Emily Powley¹, Steven Lane², Cyriac Abraham^1
1Mater Pathology, ²Royal Brisbane and Women's Hospital, Cancer care services

Acute Myeloid Leukaemia (AML) occurring in patients treated for Chronic Lymphocytic Leukaemia (CLL) is widely reported and usually attributed to prior cytotoxic therapy. AML developing in the setting of treatment naïve CLL is extremely rare with conflicting evidence for a single cell of origin and an unknown optimal treatment.^1-5 

A 76 year old female presented with 1 week of fatigue and bruising. The patient had an incidental diagnosis of CLL-type high count monoclonal B lymphocytosis (MBL) seven years earlier which subsequently progressed to CLL, that was asymptomatic and not requiring treatment. Automated full blood count (FBC) results demonstrated an increase in White Cell Count (WCC) to 175x10⁹/L on admission, from 19.6x10⁹/L 9 months earlier. Blood film examination demonstrated 40% blast cells and 50% small mature lymphocytes with smudge cells present.

A diagnosis of NPM1 mutated AML (WHO2022) was made following bone marrow biopsy and further molecular testing. Core myeloid gene panel of 37 genes identified a Type A NPM1 mutation at a variant allele frequency (VAF) of 23.89%, FLT3 ITD mutation at a VAF of 43.08% and two DNMT3A-non R882 variants at VAFs of 33.22% and 33.32%. 

This case raises a number of interesting discussion points. Whether these malignancies arise from a single common progenitor cell population is unclear from routine molecular analysis. The mutational profile in the setting of AML developing in a patient with treatment naïve CLL is not well described. The potential implications for therapeutic approaches are also unclear.

 
References

1.     Ornellas De Souza MH, de Souza Fernandez T, Diamond HR et al. Cytogenetic and immunophenotypic evidence of independent clonal origins of concomitant chronic lymphocytic leukaemia and acute myeloid leukaemia. Eur J Haematol 2001; 66: 281-283.

2.     Gottardi M, Gattei V, Degan M et al. Concomitant chronic lymphocytic leukemia and acute myeloid leukemia: evidence of simultaneous expansion of two independent clones. Leuk Lymphoma 2006; 47: 885-889.

3.     Lu CM, Murata-Collins JL, Wang E, et al. Concurrent acute myeloid leukemia with            

inv(16)(p13.1q22) and chronic lymphocytic leukemia: molecular evidence of two separate diseases. Am J Hematol 2006; 81: 963-968.

4.     Zhang R, Kim YM, Lu X et al. Characterization of a novel t(2;5;11) in a patient with concurrent AML and CLL: a case report and literature review. Cancer Genet 2011; 204: 328-333.

5.     Chen RR, Zhu LX, Wang LL et al. Synchronous diagnosis and treatment of acute myeloid leukaemia and chronic lymphocytic leukaemia: Two case reports. World J Clin Cases 2021; 9(30): 9114-9150.

Mandy Hubbard¹, Cale Burge², Geoff Kershaw²

¹NSWHP Coffs Harbour Base Hospital; 2 NSWHP Royal Prince Alfred

When patients taking direct Xa inhibitors Apixaban or Rivaroxaban are switched to UFH or LMWH the disappearance of the DOAC sometimes needs to be measured. This study aimed to validate a plasma heparin neutralisation procedure that allows accurate measurement of apixaban and rivaroxaban during the bridging period.

Samples from healthy volunteers, as well as excess plasma from patients treated with Apixaban/Rivaroxaban/UFH/LMWH were double spun and frozen at ≤40ºC before testing. Normal donor plasma and plasma from patients receiving DOACs were spiked with UFH/LMWH then treated with Hepzyme® (Siemens) then re-tested for apixaban, rivaroxaban, UFH and LMWH. Scenarios assessed:

1.     UFH and clexane spiked into normal plasma to assess the degree of false apixaban/rivaroxaban levels, followed by reversal with Hepzyme.

2.     Spiking of UFH/LMWH to 0.5 and 1.0IU/mL into plasma containing apixaban or rivaroxaban to assess degree of DOAC overestimation relative to baseline, followed by treatment with Hepzyme and re-assaying of apixaban/rivaroxaban to compare baseline levels.

Accurate measurement of apixaban and rivaroxaban is possible using Hepzyme to remove UFH or LMWH when it is concurrently present in test plasma. This may have benefits in an urgent pre-surgical setting.

Tsz Long Mathew CHEUNG¹, Sze Pui Christy TSUI¹, Wai Kwong YAU¹, Ho Ting Allison LEUNG¹, Ho Wan IP¹, Yuk Yan Rock LEUNG^1
1Division of Haematology, Department of Pathology, Queen Mary Hospital, Hong Kong

Background: While the molecular pathogenesis of von Willebrand disease (VWD) is well-studied, the genetic landscape of VWD in the Hong Kong population is less clear. 

Methods: 71 patients from 64 families were enrolled. A multitude of VWF assays were performed. While whole exome sequencing was performed for the newly recruited patients, previous genetic data generated by targeted NGS gene panels or Sanger sequencing were also included for analysis. 

Results: Majority of the patients had either type 1 VWD / low VWF (41%), or type 2 VWD (52%). 45 VWF variants, including seven novel variants, were detected in 41 patients. Three novel variants, namely VWF p.C1165Y, p.L1384P and p.A1461T, were classified as likely pathogenic for type 2 VWD. Type 2 VWD showed good genotype-phenotype correlation, but the correlation in type 1 VWD was less clear. Negative VWF genotyping results provided diagnostic clues to alternative diagnoses including haemophilia A and acquired von Willebrand syndrome. Some issues regarding the phenotypic and genotypic diagnosis of VWD were observed. 

Conclusion: The phenotypes of the Hong Kong patients with novel variants may provide insights into the complex pathogenesis of VWD. Moreover, the role of genetic tests in enabling correct diagnosis in a simplified manner is highlighted. 

Jun Yen Ng¹, Maya Latimer¹, Mark Polizzotto¹

¹Department of Haematology, Canberra Hospital, Canberra, Australia

Clonal Haematopoiesis (CH) refers to the clonal outgrowth of a population of hematopoietic stem cells in the absence of haematologic neoplasms. CH is common in older populations.(1) It is also common in people living with HIV.(2)
 

CH screening is not currently performed in routine clinical practice. Most individuals with CH are asymptomatic; however, the condition increases the risk of multiple life-limiting complications, including myeloid neoplasms (MN), cardiovascular disease, and cerebrovascular disease.(1) While CH is not yet treatable, identifying the condition may assist individuals in making informed decisions, including an individualised management plan for early detection of CH-associated complications. 
 

The optimal approach to surveillance for MN in individuals with CH remains undefined. Some individuals undergo active surveillance with regular blood count monitoring. 
 

Given the uncertainties surrounding the identification and management, dedicated CH research clinics have been developed in the United States. However, these clinics are not yet available in Australia.
 

This cohort study will establish a screening clinic and a prospectively characterised CH registry. With consent, individuals with possible CH will undergo screening by molecular testing in the first dedicated multidisciplinary CH clinic in Australia. The study findings will serve as the basis for future clinical and translational studies in CH. 

1.       Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. New England Journal of Medicine. 2014;371(26):2488-98.

2.       Dharan NJ, Yeh P, Bloch M, Yeung MM, Baker D, Guinto J, et al. HIV is associated with an increased risk of age-related clonal hematopoiesis among older adults. Nat Med. 2021;27(6):1006-11.

Thornton Macauley^1
1St. Vincent's Hospital Melbourne

Background: In Australia, use of FISH testing for high-risk primary and secondary cytogenetic abnormalities (HRSCA) is well-established in PCM, and Medicare-rebated once per lifetime¹, despite HRSCA also being acquired at relapse. With development of risk-adapted, targeted therapies against these lesions^2,3, benefit may exist in FISH testing at relapse.

Methods: Retrospective cohort study of PCM patients who had FISH testing at a statewide cytogenetics service at diagnosis and at one or more relapses between 01/09/2020-01/09/2023. Testing must have included IGH break-apart and dual-fusion FISH probe testing on a diagnostic bone marrow aspirate specimen, and CDKN2C/CKS1B and TP53/NF1 dual-colour probe testing on both diagnostic and relapse specimen/s. Prevalence and acquisition rates were quantified.

Results: Of 101 eligible patients identified, 12.9% acquired HRSCA at relapse: gain(1q21) 5.9%, del(17p13) 2.0%, del(1p32) 2.0%. 3 patients synchronously acquired multiple HRSCA. 51.5% of patients had one or multiple HRSCA at PCM diagnosis. The primary cytogenetic abnormality of IGH rearrangement was seen in 53.5% of patients. Clone size changes when persisting at relapse were positive, except in del17p cases. 

Conclusion: Acquisition of new HRSCA occurs at PCM relapse. Portending poorer prognosis when detected, this study supports the need for FISH testing at relapse and review of Medicare funding.

 

References:

1. Item 73370 | Medicare Benefits Schedule [Internet]. [cited 2024 Jun 16]. Available from: https://www9.health.gov.au/mbs/fullDisplay.cfm?type=item&q=73370&qt=ItemID

2. Mina R, Musto P, Rota-Scalabrini D, Paris L, Gamberi B, Palmas A, et al. Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial. Lancet Oncol. 2023 Jan 1;24(1):64–76.

3. Li J, Stagg NJ, Johnston J, Harris MJ, Menzies SA, DiCara D, et al. Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing. Cancer Cell. 2017 Mar 13;31(3):383–95.