Higher prevalence of harbouring BCR::ABL1 in first-degree relatives of chronic myeloid leukaemia (CML) patients compared to normal population.

BACKGROUND: The role of familial influence in chronic myeloid leukaemia (CML) occurrence is less defined. Previously, we conducted a study to determine the prevalence of harbouring BCR::ABL1 in our local adult normal population (designated as StudyN). We present our current study, which investigated the prevalence of harbouring BCR::ABL1 in the normal first-degree relatives of local CML patients (designated as StudyR). We compared and discussed the prevalence of StudyR and StudyN to assess the familial influence in CML occurrence. METHODS: StudyR was a cross-sectional study using convenience sampling, recruiting first-degree relatives of local CML patients aged ≥ 18 years old without a history of haematological tumour. Real-time quantitative polymerase chain reaction standardised at the International Scale (BCR::ABL1-qPCRIS) was performed according to standard laboratory practice and the manufacturer's protocol. RESULTS: A total of 96 first-degree relatives from 41 families, with a mean age of 39 and a male-to-female ratio of 0.88, were enrolled and analysed. The median number of relatives per family was 2 (range 1 to 5). Among them, 18 (19%) were parents, 39 (41%) were siblings, and 39 (41%) were offspring of the CML patients. StudyR revealed that the prevalence of harbouring BCR::ABL1 in the first-degree relatives was 4% (4/96), which was higher than the prevalence in the local normal population from StudyN, 0.5% (1/190). All four positive relatives were Chinese, with three of them being female (p > 0.05). Their mean age was 39, compared to 45 in StudyN. The BCR::ABL1-qPCRIS levels ranged between 0.0017%IS and 0.0071%IS, similar to StudyN (0.0023%IS to 0.0032%IS) and another study (0.006%IS to 0.016%IS). CONCLUSION: Our study showed that the prevalence of harbouring BCR::ABL1 in the first-degree relatives of known CML patients was higher than the prevalence observed in the normal population. This suggests that familial influence in CML occurrence might exist but could be surpassed by other more dominant influences, such as genetic dilutional effects and protective genetic factors. The gender and ethnic association were inconsistent with CML epidemiology, suggestive of a higher familial influence in female and Chinese. Further investigation into this topic is warranted, ideally through larger studies with longer follow-up periods.

The epidemiology of haematological cancers in Sarawak, Malaysia (1996 to 2015).

BACKGROUND: Published epidemiological studies of haematological cancers are few. Hereby we present a 20-year epidemiological data of haematological cancers in Sarawak from a population-based cancer registry. METHODS: Haematological cancer cases with ICD-10 coded C81-C96 and ICD-O coded /3 diagnosed from 1996 to 2015 were retrieved from Sarawak Cancer Registry. Adult was defined as those 15 years and above. Incidence rate (IR) was calculated based on yearly Sarawak citizen population stratified to age, gender, and ethnic groups. Age-standardised IR (ASR) was calculated using Segi World Standard Population. RESULTS: A total of 3,947 cases were retrieved and analysed. ASR was 10 and male predominance (IR ratio 1.32, 95%CI 1.24,1.41). Haematological cancers generally had a U-shaped distribution with lowest IR at age 10-14 years and exponential increment from age 40 years onwards, except acute lymphoblastic leukaemia (ALL) with highest IR in paediatric 2.8 versus adult 0.5. There was a significant difference in ethnic and specific categories of haematological cancers, of which, in general, Bidayuh (IR ratio 1.13, 95%CI 1.00, 1.27) and Melanau (IR ratio 0.54, 95%CI 0.45, 0.65) had the highest and lowest ethnic-specific IR, respectively, in comparison to Malay. The ASR (non-Hodgkin lymphoma, acute myeloid leukaemia, ALL, chronic myeloid leukaemia, and plasma cell neoplasm) showed a decreasing trend over the 20 years, -2.09 in general, while Hodgkin lymphoma showed an increasing trend of + 2.80. There was crude rate difference between the 11 administrative divisions of Sarawak. CONCLUSIONS: This study provided the IR and ASR of haematological cancers in Sarawak for comparison to other regions of the world. Ethnic diversity in Sarawak resulted in significant differences in IR and ASR.

Systematic Review of Normal Subjects Harbouring BCR-ABL1 Fusion Gene.

The treatment of chronic myeloid leukaemia (CML) requires quantitative polymerase chain reaction (qPCR) to monitor BCR-ABL1 in International Scale (IS). Some normal subjects were found to harbour BCR-ABL1. We performed a systematic review on normal subjects harbouring BCR-ABL1. A literature search was done on July 16, 2017 using EBSCOhost Research Databases interface and Western Pacific Region Index Medicus. Two authors selected the studies, extracted the data, and evaluated the quality of studies using the modified Appraisal Tool for Cross-Sectional Studies independently. The outcomes were prevalence, level of BCR-ABL1IS, proportion, and time of progression to CML. The initial search returned 4,770 studies. Eleven studies, all having used convenient sampling, were included, with total of 1,360 subjects. Ten studies used qualitative PCR and one used qPCR (not IS). The mean prevalence of M-BCR was 5.9, 15.5, and 15.9% in cord blood/newborns/infants (CB/NB/I) (n = 170), children (n = 90), and adults (n = 454), respectively, while m-BCR was 15, 26.9, and 23.1% in CB/NB/I (n = 786), children (n = 67), and adults (n = 208), respectively. No study reported the proportion and time of progression to CML. Nine studies were graded as moderate quality, one study as poor quality, and one study as unacceptable. The result of the studies could neither be inferred to the general normal population nor compared. Follow-up data were scarce.

Clinical Significance of BCL2, C-MYC, and BCL6 Genetic Abnormalities, Epstein-Barr Virus Infection, CD5 Protein Expression, Germinal Center B Cell/Non-Germinal Center B-Cell Subtypes, Co-expression of MYC/BCL2 Proteins and Co-expression of MYC/BCL2/BCL6 Proteins in Diffuse Large B-Cell Lymphoma: A Clinical and Pathological Correlation Study of 120 Patients.

Background: Clinical significance of germinal center B-cell (GCB) and non-GCB sub-categorization, expression of MYC, BCL2, BCL6, CD5 proteins and Epstein Barr virus encoded RNA (EBER) positivity in diffuse large B-cell lymphoma (DLBCL) remain controversial. Could these biomarkers accurately identify high risk DLBCL patients? Are MYC, BCL2 and BCL6 proteins expression feasible as baseline testing to predict c-Myc, BCL2 or BCL6 gene rearrangements? Aims: To investigate prognostic values of GCB/non-GCB sub-categorization, Double Protein Expression Lymphoma (DPL), Triple Protein Expression Lymphoma (TPL), positivity of CD5 protein and EBER in patients with DLBCL disease. To evaluate correlation between BCL2 , c-Myc and BCL6 gene rearrangements with BCL2, MYC and BCL6 proteins expression. Methods: Diagnostic tissue samples of 120 DLBCL patients between January 2012 to December 2013 from four major hospitals in Malaysia were selected. Samples were subjected to immunohistochemical staining, fluorescent in-situ hybridization (FISH) testing, and central pathological review. Pathological data were correlated with clinical characteristics and treatment outcome. Results: A total of 120 cases were analysed. Mean age of diagnosis was 54.1 years ± 14.6, 64 were males, 56 were females, mean follow up period was 25 months (ranged from 1 to 36 months). Of the 120 cases, 74.2% were non-GCB whereas 25.8% were GCB, 6.7% were EBER positive, 6.7% expressed CD5 protein, 13.3% were DPL and 40% were TPL. The prevalence of c-Myc, BCL2, BCL6 gene rearrangements were 5.8%, 5.8%, and 14.2%, respectively; and 1.6% were Double Hit Lymphoma (DHL). EBER positivity, DPL, TPL, c-Myc gene rearrangement, BCL2 gene rearrangement, extra copies of BCL2 gene and BCL6 gene rearrangement were associated with shorter median overall survival (P<0.05). IPI score was the significant determinants of median overall survival in DPL and TPL (P<0.05). CD5 protein expression and GCB/non-GCB sub-categorization did not affect treatment outcome (P>0.05). Overall, c-Myc, BCL2 and BCL6 gene rearrangements showed weak correlation with expression of MYC, BCL2 and BCL6 proteins (P>0.05). Fluorescent in situ hybridization is the preferred technique for prediction of treatment outcome in DLBCL patients. Conclusion: c-Myc, BCL2, and BCL6 gene rearrangements, EBER expression, DHL, TPL and IPI score are reliable risk stratification tools. MYC, BCL2 and BCL6 proteins expression are not applicable as baseline biomarkers to predict c-Myc, BCL2, and BCL6 gene rearrangements.

A randomized double blind control trial comparing filgrastim and pegfilgrastim in cyclophosphamide peripheral blood hematopoietic stem cell mobilization.

There are few randomized trials comparing filgrastim and pegfilgrastim in peripheral blood stem cell mobilization (PBSCM). None of the trials studied the effects of the timing of pegfilgrastim administration on the outcomes of mobilization. We conducted a randomized triple blind control trial comparing the outcomes of filgrastim 5 µg/kg daily from day 3 onwards, 'early' pegfilgrastim 6 mg on day 3 and 'delayed' pegfilgrastim 6 mg on day 7 in cyclophosphamide PBSCM in patients with no previous history of mobilization. Peripheral blood (PB) CD34+ cell count was checked on day 8 and day 11 onward. Apheresis was started when PB CD34+ ≥ 10/µl from day 11 onward. The primary outcome was the successful mobilization rate, defined as cumulative collection of ≥ 2 × 10(6)/kg CD34+ cells in three or less apheresis. The secondary outcomes were the day of neutrophil and platelet engraftment post transplantation. There were 156 patients randomized and 134 patients' data analyzed. Pegfilgrastim 6 mg day 7 produced highest percentage of successful mobilization, 34 out of 48 (70.8%) analyzed patients, followed by daily filgrastim, 28 out of 44 (63.6%) and day 3 pegfilgrastim, 20 out of 42 (47.6%) (p = 0.075). Pegfilgrastim day 7 and daily filgrastim reported 1.48 (p = 0.014) and 1.49 (p = 0.013) times higher successful mobilization rate respectively as compared to pegfilgrastim day 3 after adjusting for disease, gender and exposure to myelotoxic agent. Multiple myeloma patients were three times more likely to achieve successful mobilization as compared to acute leukemia or lymphoma patients. Pegfilgrastim avoided the overshoot of white cells compared to filgrastim. There was no difference in the duration of both white cells and platelet recovery post transplantation between the three interventional arms.

The measurement of mental fatigue following an overnight on-call duty among doctors using electroencephalogram.

This study aimed to measure the spectral power differences in the brain rhythms among a group of hospital doctors before and after an overnight on-call duty. Thirty-two healthy doctors who performed regular on-call duty in a tertiary hospital in Sarawak, Malaysia were voluntarily recruited into this study. All participants were interviewed to collect relevant background information, followed by a self-administered questionnaire using Chalder Fatigue Scale and electroencephalogram test before and after an overnight on-call duty. The average overnight sleep duration during the on-call period was 2.2 hours (p<0.001, significantly shorter than usual sleep duration) among the participants. The mean (SD) Chalder Fatigue Scale score of the participants were 10.8 (5.3) before on-call and 18.4 (6.6) after on-call (p-value < 0.001). The theta rhythm showed significant increase in spectral power globally after an overnight on-call duty, especially when measured at eye closure. In contrast, the alpha and beta rhythms showed reduction in spectral power, significantly at temporal region, at eye closure, following an overnight on-call duty. These effects are more statistically significant when we derived the respective relative theta, alpha, and beta values. The finding of this study could be useful for development of electroencephalogram screening tool to detect mental fatigue.

A Case Report of Leptomeningeal Myelomatosis and Rapid Improvement with Regimen Consisting of Daratumumab, Pomalidomide, Vincristine, Procarbazine, and Dexamethasone.

Central nervous system (CNS) involvement in multiple myeloma (MM) (MM-CNS) in the form of leptomeningeal myelomatosis or brain parenchyma plasmacytoma is rare, causing challenges in clinical diagnosis and treatment. We would like to report a case of leptomeningeal myelomatosis and illustrated the challeges. A 61-year-old man was diagnosed with MM with left paravertebral plasmacytoma, R-ISS II with high suspicion of double-hit MM, either biallelic aberrancy of TP53 or del(17p) and IGH aberrancy depending on the definition chosen, treated with lenalidomide-bortezomib-dexamethasone and local radiotherapy, later developed systemic relapse and progression to MM-CNS in the form of leptomeningeal myelomatosis. A modified CNS-based treatment not reported before, consisting of daratumumab, pomalidomide, vincristine, procarbazine, and dexamethasone, brought a rapid clinical improvement and warrants a further study. Incorporation of intrathecal thiotepa into the regimen would likely increase the efficacy.

Low prevalence of the BCR-ABL1 fusion gene in a normal population in southern Sarawak.

The BCR-ABL1 fusion gene is the driver mutation of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Its expression level in CML patients is monitored by a real-time quantitative polymerase chain reaction defined by the International Scale (qPCRIS). BCR-ABL1 has also been found in asymptomatic normal individuals using a non-qPCRIS method. In the present study, we examined the prevalence of BCR-ABL1 in a normal population in southern Sarawak by performing qPCRIS for BCR-ABL1 with ABL1 as an internal control on total white blood cells, using an unbiased sampling method. While 146 of 190 (76.8%) or 102 of 190 (53.7%) samples showed sufficient amplification of the ABL1 gene at > 20,000 or > 100,000 copy numbers, respectively, in qPCRIS, one of the 190 samples showed amplification of BCR-ABL1 with positive qPCRIS of 0.0023% and 0.0032% in two independent experiments, the sequence of which was the BCR-ABL1 e13a2 transcript. Thus, we herein demonstrated that the BCR-ABL1 fusion gene is expected to be present in approximately 0.5-1% of normal individuals in southern Sarawak.

Correction to: Systematic review of pre-clinical chronic myeloid leukaemia.

The author would like to correct the error in the publication of the original article. The corrected detail is given below for your reading.

Systematic review of pre-clinical chronic myeloid leukaemia.

BACKGROUND: Studies of a provisional entity pre-clinical chronic myeloid leukaemia (CML), which precedes chronic phase (CP) without leucocytosis or blood/marrow feature of CML CP, has been increasing. OBJECTIVE: To perform a systematic review of pre-clinical CML and analysis the data relevant to disease progression to CML CP. METHOD: We performed a literature search on 16 July 2017 using EBSCOhost Research Databases interface and Western Pacific Region Index Medicus. Two authors selected the studies, extracted the data and evaluated the quality of studies using an 8-item tool, independently. The outcomes were percentage of Philadelphia chromosome in the number of metaphases examined (Ph%), correlation between Ph% and blood count and time progress to CML. RESULT: Our initial search returned 4770 studies. A total of 10 studies with a total 17 subjects were included. The lowest Ph%, which eventually progresses to CML, was 10%. Absolute basophil count seemed to correlate better with Ph% compared to total white cell and absolute eosinophil count. The time from the first documented pre-clinical CML to CML ranged from 12 to 48 months. The overall quality of the included studies was average. CONCLUSION: This is the first systematic review on pre-clinical CML. This entity requires additional large-scale studies.

A pioneer experience in Malaysia on In-house Radio-labelling of (131)I-rituximab in the treatment of Non-Hodgkin's Lymphoma and a case report of high dose (131)I-rituximab-BEAM conditioning autologous transplant.

Radioimmunotherapy is an established treatment modality in Non-Hodgkin's lymphoma. The only two commercially available radioimmunotherapies - (90)Y-ibritumomab tiuxetan is expensive and (131)I-tositumomab has been discontinued from commercial production. In resource limited environment, self-labelling (131)I-rituximab might be the only viable practical option. We reported our pioneer experience in Malaysia on self-labelling (131)I-rituximab, substituting autologous haematopoietic stem cell transplantation (HSCT) and a patient, the first reported case, received high dose (131)I-rituximab (6000MBq/163mCi) combined with BEAM conditioning for autologous HSCT.

The Outcome of HyperCVAD Combined with Alemtuzumab for the Treatment of Aggressive T-Cell and NK-Cell Neoplasms.

We report our experience in using six cycles of hyperCVAD in combination with alemtuzumab for the treatment of aggressive T-cell and NK/T-cell neoplasms. Seven females and six males with the median age of 41 (range 18-60) diagnosed with T-cell acute lymphoblastic lymphoma and peripheral T-cell and NK/T-cell neoplasms (n(PTCL) = 6, n(T-cell ALL) = 3, n(NK/T-cell neoplasms) = 4) from 2006 to 2008 were treated with alemtuzumab-hyperCVAD regimen. A total of nine patients (69%) responded to the regimen, with seven achieved complete remission and two achieved partial remission. The median progression free survival and overall survival duration among the responders with complete remission were 12.9 and 24.9 months respectively. The incidence of relapse among the responders was 44% and the overall survival rate was 23%. Only four (31%) patients completed the six cycles of alemtuzumab-hyperCVAD. Others were stopped earlier due to progressive disease (n = 2), cytomegalovirus (CMV) reactivation and/or disease (n = 3), death not due to disease (n = 2), and patient's refusal to continue alemtuzumab (n = 2). The incidence of death not due to disease, CMV reactivation and recurrent CMV reactivation were 50, 50 and 17%, respectively. This study shows that alemtuzumab in combination with hyperCVAD regimen is a feasible regimen but with high toxicity. The toxicity might be reduced with the incorporation of filgrastim and use of valganciclovir as CMV prophylaxis.

Aleukemic bcr-abl positive granulocytic sarcoma.

Granulocytic sarcoma (GS) can occur de novo or in association with intramedullary myeloid disorders. With the advent of sophisticated molecular detection techniques to detect diagnostic genes such as bcr-abl, PML-RARA and CBFB/MYH11 in bone marrow or peripheral blood, many cases of the so called 'primary' GS are questionable. We report a case of primary GS where the tumor mass bcr-abl translocation was demonstrated by fluorescent in situ hybridization in which there was no evidence of chronic myeloid leukemia (CML). This is an important finding as it highlights the possibility that CML may present as a sole extramedullary form, and illustrates potential treatment by tyrosine kinase inhibitor.