Chromosome 1 abnormalities in myeloid malignancies: a literature survey and karyotype-phenotype associations.

Chromosome 1 is the largest human chromosome and contains over 1600 known genes and 1000 novel coding sequences or transcripts. It is, therefore, not surprising that recurrent chromosome 1 abnormalities are regularly encountered in both neoplastic and non-neoplastic medical conditions. The current review is focused on myeloid malignancies where we summarize the relevant published literature and discuss specific karyotype-phenotype associations. We show that chromosome 1 abnormalities are most frequent in BCR-ABL-negative classic myeloproliferative neoplasms (MPN): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Specific abnormalities include duplications (e.g. 1q12-->1q32 in PV, 1q21-32-->1q32-44 in post-PV MF or PMF), deletions (e.g. 1p13-36-->pter in PV or PMF, 1q21 in PMF) and unbalanced translocations involving chromosome 6, such as der(6)t(1;6)(q21-25;p21.3-23), and other partner chromosomes involving 1q10/1p11 and 1q21-25 breakpoints. Although occasionally seen in chronic phase MPN, unbalanced 1;7 translocations, e.g. der(1;7)(q10;p10), are usually seen in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and post-MPN AML/MDS. These observations suggest that certain chromosome 1 regions, especially 1q21-1q32 and 1p11-13, might harbor oncogenes or tumor suppressor genes that are pathogenetically relevant to both chronic and advanced phases of MPN.

Transfusion-dependency at presentation and its acquisition in the first year of diagnosis are both equally detrimental for survival in primary myelofibrosis--prognostic relevance is independent of IPSS or karyotype.

The International Prognostic Scoring System (IPSS) and karyotype are useful tools for risk stratification in primary myelofibrosis (PMF). We examined the additional prognostic impact of red blood cell transfusion need among 254 consecutive patients (median age, 59 years). Sixty-two patients ( approximately 24%) required transfusions at diagnosis whereas 22 ( approximately 9%) became transfusion-dependent and 170 remained transfusion-independent during the first year postdiagnosis; after a median follow-up of 55 months, the respective median survivals were 35, 25, and 117 months (P < 0.01). Multivariable analysis confirmed the IPSS- and karyotype-independent prognostic weight of transfusion status. Among IPSS intermediate-1 risk patients, overall median survival of 82 months was modified to 60 or 118 months, based on presence or absence of transfusion need, respectively (P < 0.01). The corresponding figures for intermediate-2/high risk patients were 30 and 64 months (P < 0.01). Documented causes of death did not include iron overload. We conclude that transfusion status in PMF downgrades or upgrades prognosis within specific IPSS categories; transfusion need is a marker of aggressive disease biology in PMF, as it is in myelodysplastic syndromes.

International Prognostic Scoring System-independent cytogenetic risk categorization in primary myelofibrosis.

Among 200 patients with primary myelofibrosis, karyotype at diagnosis was abnormal in 83 (42%). To assess their individual prognostic impact, specific cytogenetic abnormalities with more than or equal to 5 informative cases were identified and the rest grouped separately as "other abnormalities." Median survival in patients with sole +9 (n = 6), sole 20q- (n = 21), sole 13q- (n = 8), normal karyotype (n = 117), "other abnormalities" (n = 28), complex karyotype (n = 13), and sole +8 (n = 7) were "not reached," 112, 105, 80, 46, 34, and 28 months, respectively (P = .01). Accordingly, 4 cytogenetic risk groups were considered: (1) favorable (sole +9, 20q-, or 13q-), (2) normal, (3) unfavorable (complex karyotype or sole +8), and (4) "other abnormalities." Multivariable analysis confirmed the International Prognostic Scoring System (IPSS)-independent prognostic value of both 4-way and 2-way (ie, favorable/normal vs unfavorable/other abnormalities; IPSS-adjusted hazard ratio = 0.37; 95% confidence interval, 0.24-0.58) cytogenetic risk categorization (P < .01). The ability to prognostically dissect a specific IPSS category has major therapeutic implications.

Mature survival data for 176 patients younger than 60 years with primary myelofibrosis diagnosed between 1976 and 2005: evidence for survival gains in recent years.

In the past 20 years, management of primary myelofibrosis (PMF) has incorporated new treatment approaches, but survival benefits have not been confirmed in controlled studies. This retrospective study includes 176 consecutive patients younger than age 60 years in whom PMF was diagnosed during a 30-year period (1976-2005). Median age at diagnosis was 50 years (range, 18-59 years), and 98 patients (55%) were men. At the time of this report, 99 patients (56%) had died; the 77 surviving patients were followed up for a median of 8 years (range, 4-24 years). Overall median survival was 9.2 years, and 15- and 20-year survival rates were 32% and 20%, respectively. According to the Dupriez Prognostic Scoring System (PSS), median survivals were 12.7, 4.8, and 2.4 years in low- (n=117), intermediate- (n=44) and high- (n=15) risk patients (P<.001). According to the International PSS, median survivals were 13.4, 9.7, 3.3, and 2.4 years in low- (n=76), intermediate-1 (n=50), intermediate-2 (n=29), and high-risk patients (n=8; P<.001). To examine the effect of decade of diagnosis on survival, we divided study patients into 3 groups by year of diagnosis: 1976-1985 (n=36), 1986-1995 (n=45), and 1996-2005 (n=95). The corresponding median survivals were 4.8, 7.3, and "not reached" (P=.003), and the difference in survival was significant during multivariable analysis that included risk scores according to the aforementioned PSSs and age as covariates. The improvement in survival in recent years was most apparent in patients with high/intermediate-risk disease (P<.002), not in those with low-risk disease (P=.42). These observations are encouraging and suggest a salutary effect from modern therapeutic approaches in PMF.

Red blood cell transfusion need at diagnosis adversely affects survival in primary myelofibrosis-increased serum ferritin or transfusion load does not.

Serum ferritin level at diagnosis was available in 185 patients with primary myelofibrosis (PMF); twenty-two (12%) patients had serum ferritin >1,000 ng/mL and 32 (17%) were red blood cell (RBC) transfusion-dependent. As expected, RBC transfusion need and increased serum ferritin displayed strong correlation (P < 0.0001); in addition, the latter but not the former correlated with advanced age (P < 0.0001). During median follow-up of 28 months (range 0.5-231), peak serum ferritin levels exceeded 1,000 ng/mL in 41 (22%) patients. On multivariable analysis that included age as a covariate, RBC transfusion need at diagnosis (P < 0.0001), but not increased serum ferritin or transfusion load, predicted shortened survival. The prognostic relevance of RBC transfusion need was independent of the International Prognostic Scoring System and was also illustrated for leukemia-free survival (P = 0.003). In PMF, the presence of a more severe erythropoietic defect, and not iron overload, has additional adverse prognostic value.

The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis.

Quality of life (QoL) in patients with myelofibrosis (MF) is severely compromised by severe constitutional symptoms (i.e. fatigue, night sweats, fever, weight loss), pruritus, and symptoms from frequently massive hepatosplenomegaly. Given that no current instrument of patient reported outcomes (PRO) exists that covers the unique spectrum of symptomatology seen in MF patients, we sought to develop a new PRO instrument for MF patients for use in therapeutic clinical trials. Utilizing data from an international Internet-based survey of 458 patients with MF we created a 20-item instrument (MFSAF: Myelofibrosis Symptom Assessment Form) which measures the symptoms reported by >10% of MF patients and includes a measure of QoL. We subsequently validated the MFSAF in a prospective trial of MF patients involving patient and provider feedback, as well as comparison to other validated instruments used in cancer patients. The MFSAF results were highly correlated with other instruments, judged comprehensive and understandable by patients, and should be considered for evaluation of MF symptoms in therapeutic trials.

Karyotype complements the International Prognostic Scoring System for primary myelofibrosis.

OBJECTIVES: The International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) is based on five independent predictors of inferior survival: age >65 yr, hemoglobin <10 g/dL, leukocyte count >25 x 10(9)/L, circulating blasts > or =1%, and presence of constitutional symptoms. The presence of 0, 1, 2, and > or =3 adverse factors defines low, intermediate-1, intermediate-2, and high risk disease, respectively. We examined the additional prognostic relevance of karyotype. METHODS: World Health Organization criteria were used for PMF diagnosis. Only patients with bone marrow cytogenetic studies at the time or within 1 yr of diagnosis and a minimum of 20 evaluable metaphases were considered. Cytogenetic findings were categorized as 'normal' vs. 'abnormal' or 'favorable' (normal or with sole abnormalities of 13q- or 20q-) vs. 'unfavorable' (all other abnormalities). RESULTS: A total of 109 patients were studied (median age 63 yr). Numbers of patients in the above-listed four IPSS risk groups were 26, 31, 28, and 24, respectively. Cytogenetic results were abnormal in 33% of the patients and unfavorable in 21%. At a median follow-up of 35 months, 45 (41%) deaths were recorded. 'Unfavorable' (P = 0.008) but not 'abnormal' (P = 0.19) karyotype predicted shortened survival and its significance remained on multivariable analysis that included the IPSS or other prognostic tools as covariates. JAK2V617F, detected in 63 (58%) patients, was inconsequential to survival. CONCLUSIONS: In PMF, specific cytogenetic abnormalities and not the mere presence of an abnormal karyotype provide important prognostic information that is not accounted for by the IPSS or other established risk factors.

Conventional cytogenetics in myelofibrosis: literature review and discussion.

The clinical phenotype of myelofibrosis (MF) is recognized either de novo (primary) or in the setting of polycythemia vera (post-PV) or essential thrombocythemia (post-ET). Approximately one-third of patients with primary MF (PMF) present with cytogenetic abnormalities; the most frequent are del(20q), del(13q), trisomy 8 and 9, and abnormalities of chromosome 1 including duplication 1q. Other less frequent lesions include -7/del(7q), del(5q), del(12p), +21 and der(6)t(1;6)(q21;p21.3). In general, cytogenetic abnormalities are qualitatively similar among PMF, post-ET MF and post-PV MF although their individual frequencies may differ. Based on prognostic effect, cytogenetic findings in MF are classified as either 'favorable' or 'unfavorable'. The former include normal karyotype or isolated del(20q) or del(13q) and the latter all other abnormalities. Unfavorable cytogenetic profile in both PMF and post-PV/ET MF confers an independent adverse effect on survival; it is also associated with higher JAK2V617F mutational frequency. In addition to their prognostic value, cytogenetic studies in MF ensure diagnostic exclusion of other myeloid neoplasms that are sometimes associated with bone marrow fibrosis (e.g. BCR-ABL1-positive or PDGFRB-rearranged) and also assist in specific treatment selection (e.g. lenalidomide therapy is active in MF associated with del(5q).

JAK2V617F mutation screening as part of the hypercoagulable work-up in the absence of splanchnic venous thrombosis or overt myeloproliferative neoplasm: assessment of value in a series of 664 consecutive patients.

The JAK2V617F mutation is recurrent in polycythemia vera and essential thrombocythemia, which are myeloproliferative neoplasms (MPNs) frequently associated with arterial and/or venous thromboembolism. More recently, the JAK2V617F mutation has been identified as a surrogate marker for subclinical or "occult" clonal myeloproliferation in patients with splanchnic venous thrombosis. However, information is limited regarding JAK2V617F-associated thrombosis outside the splanchnic district in patients without overt MPN. To address this issue, we retrospectively studied a consecutive series of 664 such patients who experienced thrombotic events characteristic of an MPN (500 with venous thromboembolism, 136 with stroke, and 28 with myocardial infarction at a young age). The JAK2V617F mutation was detected in only 6 (<1.0%) patients (5 with recurrent venous thromboembolism and 1 with stroke), and the mutant allele burden was low in all instances (range, 2.2%-7.5%). None of these 6 patients developed either overt MPN or recurrent thrombosis after a median follow-up of 40 months. We conclude that the prevalence of the JAK2V617F mutation in patients with nonsplanchnic venous thrombosis in the absence of MPN is too low to warrant mutation screening as part of the hypercoagulable work-up. Our study also suggests that the natural history of a JAK2V617F-positive "occult" MPN might be different from that of a typical MPN.

Day 14 bone marrow biopsy in predicting complete remission and survival in acute myeloid leukemia.

We retrospectively analyzed 194 previously untreated acute myeloid leukemia (AML) patients to evaluate the role of Day 14 bone marrow (BM) biopsy in predicting complete remission (CR). Sixty-seven percent received induction therapy. Achieving Day 14 BM < or =5% blasts was strongly predictive of Day 28 CR with 90% sensitivity and 79% positive predictive value; but weak 43% specificity and 29% negative predictive value. Day 14 BM biopsy is highly sensitive in predicting CR, but did not predict overall survival. Some patients with BM blast >5% at Day 14 may still achieve a Day 28 CR, and not necessarily need reinduction therapy though high risk cytochemical or cytogenetic phenotype predicts a need for retreatment.

Peripheral blood cytogenetic studies in myelofibrosis: overall yield and comparison with bone marrow cytogenetic studies.

Among 59 consecutive patients with myelofibrosis (MF) in whom peripheral blood (PB) cytogenetic studies were performed, at least two analyzable metaphases (median 20, range 2-31) were obtained in 49 (81%) patients and in all 37 (100%) cases with PB myeloid progenitor cell count of 0.1 x 10(9)L(-1) or above (p=0.02). Twenty-two patients had concomitant PB and bone marrow (BM) cytogenetic studies; 6 showed similarly abnormal findings in both BM and PB. In another 2 cases, results were abnormal in BM but normal in PB; the opposite was seen in 1 case. These results suggest that PB can be considered as an alternative to BM for cytogenetic studies as currently used in MF but additional prospective studies are needed to support change in practice.

Peripheral blood cytogenetic studies in hematological neoplasms: predictors of obtaining metaphases for analysis.

Peripheral blood (PB) is sometimes used in place of bone marrow (BM) for cytogenetic studies during the evaluation of hematologic malignancies. A total of 242 PB cytogenetic studies from adult patients were performed: clinical diagnosis was a myeloid neoplasm in 169 patients (70%), lymphoid or plasma cell neoplasm in 50 (21%), and a benign/reactive cytopenia or leukocytosis in 23 (9%). PB cytogenetic studies resulted in at least two analyzable metaphases in 142 of the 242 study cases (59%); in univariate analysis, this was predicted by the specific clinical diagnosis (P < 0.0001), presence and degree of circulating myeloid progenitor cells or blasts of any lineage (P < 0.0001), higher leukocyte count (P < 0.001), lower platelet count (P = 0.003), lower hemoglobin level (P = 0.002), and presence of palpable splenomegaly (P = 0.002). In multivariable analysis, only the presence of circulating myeloid progenitor cells or blasts sustained significance and this was consistent with the high yield rates seen in primary myelofibrosis (PMF) (80%), post-PV/ET PMF (85%), acute myeloid leukemia (76%), and acute lymphoblastic leukemia (80%) in contrast with the low rates seen in ET (0%) and PV (2%). In 104 cases, BM cytogenetic studies were performed within 1 month of the PB cytogenetic studies; an abnormal BM cytogenetic finding was another independent predictor of a successful PB study (P = 0.002). PB cytogenetic studies are most appropriate in diseases of adults characterized by presence of circulating myeloid progenitors or blasts; the yield otherwise is too small to be cost-effective.