Addressing the room for improvement in management of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is highly curable. To achieve high cure rates, targeted therapy with retinoic acid (ATRA) must be started promptly at time of suspected diagnosis. Early death rates (EDRs, ≤30 days from diagnosis) differ markedly in patients treated on clinical trials compared to the general population. OBJECTIVES AND METHODS: We used the comprehensive Danish National Acute Leukemia Registry (DNLR) to investigate the incidence, treatment, EDR, and long-term clinical outcome in APL between 2000 and 2014. RESULTS: Twenty-two of 41 deaths occurring in 122 APL patients were EDs which were primarily caused by intracranial hemorrhage, disseminated intravascular coagulation (DIC), sepsis, and multiorgan failure. The overall EDR was 18.0%, whereas clinical trial participants had an EDR of 6.7%. Fifteen patients recruited to the NCRI AML17 APL trial from 2010 to 2013 were younger and had decreased mortality (HR 0.18, CI 0.04-0.86, P = 0.02) compared to contemporarily treated patients (n = 15) not recruited to a clinical trial. Performance status, leukemia origin, and Sanz-score were independent prognostic variables. CONCLUSIONS: The very low EDR for on-trial patients is not observed in the general cohort of APL patients. Diagnostic awareness emerges as the greatest clinical challenge in management of APL.

Myc protein overexpression is a feature of progression and adverse prognosis in multiple myeloma.

OBJECTIVE: Prognostic and predictive markers in multiple myeloma are continuously explored because of the heterogeneity of the tumor biology. Myc protein is the final product from activating MYC oncogene, but the prognostic impact in multiple myeloma is not well described. METHODS: In a population-based cohort of 194 untreated, newly diagnosed patients with multiple myeloma, we assessed myc protein expression using CD138/myc immunohistochemical double stain and collected clinicopathological data. RESULTS: Cases with myc protein expression ≥40% (mycHIGH ) had a median overall survival of 11 months compared to 48 months in cases of myc protein expression <40% (mycLOW ) (P < 0.01). MycHIGH was significantly correlated to R-ISS, high proliferation index, high percentage of plasma cell in bone marrow, plasmablastic morphology, high calcium level, and abnormal karyotype. In multivariate survival analyses, mycHIGH was independently associated with inferior overall survival with a hazard ratio of 2.5. CONCLUSION: Our results indicate myc protein overexpression to be associated with advanced multiple myeloma and poor prognosis.

Clinicopathological features of plasmablastic multiple myeloma: a population-based cohort.

Multiple myeloma (MM) is a common malignant hematological disease displaying considerable heterogeneity. Historical data indicate a prognostic significance of plasmablastic morphology, proliferation, and adverse cytogenetics, but there is little knowledge on the degree of interdependency of these parameters. The aim of this study was to study the degree of overlap between these variables. In a consecutive population-based cohort of 194 untreated MM patients, morphology, and proliferation index, using immunohistochemical double staining for Ki-67 and CD138, was analyzed. In addition, cytogenetic changes were studied by karyotyping and fluorescence in situ hybridization (FISH). Plasmablastic morphology correlated with unfavorable clinical features, high proliferation index, high percentage of plasma cell infiltration in the bone marrow, abnormal karyotype, and del(13q) detected by karyotyping, which indicates that plasmablastic morphology reflects advanced and highly proliferative disease. However, plasmablastic morphology did not correlate with established adverse prognostic cytogenetics identified by FISH, for example, t(4;14), t(14;16) and del(17p).

Upregulation of Syndecan-1 in the bone marrow microenvironment in multiple myeloma is associated with angiogenesis.

OBJECTIVES: Syndecan-1 (SDC1), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL6) are expressed by malignant plasma cells and cells in the bone marrow microenvironment and may be involved in the angiogenic process in multiple myeloma (MM). METHODS: In this study, we examined the association between bone marrow angiogenesis estimated as micro-vessel density (MVD) and gene expression of SDC1, HGF, VEGF and IL6 in whole bone marrow biopsies from healthy volunteers (n = 10), patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 35) and MM (n = 65). RESULTS: MVD was significantly higher in patients with MM than MGUS (P = 0.03) and was positively correlated with plasma cell percentage (P = 0.002). SDC1 gene expression increased with increasing MVD in patients with MGUS and MM (P < 0.001). A positive correlation between bone marrow plasma cell percentage and SDC1 gene expression was detected in patients with MM (P < 0.001). Importantly, after adjustment for plasma cell percentage, the association between MVD and SDC1 gene expression remained significant (P = 0.026). No association between bone marrow angiogenesis and gene expression of HGF, VEGF and IL6 was seen. CONCLUSION: Our study indicates that SDC1 expressed by the bone marrow microenvironment is involved in angiogenesis in MM.

Cytogenetic findings in adult secondary acute myeloid leukemia (AML): frequency of favorable and adverse chromosomal aberrations do not differ from adult de novo AML.

During a 15-year period, 161 adult patients were diagnosed with secondary acute myeloid leukemia (s-AML) in the region of Southern Denmark. In 73 patients, the AML diagnosis was preceded by myelodysplastic syndrome (MDS-AML), in 31 patients by an antecedent hematologic disease, and in 57 patients by treatment with chemotherapy and/or irradiation (t-AML). Cytogenetic analysis was carried out in 93%, of which 61% had clonal chromosome aberrations. MDS-AML correlated to a normal karyotype (P < 0.001). t-AML correlated to abnormal clones with numerical and structural aberrations (P = 0.03), five or more unrelated aberrations (P = 0.03), marker chromosomes (P = 0.006), abnormal mitoses only (P = 0.01), female sex (P < 0.001), and -7 (P = 0.006). Centromeric breakage correlated to a complex karyotype (P = 0.01). The frequencies of aberrations in s-AML patients were compared with an age-matched group of de novo AML patients diagnosed in the same area and period. In this comparison, s-AML only correlated to -7 (P = 0.02). In 42 patients, we found that MDS patients with an abnormal karyotype were more likely to show cytogenetic evolution during progression to AML than MDS patients with a normal karyotype (P = 0.01). We conclude that population-based cytogenetic studies of adult s-AML and age- and sex-matched de novo AML show comparable distributions of chromosome abnormalities.

Contribution of multiparameter genetic analysis to the detection of genetic alterations in hematologic neoplasia. An evaluation of combining G-band analysis, spectral karyotyping, and multiplex reverse-transcription polymerase chain reaction (multiplex RT-PCR).

We investigated 150 acute myeloid leukemia (AML) patients and 48 acute lymphoblastic leukemia (ALL) patients by multiplex RT-PCR to 7evaluate the adjuvant diagnostic effect, vis-à-vis G-banding and spectral karyotyping (SKY), and the potentials of this method for providing means for monitoring residual disease by real-time quantitative RT-PCR. An abnormal G-banded karyotype was found in 57% of AML and 68% of ALL cases. Ninety-six patients were investigated by SKY in parallel which extended or confirmed the G-banding finding in 94/96 cases. In patients with an abnormal G-banded karyotype, classification of chromosomes involved in structural aberrations by SKY was possible in 98% of the cases and SKY extended the G-banded karyotype in 34% of cases. In 32 cases, an mRNA hybrid was detected by PCR. These cases constitute 16% of the cases investigated at diagnosis (AML: 11% and ALL: 31%). In 13 of these cases, we detected an mRNA hybrid the equivalent of which was not found by G-banding or SKY (AML: 4% and ALL: 13%). By including multiplex RT-PCR, we were able to detect abnormalities in 62% of the investigated patients as opposed to 59% by G-banding. Genetic techniques complement each other and selection of relevant and targeted primer kits for the multiplex RT-PCR assay is recommended.

Cytogenetic findings in adult de novo acute myeloid leukaemia. A population-based study of 303/337 patients.

During a 10-year period (1992-2001) in the region of Southern Denmark, 337 patients aged 15 years or older (range 16-93 years, median 67 years) were diagnosed with acute myeloid leukaemia (AML). Cytogenetic analysis was carried out in 90%, of whom 53% had clonal chromosome aberrations. Some 24% and 31% had only numerical or structural abnormalities respectively. The remaining patients showed both types of abnormalities. Ploidy levels in decreasing order were: pseudodiploidy, 41%; hyperdiploidy, 32%; and hypodiploidy, 27%. Pseudodiploidy characterizes type M3 (70%) and hypodiploidy M6 (56%). Recurrent cytogenetic abnormalities--t(8;21), t(15;17) and inv(16)--were found in 3.3%, 3.3% and 2.0% of all patients respectively. Prognostically intermediate and adverse aberrations were found in 39% and 44%, respectively, of those with an abnormal karyotype. Rare recurrent aberrations were found in two patients in this material. A previously described non-recurrent abnormality was found to be recurrent in one patient [der(20)t(11;20)(q13.2;p13)]. New, previously undescribed abnormalities were found in 41 patients. Statistically significant correlations were found between t(15;17) and young age (P < 0.001), inv(16) and young age (P < 0.006), -17 and M6 (P = 0.007), and M6 and complex karyotype with five or more unrelated aberrations (P = 0.004). We conclude that this truly population-based cytogenetic study of adult AML showed distributions of chromosome abnormalities that differ from those described so far.