Hsi, Eric D

Abstract The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p<0.0001) and overall survival (7.8 years vs. 11.8 years, p<0.0001) were significantly inferior in the short DTI group than the long DTI cohort and remained significant for progression-free survival and overall survival in multivariable analysis. We show that the DTI is an important prognostic factor in patients newly diagnosed with MCL and is strongly associated with adverse clinical factors and poor outcomes. DTI should be reported in all the patients newly diagnosed with MCL who are enrolling in clinical trials and steps must be taken to ensure selection bias is avoided.

PURPOSE Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)–adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET−) disease and intensifying treatment in patients with PET-positive (PET+) disease. METHODS Eligible patients with bulky disease (mass > 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray) received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by interim fluorodeoxyglucose PET (PET2). Patients with PET2–, defined as 1-3 on the 5-point scale, received four additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with PET2+ received four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone followed by 30.6 Gy involved-field radiation. RESULTS Of 94 evaluable patients, 53% were female with median age 30 years (range, 18-58 years). Eight-five (90%) had stage II disease, including 48 (51%) with stage IIB/IIBE. Seventy-eight (78%) were PET2– and 21 (22%) were PET2+. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia and one developing sepsis. The primary end point of 3-year progression-free survival (PFS) was 93.1% in PET2– and 89.7% in PET2+ patients. Three-year overall survival was 98.6% and 94.4%, respectively. The estimated hazard ratio comparing PFS of patients with PET2+ and patients with PET2− was 1.03 (85% upper bound 2.38) and was significantly less than the null hypothesis of 4.1 (one-sided P = .04). CONCLUSION Our study of PET-adapted therapy in bulky stage I/II cHL met its primary goal and was associated with an excellent 3-year PFS rate of 92.3% in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

Abstract With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

AbstractEnumeration of blasts and promonocytes is essential for World Health Organization (WHO) classification of myelomonocytic neoplasms. The accuracy of distinguishing blasts, promonocytes and monocytes, including normal vs abnormal monocytes, remains controversial. The objective of this analysis is to assess concordances between experienced hematopathologists in classifying cells as blasts, promonocytes, and monocytes according to WHO criteria. Each of 11 hematopathologists assessed glass slides from 20 patients [12 with chronic myelomonocytic leukemia (CMML) and 8 with acute myeloid leukemia (AML)] including blood and BM aspirate smears, and limited nonspecific esterase (NSE) stains. All cases were blindly reviewed. Fleiss’ extension of Cohen's kappa for multiple raters was used on these variables, separately for peripheral blood (PB) and bone marrow (BM). Spearman's rank correlation was used to assess correlations between each pair of hematopathologists for each measurement. For the classification based on the sum of blasts and promonocytes in the BM, Fleiss’ kappa was estimated as 0.744. For PB, categorizing patients according to the sum of blasts and promonocytes, Fleiss’ kappa was estimated as 0.949. Distinction of abnormal monocytes from normal monocytes in PB did not achieve a good concordance and showed strong evidence of differences between hematopathologists (P < .0001). The hematopathologists achieved a good concordance rate of 74% in CMML vs AML classification and a high k rate, confirming that criteria for defining the blasts equivalents (blasts plus promonocytes) could be applied consistently. Identification of monocyte subtypes (abnormal vs normal) was not concordant. Our results support the practice of combining blasts/promonocytes into a single category.