Asim F. Belgaumi

Clinical characteristics and outcome of children with biphenotypic acute leukemia

This study from Saudi Arabia found that 4% of 633 cases of pediatric acute leukemia were biphenotypic. The authors describe the clinical features of these patients and their response to treatment including stem cell transplantation. Background Knowledge concerning the clinical and biological presentation, as well as the outcome of treatment, of biphenotypic acute leukemia in children is limited. Design and Methods This retrospective review analyzes the clinical features and outcome of children with biphenotypic acute leukemia diagnosed and treated over an 8-year period. According to the EGIL scoring system 24 (3.7%) of 633 patients with acute leukemia were classified as having biphenotypic acute leukemia. The diagnostic work-up and results were reviewed specifically for this study in the light of the newly published WHO criteria for the diagnosis of leukemia of ambiguous lineage. Based on these criteria, 11 (1.7%) patients were categorized according to the new nomenclature as having mixed phenotype acute leukemia. The majority of the patients (58.3%) had a B-lymphoid/myeloid phenotype, followed by the T-lymphoid/myeloid phenotype. The most frequent chromosomal abnormality involved the 14q32 locus. Patients received therapy based on a treatment regimen for acute lymphocytic leukemia regimen, which included myeloid-effective agents. Results At a median follow up of 4 years (range, 6 month – 7 years) the overall survival rate was 75.7% and the event-free survival rate was 73.5%. The survival of those patients who underwent hematopoietic stem cell transplantation in first complete remission was not different from that of the patients who were treated with chemotherapy alone (overall survival: 70.1% versus 81.1%, respectively, p=0.39; event-free survival: 70.1% versus 76.2%, respectively, p=0.75). The outcome of the 11 patients who were retrospectively classified as having mixed phenotype acute leukemia according to the new WHO criteria was excellent, with no relapses or deaths occurring among these patients. Conclusions An acute lymphocytic leukemia type of induction therapy, using agents that are active against lymphoid and myeloid leukemias, appears to be more effective in achieving and maintaining complete remissions regardless of whether the patients are classified according to EGIL criteria or the new WHO criteria. Hematopoietic stem cell transplantation may not be necessary for all patients in first complete remission.

Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin

The goals of the current study were to examine the incidence and severity of toxicity resulting from dexamethasone and prednisone during induction therapy for children with precursor B‐cell acute lymphoblastic leukemia (ALL) and to determine whether the addition of daunomycin affected toxicity.

S-phase kinase protein 2 is an attractive therapeutic target in a subset of diffuse large B-cell lymphoma†

S‐phase kinase protein 2 (SKP2), an F‐box protein, targets cell‐cycle regulators including cycle‐dependent kinase inhibitor p27KiP1 via ubiquitin‐mediated degradation. SKP2 is frequently overexpressed in a variety of cancer cells and has been implicated in oncogenesis; however, its role in diffuse large B‐cell lymphoma (DLBCL) has not been elucidated. Therefore, we investigated the role of SKP2 and its ubiquitin‐proteasome pathway in a large series (301) of DLBCL patient samples and a panel of DLBCL cell lines. Using immunohistochemistry, SKP2 was detected in 41.6% of DLBCL tumours and was inversely associated with p27Kip1 protein level. The DLBCL subset with high SKP2 and low p27Kip1 showed a strong correlation with the proliferating index marker Ki‐67 (p < 0.0001) and also with the germinal centre phenotype (p = 0.0147). Treatment of DLBCL cell lines with bortezomib or expression of SKP2‐specific siRNA causes down‐regulation of SKP2 and accumulation of p27Kip1, leading to suppression of growth by inducing apoptosis. Furthermore, treatment of DLBCL cells with bortezomib causes apoptosis via involving the mitochondrial pathway and activation of caspases. Finally, treatment of DLBCL cells with bortezomib down‐regulated the expression of XIAP, cIAP1, and survivin. Altogether, these results suggest that SKP2 and the ubiquitin‐proteasome pathway may be a potential target for therapeutic intervention in DLBCL. Copyright

Hodgkin lymphoma in very young children: Clinical characteristics and outcome of treatment

In developed nations, Hodgkin lymphoma (HL) is rare in <5-year olds and represent a minority in developing countries. Little is reported about the biology and behavior of these very young patients compared with older children. 18.75% of our pediatric HL patients (0 – 14 years) were <5 years at diagnosis. This group had more boys, similar incidence of B-symptoms and stage distribution, less mediastinal involvement and bulky disease, and more mixed cellularity subtype than older children. Treatment included chemotherapy (CT; n = 55), combined modality therapy (CMT; n = 12) and XRT only (n = 2). Ten-year EFS and OS was 81.5% and 90.4%, respectively, versus 75.5% and 90.5% for older children (p > 0.5). A trend toward better survival was seen with CMT, using very LD-XRT, than with CT (OS 100% vs. 86.4%[p = 0.3]; EFS 90.9% vs. 81.0%[p = 0.4]). Although CT could be effective in a subset of LR patients, LD-XRT may be needed to effectively treat most of these patients. This dose reduction may reduce XRT-related toxicity, which can be significant in very young children.

Clinical characteristics and treatment outcome of pediatric patients with chronic myeloid leukemia

As chronic myeloid leukemia is rare in children, most data on imatinib mesylate therapy is derived from adult studies. We retrospectively evaluated pediatric (<14 years) patients with Ph+ chronic myeloid leukemia treated with imatinib mesylate, from January 2003 through June 2008. Of the 12 chronic myeloid leukemia patients (2% of all leukemias) 11 were in chronic phase while one had myeloid blast crisis. Six subsequently underwent stem cell transplantation. Five patients had grade 3–4 arthralgia requiring therapy alteration. None achieved complete molecular remission (MR) with imatinib mesylate alone. In contrast 3/6 patients post stem cell transplantation have undetectable BCR-ABL. Three patients relapsed to chronic phase (1 imatinib mesylate; 2 stem cell transplantation). Relapse free survival is 65.6% at four years and all are alive. Imatinib mesylate is effective therapy for children with chronic myeloid leukemia. However, cure probably requires stem cell transplantation. Acute toxicity of imatinib mesylate is tolerable, but long-term effects on growing children are unknown. Pediatric patients with chronic myeloid leukemia should undergo stem cell transplantation when appropriate related donors are available.

Chimerism Analysis of Cell-Free DNA in Patients Treated with Hematopoietic Stem Cell Transplantation May Predict Early Relapse in Patients with Hematologic Malignancies

Background. We studied DNA chimerism in cell-free DNA (cfDNA) in patients treated with HSCT. Methods. Chimerism analysis was performed on CD3+ cells, polymorphonuclear (PMN) cells, and cfDNA using 16 small tandem repeat loci. The resulting labeled PCR-products were size-fractionated and quantified. Results. Analyzing samples from 191 patients treated with HSCT for nonneoplastic hematologic disorders demonstrated that the cfDNA chimerism is comparable to that seen in PMN cells. Analyzing leukemia patients (N = 126) showed that, of 84 patients with 100% donor DNA in PMN, 16 (19%) had evidence of clinical relapse and >10% recipient DNA in the plasma. Additional 16 patients of the 84 (19%) showed >10% recipient DNA in plasma, but without evidence of relapse. Eight patients had mixed chimerism in granulocytes, lymphocytes, and plasma, but three of these patients had >10% recipient DNA in plasma compared to PMN cells and these three patients had clinical evidence of relapse. The remaining 34 patients showed 100% donor DNA in both PMN and lymphocytes, but cfDNA showed various levels of chimerism. Of these patients 14 (41%) showed laboratory or clinical evidence of relapse and all had >10% recipient DNA in cfDNA. Conclusion. Monitoring patients after HSCT using cfDNA might be more reliable than cellular DNA in predicting early relapse.

Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia in Saudi Arabia: A multi‐institutional retrospective national collaborative study

Treatment of childhood acute lymphoblastic leukemia (ALL) has been available in Saudi Arabia (SA) for over 30 years; however, only limited data have been published from there. This study was conducted to establish processes for collaborative data collection and provide clinical characteristics and outcome of children with ALL in SA.

Megakaryocytic blast crisis at presentation in a pediatric patient with chronic myeloid leukemia

Patients with chronic myeloid leukemia (CML) infrequently present in blast crisis (BC). While most BC are of myeloid origin, megakaryocytic BC is rare, especially at the time of CML diagnosis. We describe the first pediatric patient presenting with megakaryocytic leukemia and having BCR-ABL1 translocation as the single chromosomal abnormality. Clinical features were more suggestive of CML in megakaryocytic blast crisis than Philadelphia chromosome positive de novo AML. The patient was treated with AML-directed chemotherapy and imatinib mesylate followed by umbilical cord blood stem cell transplantation. The patient was in complete molecular response 16 months after stem cell transplantation.

High throughput tissue microarray analysis of FHIT expression in diffuse large cell B-cell lymphoma from Saudi Arabia.

Recent studies have suggested a potential prognostic role of alterations of the fragile histidine triad (FHIT) gene in diffuse large B-cell lymphoma. To evaluate possible mechanisms of FHIT inactivation and to further clarify its potential prognostic relevance, we analyzed a set of 114 diffuse large B-cell lymphoma with clinical follow-up information. Tissue microarrays were analyzed by immunohistochemistry for protein expression, and corresponding DNA samples were analyzed for FHIT promotor hypermethlyation. Reduced or absent FHIT expression was found in 75 of 114 diffuse large B-cell lymphoma (66%), but was unrelated to clinical tumor stage or patient prognosis. FHIT promotor hypermethylation was observed in 29 of 93 (23%) interpretable diffuse large B-cell lymphoma. Hypermethylation was not significantly correlated to protein expression loss, which could be explained by competing mechanisms for FHIT inactivation in a substantial fraction of non FHIT hypermethylated diffuse large B-cell lymphoma. Hypermethylation was significantly associated with poor prognosis of diffuse large B-cell lymphoma patients and predominantly seen in nongerminal center diffuse large B-cell lymphoma (27%), but less frequent (13%) in germinal center diffuse large B-cell lymphoma. In summary, these data suggest that promotor hypermethylation is responsible for reduced FHIT expression in a substantial subset of diffuse large B-cell lymphoma, which is primarily composed of nongerminal center subtype with poor patient prognosis.

Epstein – Barr virus infection is not the sole cause of high prevalence for Hodgkin's lymphoma in Saudi Arabia

The age-adjusted incidence of Hodgkins lymphoma (HL) is markedly higher in Saudi Arabia than in the USA, and accounts for 10.5% of all neoplasias in children aged 15 years or older in Saudi Arabia. Epstein – Barr virus (EBV) infection has been suspected to cause high HL incidence in developing countries. To investigate the role of EBV for the high frequency of HL in Saudi Arabia, we analysed 169 HLs from Saudi Arabia and 30 HLs from Europe for EBV infection by in situ hybridization with fluoresence in-conjugated EBV on tissue microarray sections. All Saudi Arabian and European HLs were analysed in one experiment under identical conditions. Unexpectedly, our data show only minor, insignificant differences in EBV infection rates between Saudi Arabian (42 out of 147 informative cases 28.6%) and European HL (nine out of 30 informative cases; 30%; P = 0.8752). Within the Saudi Arabian population, EBV infection was most frequently seen in mixed cellularity HL (52.4%). This was significantly more frequent than in nodular sclerosing HL (26.1%; P = 0.0236). EBV positivity was unrelated to patient prognosis. In conclusion, our data strongly suggest that EBV is not the main cause for the high prevalence of HL in Saudi Arabia. This would be consistent with a major role of genetic susceptibility genes for HL in these populations. The Saudi Arabian population, with high consanguinity and large families, would prove ideal for identifying HL susceptibility genes.