Rhett P. Ketterling

Inherited interstitial deletion of chromosomes 5p and 16q without apparent phenotypic effect: further confirmation.

We describe two families in which an inherited interstitial deletion is present without apparent associated phenotypic abnormalities. The first deletion was discovered in a 19‐year‐old male with a previously diagnosed peroxisomal disorder. High‐resolution chromosome analysis was interpreted as 46,XY,del(5)(p14.1p14.3). The patients phenotypically normal mother had the same interstitial deletion. Chromosome 5p14 deletion has been reported in a three‐generation family without phenotypic anomalies. We hypothesize that the affected sons phenotype may be coincidental or represent unmasking of an autosomal recessive peroxisomal disorder in the deleted region. The second interstitial deletion was detected by amniocentesis for advanced maternal age. High‐resolution chromosome analysis was interpreted as 46,XX,del(16)(q13q22). The same deletion was found in the healthy mother and a normal brother. The pregnancy was carried to term and resulted in the birth of a normal girl. We report these cases as further evidence that rare, unbalanced deletion of specific chromosomal regions may result in no phenotypic effect. Consequences may result from expression of an autosomal recessive disorder on the homologous chromosome. Identification of such deletions is especially important for prenatal diagnosis and genetic counselling. Copyright

Risk factors and a prognostic model for postsplenectomy survival in myelofibrosis

Palliative treatment in myelofibrosis (MF) includes transfusion support, JAK2 inhibitors, involved field radiotherapy and splenectomy. To assist in selecting patients who are likely to benefit from splenectomy, we looked into risk factors for postsplenectomy survival, in 120 consecutive cases (median age 66 years); at the time of splenectomy, 61% displayed red cell transfusion need, 49% platelet count <100 × 10(9)/L, 25% leukocyte count >25 × 10(9)/L, 60% constitutional symptoms and 13% circulating blasts ≥5%; dynamic international prognostic scoring system risk categories were 21% high, 55% intermediate‐2, 21% intermediate‐1 and 3% low. Among informative cases, karyotype was abnormal in 60% and driver mutational status was JAK2 75%, CALR 15%, MPL 4% and triple‐negative 6%. At median follow‐up of 1.3 years, from time of splenectomy, 95 (79%) deaths and 30 (25%) leukemic transformations were recorded. Median postsplenectomy survival was 1.5 years; in multivariable analysis, survival was adversely affected by age >65 years, transfusion need, leukocyte count >25 × 10(9)/L and circulating blasts ≥5%; these variables were subsequently used to devise an HR‐weighted scoring system with high (3‐4 risk factors), intermediate (2 risk factors) and low (0‐1 risk factors) risk categories; the corresponding postsplenectomy median survivals were 0.3 (HR 5.9, 95% CI 3.2‐11.0), 1.3 (HR 2.9, 95% CI 1.8‐4.6) and 2.9 years. Postsplenectomy survival was not affected by driver mutational status or occurrence of leukemic transformation. Leukemia‐free survival was predicted by very high risk karyotype. The observations from the current study might help identify appropriate candidates for splenectomy in MF.

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.

10 PHILADELPHIA CHROMOSOME MOSAICISM DUE TO ADDITIONAL CYTOGENETIC ABNORMALITIES IN CHRONIC MYELOID LEUKEMIA MIGHT ADVERSELY AFFECT PROGNOSIS AND RESPONSE TO IMATINIB.

Background Chronic myeloid leukemia (CML) is invariably associated with the reciprocal translocation of BCR and ABL to form the Philadelphia chromosome (Ph), t(9;22)(q34;q11). At diagnosis, a small proportion of patients display additional cytogenetic abnormalities and/or a variable proportion of cytogenetically normal metaphases that coexist with Ph-positive metaphases. The objective of the current study was to examine the prognostic relevance and therapy implications of this scenario. Methods The study population consisted of 65 (47.7% female) consecutive, newly diagnosed, untreated CML patients seen at the Mayo Clinic with a median age of 59 years; 44.5% were initially treated with interferon (IFN)-α, resulting in complete cytogenetic remission in 10.7%, for a median length of 5.83 years, whereas partial cytogenetic remission was achieved in 3.57%, for a median length of 2 years; 55.5% were treated with imatinib (Gleevec), resulting in complete cytogenetic remission in 54.1%, for a median length of 3.08 years, whereas partial cytogenetic remission was achieved in 13.5%, for a median length of 1.08 years. All statistical analysis was completed using SAS software (SAS Inc., Cary, NC), and statistical significance was set at the level of p ≤ .05. Results Survival at 5 years through Kaplan-Meier analysis was approximately 92% in patients demonstrating only the Ph chromosome (n = 53) versus 60% in patients with additional chromosomal abnormalities (n = 12; p < .0001 through log rank and Breslow-Gehan-Wilcox analysis). In addition, patients with additional chromosomal abnormalities demonstrated lower rates of either complete or partial cytogenetic remission with imatinib therapy. Similarly, the 5-year survival rate of patients with less than 90% Ph-positive metaphases at diagnosis (n = 4) was approximately 60% compared with 92% in patients with greater than 90% Ph-positive metaphases (n = 61; p = .01 by log rank and p = .001 by Breslow-Gehan-Wilcox analysis). Additionally, the former group of patients was significantly less responsive to imatinib. Finally, there was significant correlation between Ph-positive metaphase mosaicism and the presence of additional chromosomal abnormalities (p = .05). Conclusion Although it is tempting to speculate that Ph-chromosome mosaicism and/or additional cytogenetic abnormalities at presentation of CML is a surrogate for the presence of Ph-negative imatinib-resistant clones, the preliminary results from the current study require validation from a larger study, which is currently under way. It is possible that patients who present with less than 90% Ph-positive metaphase cells at diagnosis may harbor chromosomal abnormalities in other metaphase cells that are undetectable by conventional cytogenetics. Indeed, this clonal population might be resistant to imatinib therapy and negatively impact survival.