December 15, 2021
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors.
Blood
Bazarbachi AH, Samur AA, Hunter Z, Shammas M, Fulciniti M, Anderson KC, Parmigiani G, Treon SP, Munshi NC, Samur MK
Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenström macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and treatment. In this study, we investigated genomic and transcriptomic characteristics of IgM-MM samples using whole-genome and transcriptome sequencing to identify differentiating characteristics from non-IgM-MM and WM. Our results suggest that IgM-MM shares most of its defining structural variants and gene-expression profiling with MM, but has some key characteristics, including t(11;14) translocation, chromosome 6 and 13 deletion as well as distinct molecular and transcription-factor signatures. Furthermore, IgM-MM translocations were predominantly characterized by VHDHJH recombination-induced breakpoints, as opposed to the usual class-switching region breakpoints; coupled with its lack of class switching, these data favor a pre-germinal center origin. Finally, we found elevated expression of clinically relevant targets, including CD20 and Bruton tyrosine kinase, as well as high BCL2/BCL2L1 ratio in IgM-MM, providing potential for targeted therapeutics.
Blood
Yang G, Wang J, Tan L, Munshi M, Liu X, Kofides A, Chen JG, Tsakmaklis N, Demos MG, Guerrera ML, Xu L, Hunter ZR, Che J, Patterson CJ, Meid K, Castillo JJ, Munshi NC, Anderson KC, Buhrlage SJ, Gray NS, Treon SP
Activating mutations in MYD88 promote malignant cell growth and survival through hematopoietic cell kinase (HCK)-mediated activation of Bruton tyrosine kinase (BTK). Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88. Mutations in BTKCys481, particularly BTKCys481Ser, are common in patients with acquired ibrutinib resistance. We therefore performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88-mutated lymphoma cells, including ibrutinib-resistant BTKCys481Ser-expressing cells. KIN-8194 demonstrated excellent bioavailability and pharmacokinetic parameters, with good tolerance in rodent models at pharmacologically achievable and active doses. Pharmacodynamic studies showed sustained inhibition of HCK and BTK for 24 hours after single oral administration of KIN-8194 in an MYD88-mutated TMD-8 activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) and BCWM.1 Waldenström macroglobulinemia (WM) xenografted mice with wild-type BTK (BTKWT)- or BTKCys481Ser-expressing tumors. KIN-8194 showed superior survival benefit over ibrutinib in both BTKWT- and BTKCys481Ser-expressing TMD-8 DLBCL xenografted mice, including sustained complete responses of >12 weeks off treatment in mice with BTKWT-expressing TMD-8 tumors. The BCL_2 inhibitor venetoclax enhanced the antitumor activity of KIN-8194 in BTKWT- and BTKCys481Ser-expressing MYD88-mutated lymphoma cells and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser-expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK.
Blood
Venetoclax plus Dose-Adjusted R-EPOCH (VR-EPOCH) for Richter's Syndrome
Davids MS, Tyekucheva S, Wang Z, Pazienza S, Montegaard J, Ihuoma UO, Lehmberg TZ, Parry EM, Wu CJ, Jacobson CA, Fisher DC, Brown JR
Richter's Syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ‚â•3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to hemoimmunotherapy alone are warranted. (Funded by Genentech/AbbVie; ClinicalTrials.gov number, NCT03054896).
Journal of Clinical Oncology
Checkpoint Blockade: Not Yet NINJA Status in Ovarian Cancer
Porter RL, Matulonis UA
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, and although surgery and platinum-based chemotherapy effectively induce initial remission, most women will ultimately succumb to recurrent and therapy-resistant disease. High-grade serous histology is the most common EOC pathology and is molecularly characterized by defects in DNA repair, copy number alterations, microsatellite stable status, and low tumor mutational burden. Platinum-resistant ovarian cancer (PROC), defined as cancer that has progressed within 6 months of last platinum exposure, has a median overall survival (OS) of < 16 months, and new treatment strategies are exigently needed.
Journal of Clinical Oncology
Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation
Gibson CJ, Kim HT, Murdock HM, Ogata A, Green L, Fleharty M, Dougan T, Cheng CA, Blumenstiel B, Cibulskis C, Tsuji J, Antin JH, Nikiforow S, Chen YB, Ho VT, Lennon NJ, Walt DR, Ritz J, Soiffer RJ, Lindsley RC
PURPOSE: Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.
PATIENTS AND METHODS: We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant.
RESULTS: CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed long-term engraftment in recipients after transplantation, including clones with a variant allele fraction < 0.01. DNMT3A-CH with a variant allele fraction 0.01, but not smaller clones, was associated with improved recipient overall (hazard ratio [HR], 0.79; P = .042) and progression-free survival (HR, 0.72; P = .003) after adjustment for significant clinical variables. In patients who received calcineurin-based graft-versus-host disease prophylaxis, donor DNMT3A-CH was associated with reduced relapse (subdistribution HR, 0.59; P = .014), increased chronic graft-versus-host disease (subdistribution HR, 1.36; P = .042), and higher interleukin-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In seven of eight cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations.
CONCLUSION: Donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome-associated mutations or germline predisposition in donors.
Journal of Clinical Oncology
Hodi FS
PURPOSE: In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes.
PATIENTS AND METHODS: Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated.
RESULTS: Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF-wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed.
CONCLUSION: These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy.
Journal of Clinical Oncology
nab-Sirolimus for Patients with Malignant Perivascular Epithelioid Cell Tumors
Wagner AJ, Hornick JL, Du H, Kwiatkowski DJ
PURPOSE: Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab-sirolimus (AMPECT, NCT02494570).
PATIENTS AND METHODS: Patients with malignant PEComa were treated with nab-sirolimus 100 mg/m2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis.
RESULTS: Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range, 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation (P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade 4 treatment-related events occurred.
CONCLUSION: nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.
Journal of Clinical Oncology
D'Amico AV, Xie W
We would like to thank Francolini et al1 for their interest in our study2 and thoughtful letter. Our study prospectively assessed the impact on both overall survival and radiation therapy (RT)–induced cancer incidence of adding docetaxel to RT and androgen deprivation therapy (ADT) in men with unfavorable-risk prostate cancer. Although overall survival was not prolonged among all men, there was a signal of possible benefit (hazard ratio [HR] 0.33) among men with a prostate-specific antigen < 4 ng/mL, which will be further explored in a meta-analysis using data compiled by the Intermediate Clinical Endpoints in Prostate Cancer (ICECaP) consortium. In addition, despite only nine RT-induced cancers, a significant reduction in these second cancers (age-adjusted HR, 0.13; 95% CI, 0.02 to 0.97) was observed in men randomly assigned to the docetaxel arm. The availability of oral docetaxel and its favorable toxicity profile provides an option for future study to minimize and possibly prevent the occurrence of RT-induced cancers.
Journal of Clinical Oncology
Venetoclax in Previously Treated Waldenström Macroglobulinemia
Castillo JJ, Meid K, Leventoff C, White TP, Flynn CA, Sarosiek S, Branagan AR, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Patterson CJ, Hunter ZR, Davids MS, Treon SP
PURPOSE: BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified.
PATIENTS AND METHODS: We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years.
RESULTS: Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P-mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred.
CONCLUSION: Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response.
Journal of Clinical Oncology
Who Is MB and What Does She Want?
Jacobson JO
My initial glimpse of MB was a virtual one as I reviewed her chart in preparation for her first visit. She was 87, living in a skilled nursing facility, nearly blind, and mostly deaf. She used a wheelchair, had early dementia, and had recently been diagnosed with neglected lung cancer. This is someone who needs to be quickly channeled toward a symptom-based approach, I judged. Pain medication and a brief course of palliative radiation to help for the short term should suffice. Unwillingly, my mind slid back to the long, exhausting days of my internal medicine residency decades ago. I recalled dreading admissions from nursing homes. These patients were widely perceived as old, infirm, difficult to manage, and worst of all, they inevitably presented disposition problems; the nursing homes almost never accepted them back. They could linger in the hospital for weeks on end awaiting placement.
Lancet Oncology
Wen PY
BACKGROUND: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma.
METHODS: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110.
FINDINGS: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12¬?7 months (IQR 5¬?4-32¬?3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32¬?2 months (IQR 25¬?1-47¬?8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).
INTERPRETATION: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma.
FUNDING: Novartis.
Nature Genetics
Decoding Complex Patterns of Oncogene Amplification
Pellman D, Zhang CZ
Oncogene amplification is a major driver of tumorigenesis; yet, the mechanisms generating amplification are only partially understood. New research reports on the identification of a new focal amplification pattern termed ‘seismic amplification’ that is hypothesized to originate from recombination between extrachromosomal DNA circles.
New England Journal of Medicine
Belzutifan, a Potent HIF2a Inhibitor, in the Pacak-Zhuang Syndrome
Kamihara J, Hamilton KV, Pollard JA, Clinton CM, Madden JA, Lin J, Imamovic A, Wall CB, Wassner AJ, Weil BR, Heeney MM, Vargas SO, Janeway KA, Voss SD, DuBois SG
The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
American Journal of Human Genetics
H3K27ac HiChIP in Prostate Cell Lines Identifies Risk Genes for Prostate Cancer Susceptibility
Seo JH, Spisak S, Baca SC, Gusev A, Freedman ML
Bioconjugate Chemistry
Direct N- or C-Terminal Protein Labeling Via a Sortase-Mediated Swapping Approach
Cong M, Tavakolpour S, Berland L, Glöckner H, Andreiuk B, Rakhshandehroo T, Uslu S, Mishra S, Clark L, Rashidian M
Blood Advances
Penter L, Huang T, Thrash EM, Li S, Severgnini M, Neuberg D, Hodi FS, Livak KJ, Bachireddy P, Wu CJ
Blood Advances
Ho VT, Kim HT, Brock J, Galinsky I, Daley H, Reynolds CG, Weber A, Pozdnyakova O, Severgnini M, Nikiforow S, Cutler CS, Koreth J, Antin JH, Gooptu M, Romee R, Shapiro RM, Chen YB, Rosenblatt J, Avigan D, Hodi FS, Wu CJ, Ritz J, Soiffer RJ
Breast
Accelerating Progress to Innovation for Patients: Trial Design and Risk Stratification
Regan MM
Cancer Epidemiology, Biomarkers, and Prevention
Cardiometabolic Risk in Childhood Cancer Survivors: A Report from the Children's Oncology Group
Vrooman LM
Cancer Research
Plasticity in the Absence of NOTCH Uncovers a RUNX2-Dependent Pathway in Small Cell Lung Cancer
Hong D, Knelson EH, Li Y, Durmaz YT, Gao W, Walton E, Vajdi A, Thai T, Sticco-Ivins M, Jones KL, Schinzel AC, Bronson RT, Nguyen QD, Tolstorukov MY, Vivero M, Signoretti S, Barbie DA, Oser MG
Cell Communication and Signaling
Kuljanin M, Mancias JD, Fendler W
Cell Reports
Fu A, van Rooyen L, Evans L, Armstrong N, Bird GH, Reddy A, Chouchani ET, Walensky LD, Danial NN
Cell Research
The Hens Guarding Epithelial Cancer Fox-Houses
Gaynor LT, Shivdasani RA
Clinical Cancer Research
McGregor BA, Choueiri TK
Haematologica
Brown JR
iScience
Wang Q, Anang S, Zhang S, Nguyen H, Sodroski JG
Journal of Virology
Zhang S, Wang WL, Nguyen HT, Steinbock RT, Sodroski J, Mao Y
Journal of Virology
Glycosylation and Disulfide Bonding of Wild-Type SARS-CoV-2 Spike Glycoprotein
Zhang S, Anang S, Sodroski JG
Molecular Cancer Therapeutics
Bahcall M, Paweletz CP, Kuang Y, Taus LJ, Dholakia KH, Lau CJ, Gokhale PC, Chopade PR, Hong F, Wei Z, Köhler J, Kirschmeier PT, Wang S, Jänne PA
Pediatric Blood and Cancer
Early Parental Knowledge of Late Effect Risks in Children with Cancer
Carpenter K, Scavotto M, McGovern A, Kenney LB, Mack JW, Greenzang KA
Practical Radiation Oncology
Bychkovsky BL