This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from November 16 through November 30.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing ericd_schuller@dfci.harvard.edu.
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Blood
Functional Cure Reported in CLL
Davids MS
In this issue of Blood, Thompson et al report on the very-long-term follow-up of a phase 2 study of fludarabine, cyclophosphamide, and rituximab (FCR) as initial therapy for young, fit patients with chronic lymphocytic leukemia (CLL). When helping young, fit patients with CLL to decide on initial therapy, a common question I get is: “What would you choose, doc?” A few years ago, my answer to this question for patients with mutated immunoglobulin variable heavy chain (IGHV-M) CLL was fairly straightforward — FCR. We have known for several years that about half of patients with IGHV-M CLL will have durable remission with FCR with only 6 months of therapy.
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Blood
Unraveling KMT2A-Rearranged ALL
Shimony S, Luskin MR
In this issue of Blood, Kim et al from the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) take us one giant leap forward in our understanding of adult KMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (B-ALL). For the first time, they demonstrate the ability to risk stratify young adults within this high-risk group and identify patients with KMT2A-r B-ALL with outstanding outcomes when treated with intensive, pediatric-inspired chemotherapy, even without allogeneic hematopoietic stem cell transplant (HSCT).
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Journal of Clinical Oncology
Everolimus for Children with Recurrent or Progressive Low-Grade Glioma: Results from the Phase II PNOC001 Trial
Haas-Kogan DA, Liu KX
PURPOSE: The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation as measured by phosphorylated-ribosomal protein S6 and to identify prognostic and predictive biomarkers.
PATIENTS AND METHODS: Patients, age 3-21 years, withprogressive/recurrent pLGG received everolimus orally, 5 mg/m2 once daily. Frequency of driver gene alterations was compared among independent pLGG cohorts of newly diagnosed and progressive/recurrent patients. PFS at 6 months (primary end point) and median PFS (secondary end point) were estimated for association with everolimus therapy.
RESULTS: Between 2012 and 2019, 65 subjects with progressive/recurrent pLGG (median age, 9.6 years; range, 3.0-19.9; 46% female) were enrolled, with a median follow-up of 57.5 months. The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common grade ≥3 adverse event. PI3K/AKT/mTOR pathway activation did not correlate with clinical outcomes (6-month PFS, active 68.4% v nonactive 63.3%; median PFS, active 11.2 months v nonactive 11.1 months; P = .80). Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, in patients with progressive/recurrent disease, and correlated with poor clinical outcomes (median PFS, rare/novel KIAA1549::BRAF fusion breakpoints 6.1 months v common KIAA1549::BRAF fusion breakpoints 16.7 months; P < .05). Multivariate analysis confirmed their independent risk factor status for disease progression in PNOC001 and other, independent cohorts. Additionally, rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of PNOC001 patients.
CONCLUSION: Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.
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Journal of Clinical Oncology
Flashback Foreword: Oxaliplatin Plus LV5FU2 in Colorectal Cancer
Mayer RJ
For several decades, beginning in the 1960s, the treatment for patients with metastatic colorectal cancer was limited to the use of fluorouracil (FU). The drug, which acts by inhibiting the enzyme thymidylate synthase, prolonged survival from approximately 6 months (without any treatment) to 9 months in this patient population. Clinical research during the 1980s, when JCO initially started publishing, focused on identifying the optimal dose schedule of FU administration, with various methods of parenteral administration shown to be therapeutically equivalent but associated with different dose-limiting symptoms. Adding leucovorin (folinic acid) to FU seemed to enhance the likelihood of benefit, presumably by increasing the inhibition of thymidylate synthase. A randomized clinical trial published in JCO in 1997 demonstrated that an every-2-weeks schedule of leucovorin and a bolus followed by a 2-day continuous infusion of FU (LV5FU2) was superior to a monthly 5-day bolus regimen in terms of response rate, median progression-free survival, and tolerance, but did not prolong overall survival.
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Journal of Clinical Oncology
RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults
Wen PY, Youssef G, Rahman R, Reardon DA
PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria.
METHODS: Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0).
RESULTS: We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment.
CONCLUSION: The revised RANO 2.0 criteria refine response assessment in gliomas.
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Journal of Clinical Oncology
Too Much, Too Little, or Just Right? Obesity and Dosing of Targeted Therapies in Breast Cancer
Cao C, Ligibel JA
Obesity, a global pandemic, is a well-established prognostic factor in early breast cancer. A recent review from the World Cancer Research Fund including 64 studies evaluating the relationship between obesity and cancer outcomes in early breast cancer found that each 5-kg/m increase in BMI was associated with a concomitant increase in the risk of all-cause mortality, breast cancer–specific mortality, and second cancers. Notably, the poor outcomes associated with obesity have been seen in both pre- and postmenopausal women and across tumor subtypes and treatments.
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JAMA Oncology
Nivolumab for Patients with High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial
Hanna GJ, Shi R, ONeill A, Liu M, Quinn CT, Treister NS, Sroussi HY, Vacharotayangul P, Goguen LA, Annino DJ Jr, Rettig EM, Jo VY, Wong KS, Lizotte P, Paweletz CP, Uppaluri R, Haddad RI, Woo SB
IMPORTANCE: Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell-rich microenvironment, providing strong rationale to investigate immune checkpoint therapy.
OBJECTIVE: To determine the safety and clinical activity of anti-programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL.
DESIGN, SETTING, AND PARTICIPANTS: This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia).
INTERVENTION: Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit.
MAIN OUTCOMES AND MEASURES: The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response.
RESULTS: A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss.
CONCLUSIONS AND RELEVANCE: This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03692325.
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Nature
Structural Basis of Gabija Anti-Phage Defence and Viral Immune Evasion
Antine SP, Johnson AG, Mooney SE, Mayer ML, Kranzusch PJ
Bacteria encode hundreds of diverse defense systems that protect from viral infection and inhibit phage propagation1-5. Gabija is one of the most prevalent anti-phage defense systems, occurring in >15% of all sequenced bacterial and archaeal genomes but the molecular basis of how Gabija defends cells from viral infection remains poorly understood. Here we use X-ray crystallography and cryo-EM to define how Gabija proteins assemble into an ~500 kDa supramolecular complex that degrades phage DNA. Gabija protein A (GajA) is a DNA endonuclease that tetramerizes to form the core of the anti-phage defense complex. Two sets of Gabija protein B (GajB) dimers dock at opposite sides of the complex and create a 4:4 GajAB assembly that is essential for phage resistance in vivo. We show that a phage-encoded protein Gabija anti-defense 1 (Gad1) directly binds the Gabija GajAB complex and inactivates defense. A cryo-EM structure of the virally inhibited state reveals that Gad1 forms an octameric web that encases the GajAB complex and inhibits DNA recognition and cleavage. Our results reveal the structural basis of assembly of the Gabija anti-phage defense complex and define a unique mechanism of viral immune evasion.
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Proceedings of the National Academy of Sciences of the U.S.A.
Peripheral Blood TCR Clonotype Diversity as an Age-Associated Marker of Breast Cancer Progression
Nishida J, Cristea S, Bodapati S, Puleo J, Bai G, Patel A, Hughes M, Snow C, Collins LC, Feeney AM, Slowik K, Bossuyt V, Dillon D, Lin NU, Partridge AH, Michor F, Polyak K
Immune escape is a prerequisite for tumor growth. We previously described a decline in intratumor activated cytotoxic T cells and T cell receptor (TCR) clonotype diversity in invasive breast carcinomas compared to ductal carcinoma in situ (DCIS), implying a central role of decreasing T cell responses in tumor progression. To determine potential associations between peripheral immunity and breast tumor progression, here, we assessed the peripheral blood TCR clonotype of 485 breast cancer patients diagnosed with either DCIS or de novo stage IV disease at younger (<45) or older (≥45) age. TCR clonotype diversity was significantly lower in older compared to younger breast cancer patients regardless of tumor stage at diagnosis. In the younger age group, TCR-α clonotype diversity was lower in patients diagnosed with de novo stage IV breast cancer compared to those diagnosed with DCIS. In the older age group, DCIS patients with higher TCR-α clonotype diversity were more likely to have a recurrence compared to those with lower diversity. Whole blood transcriptome profiles were distinct depending on the TCR-α Chao1 diversity score. There were more CD8+ T cells and a more active immune environment in DCIS tumors of young patients with higher peripheral blood TCR-α Chao1 diversity than in those with lower diversity. These results provide insights into the role that host immunity plays in breast cancer development across different age groups.
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Clinical Case Reports
Treatment of Recurrent Pediatric Myelodysplastic Syndrome Post Hematopoietic Stem Cell Transplantation
Wachter F, Pikman Y, Bledsoe J, Kapadia M, Baumeister S, Rowe J, Shimamura A, Place AE, Prockop S, Whangbo J, Lehmann L, Horan J, Pollard J
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iScience
Replicative Stress in Gastroesophageal Cancer is Associated with Chromosomal Instability and Sensitivity to DNA Damage Response Inhibitors
Sahgal P, Patil DT, Bala P, Sztupinszki ZM, Tisza V, Spisak S, Luong AG, Huffman B, Singh H, Lazaro JB, Szallasi Z, Cleary JM, Sethi NS
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Science Advances
ATM Deficiency Confers Specific Therapeutic Vulnerabilities in Bladder Cancer
Zhou Y, Adib E, Kamran SC, Neil AJ, Stawiski K, Freeman D, Stormoen DR, Sztupinszki Z, Samant A, Bekele RT, Hanlon T, Epstein I, Sharma B, Felt K, Wu CL, Efstathiou JA, Miyamoto DT, Anderson W, Szallasi Z, Mouw KW
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Transplantation and Cellular Therapy
Opportunistic Infections in Patients Receiving Post-Transplant Cyclophosphamide: Impact of Haploidentical Versus Unrelated Donor Allograft
Little JS, Duléry R, Shapiro RM, Aleissa MM, Prockop SE, Koreth J, Ritz J, Antin JH, Cutler C, Nikiforow S, Romee R, Issa NC, Ho VT, Baden LR, Soiffer RJ, Gooptu M
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