Juergen Thiele

The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes

Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.

Histomorphologic Tumor Regression and Lymph Node Metastases Determine Prognosis Following Neoadjuvant Radiochemotherapy for Esophageal Cancer: Implications for Response Classification

Objective:We sought to quantitatively and objectively evaluate histomorphologic tumor regression and establish a relevant prognostic regression classification system for esophageal cancer patients receiving neoadjuvant radiochemotherapy. Patients and Methods:Eighty-five consecutive patients with localized esophageal cancers (cT2-4, Nx, M0) received standardized neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, 36 Gy). Seventy-four (87%) patients were resected by transthoracic en bloc esophagectomy and 2-field lymphadenectomy. The entire tumor beds of the resected specimens were evaluated histomorphologically, and regression was categorized into grades I to IV based on the percentage of vital residual tumor cells (VRTCs). A major response was achieved when specimens contained either less than 10% VRTCs (grade III) or a pathologic complete remission (grade IV). Results:Complete resections (R0) were performed in 66 of 74 (89%) patients with 3-year survival rates of 54% ± 7.05% for R0-resected cases and 0% for patients with incomplete resections ortumor progression during neoadjuvant therapy (P < 0.01). Minor histopathologic response was present in 44 (59.5%) and major histopathologic response in 30 (40.5%) tumors. Significantly different 3-year survival rates (38.8% ± 8.1% for minor versus 70.7 ± 10.1% for major response) were observed. Univariate survival analysis identified histomorphologic tumor regression (P < 0.004) and lymph node category (P < 0.01) as significant prognostic factors. Pathologic T category (P < 0.08), histologic type (P = 0.15), or grading (P = 0.33) had no significant impact on survival. Cox regression analysis identified dichotomized regression grades (minor and major histomorphologic regression, P < 0.028) and lymph node status (ypN0 and ypN1, P < 0.036) as significant independent prognostic parameters. A 2-parameter regression classification system that includes histomorphologic regression (major versus minor) and nodal status (ypN0 versus ypN1) was established (P < 0.001). Conclusions:Histomorphologic tumor regression and lymph node status (ypN) were significant prognostic parameters for patients with complete resections (R0) following neoadjuvant radiochemotherapy for esophageal cancer. A regression classification based on 2 parameters could lead to improved objective evaluation of the effectiveness of treatment protocols, accuracy of staging and restaging modalities, and molecular response prediction.

Survival and Disease Progression in Essential Thrombocythemia Are Significantly Influenced by Accurate Morphologic Diagnosis: An International Study

PURPOSE The WHO diagnostic criteria underscore the role of bone marrow (BM) morphology in distinguishing essential thrombocythemia (ET) from early/prefibrotic primary myelofibrosis (PMF). This study examined the clinical relevance of such a distinction. METHODS Representatives from seven international centers of excellence for myeloproliferative neoplasms convened to create a clinicopathologic database of patients previously diagnosed as having ET (N = 1,104). Study eligibility criteria included availability of treatment-naive BM specimens obtained within 1 year of diagnosis. All bone marrows subsequently underwent a central re-review. RESULTS Diagnosis was confirmed as ET in 891 patients (81%) and was revised to early/prefibrotic PMF in 180 (16%); 33 patients were not evaluable. In early/prefibrotic PMF compared with ET, the 10-year survival rates (76% and 89%, respectively) and 15-year survival rates (59% and 80%, respectively), leukemic transformation rates at 10 years (5.8% and 0.7%, respectively) and 15 years (11.7% and 2.1%, respectively), and rates of progression to overt myelofibrosis at 10 years (12.3% and 0.8%, respectively) and 15 years (16.9% and 9.3%) were significantly worse. The respective death, leukemia, and overt myelofibrosis incidence rates per 100 patient-years for early/prefibrotic PMF compared with ET were 2.7% and 1.3% (relative risk [RR], 2.1; P < .001), 0.6% and 0.1% (RR, 5.2; P = .001), and 1% and 0.5% (RR, 2.0; P = .04). Multivariable analysis confirmed these findings and also identified age older than 60 years (hazard ratio [HR], 6.7), leukocyte count greater than 11 × 10(9)/L (HR, 2.01), anemia (HR, 2.95), and thrombosis history (HR, 2.81) as additional risk factors for survival. Thrombosis and JAK2V617F incidence rates were similar between the two groups. Survival in ET was similar to the sex- and age-standardized European population. CONCLUSION This study validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET and provides important information on survival, disease complication rates, and prognostic factors in strictly WHO-defined ET and early/prefibrotic PMF.

Development and validation of an International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSET-thrombosis)

Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO)-defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis-derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events.

Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis

Janus kinase 2 (JAK2) mutations define polycythemia vera (PV). Calreticulin (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations are specific to JAK2-unmutated essential thrombocythemia (ET) and primary myelofibrosis (PMF). We examined the effect of these mutations on long-term disease outcome. One thousand five hundred eighty-one patients from the Mayo Clinic (n = 826) and Italy (n = 755) were studied. Fifty-eight percent of Mayo patients were followed until death; median survivals were 19.8 years in ET (n = 292), 13.5 PV (n = 267; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4-2.2), and 5.9 PMF (n = 267; HR, 4.5; 95% CI, 3.5-5.7). The survival advantage of ET over PV was not affected by JAK2/CALR/MPL mutational status. Survival in ET was inferior to the age- and sex-matched US population (P < .001). In PMF (n = 428), but not in ET (n = 576), survival and blast transformation (BT) were significantly affected by mutational status; outcome was best in CALR-mutated and worst in triple-negative patients: median survival, 16 vs 2.3 years (HR, 5.1; 95% CI, 3.2-8.0) and BT, 6.5% vs 25% (HR, 7.6; 95% CI, 2.8-20.2), respectively. We conclude that life expectancy in morphologically defined ET is significantly reduced but remains superior to that of PV, regardless of mutational status. In PMF, JAK2/CALR/MPL mutational status is prognostically informative.

Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients

In an international collaborative study, a central histologic review identified 891 patients with essential thrombocythemia, strictly defined by World Health Organization criteria. After a median follow-up of 6.2 years, 109 (12%) patients experienced arterial (n = 79) or venous (n = 37) thrombosis. In multivariable analysis, predictors of arterial thrombosis included age more than 60 years (P = .03; hazard ratio [HR] = 1.7), thrombosis history (P = .003; HR = 2.1), cardiovascular risk factors including tobacco use, hypertension, or diabetes mellitus (P = .007; HR = 1.9), leukocytosis (> 11 × 10(9)/L; P = .04; HR = 1.7), and presence of JAK2V617F (P = .009; HR = 2.6). In contrast, only male gender predicted venous thrombosis. Platelet count more than 1000 × 10(9)/L was associated with a lower risk of arterial thrombosis (P = .007; HR = 0.4). These associations, except the one with leukocytosis, remained significant (or near significant) when analysis was restricted to JAK2V617F-positive cases. The current study clarifies the contribution of specific disease and host characteristics to the risk of arterial versus venous thrombosis in essential thrombocythemia.

Pomalidomide is active in the treatment of anemia associated with myelofibrosis

PURPOSE Thalidomide and lenalidomide can alleviate anemia in myelofibrosis. However, their value is undermined by their respective potential to cause peripheral neuropathy and myelosuppression. We therefore evaluated the safety and therapeutic activity of another immunomodulatory drug, pomalidomide. METHODS In a phase II randomized, multicenter, double-blind, adaptive design study, four treatment arms were evaluated: pomalidomide (2 mg/d) plus placebo, pomalidomide (2 mg/d) plus prednisone, pomalidomide (0.5 mg/d) plus prednisone, and prednisone plus placebo. Pomalidomide was administered for up to 12 28-day treatment cycles. Prednisone (30 mg/d) was given in a tapering dose schedule during the first three cycles. Response was assessed by International Working Group criteria. RESULTS Eighty-four patients with myelofibrosis-associated anemia were randomly assigned to the aforementioned treatment arms: 22, 19, 22, and 21, respectively. Response in anemia was documented in 20 patients, including 15 who became transfusion independent. Response rates in the four treatment arms were 23% (95% CI, 5% to 41%), 16% (95% CI, 0% to 33%), 36% (95% CI, 16% to 56%), and 19% (95% CI, 2% to 36%). The corresponding figures for patients receiving > or = 3 cycles of treatment (n = 62) were 38%, 23%, 40%, and 25%. Response to pomalidomide with or without prednisone was durable (range, 3.2 to 16.9+ months) and significantly better in the absence of leukocytosis (37% v 8%; P = .01); JAK2V617F or cytogenetic status did not affect response. Grade > or = 3 toxicities were infrequent and included (in each treatment arm) neutropenia (9%; 16%; 5%; 5%), thrombocytopenia (14%; 16%; 9%; 5%), and thrombosis (9%; 5%; 0%; 0%). CONCLUSION Pomalidomide therapy at 0.5 or 2 mg/d with or without an abbreviated course of prednisone is well tolerated in patients with myelofibrosis and active in the treatment of anemia.

Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial

High platelet counts in essential thrombocythemia (ET) can be effectively lowered by treatment with either anagrelide or hydroxyurea. In 259 previously untreated, high-risk patients with ET, diagnosed according to the World Health Organization classification system, the efficacy and tolerability of anagrelide compared with hydroxyurea were investigated in a prospective randomized noninferiority phase 3 study in an a priori-ordered hypothesis. Confirmatory proof of the noninferiority of anagrelide was achieved after 6 months using the primary end point criteria and was further confirmed after an observation time of 12 and 36 months for platelet counts, hemoglobin levels, leukocyte counts (P < .001), and ET-related events (HR, 1.19 [95% CI, 0.61-2.30], 1.03 [95% CI, 0.57-1.81], and 0.92 [95% CI, 0.57-1.46], respectively). During the total observation time of 730 patient-years, there was no significant difference between the anagrelide and hydroxyurea group regarding incidences of major arterial (7 vs 8) and venous (2 vs 6) thrombosis, severe bleeding events (5 vs 2), minor arterial (24 vs 20) and venous (3 vs 3) thrombosis and minor bleeding events (18 vs 15), or rates of discontinuation (adverse events 12 vs 15 or lack of response 5 vs 2). Disease transformation into myelofibrosis or secondary leukemia was not reported. Anagrelide as a selective platelet-lowering agent is not inferior compared with hydroxyurea in the prevention of thrombotic complications in patients with ET diagnosed according to the World Health Organization system. This trial was registered at http://www.clinicaltrials.gov as #NCT01065038.

The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos.

The first formal classification of chronic myeloid neoplasms is credited to William Dameshek, who in 1951 described the concept of “myeloproliferative disorders (MPD)” by grouping together chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2001 World Health Organization (WHO) classification of myeloid malignancies included these MPDs under the broader category of chronic myeloproliferative diseases (CMPD), which also included chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), and “CMPD, unclassifiable.” The revised 2008 WHO classification system featured the following changes: 1) the term “CMPD” was replaced by “myeloproliferative neoplasm (MPN),” 2) mast cell disease was formally included under the category of MPN, and 3) the subcategory of CEL/HES was reorganized into “CEL not otherwise specified (CEL‐NOS)” and “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1”; CEL‐NOS remained a subcategory of “MPN,” whereas the latter neoplasms were now assigned a new category of their own. Furthermore, diagnostic criteria for PV, ET, and PMF were revised by incorporating recently described molecular markers (eg, JAK2 and MPL mutations) as well as underscoring the role of histology in differentiating reactive from clonal myeloproliferations. As a result, red cell mass measurement is no longer necessary for the diagnosis of PV, and ET can now be diagnosed at a lower platelet count threshold. The revised WHO document continues to promote the recognition of histologic categories as a necessary first step toward the genetic characterization of myeloid malignancies. Cancer 2009.

Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report

The current document is a revision of the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for treatment response in myelofibrosis (MF) and represents a collaborative effort by the IWG-MRT and the European LeukemiaNet to objectively assess the value of new drugs in inducing morphologic remission or improvement in MF-associated symptomatic burden (MF-SB). Some of the changes in the current revision include stricter definitions of red cell transfusion dependency and independency and consideration of the Myeloproliferative Neoplasm Symptom Assessment Form as a tool to quantify meaningful changes in disease-related symptoms. Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-SB were annotated as clinical improvement, anemia response, spleen response, or symptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The document also includes recommendations for assessing cytogenetic and molecular remissions, without mandating their inclusion for CR assignment.