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Originally published as JCO Early Release 10.1200/JCO.2007.12.6896 on November 12 2007 © 2007 American Society of Clinical Oncology. Familial Chronic Myeloproliferative Disorders: Clinical Phenotype and Evidence of Disease Anticipation
From the Department of Hematology and Department of Pathology, University of Pavia Medical School, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy Address reprint requests to Elisa Rumi, MD, Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Viale Golgi 49, 27100 Pavia, Italy; e-mail: elisarumi{at}hotmail.com
Purpose Chronic myeloproliferative disorders (CMDs) have sporadic occurrence. However, familial clustering is reported. The purpose of this study was to assess the prevalence and the clinical phenotype of familial CMDs, and to study the anticipation of disease onset in successive generations. Patients and Methods Among 458 patients with apparently sporadic CMDs, an interview-based investigation of family history was performed to identify familial cases. The clinical phenotype of familial CMDs was compared with that of sporadic CMDs. Anticipation was studied evaluating age at diagnosis and telomere length in successive generations. Results Among 458 patients with apparently sporadic CMDs, the prevalence of familial cases was 7.6% (35 pedigrees; 75 patients). Kolmogorov-Smirnov and two-tailed Fisher's exact tests did not demonstrate significant differences in clinical presentation between patients with familial and sporadic CMDs. Within 544 person-years of follow-up, patients with familial CMDs developed similar complications and disease evolutions as those with sporadic CMDs. The comparison of second-generation and first-generation patients showed a significantly younger age at diagnosis (Wilcoxon matched-pair test, P = .001) and a significantly higher age-dependent hazard of CMD onset (Nelson-Aalen method, P < .001) in patients of the second generation. A significant shortening of telomere length was highlighted in offspring compared with parent (P = .043). Conclusion This study indicates that a thorough investigation of family history should be part of the initial work-up of patients with CMDs. Patients with familial CMDs show the same clinical features and suffer the same complications as patients with sporadic disease. Age distribution between parent and offspring and telomere length shortening provide evidence of disease anticipation.
Chronic myeloproliferative disorders (CMDs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) have a sporadic occurrence in most instances. However, familial clustering of CMDs has been reported.1-5 Studies of familial CMDs have demonstrated that the JAK2 (V617F) mutation6 does not represent the genetic predisposing factor.2,3 Clinical features of sporadic CMDs are well defined. PV and ET share many characteristics, including propensity to thrombosis and hemorrhage, and risk of developing myelofibrosis or leukemia in the long term.7 Clinical features of PMF are progressive splenomegaly, anemia, infections, and leukemic transformation.8 Median survival of patients with PV and ET may exceed 20 years,7 whereas that of patients with PMF ranges from 3.5 to 5.5 years.8 Regarding familial CMDs, the prevalence of the problem is still unknown. In a prior study we identified 20 pedigrees within 264 patients with apparently sporadic CMDs.3 However, the clinical presentation, complications, and outcome of patients with familial CMDs are still undefined issues. Homozygosity for JAK2 (V617F) seems to identify a higher risk of disease evolution.2 In this study we investigated 458 patients with apparently sporadic CMDs. By an interview-based investigation of family history, we identified 35 families with two or more members with CMDs, totaling 75 patients. The clinical phenotype of patients with familial CMDs was compared with that of patients with sporadic CMDs. Anticipation of disease onset in successive generations was studied.
Patients We studied 458 consecutive patients with apparently sporadic CMDs observed from 1973 to 2007 at the Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo (Pavia, Italy). This series includes patients reported in a prior study.3 Patients were interviewed about their family history of CMDs. The interview focused on two key points: the knowledge of a relative affected with CMD, and whether a diagnosis of CMD in a member of the family prompted specific investigations in other members of the family. Familial cases were defined when two or more individuals within the same pedigree were affected with CMDs. Clinical records of affected relatives were reviewed systematically to confirm CMD diagnosis. All affected relatives except seven relatives (for logistic reasons) underwent a disease restaging in our department. Patients without family history of CMDs were defined as having sporadic CMDs. Diagnosis of CMDs was made in accordance with the criteria in use at the time of the first observation.9-13 This study was approved by the Institutional Ethics Committee of Pavia and the procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000. Samples for molecular analysis were obtained after patients provided written informed consent.
JAK2 (V617F) Mutational Analysis
Flow Cytometric Analysis of Telomere Length
Statistics To assess the anticipation of age at disease onset in familial CMDs, we selected patients with two-generation pairs. The nonparametric Wilcoxon matched-pairs test was used to compare age at diagnosis and telomere length between the two-generation pairs. We also compared the rate of disease onset in the first and second generation, adopting age as a time scale. The Nelson-Aalen estimate of the cumulative hazard of disease onset was obtained and plotted. Survival functions were compared by means of the log-rank test. Data management and statistical computations were carried out using the following software: FileMaker Pro 6.0 (FileMaker Inc, Santa Clara, CA), Microsoft Excel 2000 (Microsoft Corp, Redmond, WA), Statistica software version 7.1 (Statsoft, Tulsa, OK), and Stata 9.2 (StataCorp LP, College Station, TX).
Interview-Based Prevalence of Familial Cases in CMDs Of 458 patients with apparently sporadic CMDs, 35 pedigrees (7.6%) were identified with two or more relatives affected. Figure 1 shows the diagnosis of the whole cohort of patients with CMDs and allocation of diagnosis within familial and sporadic cases. In detail, familial cases were identified in 18 (8.7%) of 206 patients with PV, in 10 (5.9%) of 167 patients with ET, and in seven (8.2%) of 85 patients with PMF. Diagnosis of CMDs in a member of the family did not prompt specific investigations among relatives.
Clinical Phenotype at Diagnosis Regarding the clinical phenotype within the familial cluster (Fig 2), 21 (60%) of 35 families showed a homogeneous pattern, which means the same disease in all affected relatives (PV in 13 families, ET in five families, PMF in three families). Fourteen families (40%) exhibited a mixed phenotype (ET and PMF in six families; ET and PV in five families; PV and PMF in two families; and PV, ET, and PMF in one family). Of the 35 families, 14 (40%) families included patients in a single generation and 21 (60%) families included patients in multiple generations (in 19 families the affected members belonged to the first and second generations; in two families the affected members belonged to the first and third generations).
Patients with PV were observed for 271 person-years of follow-up, those with ET were observed for 189 person-years of follow-up, and those with PMF were observed for 84 person-years of follow-up. Demographic and clinical characteristics at diagnosis are summarized in Table 1. Patients with PMF were at prefibrotic (five patients) or at fibrotic stage (10 patients). Patients received conventional treatments in use at the time of the observation.
Comparison of Clinical Phenotype Between Familial and Sporadic CMDs To evaluate whether clinical presentation of familial CMDs differs from that of sporadic CMDs, we compared the clinical and hematologic features at diagnosis of the 75 patients with familial CMDs with the 423 patients with sporadic CMDs (Table 1). Kolmogorov-Smirnov test and two-tailed Fisher's exact test showed that the clinical presentation of patients with familial and sporadic CMDs was not statistically different.
Disease Complications, Evolution, and Outcome
Thrombosis occurred in seven (19%) of 36 patients with PV, in two (8%) of 24 patients with ET, and in one (7%) of 15 patients with PMF. Thrombotic events included deep vein thrombosis (five; 50%), superficial thrombophlebitis of lower limb (one; 10%), myocardial infarction (one; 10%), ischemic stroke (one; 10%), transient ischemic attack (one; 10%), and splenic infarction (one; 10%). Of the 10 patients who had thrombosis, seven (70%) were receiving cytoreduction and seven (70%) were receiving antiplatelet therapy. Hemorrhage (gastric bleeding) occurred in one (3%) of 36 patients, with PV 3 months after diagnosis while receiving aspirin. Myelofibrosis occurred in one (3%) of 36 patients with PV 15 years from diagnosis. Post-ET myelofibrosis occurred in two (8%) of 24 patients with ET. Acute myeloid leukemia occurred in two (6%) of 36 patients with PV at 122 and 156 months from diagnosis, respectively (treatment was busulfan and hydroxyurea, respectively). Regarding patients with PMF, four (27%) of 15 patients developed leukemia after a median time of 105 months (range, 12 to 123 months). Patients with familial ET did not have leukemic transformation. As of January 2007, 62 (83%) of 75 patients with familial CMDs were alive: 29 (81%) of 36 with PV, 23 (96%) of 24 with ET, and 10 (67%) of 15 with PMF. The 10-year survival was 83% for patients with familial PV, 100% for those with familial ET, and 56% for those with familial PMF (30% for patients at the fibrotic stage).
JAK2 (V617F) Mutational Status
Disease Anticipation To evaluate anticipation of disease onset in familial CMDs, we studied 19 families including patients belonging to successive generations. At diagnosis, the median age of patients was 64 years (range, 43 to 78 years) in the first generation, and 40 years (range, 23 to 57 years) in the second generation. Wilcoxon matched-pair test demonstrated that second-generation patients had a significantly younger age at diagnosis than first-generation patients (P < .001). Similar age distribution was observed in the two families with third-generation patients: in both families the third-generation patient was younger at diagnosis than the first-generation patient (20 and 78 years;16 and 64 years, respectively). Applying the Nelson-Aalen method, we compared the cumulative hazard of CMD onset between patients in the first generation and those in the second generation, adopting age as a time scale (Fig 3A). The age-dependent hazard of CMD onset was significantly higher for second-generation patients than for first-generation patients (P < .001).
We also studied the  TEL by flow cytometry combined with fluorescent in situ hybridization in five families with two-generation pairs. We found a significantly shorter telomere length in patients of the second generation than in those of the first generation (P = .043; Fig 3B). Diagnoses were equally distributed among generations: one PV, three ET, and one PMF in both the first and the second generation. Within families, diagnosis was homogeneous in three pedigrees (both generations with ET in two families and both generations with PV in one family) and mixed in two pedigrees (PMF in the first and ET in the second generation; ET in the first and PMF in the second generation).
Although familial clustering of CMDs has been reported,1-5 the prevalence of the problem is still unknown. In this study we investigated 458 patients with apparently sporadic CMDs with the purpose to define the prevalence of familial cases. An interview-based investigation allowed us to identify 35 families with two or more members with CMDs, totaling 75 patients with familial CMDs. Although an interview-based analysis may underestimate the real prevalence of the problem, this analysis shows that the prevalence of familial cases within CMDs is at least 7.6%. This result reshapes clinical practice, indicating that a thorough investigation of family history should be part of the initial work-up of patients with CMDs. The pattern of inheritance we observed in patients with familial CMDs is consistent with an autosomal dominant trait with decreased penetrance, in keeping with previous studies.3,5 The clinical phenotype within the same pedigree was variable, given that 60% of families showed the same disease in all affected relatives and 40% had different CMDs. This observation is in favor of the presence of a mutation predisposing to familial CMDs in a multipotent stem cell,16 resulting in a selective expansion of myeloid-lineage cell progeny.17 According to recent studies on familial CMDs, the JAK2 (V617F) mutation does not represent the predisposing gene.1-4 This study shows that the clinical and hematologic features at diagnosis of familial cases do not significantly differ from those of sporadic cases. During 544 person-years of follow-up, patients with familial CMDs developed the same types of complications (thrombosis and hemorrhage) and disease evolution (post-PV myelofibrosis, post-ET myelofibrosis, and leukemia) reported in patients with sporadic CMDs.7,8,18-23 Among patients with familial CMDs, thrombosis occurred more frequently in those with PV, whereas hemorrhage was a rare event. Myelofibrosis occurred in both PV and ET in the long term. Leukemia occurred mainly in patients with PMF. The study design (on the basis of interview of alive patients) does not allow us to compare the incidences of events between familial and sporadic cases. The 10-year survival was 83% in patients with familial PV and 100% in those with familial ET, as observed in sporadic cases.7 The 10-year survival of patients with PMF at fibrotic stage was only 30%, and reached 56% when PMF patients at prefibrotic stage were included. These data indicate that familial and sporadic CMD patients have a similar clinical phenotype. Regarding the JAK2 (V617F) mutation among patients with sporadic CMDs, the rate of detection exceeds 90% in those with PV and 50% each in those with ET and PMF.14 The distribution of the JAK2 (V617F) mutation within familial CMDs seems different, in keeping with a prior French study.2 The segregation of the mutation within the same pedigree may explain the difference, given that 68% of families showed a homogenous pattern of the mutation. Within familial CMDs, the JAK2 (V617F) mutation burden parallels the proportions observed in sporadic cases.14,24,25 We also investigated the anticipation of disease onset in patients with familial CMDs with successive generations affected. This phenomenon suggests a progressively earlier disease onset or a more severe disease in successive generations.26 Disease anticipation is observed in genetic diseases involving unstable trinucleotide repeats.27 It has been reported also in families with acute leukemia,26 plasma cell dyscrasias,28 and chronic lymphocytic leukemia,29 but has never been studied in familial CMDs. This study provides evidence of disease anticipation in familial CMDs. In fact, patients in the second generation were significantly younger at diagnosis than those in the first generation, and had an higher age-dependent hazard of CMD onset. The presence of probands belonging to both younger and older generations prevents ascertainment bias.28 In addition, diagnosis of a CMD in a member of the family did not prompt specific investigations within relatives.
Given that telomere shortening may be involved in disease anticipation,30 we compared granulocyte In conclusion, this study shows that familial CMDs are relatively frequent and suggests a thorough investigation of family history in the clinical management of patients with apparently sporadic CMDs. Patients with familial CMDs show the same clinical and hematologic features and suffer the same complications as patients with sporadic disease. Age distribution between parent and offspring and telomere length shortening provide evidence of disease anticipation in familial CMDs.
The author(s) indicated no potential conflicts of interest.
Conception and design: Elisa Rumi, Francesco Passamonti, Mario Lazzarino Financial support: Francesco Passamonti, Mario Cazzola Provision of study materials or patients: Elisa Rumi, Francesco Passamonti, Chiara Elena, Luca Arcaini, Cecilia Del Curto Collection and assembly of data: Elisa Rumi, Francesco Passamonti, Mario Cazzola, Mario Lazzarino Data analysis and interpretation: Elisa Rumi, Francesco Passamonti, Cristiana Pascutto, Mario Cazzola, Mario Lazzarino Manuscript writing: Elisa Rumi, Francesco Passamonti Final approval of manuscript: Elisa Rumi, Francesco Passamonti, Matteo G. Della Porta, Chiara Elena, Luca Arcaini, Laura Vanelli, Cecilia Del Curto, Daniela Pietra, Emanuela Boveri, Cristiana Pascutto, Mario Cazzola, Mario Lazzarino
published online ahead of print at www.jco.org on November 12, 2007. Supported by grants from Associazione Italiana per la Ricerca sul Cancro, Milan; Fondazione Cariplo, Milan; Fondazione Ferrata Storti, Pavia; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia; and Ministry of University and Research, Rome, Italy. The first two authors contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Murphy S, Iland H, Rosenthal D, et al: Essential thrombocythemia: An interim report from the Polycythemia Vera Study Group. Semin Hematol 23:177-182, 1986[Medline] 13. Murphy S, Peterson P, Iland H, et al: Experience of the Polycythemia Vera Study Group with essential thrombocythemia: A final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol 34:29-39, 1997[Medline] 14. Passamonti F, Rumi E, Pietra D, et al: Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood 107:3676-3682, 2006 15. Brümmendorf TH, Holyoake TL, Rufer N, et al: Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. Blood 95:1883-1890, 2000 16. Delhommeau F, Dupont S, Tonetti C, et al: Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood 109:71-77, 2007 17. Lu X, Levine R, Tong W, et al: Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Proc Natl Acad Sci U S A 102:18962-18967, 2005 18. Gangat N, Wolanskyj AP, McClure RF, et al: Risk stratification for survival and leukemic transformation in essential thrombocythemia: A single institutional study of 605 patients. Leukemia 21:270-276, 2007[CrossRef][Medline] 19. Passamonti F, Rumi E, Arcaini L, et al: Leukemic transformation of polycythemia vera: A single center study of 23 patients. Cancer 104:1032-1036, 2005[Medline] 20. Cervantes F, Alvarez-Larran A, Arellano-Rodrigo E, et al: Frequency and risk factors for thrombosis in idiopathic myelofibrosis: Analysis in a series of 155 patients from a single institution. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) males; (
) proband; blue symbols, patients with CMD; slashes through symbols, dead relatives. Data below each patient are diagnosis, age at diagnosis, and JAK2 (V617F) allele burden.
