ABSTRACT
T‐cell prolymphocytic leukemia (T‐PLL) is a rare and aggressive mature T‐cell malignancy characterized by marked lymphocytosis, B symptoms, lymphadenopathy, and hepatosplenomegaly. There is ...no standard treatment approach, and in the absence of an allogeneic transplant, the prognosis remains poor. The disease‐defining cytogenetic abnormality in T‐PLL is the juxtaposition of the TCL1‐family oncogene to the TCR gene enhancer locus primarily due to an inversion of chromosome 14, that is, inv(14). The application of next‐generation sequencing technologies led to the discovery of highly recurrent gain‐of‐function mutations in JAK1/3 and STAT5B in over 70% of T‐PLL providing opportunities for therapeutic intervention using small molecule inhibitors. Additional genetic mechanisms that may contribute to the pathogenesis of T‐PLL remain unknown. Herein we describe the identification of a novel gene fusion SMCHD1::JAK2 resulting from a translocation between chromosome 9 and 18 involving SMCHD1 exon 45 and JAK2 exon 14 (t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)), a previously undescribed genetic event in a patient with T‐PLL harboring the key disease defining inv(14) resulting in rearrangement of TCL1 and TRA/D. In this manuscript, we describe the clinical and genetic features of the patient's disease course over a 25‐month post‐treatment duration using ruxolitinib and duvelisib.
MDX-060 is a human anti-CD30 immunoglobulin (Ig) G1kappa monoclonal antibody that inhibits growth of CD30-expressing tumor cells in preclinical models. To determine the safety, maximum-tolerated dose ...(MTD), and efficacy of MDX-060 in patients with relapsed or refractory CD30+ lymphomas, sequential phase I and II studies were performed.
In the phase I portion, MDX-060 was administered intravenously at doses of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of three to six patients. Twenty-one patients--16 with Hodgkin's lymphoma (HL), three with anaplastic large-cell lymphoma (ALCL), and two with CD30+ T-cell lymphoma--were enrolled. Because of the lack of a defined MTD or dose-response correlation, the phase II portion was amended to include several dose levels. In the phase II portion, an additional 51 patients, 47 with HL and four with ALCL, were treated at doses of 1, 5, 10, and 15 mg/kg.
MDX-060 was well tolerated, and an MTD has not been identified. Only 7% of patients experienced grade 3 or 4 treatment-related adverse events. Among the 72 patients treated, clinical responses were observed in six. Twenty-five patients had stable disease, including five who remained free from progression 1 year after treatment.
MDX-060 was well tolerated at doses up to 15 mg/kg. MDX-060 has limited activity as a single agent, but the minimal toxicity observed and the significant proportion of patients with stable disease suggests that further study of MDX-060 in combination with other therapies is warranted.
Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data.
COMPLETE ...is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease.
Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days.
Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months.
Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.
The rarity and biological heterogeneity of the peripheral T-cell lymphomas has made subtype- and biomarker-driven approaches challenging to realize and even more challenging to evaluate in clinical ...practice. Out of necessity, treatment of T-cell lymphomas has historically been derivative of other aggressive lymphomas, utilizing intensive combination chemotherapy programs in the upfront setting and non-overlapping cytotoxic regimens upon relapse. However, due to tremendous work in understanding the oncogenic basis of these varied diseases, an increasing exploration of rational, targeted therapies is underway. Still, clinical successes have at times lagged behind pathobiological realizations, and there is an evolving need for biologically based, subtype-specific strategies in the clinic. Herein we propose a framework for future success that relies upon optimizing standard therapy in populations known to benefit from combination chemotherapy, building upon CHOP (or CHOP-like) induction with the CHOP + X model, exploring the use of targeted platforms in the relapsed and refractory setting, and designing biomarker-informed clinical trials that target-specific subhistologies and unique molecular subsets.
Multisystem inflammatory syndrome in children (MIS-C) is associated with recent or current SARS-CoV-2 infection. Information on MIS-C incidence is limited.
To estimate population-based MIS-C ...incidence per 1 000 000 person-months and to estimate MIS-C incidence per 1 000 000 SARS-CoV-2 infections in persons younger than 21 years.
This cohort study used enhanced surveillance data to identify persons with MIS-C during April to June 2020, in 7 jurisdictions reporting to both the Centers for Disease Control and Prevention national surveillance and to Overcoming COVID-19, a multicenter MIS-C study. Denominators for population-based estimates were derived from census estimates; denominators for incidence per 1 000 000 SARS-CoV-2 infections were estimated by applying published age- and month-specific multipliers accounting for underdetection of reported COVID-19 case counts. Jurisdictions included Connecticut, Georgia, Massachusetts, Michigan, New Jersey, New York (excluding New York City), and Pennsylvania. Data analyses were conducted from August to December 2020.
Race/ethnicity, sex, and age group (ie, ≤5, 6-10, 11-15, and 16-20 years).
Overall and stratum-specific adjusted estimated MIS-C incidence per 1 000 000 person-months and per 1 000 000 SARS-CoV-2 infections.
In the 7 jurisdictions examined, 248 persons with MIS-C were reported (median interquartile range age, 8 4-13 years; 133 53.6% male; 96 persons 38.7% were Hispanic or Latino; 75 persons 30.2% were Black). The incidence of MIS-C per 1 000 000 person-months was 5.1 (95% CI, 4.5-5.8) persons. Compared with White persons, incidence per 1 000 000 person-months was higher among Black persons (adjusted incidence rate ratio aIRR, 9.26 95% CI, 6.15-13.93), Hispanic or Latino persons (aIRR, 8.92 95% CI, 6.00-13.26), and Asian or Pacific Islander (aIRR, 2.94 95% CI, 1.49-5.82) persons. MIS-C incidence per 1 000 000 SARS-CoV-2 infections was 316 (95% CI, 278-357) persons and was higher among Black (aIRR, 5.62 95% CI, 3.68-8.60), Hispanic or Latino (aIRR, 4.26 95% CI, 2.85-6.38), and Asian or Pacific Islander persons (aIRR, 2.88 95% CI, 1.42-5.83) compared with White persons. For both analyses, incidence was highest among children aged 5 years or younger (4.9 95% CI, 3.7-6.6 children per 1 000 000 person-months) and children aged 6 to 10 years (6.3 95% CI, 4.8-8.3 children per 1 000 000 person-months).
In this cohort study, MIS-C was a rare complication associated with SARS-CoV-2 infection. Estimates for population-based incidence and incidence among persons with infection were higher among Black, Hispanic or Latino, and Asian or Pacific Islander persons. Further study is needed to understand variability by race/ethnicity and age group.
The prevalence of mycosis fungoides/Sézary syndrome (MF/SS) is higher in the black population than in the white population in the United States and worse outcomes have been observed in black ...patients.
To describe the outcomes and to identify prognostic factors in African American and black patients with MF/SS.
Clinical features and follow-up data were analyzed in 157 self-identified African American or black patients seen during 1994-2018.
We included 122 patients with early stage MF and 35 patients with advanced-stage disease (median follow-up of 25 months). Overall, >80% of the patients who died from disease or progressed had erythema or hyperpigmentation without hypopigmentation. Patients with hypopigmentation, either as the sole manifestation or in combination with other lesions, had better overall survival (P = .002) and progression-free survival (P = .014). Clinical stage, TNMB classification, plaque disease, and elevated serum lactate dehydrogenase were also significantly associated with outcomes. Demographic and socioeconomic parameters were not associated with prognosis.
A retrospective study at a single cancer center.
MF/SS manifestations and outcomes in African American and black patients are heterogeneous. Demographic and socioeconomic factors do not seem to have a prognostic role, while clinical characteristics might help in the stratification of risk of progression and shorter survival, allowing for individually tailored therapeutic interventions.
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