Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear.
We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients ...from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses.
PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I–II disease was the only significant pretreatment prognostic factor PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34–0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22–0.78, P = 0.006. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT PFS: HR 0.19, 95% CI 0.14–0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17–0.40, P < 0.0001. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission.
This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.
Patients with diffuse large B-cell lymphoma treated with first-line anthracycline-based immunochemotherapy and remaining in remission at 2 years have excellent outcomes. This study assessed overall ...survival (OS) stratified by progression-free survival (PFS) at 24months (PFS24) using individual patient data from patients with DLBCL enrolled in multi-center, international randomized clinical trials as part of the Surrogate Endpoint for Aggressive Lymphoma (SEAL) Collaboration.
PFS24 was defined as being alive and PFS24 after study entry. OS from PFS24 was defined as time from identified PFS24 status until death due to any cause. OS was compared with each patient’s age-, sex-, and country-matched general population using expected survival and standardized mortality ratios (SMRs).
A total of 5853 patients enrolled in trials in the SEAL database received rituximab as part of induction therapy and were included in this analysis. The median age was 62years (range 18–92), and 56% were greater than 60years of age. At a median follow-up of 4.4years, 1337 patients (23%) had disease progression, 1489 (25%) had died, and 5101 had sufficient follow-up to evaluate PFS24. A total of 1423 assessable patients failed to achieve PFS24 with a median OS of 7.2months (95% CI 6.8–8.1) after progression; 5-year OS after progression was 19% and SMR was 32.1 (95% CI 30.0–34.4). A total of 3678 patients achieved PFS24; SMR after achieving PFS24 was 1.22 (95% CI 1.09–1.37). The observed OS versus expected OS at 3, 5, and 7years after achieving PFS24 was 93.1% versus 94.4%, 87.6% versus 89.5%, and 80.0% versus 83.7%, respectively.
Patients treated with rituximab containing anthracycline-based immunochemotherapy on clinical trials who are alive without progression at 24months from the onset of initial therapy have excellent outcomes with survival that is marginally lower but clinically indistinguishable from the age-, sex-, and country-matched background population for 7 years after achieving PFS24.
Because follicular lymphoma (FL) patients have heterogeneous outcomes, the FL international prognostic index (FLIPI) was developed to risk-stratify patients and to predict survival. However, limited ...data exist regarding the role of FLIPI in the era of routine first-line rituximab (R) and R-chemotherapy regimens and in the setting of community oncology practices.
We evaluated the outcome data from the National LymphoCare Study (NLCS), a prospective, observational cohort study, which collects data on patients with FL in the United States (US) community practices.
Among 1068 male and 1124 female patients with FLIPI data, most were treated in US community practices (79%); 35% were FLIPI good risk, 30% intermediate risk, and 35% poor risk. FLIPI risk groups were significant predictors of overall survival (OS) and progression-free survival (PFS) for patients who undergo watchful waiting (WW), and those who receive non-R-containing regimens, R-alone, and R-chemotherapy combinations.
In the setting of contemporary practice with routine R use, stratifying patients into good, intermediate, and poor FLIPI risk groups predicts distinct outcomes in terms of OS and PFS. FLIPI remains an important prognostic index in the R era and should be used in clinical practices to support discussions about prognosis.
Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of ...venetoclax in combination with bendamustine–rituximab (BR) in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL).
BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50–1200mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy.
Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n=4) or respiratory failure (n=1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3months 95% confidence interval (CI) 10.4–NR, not yet reached, and 10.7months (95% CI 4.3–21.0), respectively.
This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL.
Clinicaltrials.gov, NCT01594229.
For the majority of patients with newly diagnosed follicular lymphoma (FL), current treatments, while not curative, allow for long remission durations. However, several important needs remain ...unaddressed. Studies have consistently shown that ∼20% of patients with FL experience disease progression within 2years of first-line treatment, and consequently have a 50% risk of death in 5years. Better characterization of this group of patients at diagnosis may provide insight into those in need of alternate or intensive therapies, facilitate a precision approach to inform clinical trials, and allow for improved patient counseling. Prognostic methods to date have employed clinical parameters, genomic methods, and a wide assortment of biological and biochemical markers, but none so far has been able to adequately identify this high-risk population. Advances in the first-line treatment of FL with chemoimmunotherapy have led to a median progression-free survival (PFS) of approximately 7years; creating a challenge in the development of clinical trials where PFS is a primary end point. A surrogate end point that accurately predicts PFS would allow for new treatments to reach patients with FL sooner, or lessen toxicity, time, and expense to those patients requiring little to no therapy. Quality of response to treatment may predict PFS and overall survival in FL; as such complete response rates, either alone or in conjunction with PET imaging or minimal residual disease negativity, are being studied as surrogates, with complete response at 30months after induction providing the strongest surrogacy evidence to date. A better understanding of how to optimize quality of life in the context of this chronic illness is another important focus deserving of further study. Ongoing efforts to address these important unmet needs are herein discussed.
Venous thromboembolism (VTE), especially pulmonary embolism (PE) and lower extremity deep vein thrombosis (LE-DVT), is a serious and potentially preventable complication for patients with cancer ...undergoing systemic therapy.
Using retrospective data from patients diagnosed with incident cancer from 2011-2020, we derived a parsimonious risk assessment model (RAM) using least absolute shrinkage and selection operator regression from the Harris Health System (HHS, n = 9,769) and externally validated it using the Veterans Affairs (VA) health care system (n = 79,517). Bootstrapped c statistics and calibration curves were used to assess external model discrimination and fit. Dichotomized risk strata using integer scores were created and compared against the Khorana score (KS).
Incident VTE and PE/LE-DVT at 6 months occurred in 590 (6.2%) and 437 (4.6%) patients in HHS and 4,027 (5.1%) and 3,331 (4.2%) patients in the VA health care system. Assessed at the time of systemic therapy initiation, the new RAM included components of the KS with the modified cancer subtype, cancer staging, systemic therapy class, history of VTE, history of paralysis/immobility, recent hospitalization, and Asian/Pacific Islander race. The c statistic was 0.71 in HHS and 0.68 in the VA health care system (compared with 0.65 and 0.60, respectively, for KS). Furthermore, the new RAM appropriately reclassified 28% of patients and increased the proportion of VTEs in the high-risk group from 37% to 68% in the validation data set.
The novel RAM stratified patients with cancer into a high-risk group with 8%-10% cumulative incidence of VTE and 7% PE/LE-DVT at 6 months (
3% and 2%, respectively, in the low-risk group). The model had improved performance over the original KS and doubled the number of VTE events in the high-risk stratum. We encourage additional external validation from prospective studies.Media: see text.
The emergence of drug-resistant bacteria calls for the discovery of new antibiotics. Yet, for decades, traditional discovery strategies have not yielded new classes of antimicrobial. Here, by mining ...the human proteome via an algorithm that relies on the sequence length, net charge, average hydrophobicity and other physicochemical properties of antimicrobial peptides, we report the identification of 2,603 encrypted peptide antibiotics that are encoded in proteins with biological function unrelated to the immune system. We show that the encrypted peptides kill pathogenic bacteria by targeting their membrane, modulate gut and skin commensals, do not readily select for bacterial resistance, and possess anti-infective activity in skin abscess and thigh infection mouse models. We also show, in vitro and in the two mouse models of infection, that encrypted antibiotic peptides from the same biogeographical area display synergistic antimicrobial activity. Our algorithmic strategy allows for the rapid mining of proteomic data and opens up new routes for the discovery of candidate antibiotics.
Highlights • We examined effects of social defeat on vasopressin in males and females. • Vasopressin neurons respond similarly during defeat in both sexes. • Defeat reduced vasopressin cell counts ...and mRNA in only males after several weeks. • Social defeat abolished aggression in females but not males. • Defeat dissociated vasopressin levels from aggression in males.
PI3K inhibitors are an important new therapeutic option for the treatment of relapsed and refractory B-cell lymphoid malignancies. Idelalisib is a PI3Kδ inhibitor that has been approved for the ...treatment of lymphoma and chronic lymphocytic leukemia in the relapsed/refractory setting, and several other PI3K inhibitors are being developed targeting other isoforms of the PI3K enzyme, which results in distinct toxicities and variable efficacy in the clinical setting. Areas covered: We provide a general overview of PI3K inhibitors, recommended applications, and the mechanism and management of toxicities. We further review trials, ongoing and completed, leading to the approval of idelalisib as well other PI3K inhibitors currently in development. Articles were obtained from PubMed, and abstracts were searched for the past 5 years from the websites for ASCO, ASH, EHA, and ICML/Lugano. Expert commentary: PI3K inhibitors provide an important and powerful pharmacologic tool in the armamentarium against hematologic malignancies, especially for relapsed/refractory B-cell lymphoid malignancies. Unique toxicities are associated with inhibition of different isoforms of the PI3K enzyme, as demonstrated with the infectious and autoimmune toxicities associated with the PI3Kδ inhibitor, idelalisib. Due to these unique toxicities, PI3K inhibitors should only be used in formally approved combinations and settings.
Summary
High‐dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are used as consolidation in first remission (CR1) in some centres for untreated, transformed indolent B‐cell ...lymphoma (Tr‐iNHL) but the evidence base is weak. A total of 319 patients with untreated Tr‐iNHL meeting prespecified transplant eligibility criteria age <75, LVEF ≥45%, no severe lung disease, CR by positron emission tomography or computed tomography ≥3 months after at least standard cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R‐CHOP) intensity front‐line chemotherapy were retrospectively identified. Non‐diffuse large B‐cell lymphoma transformations were excluded. About 283 (89%) patients had follicular lymphoma, 30 (9%) marginal‐zone lymphoma and six (2%) other subtypes. Forty‐nine patients underwent HDC/ASCT in CR1, and a 1:2 propensity‐score‐matched cohort of 98 patients based on age, stage and high‐grade B‐cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBL‐DH) was generated. After a median follow‐up of 3·7 (range 0·1–18·3) years, ASCT was associated with significantly superior progression‐free survival hazard ratio (HR) 0·51, 0·27–0·98; P = 0·043 with a trend towards inferior overall survival (OS; HR 2·36;0·87–6·42; P = 0·1) due to more deaths from progressive disease (8% vs. 4%). Forty (41%) patients experienced relapse in the non‐ASCT cohort — 15 underwent HDC/ASCT with seven (47%) ongoing complete remission (CR); 10 chimeric antigen receptor‐modified T‐cell (CAR‐T) therapy with 6 (60%) ongoing CR; 3 allogeneic SCT with 2 (67%) ongoing CR. Although ASCT in CR1 improves initial duration of disease control in untreated Tr‐iNHL, the impact on OS is less clear with effective salvage therapies in this era of CAR‐T.
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