Citations

Abstract Background Estrogen-based hormone treatment (EBHT), in the form of either oral contraceptives or hormone replacement therapy, is generally felt to be associated with an increased risk of thrombosis in women with essential thrombocythemia (ET). However, there is insufficient evidence to support or refute such a concern. Methods Data was abstracted from medical records of a consecutive cohort of women with ET seen at the Mayo Clinic. Thrombotic risk was determined by the occurrence of a major thrombotic event namely myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, peripheral arterial thrombosis, pulmonary embolism, or deep venous thrombosis at or after diagnosis of ET. Results i. Information regarding EBHT at or after the diagnosis of ET The study cohort included 307 women with ET (median age, 55 years; range 16–88) with a median follow-up of 133 months from diagnosis (range, 0.2–397). EBHT at or after diagnosis was documented in 93 women (30%); 59 patients were on EBHT at time of diagnosis and treatment was initiated after diagnosis in 34 patients. Among the 59 patients who were receiving EBHT at the time of diagnosis, treatment was discontinued within one month of their ET diagnosis in 17 patients but continued in the other 42 patients for a median of 48 months (range, 2–168). In the 34 patients with EBHT that was initiated after the diagnosis of ET, median treatment period was 44 months (range, 1–144). ii. Correlation between EBHT and thrombosis at diagnosis At diagnosis, major thrombosis was documented in a total of 74 patients (24%) that included 11 of the 59 patients (19%) on EBHT and 63 of 248 patients (25%) that were not receiving such therapy at the time of diagnosis (p=0.28). iii. Correlation between EBHT and thrombosis after diagnosis A total of 95 patients (31%) experienced a subsequent (i.e. post-diagnosis) thrombotic episode during the study period. These occurred in 65 of 214 patients (30%) that were not exposed to EBHT at or after diagnosis, 5 of 17 patients (29%) in whom EBHT was discontinued with the diagnosis of ET, 13 of 42 patients (31%) in whom EBHT was continued despite the diagnosis of ET, and 12 of 34 patients (35%) in whom EBHT was started after the diagnosis of ET (p=0.95). Furthermore, duration of EBHT, using a cutoff value of 1 year, did not significantly affect the incidence of thrombotic events (p=0.67). The different comparative groups were similar in age distribution as well as frequency of other cardiovascular risk factors including smoking, diabetes mellitus, hypertension, and hyperlipidemia. Conclusion The current study addresses the important issue of safety pertaining to the use of estrogen-based hormones in women with ET and did not reveal a significant alteration of thrombosis risk as a result of hormone therapy.

Abstract Background: Leukocytosis has recently been implicated as an adverse prognostic feature for thrombosis in both ET and PV. Such an association would be therapeutically most relevant in the context of “low-risk” disease. In the current study, we sought to clarify the relationship between leukocytosis at diagnosis and the subsequent occurrence of either arterial or venous thrombosis, in “low-risk” patients with ET or PV. Methods: Data was abstracted from the medical records of a consecutive cohort of patients with WHO-defined ET or PV seen at the Mayo Clinic. Low-risk disease was defined by the absence of both thrombosis history and age 3 60 years. Cox proportional hazards model was utilized to determine the impact of clinical and laboratory variables on thrombosis-free survival (TFS). Arterial- or venous-specific TFS curves were constructed by Kaplan-Meier method. Results: i) Patient characteristics and outcome A total of 407 “low-risk” patients were studied; 153 had PV (median age 48 years; females 43%) and 254 ET (median age 42 years; females 71%). A total of 46 thrombotic events (22 arterial and 24 venous) were recorded in 41 (27%) patients with PV during a median follow up of 130 months (range 2–562 months). The corresponding figures in ET were 54 total thrombotic events (41 arterial and 14 venous) in 47 (19%) patients at a median follow up of 104 months (range 0.25–424 months). Cytoreductive therapy was avoided in the presence of < 1000 x 109/L platelet count but, at the discretion of the treating physician, some patients with higher platelet counts received prophylactic cytoreductive therapy. ii) Correlation between leukocytosis and thrombosis A leukocyte count of 3 15 x 109/L at diagnosis was documented in 42 (27%) patients with PV and 21 (8%) patients with ET; 102 patients (40%) with ET had > 9.4 x 109/L leukocyte count. Leukocyte count considered as either a continuous or categorical variable (using cutoff levels of 15 x 109/L for PV and either 15 x 109/L or 9.4 x 109/L for ET) was not significantly associated with either arterial or venous thrombosis (Figure 1). iii) Correlation between other risk factors and thrombosis In univariate analysis, presence of the JAK2V617F was significantly associated with arterial thrombosis in ET (p=0.049) but significance was lost during multivariable analysis that included age as a covariate. Only advanced age was found to be significantly associated with arterial thrombosis in PV (p=0.04) and higher hemoglobin level with venous thrombosis in ET (p<0.0001). Conclusion: The current study does not identify leukocyte count at diagnosis as a marker of increased thrombosis risk in low-risk patients with either ET or PV. Instead, the study found an association between arterial thrombosis and advanced age in PV and venous thrombosis and higher hemoglobin level in ET. Figure Figure

Abstract Background: While currently-diagnosable hematological cancer is a potent VTE risk factor (RR range =12–32), whether undiagnosable hematological cancer is a risk factor is uncertain. Objective: To estimate the hazard of subsequent hematological cancer among incident VTE patients with no apparent active hematological cancer within ± 3 months of the VTE event. Methods: In a population-based cohort study, we followed Olmsted County, MN residents with incident VTE over the 27-year period, 1973–1999, and previously matched Olmsted County residents without VTE, who survived with no apparent active hematological cancer within ± 3 months of the VTE event or a routine medical visit date, respectively, forward in time through their complete medical records in the community for hematological cancer. Data were abstracted on baseline demographic and clinical characteristics, type and stage of hematological cancer, and any prior solid tumor treatments. For cases and controls, hematological cancer-free survival from the event date was estimated by the Kaplan Meier method, and the homogeneity of survival curves was examined by the log-rank test. Cox proportional hazards regression was used to adjust for covariates. Results: 1860 VTE cases (56% females) and 1890 controls (53% females) were followed for 16,497 and 15,320 person-years, respectively, conditional on surviving 3-months free of hematological cancer. 43 VTE cases and 24 controls developed hematological cancer at a median of 63.5 months (range 0.7 – 334 months). The median age for cases was 63.2 years compared to 67.8 years for the controls (p<0.001). Hematological cancer types included non-Hodgkin’s lymphoma (n=19), chronic lymphocytic leukemia (n=11), acute myeloid leukemia (n=1), multiple myeloma (n=9), myeloproliferative disorders (n=10), and myelodysplastic syndromes (n=14). Case status was not univariately associated with subsequent hematologic cancer (HR=1.42; 95% CI: 0.85, 2.39; p=0.18). After adjusting for age, also associated with cancer, case status was significantly associated with hematological cancer (HR=1.90; 95% CI: 1.13, 3.20; p=0.015). Conclusions: Incident VTE patients have nearly a two-fold increased risk of subsequent hematological cancer. We hypothesize that VTE can be the initial manifestation of an occult hematological cancer clone.

Abstract Background: Essential thrombocythemia (ET) frequently occurs in women of childbearing age. Recently, an increased risk of pregnancy complications was reported in patients with ET carrying the JAK2V617F mutation (Passamonti et al. Blood. 2007;110:485). In the current study, we sought to validate this observation as well as identify other predictors of pregnancy loss in ET. Methods: Data was abstracted from the medical records of a consecutive cohort of patients with WHO-defined ET seen at the Mayo Clinic. Patient characteristics and pregnancy outcome are summarized using descriptive statistics. The analysis of risk factors associated with pregnancy complications was carried out by both univariate and multivariate analyses. Results: i) Patient characteristics at ET diagnosis A total of 63 pregnancies were recorded in 36 women at or after their diagnosis of ET. At diagnosis of ET, median (range) values were: age 26 years (15–36), platelet count 1350 x 109/L (683–3300), hemoglobin level 13.3 g/dL (10.5–16) and leukocyte count 9.3 x109/L (5–26.9). JAK2V617F mutation analysis was performed in 20 patients; half were positive. Only 5 patients had a history of thrombosis at diagnosis. Follow-up after ET diagnosis was for a median of 82.9 months (range, 6.5–340.8 months). ii) Outcome of first pregnancy at or after diagnosis of ET A total of 36 first pregnancies were documented at or after the diagnosis of ET. At the time, median (range) values were: time from diagnosis 25.5 months (0–155), age 28 years (20–36), platelet count 840 x 109/L (255–1998), hemoglobin 12.9 g/dl (9–16.6) and leukocyte count 8.4 x109/L (6.6–19.8). Seven of the 36 (19%) women were receiving cytoreductive therapy at time of conception: anagrelide (n=4), interferon (n=1), hydroxyurea (n=1) and radiophosphorus (n=1). Aspirin therapy was documented in 53% of the women at time of conception and in 69% during the first trimester of their pregnancy. Among the 36 first pregnancies, 61% (n=22) resulted in live birth and 39% (n=14) in fetal loss. Twelve of the 14 pregnancy losses occurred during the first trimester (10 spontaneous miscarriages, 1 ectopic pregnancy and 1 therapeutic abortion) and the remaining two during the second trimester. Maternal complications occurred in 11% (n=4) of pregnancies and included pre-eclampsia (n=1), hematoma after Cesarean-section (n=2) and post-partum hemorrhage (n=1). iii) Predictors of first pregnancy outcome in ET Pregnancy outcome, in terms of live birth versus miscarriage did not correlate with age (p=0.27), presence of cardiovascular risk factor (p=0.76), platelet count (p=0.49), leukocyte count (p=0.67) or hemoglobin level (p=0.31). Similarly, pregnancy loss was similar between JAK2V617F-positive (4 of 10 pregnancies) and JAK2V617F-negative (4 of 10 pregnancies) patients (p>0.9). Furthermore, among 5 cases of 3 consecutive miscarriages, 4 were JAK2V617F-negative. Interestingly, the rate of pregnancy loss was only 21% among 24 patients receiving aspirin therapy during the first trimester as compared to 75% among the 12 patients in whom no such treatment was documented (p=0.002). iv) Second and subsequent pregnancy outcome Seventeen second pregnancies were recorded; 71% (n=12) resulted in live birth that included 8 of 9 patients with successful and 4 of 8 with unsuccessful first pregnancies (p=0.07). The trend was similar among 7 third pregnancies, which resulted in only one live birth; 5 of the 6 fetal losses occurred in women with history of first pregnancy loss (p=0.09). Conclusion: The current study does not support the recently communicated association between the presence of JAK2V617F and increased risk of pregnancy loss in ET. Instead, two parameters of potential importance for predicting pregnancy outcome in ET were identified; the occurrence of a miscarriage might be a marker for a similar event during subsequent pregnancies whereas aspirin therapy during the first trimester might be beneficial.

Abstract Background: Previous cytogenetic studies in polycythemia vera (PV) have included a relatively small number of patients (“n” ranging 10–64). In the current study (n=137), we describe cytogenetic findings at presentation and examine their relationship to clinical and laboratory features, including bone marrow JAK2V617F allele burden. Methods: The study consisted of a consecutive group of patients with PV who fulfilled the World Health Organization (WHO) diagnostic criteria and in whom bone marrow biopsy and cytogenetic studies were performed at diagnosis. Results I: cytogenetic details At diagnosis: A total of 137 patients (median age, 64 years; 49% females) were studied at diagnosis and had adequate metaphases for interpretation. Cytogenetics were normal in 117 patients (85%) and displayed either a sole -Y abnormality in 5 patients (7% of the male patients), and other chromosomal abnormalities in 15 (11%). The latter included trisomy 8 in five patients, trisomy 9 in three patients, two patients each with del(13q), del(20q), and abnormalities of chromosome 1, and one patient each with del(3)(p13p21), dup(13)(q12q14), and del(11)(q21). At follow-up: Repeat cytogenetic studies while still in the chronic phase of the disease were performed in 19 patients at a median of 60 months (range, 8–198) from diagnosis. Of these, 4 had aquired new cytogenetic clones including 3 with normal cytogenetics at time of initial PV diagnosis. The new abnormalities included del(20q), del(5q), del(1p), chromosome 1 abnormality, and inv(3)(q21q26.2). At time of disease transformation: Leukemic transformation was documented in 3 patients of whom cytogenetic information at the time was available in 2 patients; both patients had normal results at time of initial PV diagnosis and complex cytogenetic abnormalities at time of leukemic transformation. In contrast, among 6 patients with available cytogenetic information at time of fibrotic transformation, the results were unchanged from those obtained at time of diagnosis in 5 patients. ii) Correlation between cytogenetics at diagnosis and JAK2V617F allele burden: Allele-specific, quantitative PCR analysis for JAK2V617F was performed in 71 patients using genomic DNA from archived bone marrow obtained at the time of the initial cytogenetic studies. JAK2V617F mutation was detected in 64 of the 71 (90%) patients; median mutant allele burden was 16% (range 3–80%) without significant difference among the different cytogenetic groups: normal vs. –Y vs. other cytogenetic abnormalities (p=0.72). iii) Clinical correlates and prognostic relevance of cytogenetic findings at diagnosis: Among several parameters studied for significant correlations with cytogenetic findings at diagnosis, an association was evident only for age (p=0.02); all –Y abnormalities (n=5) as well as 13 of the 15 (87%) other cytogenetic abnormalities occurred in patients ≥ 60 years of age. Stated another way, the incidence of abnormal cytogenetics (other than -Y) was 4% for patients younger than age 60 years and 15% otherwise. The presence of abnormal cytogenetics at diagnosis had no significant impact on either overall or leukemia-free survival. Conclusions: Abnormal cytogenetic findings at diagnosis are infrequent in PV, especially in patients below age 60 years. Furthermore, their clinical relevance is limited and there is not significant correlation with bone marrow JAK2V617F allele burden.

Abstract Background: Pruritus in polycythemia vera (PV) has been associated with a high JAK2V617F allele burden (Tefferi et al. Cancer. 2006;106:631, Vannucchi et al, Leukemia2007, in press). However, there is limited information regarding clinical correlates of pruritus per se in PV. Accordingly, we conducted a large (n=418) retrospective study in PV to accurately assess the prevalence and severity of pruritus as well as its relationship with presenting clinical features, bone marrow JAK2V617F allele burden, and prognosis. Methods: The study cohort consisted of a consecutive group of patients with PV who fulfilled the World Health Organization (WHO) diagnostic criteria and in whom information regarding the presence or absence of pruritus at diagnosis was fully documented. Pruritus was graded as being mild, moderate, or severe based on careful review of patient history. Results: Prevalence and severity of pruritus: A total of 418 patients fulfilled the above stipulated criteria for study inclusion (median age of 60 years; 56% males; median follow-up of 73 months). Of these, 131 (31%) experienced pruritus at time of initial diagnosis: mild in 97 patients (74%), moderate in 22 (17%), and severe in 12 (9%). Most patients with mild pruritus (n=92) received no specific therapy for pruritus whereas all 12 patients with severe pruritus required treatment; all 7 patients who received treatment with paroxetine responded. Pruritus and JAK2V617F allele burden: Quantitative measurement of JAK2V617F was performed in 64 patients using genomic DNA from archived bone marrow obtained at the time of PV diagnosis. Mutational frequency was 97%; median mutant allele burden was 25.4% (range 0.2 - 93.3%). Among the 62 V617F-positive patients, 24 (39%) had pruritus; the proportion of patients in the upper and lower quartile allele burden ranges were 50% and 0% in the presence of pruritus and 18% and 34% in its absence (p=0.002). Clinical correlates of pruritus: Pruritus was more prevalent in non-smokers (35% vs. 19%; p=0.004) and non-diabetics (33% vs. 16%; p=0.04) and was associated with a lower rate of arterial thrombosis at diagnosis (8% vs. 17%; p=0.01) as well as during follow-up (16% vs. 30%; p=0.003). These significant associations remained intact during multivariable analysis. Pruritus did not have an impact on the rate of leukemic or fibrotic transformation. Conclusions: Pruritus in PV is independently associated with a lower risk of arterial thrombosis despite high JAK2V617F allele burden and is also more prevalent in non-smokers. These observations suggest that pruritus might be a surrogate for an underlying platelet pathology with functional relevance.

In this phase 1 trial, inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was associated with clinically meaningful responses in 5 of 15 patients with relapsed or refractory chronic myelomonocytic leukemia (CMML). Preliminary data suggest that this approach may be tractable in CMML bearing activating NRAS mutations.

SummaryMyelofibrosis is an enigmatic myeloproliferative neoplasm, despite noteworthy strides in understanding its genetic underpinnings. Driver mutations involving JAK2, CALR or MPL in 90% of patients mediate constitutive JAK‐STAT signaling which, in concert with epigenetic alterations (ASXL1, DNMT3A, SRSF2, EZH2, IDH1/2 mutations), play a fundamental role in disease pathogenesis. Aberrant immature megakaryocytes are a quintessential feature, exhibiting reduced GATA1 protein expression and secreting a plethora of pro‐inflammatory cytokines (IL‐1 ß, TGF‐ß), growth factors (b‐FGF, PDGF, VEGF) in addition to extra cellular matrix components (fibronectin, laminin, collagens). The ensuing disrupted interactions amongst the megakaryocytes, osteoblasts, endothelium, stromal cells and myofibroblasts within the bone marrow culminate in the development of fibrosis and osteosclerosis. Presently, prognostic assessment tools for primary myelofibrosis (PMF) are centered on genetics, with incorporation of cytogenetic and molecular information into the mutation‐enhanced (MIPSS 70‐plus version 2.0) and genetically‐inspired (GIPSS) prognostic scoring systems. Both models illustrate substantial clinical heterogeneity in PMF and serve as the crux for risk‐adapted therapeutic decisions. A major challenge remains the dearth of disease‐modifying drugs, whereas allogeneic transplant offers the chance of long‐term remission for some patients. Our review serves to synopsise current appreciation of the pathogenesis of myelofibrosis together with emerging management strategies.