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 [email protected].

For more about Dana-Farber science, tune in to our Unraveled podcast, available at dana-farber.org/unraveled, or wherever you get your podcasts.

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.

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).

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.

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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