An 86-year-old man presented with acute hepatic failure, worsening thrombocytopenia, and anemia having been diagnosed and managed expectantly with cytogenetically normal RAEB-1. After 20 months a diagnosis of disease transformation to acute monocytic leukemia (M5b) was made. Conventional G-banded analysis of unstimulated bone marrow cultures demonstrated a jumping translocation (JT) involving proximal and distal breakpoints on donor chromosome 3 at bands 3q1?2 and 3q21, respectively. Recipient chromosomes included the long-arm telomeric regions of chromosomes 5, 10, 14, 16, and 19. A low-level trisomy 8 clone was also found in association with both proximal and distal JT clones. Conventional G-banded analysis of unstimulated peripheral blood cultures detected the proximal 3q1?2 JT clone involving recipient chromosome 10 several weeks after transformation to acute monocytic leukemia. Interestingly, JTs involving recipient chromosomes 5, 14, 16, and 19 were not detected in this peripheral blood sample. Palliative care was administered until his demise 2.2 months after disease transformation. There have been fewer than 70 cases of acquired JTs reported in the literature, including one myeloproliferative neoplasm and five acute myeloid leukemias involving a single breakpoint site on donor chromosome 3. Our case is unique as it is the first acquired case to demonstrate a JT involving alternative pericentromeric breakpoint sites on a single donor chromosome consisting of a proximal breakpoint at 3q1?2 and a more distal breakpoint at 3q21.
BCR-ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B cell precursor (BCP) ALL, which has a similar gene expression profile to BCR-ABL1 positive ALL and shares the same high risk of relapse. BCR-ABL1-like ALL is genetically heterogeneous and no single abnormality defines them. However a number of novel fusion genes have been reported in this subgroup, which involve the kinase genes: PDGFRB, CSF1R, ABL1, ABL2 and JAK2. Studies have shown that patients with these fusions may also respond to tyrosine kinase inhibitors (TKI), such as imatinib. Here we present a subset of patients with the SSBP2-CSF1R fusion, including a patient treated with imatinib after relapse. Five patients with BCP-ALL were identified with cytogenetically visible abnormalities of chromosome 5, which resulted in fusion of the SSBP2 at 5q14 to CSF1R at 5q33. Three patients showed balanced translocations, t(5;5)(q14;q33) and 2 showed duplication of the long arm of chromosome 5, dup(5)(q14q33). FISH analysis using in-house dual colour break-apart probes confirmed rearrangement of the CSF1R and SSBP2 genes in 4 patients. In the two cases showing dup(5)(q14q32) the duplication was confirmed by single nucleotide polymorphism (SNP) array analysis with the breakpoints occurring within SSBP2 and CSF1R. Paired end sequencing in 3 cases confirmed that the breakpoints within SSBP2 and CSF1R with the predicted transcriptional consequence being an in-frame fusion of SSBP2 exon 5 or 6 to CSF1Rexon 12. Genome wide SNP array analysis was performed in 4 cases, which revealed few copy number abnormalities (CNA) at diagnosis, with less than 5 CNA per patient. The only recurrent CNA was loss of IKZF1, seen in 2 patients; one had an intragenic deletion of exons 4-7 and the other a large deletion of approximately 22.5 Mb, spanning 7p11 to 7p14.2 and including biallelic loss of IKZF1exons 2-3. The clinical and demographic data for the five patients are shown in Table 1. Complete remission (CR) was achieved in all cases. Two patients, who were <10 years at diagnosis and received standard chemotherapy, have continued in CR1 for >10 years. The oldest patient was a 40 year old female who died due to graft versus host disease following a bone marrow transplant. Patients 4 and 5 were treated as high risk due to age, high WCC (>50 x109/L) and minimal residual disease (MRD) risk. Despite receiving intensive therapy, both patients suffered relapses. Patient 4, who relapsed while receiving consolidation therapy, failed to achieve CR2 and subsequently died. Patient 5 suffered an isolated bone marrow relapse one month after the end of treatment. She was treated according to the ALLR3 trial high risk arm and achieved CR2 and MRD negativity by day 35. The detection of the SSBP2-CSF1R fusion prompted the addition of imatinib (400 mg/d) to her regimen with the intention of maintaining remission until unrelated donor stem cell transplant. Unfortunately the patient died 11 weeks after relapse from infection (E. coli septicaemia). Although these cases were identified by cytogenetics, unbiased screening of a single childhood trial, UKALL2003 was carried out. Among 276 BCP-ALL patients without any of the established cytogenetic changes, a single case (Patient 4) with the SSBP2-CSF1Rfusion was identified. This equates to less than 0.1% of childhood BCP-ALL. The incidence and outcome in adult BCP-ALL remains to be determined. This study highlights the rarity and variable outcome for paediatric patients with SSBP2-CSF1R fusions. Two young children treated as low risk achieved long-term event free survival, however 2 older children classified as high risk suffered early relapses. It is possible that children with ALL who are SSBP2-CSF1Rpositive may benefit from the incorporation of TKI into their treatment regime in the early stages of their disease. Given the rarity of this abnormality, it may not be necessary to screen all children, however those with refractory or high risk ALL should be investigated for lesions potentially responsive to TKI. Table 1 Patient no. Age Sex Trial WCC(x109/L) Karyotype Follow up 1 2 M ALL97 50.3 46,XY,t(5;5)(q14q33) CR1 >10yrs 2 4 F ALL97 18.2 47,XX,t(5;5)(q14;q33),+21 CR1 >10yrs 3 40 F UKALLXII 12.1 Failed. arr [hg19] 5q14q33(80721553-149443298)x3 Remission death 4 10 M UKALL2003 301.8 46,XY,t(5;5)(q14;q33)/46,XY,idem,t(3;20)(p21;q13) Relapsed and died 5 11 F Non-trial 8 46,XX,dup(5)(q14q33)† Relapsed and died in CR2 † karyotype at relapse Disclosures No relevant conflicts of interest to declare.
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