Kathy Chun

THE T(4,14) IS ASSOCIATED WITH POOR PROGNOSIS IN MYELOMA PATIENTS UNDERGOING AUTOLOGOUS STEM CELL TRANSPLANT

The frequency and prognostic relevance of translocations t(11;14) and t(4;14), the most common translocations involving the immunoglobulin heavy chain (IgH) gene in multiple myeloma (MM), were investigated in 128 patients treated with intensive chemotherapy and autologous stem cell transplant. Myeloma cells were identified by cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization (cIg‐FISH) for detection of translocations t(11;14) and t(4;14). Overall, t(11;14) was detected in 16 of 125 (12·8%) and t(4;14) in 15 of 120 (12·5%) patients. Progression‐free and overall survivals were similar for patients with or without t(11;14). However, patients with t(4;14) had significantly shorter progression‐free (median 9·9u2003months vs. 25·8u2003months; Pu2003=u20030·0003) and overall survivals (median 18·3u2003months vs. 48·1u2003months; Pu2003<u20030·0001) than patients without t(4;14). The t(4;14) was associated with IgA and t(11;14) with light chain MM. There was no association between the t(11;14) or t(4;14) and other biological parameters including age, gender, haemoglobin, β‐2 microglobulin, C‐reactive protein, calcium, creatinine, albumin, or the percentage of bone marrow plasma cells. Multivariate analysis identified t(4;14) as the only adverse prognostic factor for both progression‐free survival and overall survival. Our results indicate that the t(4;14) detected by cIg‐FISH is associated with a poor prognosis in MM patients receiving intensive chemotherapy and autotransplant.

Disease biology rather than age is the most important determinant of survival of patients ≥ 60 years with acute myeloid leukemia treated with uniform intensive therapy

The objectives of the current study were to evaluate the outcome of patients ≥ 60 years with acute myeloid leukemia (AML) treated uniformly with high‐dose daunorubicin containing induction and modified high‐dose cytosine arabinoside containing postremission therapy, and to identify factors predictive of complete disease remission (CR) and survival.

Prognostic significance of trisomy 4 as the sole cytogenetic abnormality in acute myeloid leukemia

Trisomy 4 is a recurrent but rare cytogenetic abnormality reported in patients with acute myeloblastic leukemia (AML). The prognostic significance of this abnormality in patients with AML is not clear. We report here four cases of trisomy 4 as the sole cytogenetic abnormality in AML patients treated at our institute during the last 15 years and systematically review all reported cases of trisomy 4 as a solitary cytogenetic abnormality in AML with the aim of studying the disease demography and prognostic significance of this abnormality. Collective data on 30 patients (including four in the present report) showed complete remission (CR) rates of 76.6%. Median relapse free survival and overall survival were 7 months (95% CI 5-17) and 9 months (95% CI 3-17), respectively. Given the limitations of reported literature, the prognosis of AML patients with trisomy 4 appears to be poor compared with the intermediate risk cytogenetics. Collaborations between major institutions and cooperative groups are needed to collect better quality data to understand the prognostic significance of such rare karyotypic abnormalities.

Outcome of patients who develop acute leukemia or myelodysplasia as a second malignancy after solid tumors treated surgically or with strategies that include chemotherapy and/or radiation

Evaluation of therapeutic outcomes and risk factors was undertaken for patients with primary solid tumors (PST) developing acute leukemia or myelodysplasia (MDS) as a second malignancy.

Clinico-Biological Features and Prognostic Significance of PML/RARα Isoforms in Adult Patients with Acute Promyelocytic Leukemia Treated with All Trans Retinoic Acid (ATRA) and Chemotherapy

Debate exists over the clinical relevance of molecular heterogeneity of acute promyelocytic leukemia (APL). Based on the genomic breakpoint in PML gene, three different PML/RARα isoforms are recognized: intron 3 [short (S)], intron 6 [long (L)] and exon 6 [variable (V)]. Studies on the prognostic significance of PML/RARα isoforms have reported contradictory results. This discrepancy may be related to differences in the treatment protocols, as some studies used ATRA alone during induction therapy. We analyzed the clinical course of 61 consecutive newly diagnosed patients with a genetically confirmed diagnosis of APL, treated with ATRA and chemotherapy at Princess Margaret Hospital from January 1994 to January 2002. The results of RTu200a–u200aPCR at diagnosis were available on 48 patients. In this study, we report on clinico-biological features and prognostic significance of PML/RARα isoforms in these 48 patients. Of 48 patients, 19(40%) had the S isoform and 29 (60%) had the L/V isoform. Median white blood cell (WBC) count for patients with S isoform was 8.6 [interquartile range Q1-Q3 i.e. IQR 3.2u200a–u200a29] compared to 1.8 [IQR 1.0u200a–u200a4.9] for the L/V isoform group (P 0.001). No difference was seen in number of patients achieving of molecular remission after induction and consolidation treatment in the two-isoform groups. The patients with S isoform had significantly inferior relapse-free survival (RFS) at 3 years compared to L/V isoform patients [48% (95% C.I. 19u200a–u200a77) vs. 92% (95% C.I. 82u200a–u200a100), P 0.006]. In a univariate analysis, S isoform status (P 0.006) and high WBC count (u200a⩾u200a5u200a×u200a109/l) (P 0.017) were significant prognostic factors for RFS. No difference in overall survival was seen between the two isoform groups (P 0.35). Our results suggest that based on molecular characterization, it may be possible to identify a subgroup of APL patients at higher-risk of relapse.

Response to correspondence from Gripp et al.—“clinical and molecular diagnosis should be consistent”

WethankDr.Gripp,Dr. Zackai, andDr.Cohen, Jr. for their communication [Gripp et al., 2003]. We agree that a complete physical examination and review of the medical and family history by themedical geneticist are the first and most important steps in evaluating a patient. Based on these findings, the most appropriate molecular test should then be ordered. We are a referral center for craniosynostosis testing and therefore, receive specimens for testing from many genetics centers. Three of the four patients with the FGFR3P250Rmutation had been referred for Saethre– Chotzen syndrome testing before theMuenke syndrome was described in 1997 [Muenke et al., 1997]. The fourth patient was referred very shortly after. Furthermore, although all the patients described in the publication of Chun et al. [2002] were assessed by clinical geneticists, clinical overlap of the Muenke syndrome with the Saethre–Chotzen syndrome made it a challenge for those geneticists less experienced with the craniosynostosis syndromes. Since then, many more patients with craniosynostosis have been diagnosed by mutational analysis and more clinical information has become available. Nowwith the clinical phenotypesmore firmly established, clinical geneticists are better equipped to distinguish patients with Saethre–Chotzen syndrome from those with Muenke syndrome. To this end, we are in agreement with Dr. Gripp, Dr. Zackai, and Dr. Cohen Jr that sequencing of TWIST should be the first molecular test performed for a patient with Saethre– Chotzen syndrome, and that if this is negative, testing for the FGFR3 P250R mutation be done. Indeed, the testing algorithm for Saethre–Chotzen syndrome had already been modified since our publication, which is reflected in a paper [Chun et al., 2003] that describes a stepwise molecular diagnostic approach to syndromic craniosynostosis testing.