Abstract: PB1613
Type: Publication Only
Background
A 7-year old girl presented with backache, leg pain and difficulty walking. She was referred to the local paediatric oncology service, as she was known with Li-Fraumeni Syndrome (LFS). Cancers linked to this disorder include soft tissue sarcomas, osteosarcoma, breast cancer, brain cancer, leukaemia and adrenocortical carcinoma. The patient’s mother had breast cancer twice, and both her (monozygotic) twin sister and older sister had adrenal cortical carcinomas removed.
The patient was born with left sided twinning defects (absent left kidney, malrotation, absent left ear and ear canal, Arnold-Chiari malformation with spinal cord syrinx and hydrocephalus).
At presentation there was a suspicion of a disseminated malignancy. She underwent an MRI scan which showed extensive changes in her spinal column and hips. Bone marrow biopsy revealed Acute Lymphoblastic Leukaemia (ALL). Paucity of diagnostic material restricted the cytogenetic analyses. G-banding showed 46,XX[14], with FISH demonstrating loss of FOXO1/13q14.11 [44%], gain of MYC/8q24.21 [9%], ETV6-RUNX1 NEGATIVE, gain of RUNX1/21q22.12 [21%] and BCR-ABL1 NEGATIVE.
The patient was treated according to NCRI risk criteria on the least intensive regimen of the UK ALL 2003 trial. She achieved morphological remission after a 3-drug induction, and successfully completed further treatment, including intensification/CNS directed phase, interim maintenance and 2 delayed intensification blocks.
She completed 5 years of follow-up and was transferred to the Long Term Follow-Up Clinic, when she presented with hypercalcaemia. Peripheral blood and bone marrow biopsy confirmed a diagnosis of ALL. Although the phenotype resembled the profile of the first presentation of leukaemia, the genetic aberrations appeared incongruent.
Aims
Establish the origin of the second episode of ALL in a patient with known Li-Fraumeni Syndrome. As treatment and outcome for relapsed ALL in comparison with a second, primary, ALL are completely different, this information was critical to guide further management.
Methods
We set out to comprehensively characterise the second ALL, including conventional G-banding and fluorescence in situ hybridisation (FISH). The acquired results were compared with those derived from the first ALL diagnosis.
Results
The G-banding analysis showed 36,XX,-2,-3,-4,del(5)(q31q35),-7,-12,-13,-14,-15,-16,-17[13]/46,XX[7]. Extensive FISH analysis confirmed the diagnosis of low hypodiploidy ALL. This result was in line with the reported association between TP53 gene mutations in 90% of cases of low hypodiploid ALL, with these mutations often present in normal cells. [Holmfeldt, Nat Gen, 2013] At first sight, this did not recapitulate the original cytogenetic analysis and suggested the occurrence of a second episode of ALL. In order to further characterise the diagnostic genetics, FISH probes were used on archived diagnostic slides. Careful selection of probes demonstrated that the original leukaemia sample contained two co-existing clones – one low hypodiploid clone (with an identical pattern of loss and gain of chromosomes as the second ALL) and one clone resembling a doubled up/near triploid low hypodiploid clone.
Conclusion
This case report demonstrates the value of in-depth genetic analyses to guide management of patients with ALL. This patient proceeded with re-induction according to our current relapsed therapy guidelines (R3), to which she has shown a promising response. She is considered for allogeneic bone marrow transplantation using an unrelated donor.
In hindsight, the treatment regimen used for the initial ALL was incorrect. If it had been established that she had low hypodiploid ALL the first time around, she would have been allocated the most intensive regimen within the trial. Nevertheless, she maintained remission status for 5 years with low intensity treatment and ironically relapsed when most patients are told they are cured.
Since the original diagnosis of ALL in 2007, research has vastly improved our understanding of the biology and genetic landscape of ALL. This has facilitated risk stratification, improved outcome after treatment and identified novel drug targets. Genomic profiling of low hypodiploid ALL has identified oncogenic activation of Ras and phosphoinositide 3-kinase (PI3K) signalling conferring sensitivity to PI3K inhibitors, thus providing therapeutic avenues if conventional treatment were to fail.
Session topic: 1. Acute lymphoblastic leukemia - Biology
