BCR‐ABL1‐like B‐lymphoblastic leukemia/lymphoma: Review of the entity and detection methodologies

BCR‐ABL1‐like B‐lymphoblastic leukemia/lymphoma (BCR‐ABL1‐like ALL or Ph‐like ALL) is a neoplastic proliferation of lymphoblasts that has a gene expression profile similar to that of B‐ALL with t(9;22)(q34.1;q11.2) BCR‐ABL1, but lacks that gene fusion. It is associated with poor prognosis and is seen in 10%‐20% of pediatric cases and 20%‐30% of adult cases of ALL. It is included as a provisional entity in the revised 4th edition of the WHO Classification. A variety of different genetic abnormalities are identified in this entity, but they all converge on pathways that are potentially responsive to the addition of targeted therapy to conventional chemotherapy. Thus, it is important to screen for BCR‐ABL1‐like ALL, particularly in adults and pediatric patients with high‐risk clinical features. Here, we provide a brief overview of the genetic profile and clinical features of BCR‐ABL1‐like ALL and review laboratory methodologies for routine identification of this genetically heterogeneous entity.     

Impact of ELN recommendations in the management of first‐line treated chronic myeloid leukaemia patients: a French cross‐sectional study

The availability of tyrosine kinase inhibitors has extended therapeutic options for chronic myeloid leukaemia (CML) patients. Monitoring recommendations and clinical response goals have recently been updated. The objective of this study was to describe the profile of CML patients in chronic phase currently receiving first‐line therapy, including treatment, monitoring and response kinetics. A multicentre, cross‐sectional, epidemiological survey in unselected chronic phase CML patients in France attending consultations during a one‐month period was performed. 438 of 697 (62·8%) reported patients were currently receiving first‐line treatment and were analysed. Imatinib was the most frequently received treatment (72·4% of patients). Retrospective cytogenetic and molecular assessments at 3, 6, 12 or 18 months were available in 88·4% of patients. At the 12‐month assessment, 32·2% were not in major molecular response (MMR). At last assessment, among 355 patients with duration of treatment ≥ 12 months, 91·5% had achieved MMR and 66·5% were in deep molecular response. This study, performed in everyday practice population of CML patients, suggests that monitoring of molecular responses in real‐life practice is aligned with European LeukaemiaNet recommendations. The majority of patients still receiving first‐line treatment are in optimal response, with a few being classified as in the warning area or responding to failure.     

Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1

The p21‐activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1⁺ haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2‐ but not shPAK1‐expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2‐deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. PAK2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome‐mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the PAK2 isoform represents a promising target for the treatment of haematological diseases.     

BCR‐ABL1 molecular remission after 90Y‐epratuzumab tetraxetan radioimmunotherapy in CD22+ Ph+ B‐ALL: proof of principle

Although targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B‐acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome‐positive B‐ALL in third relapse who received RAIT with ⁹⁰yttrium (⁹⁰Y)‐labeled anti‐CD22 epratuzumab tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR‐ABL1 molecular remission documented by RT‐qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. ⁹⁰Y‐Epratuzumab tetraxetan may be a promising therapeutic option for CD22⁺ B‐ALL patients.     

Poor responses to tyrosine kinase inhibitors in a child with precursor B‐cell acute lymphoblastic leukemia with SNX2‐ABL1 chimeric transcript

In addition to BCR, various rare fusion partners for the ABL1 gene have been reported in leukemia. We have identified the fusion gene SNX2‐ABL1 in a pediatric case of acute lymphoblastic leukemia (ALL), which has only once previously been reported in an adult patient. Cytogenetic analysis detected this fusion gene arising from a t(5;9)(q22;q34) translocation. ALL cells carrying a SNX2‐ABL1 fusion exhibited a BCR‐ABL1+ ALL‐like gene expression profile. The patient poorly responded to dasatinib but partially responded to imatinib. Treatment using tyrosine kinase inhibitors requires further investigation to optimize the genotype‐based treatment stratification for patients with SNX2‐ABL1 fusion.