI) of 0.65 (0.58, 0.74) for Cmax/dose and 0.87 (0.81, 0.92) for AUC/dose, was detected when administered as granule versus capsule. For granule in fed versus fasted states, geometric mean Cmax and AUC ratios (90% CI) were 0.61 (0.51, 0.72) and 0.97 (0.91, 1.02). For capsule in fed versus fasted states, geometric mean Cmax and AUC ratios (90% CI) were 0.40 (0.33, 0.48) and 0.62 (0.55, 0.70). Granule palatability was acceptable; volunteers indicated they would take it again. Selumetinib was well-tolerated; for both formulations, few adverse events of mild intensity were reported; dry eyes (fasted) versus dry eyes and rhinorrhea (fed) were most frequent. This was the first study to test the granule formulation in humans; results indicate the granule formulation has similar AUC to the capsule formulation and minimal food effect, supporting planned clinical trials in pediatric patients.
CTNI-13. UPDATES ON CLINICAL OUTCOMES AND TUMOR RECURRENCE PATTERNS OF A HUMAN PILOT STUDY ASSESSING EFFICACY OF BELINOSTAT (PXD-101) COMBINING WITH CHEMORADIATION IN TREATING GLIOBLASTOMA
Authors: Xu Karen , Huang Vicki , Ramesh Karthik , Gurbani Saumya , Schreibmann Eduard , Weinberg Brent , Sengupta Soma , Voloschin Alfredo , Holdhoff Matthias , Barker Peter , Kleinberg Lawrence , Olson Jeffrey , Shim Hyunsuk , Shu Hui-Kuo
Published: December 2020

INTRODUCTION

Glioblastoma (GBM) is highly aggressive with poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability that has anti-GBM activity and may enhance effects of chemoradiation. Our institution conducted a clinical trial evaluating clinical efficacy of belinostat with standard-of-care therapy for GBMs.

METHODS

13 and 14 patients were enrolled into cohort 1 (c1, control) or cohort 2 (c2, belinostat) with 12 in each group with sufficient follow-up MRIs for recurrence analysis. All patients received concurrent, adjuvant temozolomide and focal radiation therapy (RT). For c2 patients, the belinostat regimen (500-750mg/m2 1x/day x 5 days) was given over three cycles every 3 weeks (weeks -1, 2, and 5 of RT). RT margins of 5–10 mm and 3 mm were added to generate clinical tumor volumes and planning target volumes (PTVs). PTV1 (based on FLAIR MRI) and PTV2 (based on CE-T1w MRI) received 51 and 60 Gy, respectively, over 30 fractions. Volume at initial recurrence (rGTV) was contoured.

RESULTS

Mean age was 58.3 years for c1 and 51.1 years for c2. Patient/tumor characteristics were similar between cohorts. Median OS were 16.6 and 18.5 months for c1 and c2 (p=0.538), respectively. Average minimum, maximum and mean radiation dose to rGTV was 54.1 Gy, 64.2 Gy and 62 Gy, for c1, and 47.5 Gy, 57.6 Gy and 53.5 Gy, for c2 (p=0.322, 0.088 and 0.071), respectively. The mean overlap between rGTV and PTV1/PTV2 for c1 & c2 were 99.2% & 96.9%/99.8% & 78.7% (p=0.489/0.133), respectively.

CONCLUSION

Median OS was slightly longer for c2 though not statistically significant. rGTV in c1 received higher radiation doses and had more overlap with PTV2 than in c2. Out-of-field recurrence appears more likely in c2 suggesting better infield control with belinostat. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM treatment.
CTNI-15. CLINICAL EFFICACY OF ONC201 IN NEWLY DIAGNOSED DIPG AND IN PREVIOUSLY IRRADIATED PEDIATRIC H3 K27M-MUTANT GLIOMAS
Authors: Gardner Sharon , Koschmann Carl , Tarapore Rohinton S , Allen Jeffrey , Zaky Wafik , Odia Yazmin , Hall Matthew , Daghistani Doured , Khatib Ziad , Aguilera Dolly , MacDonald Tobey , Fouladi Maryam , McGovern Susan , Mueller Sabine , Kline Cassie , Vitanza Nicholas , Lu Guangrong , Allen Joshua , Khatua Soumen
Published: December 2020

ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. In adults, the recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated. Radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. This multi-arm, dose-escalation and dose-expansion trial determined the pediatric RP2D of ONC201 administered as an oral capsule (Arm A) or liquid formulation (Arm E) in post-radiation H3 K27M-mutant glioma (Arm A) or in newly diagnosed DIPG (Arm B) patients. Molecular assessments include intratumoral ONC201 concentrations (Arm C) and CSF H3 K27M DNA levels (Arm D). Enrollment as of April 30, 2020 is complete in Arm A (22) and Arm E (26) and continues in Arm B (18/24), Arm C (5/12), and Arm D (22/24). The RP2D of weekly 625mg ONC201 scaled by body weight was confirmed when administered as a capsule or a liquid formulation as a single agent or in combination with radiation without dose-limiting toxicity. The most frequent adverse events regardless of attribution to the drug were predominantly low grade: ONC201 capsule alone was headache (54.5%), nausea (36.4%), and fatigue (36.4%); ONC201 liquid formulation was vomiting (31.8%), headache (22.7%), VIth nerve disorder (22.7%); ONC201 capsules in combination with radiation (Arm B) was headache (47.1%), vomiting (52.9%), nausea (41.2%). Pharmacokinetic analysis in plasma of Arm A patients revealed T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL, with similar exposure across body weights. In conclusion, when scaled by body weight the ONC201 capsule or liquid formulation alone or in combination with radiation were associated with safety and pharmacokinetic profiles in pediatric H3 K27M-mutant diffuse midline glioma patients that are similar to the experience in adults.
CTNI-16. FEASIBILITY PILOT STUDY OF OKN-007 IN COMBINATION WITH ADJUVANT TEMOZOLOMIDE CHEMORADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Battiste James , Sung Sarah , Wright Deborah , Glenn Chad , Algan Ozer , Teague April , Zhao Yan , Cohoon Andrew , Kim Hyun Sook , Towner Rheal
Published: December 2020

BACKGROUND

Temozolomide (TMZ) is the standard of care chemotherapy agent for glioblastoma. Unfortunately, intrinsic or acquired resistance eventually renders TMZ ineffective. The novel anti-cancer agent OKN-007 plus TMZ increased survival in glioma-bearing mice compared to TMZ alone. Furthermore, OKN-007 increased TMZ sensitivity in both TMZ-sensitive and TMZ-resistant cell lines. Therefore, we initiated a clinical trial (NCT03587038) of OKN-007 in combination with TMZ and radiation therapy (RT). Here we report the safety and tolerability findings of this trial in-progress.

METHODS

Adults with newly-diagnosed and resected GBM are eligible. OKN-007 is administered by IV at 60 mg/kg. There are three treatment phases: Concomitant, Pre-Maintenance, and Maintenance. In the Concomitant Phase, patients receive OKN-007 three times per week (Cohort 1) or five times per week (Cohort 2); all patients receive TMZ at 75 mg/m2 daily and RT at 60 Gy over 30 fractions. In the 28-day Pre-Maintenance Phase, all patients receive OKN-007 thrice weekly. In the Maintenance Phase (MP), comprising up to eighteen 28-day cycles, TMZ is dosed at 150–200 mg/m2 on days 1–5 of each cycle for six cycles. OKN-007 is administered thrice weekly for six cycles, then twice weekly for three cycles, then once weekly for nine cycles. An expansion cohort of up to 25 patients will use the highest tolerated dosing protocol.

RESULTS

To date, five patients have been enrolled. Three patients in Cohort 1 and one in Cohort 2 advanced to the MP, and no dose-limiting toxicities (DLTs) occurred. One patient in Cohort 2 was removed due to a DLT (grade 3 neutropenic fever).

CONCLUSIONS

The treatment plan in Cohort 1 appears safe and well-tolerated. Recruitment for Cohort 2 is ongoing and will be expanded to further evaluate safety. Once the outcome of Cohort 2 is known, the regimen for the expansion cohort will be determined.
CTNI-17. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Rahman Kawakibi Abed , Tarapore Rohinton S , Gardner Sharon , Thomas Chase , Cartaxo Rodrigo , Yadav Viveka Nand , Chi Andrew , Kurz Sylvia , Wen Patrick , Arrillaga-Romany Isabel , Batchelor Tracy , Butowski Nicholas , Sumrall Ashley , Shonka Nicole , Harrison Rebecca , de Groot John , Mehta Minesh , Odia Yazmin , Hall Matthew , Daghistani Doured , Cloughesy Timothy , Ellingson Benjamin , Umemura Yoshie , Garton Hugh , Franson Andrea , Robertson Patricia , Schwartz Jonathan , Cantor Evan , Miklja Zachary , Mullan Brendan , Bruzek Amy , Siada Ruby , Cummings Jessica , Paul Alyssa , Wolfe Ian , Jiang Li , Filbin Mariella , Vats Pankaj , Kumar-Sinha Chandan , Mody Rajen , Chinnaiyan Arul , Venneti Sriram , Lu Guangrong , Mueller Sabine , Martinez Daniel , Resnick Adam , Nazarian Javad , Waszak Sebastian , Allen Joshua , Koschmann Carl
Published: December 2020

Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation rarely survive longer than two years and have no proven therapies following first-line radiation. ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in early phase studies in H3 K27M-mutant DMG. In order to define response rates in H3 K27M DMG patients and to clarify the genomic, anatomic and molecular predictors of response, we performed an integrated pre-clinical and clinical analysis of ONC201 treatment. ONC201 was effective in intra-uterine electroporation (IUE)-generated H3 K27M-mutant murine glioma models with excellent CNS penetration and survival benefit. Patients with H3 K27M-mutant DMG treated with ONC201 on active clinical trials (n=50, 27 thalamic, 23 brainstem) showed an overall survival (OS) of 28.1 (range: 5.9–105) months from diagnosis (enrollment by 4/29/19, data cut-off 12/28/19), compared to historical median OS of 12 months. Median OS for non-recurrent patients has not been reached (n=16, median follow-up: 16.8 from diagnosis). For non-recurrent thalamic patients (n=8), median PFS is 20.1 (range: 9.3–27.6) months from diagnosis (median time on drug: 14.5 months). Best response for thalamic patients by RANO: 1 CR, 5 PR, 7 SD, 8 PD, 6 not reported. Decreased H3 K27M cell-free tumor DNA in plasma and CSF at 6 months correlated with long-term response. Baseline tumor gene expression profiling in patients treated with ONC201 (n=14) identified EGFR and the cortical developmental transcription factor FOXG1 as the strongest biomarkers of radiographic response to ONC201. Analysis of 541 ONC201-treated human cancer cell lines from DepMap, provided evidence for an EGFR-dependent ONC201 resistance mechanism. Analysis of 38 glioma cell lines further supports FOXG1 as a glioma-specific predictive biomarker of ONC201 response. The unprecedented survival results and radiographic responses to ONC201 in H3K27M DMG make a compelling case for later phase and combinatorial studies.
CTNI-25. PHASE IB CLINICAL TRIAL OF CHRONIC CONVECTION-ENHANCED DELIVERY OF TOPOTECAN FOR RECURRENT GLIOBLASTOMA
Authors: Bruce Jeffrey , Spinazzi Eleonora , Lassman Andrew , Iwamoto Fabio , Welch Mary , Banu Matei , Argenziano Michael , Upadhyayula Pavan , Agar Nathalie Y R , Humala Nelson , Marie Tamara , Pereira Brianna , Sudhakar Tejaswi , Mahajan Aayushi , Neira Justin , Lignelli-Dipple Angela , Grinband Jack , Sims Peter , D’Amico Randy , Canoll Peter
Published: December 2020

OBJECTIVES

Convection-enhanced delivery (CED) provides pharmacokinetic advantages over systemic delivery for achieving cytotoxic drug levels into targeted regions of the brain. A major shortcoming of CED has been the need to limit treatment duration because of infection risks associated with external pumps. We engineered a subcutaneously implanted catheter-pump construct for prolonged CED which was successfully tested in a large animal model and then approved by the FDA for a Phase Ib clinical trial with topotecan in patients with refractory glioblastoma (IND 131889).

METHODS

Five patients with recurrent glioblastoma underwent surgical implantation of a subcutaneous pump and catheter that infused intracerebral topotecan over 30 days. Gadolinium was co-infused as a surrogate tracer and advanced non-invasive radiographic imaging was used to monitor drug distribution and pharmacological effects. Tissue from multiple radiographically-localized regions of each tumor and surrounding brain was procured pre-treatment at the time of catheter implantation and then post-treatment when tumors were surgically resected. Tissue was used for drug level measurements and advanced molecular, genomic and cellular analysis of treatment effects.

RESULTS

Treatments were successfully completed in all five patients without significant complications. The safety and tolerability of treatment was validated by quality-of-life measures and neurological assessments. Noninvasive imaging demonstrated large and stable drug distribution volumes. Comprehensive tissue analysis demonstrated effective targeting of mitotically active tumor cells while sparing neurons.

CONCLUSIONS

We engineered a subcutaneously implanted catheter-pump construct for chronic CED that was successfully tested in a Phase Ib clinical trial with topotecan in recurrent glioblastoma patients. Analysis of pre- and post-treatment tissue showed significant anti-tumor activity from topotecan that was not harmful to normal brain. Chronic CED combined with non-invasive real time drug distribution monitoring provides a safe and effective glioma strategy suitable for clinical use.
CTNI-32. PHASE I/II STUDY OF TEMOZOLOMIDE PLUS NIMUSTINE CHEMOTHERAPY FOR RECURRENT MALIGNANT GLIOMAS: KYOTO NEURO-ONCOLOGY GROUP
Authors: Aoki Tomokazu , Arakawa Yoshiki , Ueba Tetsuya , Oda Masashi , Nishida Namiko , Akiyama Yukinori , Aoki Tomokazu , Iwasaki Koichi , Mikuni Nobuhiro , Miyamoto Susumu
Published: December 2020

The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.
CTNI-35. SURVIVAL OUTCOME AND PROGNOSTIC FACTORS IN ANAPLASTIC OLIGODENDROGLIOMA: A SINGLE-INSTITUTION STUDY OF 95 CASES
Authors: Shin Dongwon , Kim Young Hoon
Published: December 2020

OBJECTIVE

Anaplastic oligodendroglioma (AO) is a rare intracranial malignant neoplasm and its treatment remains challenging. The aim of this study was to evaluate prognostic factors including surgical, radiographic, and histopathologic analyses in AO patients.

METHODS

We reviewed the electronic records of 95 consecutive patients who underwent surgical procedures and were diagnosed with AO from 1998 to 2018. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Univariate and multivariable analyses included clinical, histopathological, and radiographic prognostic factors. Subgroup analysis was performed in isocitrate dehydrogenase (IDH1/2)-mutant and 1p/19q-codeleted patients.

RESULTS

The median PFS and OS were 24.7 months and 50.8 months, respectively. The progression-free 1-, 3-, 5-, and 10-year survival were 75.8%, 42.9%, 32.4%, and 16.4%, respectively. Furthermore, the overall 1-, 3-, 5-, and 10-year survival were 98.9%, 76.9%, 42.9%, and 29.7%, respectively. The median PFS and OS of the IDH1/2-mutant and 1p/19q-codeleted patients were 54.2 and 57.8 months, respectively. Age under 60, frontal lobe location, weak enhancement, gross total resection (GTR), lower Ki-67 index, 1p/19q codeletion, and IDH1/2 mutations were associated with a favorable outcome. Among them, IDH1/2 mutation was the only variable related to better PFS and OS in multivariable analysis. GTR was associated with favorable outcomes in the subgroup analysis.

CONCLUSIONS

IDH1/2 mutation status was the most important prognostic factor in AO patients. Additionally, in the subgroup analysis, GTR showed better prognosis for IDH1/2-mutant and 1p/19q-codeleted patients.
CTNI-41. PHASE I STUDY OF RUXOLITINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GRADE III GLIOMAS AND GLIOBLASTOMA
Authors: Rauf Yasmeen , Hufsey Rachel , Robinson Kathy , Suh John , Chao Samuel , Murphy Erin , Yu Jennifer , Peereboom David , Ahluwalia Manmeet
Published: December 2020

BACKGROUND

Ruxolitinib is a novel, potent, and selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3, respectively. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells.

METHODS

Newly diagnosed patients with unmethylated MGMT Glioblastoma or grade III glioma were recruited to Arm I. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily and level -1 was 5 mg twice daily. Arm two was started once safe dose was established for Arm 1 for each dose level. Patients with methylated MGMT glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks.

RESULTS

30 patients were randomized to Arm I and 16 to arm II. There was one partial response in the methylated Arm and one partial response in the unmethylated arm. The maximum tolerated dose of Ruxolitinib was 20 mg BID in both methylated and unmethylated arm. There were 14 incidences of Grade 3 toxicity including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and bacterial meningitis. There were 4 incidences of Grade 4 toxicity including seizure, respiratory distress, somnolence and thromboembolic events.

CONCLUSION

This is an ongoing clinical trial and final results will be presented once the trial is complete. We will perform single cell sequencing on good and poor responders, that data will be presented in the meeting.
CTNI-46. A PHASE II TRIAL OF TUMOR TREATING FIELDS (TTFIELDS) CONCOMITANT WITH RADIOSURGERY FOR THE TREATMENT OF RECURRENT, BEVACIZUMAB-NAÏVE GLIOBLASTOMA
Authors: Harat Maciej , Blok Maciej , Adamczak-Sobczak Magda , Szymanski Pawel , Miechowicz Iza , Malkowski Bogdan
Published: December 2020

BACKGROUND

Almost all GBM patients experience recurrent disease, and median survival after recurrence is 6 months. A phase III trial conducted to test safety and efficacy of TTFields alone versus chemotherapy (including bevacizumab) in recurrent GBM showed improved PFS at six months and one-year survival was 20% in both treatment arms. Stereotactic radiosurgery (SRS), another treatment option recommended at recurrence, has limitations due to the invasive nature of glioblastoma. TTFields may decrease the tumor aggressiveness outside the target area potentially by multiple pathways, including immunogenic cell death and DNA repair inhibition sensitizing to radiation. We hypothesize that combined SRS and TTFields will be complementary, improving outcomes with minimal toxicity.

METHODS

In this open-label, phase II trial 40 participants with recurrence will be treated with SRS and TTFields, starting in 2020. Recurrence will be defined on FET-PET or MRI using RANO criteria. At least 6 months between the end of the first course of radiotherapy and SRS is mandatory with recurrent tumor visible on FET-PET and/or MRI, with the maximum diameter < 5 cm by either technique. SRS must be delivered within 7 days of TTFields start. A 5-day SRS regimen is allowed. TTFields should be interrupted only during SRS. The sample size of the study was calculated for the comparison of survival against a historical control. With 40 patients followed until death, there is at least an 80% ability to detect a 19% difference in one-year survival rate and 17% difference in ORR (p=0.05) compared to the EF-11 clinical trial. The one-year survival and ORR rate were seen in 20% and 14% of TTFields patients in the historical control. Overall survival will be stratified by volume, PET-based treatment, SVZ invasion, MGMT methylation status, time to first progression, and TTFields compliance. Estimated study primary completion date is July 2023.
CTNI-49. PHASE I STUDY OF MGMT-P140K TRANSFECTED HEMATOPOETIC PROGENITOR CELLS COMBINED WITH TMZ/O6BG DOSE ESCALATION FOR NEWLY DIAGNOSED, UNMETHYLATED GLIOBLASTOMA: TOLERANCE AND EVIDENCE OF SURVIVAL BENEFIT
Authors: Sloan Andrew E , Fung Hua , Reese Jane , Rgers Lisa , Murphy Christopher , Lazarus Hillard , Dropulic Boro , Gerson Stanton
Published: December 2020

INTRODUCTION

GBM has median survival of 12 months despite current SOC therapy. The most important mechanism of TMZ resistance is the O6-methylguanine-DNA methyltransferase (MGMT) gene. The MGMT inhibitor O6-benzylguanine (BG) demonstrated efficacy in depleting MGMT but approach led to unacceptable bone marrow toxicity and has thus been abandoned. We hypothesized that chemoprotection of hematopoietic HPC with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity, coupled with low affinity for BG would maximize anti-tumor response while enabling patients to tolerate TMZ & BG dose escalation with minimal toxicity. A phase I trial was performed to test this hypothesis.

METHODS

10 adults with newly diagnosed MGMT unmethylated, IDH-1 WT, GBM underwent standard surgery and radiation, followed by transplantation with autologous CD34+ HPC transfected with MGMT-P140K using a lentiviral vector. We tested tolerance and efficacy of three different paradigms for conditioning bone marrow and re-infusion of HPC.

RESULTS

Treatment was moderately toxic with 3/10 patients suffering grade 3–4 hematologic toxicity; no high grade non-hematologic toxicity was observed. Viral transduction rates ranged from 3–75% and were clearly improved in Arm III utilizing BCNU conditioning and intra-patient dose escalation of TMZ/O6GB. In patients tolerating 3 cycles or more, P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3-26-fold with only mild (Grade 2–3) myelosuppression consistent with chemo-protection as hypothesized. Median PFS and OS was 24 and 33 months respectfully, and three patients in Arm III were progression free at 36 months with one progression free at 48 months. OS exceeded RPA & Nomogram predicted survival by 3.6-fold, suggesting clinical benefit. Viral insertion site analysis demonstrate no clonal dominance.

CONCLUSIONS

P140K-MGMT transfected HPC enables TMZ/ BG dose escalation with acceptable toxicity and increased survival in a small cohort of selected patients. A U-01 funded phase II study is ongoing at UH and NIH.
CTNI-50. NEUROCOGNITIVE FUNCTION (NCF) OF THE PHOTON COHORT IN NRG-BN001
Authors: Wefel Jeffrey S , DeMora Lyudmila , Gondi Vinai , Tsien Christina , Chenevert Thomas , Gilbert Mark , Omuro Antonio , Cao Yue , Srinivasan Ashok , Rogers Leland , Shi Wenyin , Nedzi Lucien , Chan Michael , Suh John , Battiste James , Mishra Mark , Shivnani Anand , Movsas Benjamin , Mehta Minesh
Published: December 2020

NRG BN001 is an ongoing randomized phase II trial of dose-intense (DI-RT) versus standard dose photon-based radiation therapy (SD-RT) with temozolomide (TMZ) for newly diagnosed glioblastoma. We report preliminary results of Group 1, DI-RT delivered with IMRT while SD-RT could be 3DCRT or IMRT. Group 2, DI-RT delivered with proton therapy, continues to accrue. From 10/2014 to 7/2018, 229 patients were eligible and randomized. Differences in overall survival following DI-RT versus SD-RT were not significant. Patients were scheduled to complete NCF testing at baseline, cycle 3 (within 7 days of cycle 4), and cycle 12 (day 22–28 of cycle 12, or 60 weeks from completion of chemoradiation). At baseline, 93–94% of eligible patients completed NCF testing. Compliance for evaluable patients at cycle 3 and cycle 12 was 66–68% and 51–54%, respectively, across the battery of NCF tests. The most common reasons for missing data were patient refusal (cycle 3: 14%, cycle 12: 22–23%) and institutional error (cycle 3: 9–10%, cycle 12: 14–15%). A prespecified secondary endpoint analysis was conducted to evaluate differences in NCF between SD-RT and DI-RT based on the Clinical Trial Battery Composite (CTB COMP), which is the mean of the standardized scores from the NCF test battery (HVLT-R, TMT, COWA). There was no statistically significant between arm difference in change from baseline on the CTB COMP at cycle 3 (DI-RT vs SD-RT mean/SD, 0.0 +/- 1.3 vs -0.3 +/- 1.5, p=0.370, Cohen’s d=0.22) or cycle 12 (DI-RT vs SD-RT mean/SD, 0.2 +/- 1.7 vs 0.2 +/- 1.1, p=0.977, Cohen’s d=0.01). A mixed effects longitudinal model of the CTB COMP yielded a non-significant time by treatment effect interaction (p=0.216). There were no significant differences in change scores between arms on any NCF test at cycles 3 or 12. NCF outcomes were similar for photon-based SD-RT and DI-RT.
CTNI-52. PHASE II STUDY OF EVEROLIMUS (AFINITOR®) FOR CHILDREN WITH RECURRENT OR PROGRESSIVE EPENDYMOMA
Authors: Bowers Daniel , Karajannis Matthias , Gardner Sharon , Su Jack , Baxter Patricia , Partap Sonia , Klesse Laura
Published: December 2020

Preclinical studies suggested that the mTOR signaling pathway could be a potential therapeutic target in childhood ependymomas. As a result, a phase II clinical trial (ClinicalTrials.gov identifier: NCT02155920) of single-agent everolimus was performed to test the hypothesis that inhibition of the mTOR pathway would result in tumor responses for children with recurrent and/or progressive ependymoma. Eleven patients [sex: 4 females (36.4%); median age: 8 years (range: 2 – 15 years); race: 9 white and 2 other; prior therapies: median 6 (range: 3 – 9)] were enrolled on the study. The primary tumor location for 10 participants was the posterior fossa; the primary location of the remaining tumor was the cervical spine. All patients were treated with oral everolimus 4.5 mg/m2/day (each cycle = 28 days) that was titrated to achieve serum trough levels of 5 – 15 ng/mL. Overall, everolimus was well tolerated; adverse events were grade 1 – 2 and consistent with its previously established safety profile in children. No objective tumor responses were observed. All patients discontinued therapy due to tumor progression after a median of 2 cycles of therapy (1 cycle = 2; 2 cycles = 6; 3, 4, and 8 cycles = 1 each). This study does not support the use of everolimus for children with recurrent or progressive ependymoma.
CTNI-57. LOW-RISK MENINGIOMA: OUTCOMES FROM NRG ONCOLOGY/RTOG 0539
Authors: Rogers Leland , Pugh Stephanie , Vogelbaum Michael , Perry Arie , Ashby Lynn , Modi Jignesh , Alleman Anthony , Youssef Emad , Braunstein Steve , Bovi Joseph , de Groot John , Whitton Anthony , Lindhorst Scott , Taylor Nicholas , Shrieve Dennis , Shu Hui-Kuo , Machtay Mitchell , Mishra Mark , Robinson Clifford , Mehta Minesh
Published: December 2020

PURPOSE/OBJECTIVE(S)

Outcomes of low-risk meningioma from NRG/RTOG-0539.

MATERIALS/METHODS

Outcomes of the intermediate and high-risk cohorts from this phase II trial have been previously reported. Low-risk (Group 1: new WHO grade 1) patients were observed after gross total (GTR) or subtotal resection (STR). Progression-free (PFS) and overall (OS) were estimated using Kaplan-Meier. CTCAE v3 AE grading was employed.

RESULTS

Group 1 enrolled 65 patients. 56/60 (93.4%) evaluable patients had investigator-reported GTR. Sufficient imaging for central confirmation was available for 48: GTR in 35 and STR in 13. Median follow-up for living patients was 9.1 years (y). For all evaluable patients 5 and 10 y PFS and OS rates were 89.4 and 85.0%, and 98.3 and 93.8%, respectively. For patients with centrally-confirmed STR, 5/10 y PFS rates were 72.7/72.7%, with 100% 10 y OS. For patients with centrally-confirmed GTR, 5/10 y PFS and OS rates were 94.3/87.6 and 97.1/90.4%, respectively. For combined study cohorts (Groups 1–3) with central-review (n=104), the median centrally-measured largest pre-operative tumor dimension was 4.3 cm (range 0.4 - 14.4); this was significantly associated with OS (hazard ratio [HR]=1.03, p=0.021) and PFS (HR=1.03, p=0.003). No grade 4 or 5 protocol-related adverse events were reported. There were 1 grade 3 (infection), 4 grade 2 (neurologic, pulmonary, gastrointestinal, and pain), and 5 grade 1 (3 neurologic, 1 occulovisual, 1 constitutional) events from 5 patients.

CONCLUSION

These results prospectively validate high OS and PFS outcomes for low-risk meningioma managed with surgery followed by observation, but raise questions regarding optimal management following STR (5 y PFS 72.7%), a subcohort that could potentially benefit from adjuvant therapy. However, we identified considerable discordance between local and central assessments of resection extent. Pre-operative tumor size has a significant impact on OS and PFS. Supported by: U10CA180868 and U10CA180822 from the National Cancer Institute (NCI)
CTNI-60. NEOAJUVANT CHEMOTHERAPY FOLLOWED BY CRANIOSPINAL IRRADIATION FOR INTRACRANIAL NGGCTS: CLINICAL OUTCOMES AND AGE-STRATIFIED TOXICITIES IN A COHORT OF 111 PATIENTS
Authors: Wen Lei , Li Juan , Lai Mingyao , Zhou Zhaoming , Hu Qingjun , Shan Changguo , Cai Linbo , Zhou Cheng
Published: December 2020

BACKGROUND

Intracranial non-germinomatous germ cell tumors (NGGCTs) are rare tumors with limited studies available worldwide. Despite significantly improved survivals, there are still approximately 30% of patients experience relapse and require salvage treatment. This study aimed to access the clinical-pathological features and prognostic factors with specific interests to recurrence as well as adverse effects.

METHODS

From June 2005 and December 2018, 111 consecutive intracranial NGGCTs patients (87 localized stage and 24 metastatic stage) diagnosed based on histological confirmation, or alternatively by clinical presentation, radiological outcomes and elevated tumor markers were retrospectively analyzed.

RESULTS

After a median follow-up of 46.2 months, Three- and five- year OS were 83.5% ± 3.9% and 78.6% ± 5.1%, respectively. Three- and five- year EFS were 71.0% ± 4.8% and 64.7% ± 5.7%, respectively. Patients received craniospinal irradiation (CSI) integrated combined treatment yielded superior 3-year OS (P=0.007), EFS (P=0.002), and relapse rate (P=0.004) compared to those without CSI. A combination of minimum 4 cycles of induction chemotherapy and CSI integrated approach was the independent prognostic factor (P=0.007) conferring favorable 3-year OS and EFS of 93.9%±3.5% and 84.0%±5.4%, respectively. Poor prognosis of histological subtypes were particularly benefit from this treatment modality (P< 0.001). Age-thresholds for risking therapy-related thrombocytopenia and growth impairment by ROC analysis were 14 (AUC=0.752, P< 0.0001) and 11.5 (AUC=0.806, P< 0.01) yr., respectively.

CONCLUSIONS

Our study suggested that multimodal approach consisting of ≥4 cycles of induction chemotherapy and CSI plus focal boost with or without second-look surgery was recommended for NGGCTs. However, CSI should be used with caution when patients < 11.5-yr due to growth impairment. More precise risk stratifications are highly demanded for delivery of the most appropriate management in the future.
CTNI-65. COMBINED RITUXIMAB, METHOTREXATE, PROCARBAZINE, VINCRISTINE, AND CYTARABINE (R-MPV-A) TREATMENT FOR PATIENTS WITH RELAPSED PRIMARY CNS LYMPHOMA
Authors: Nagane Motoo , Sasaki Nobuyoshi , Kobayashi Keiichi , Saito Kuniaki , Shimada Daisuke , Matsumoto Yoshie , Iijima Shohei , Yamagishi Yuki , Shimizu Saki , Takayama Nobuyuki , Shiokawa Yoshiaki
Published: December 2020

BACKGROUNDS

Standard of care for patients with primary CNS lymphoma (PCNSL) has been high-dose methotrexate (HD-MTX)-based multiagent immunochemotherapy including an induction R-MPV with consolidation whole-brain radiotherapy (WBRT) and HD-cytarabine to achieve complete remission, however, the optimal treatment for relapsed/refractory (r/r) PCNSL has not been established yet, besides the recent approval of a BTK inhibitor, tirabrutinib, in Japan. We evaluated retrospectively efficacy of R-MPV-A for r/rPCNSL.

PATIENTS

Histologically proven PCNSL patients treated at relapse in our institution from April 2000 to November 2019 were analyzed. Outcomes were compared between those treated with RMPVA or other regimens.

RESULTS

Among 148 PCNSL patients identified, 73 had at least one relapse, of whom 47 received salvage chemotherapy including 23 treated with RMPVA either at the first relapse (11) or at the second or later relapse (12). Median age/KPS of this salvage RMPVA group were 71 (42–87)/80 (40–100). Nine patients were pretreated with the first-line RMPVA. HD-cytarabine was given to 13 patients. Median number of RMPV cycles was 8 (1–4 cycles: 10; 8 cycles 13). CR/CRu were achieved in 19 (83%), response rate was 87%, while there were two PDs (9%). After median follow-up of 21.9 months, the median PFS after salvage RMPVA was 13.0 m (95%CI: 9.1–16.9), 1-year overall survival (OS) was 82%, median OS was 70.0 m (95%CI: 12.9–127.1), which were longer than those in 24 patients with salvage treatment other than RMPVA (mPFS 4.4 m, P=0.054; mOS 13.6 m, P=0.009). Among patients with salvage RMPVA, HD-cytarabine was associated with better PFS (P=0.066), and complete responses were significantly correlated with longer OS. Treatment was generally well-tolerated but there was one treatment-related death.

CONCLUSIONS

Salvage RMPVA at relapses was active and associated with longer survival compared with other regimens, necessitating further development of salvage regimens incorporating tirabrutinib in the future studies.