Discordance of MLL-Rearranged (MLL-R) Infant ALL in Monozygotic Twins with Spontaneous Clearance of Preleukemic Clone in Unaffected Twin

The concordance rate for acute leukemia in infant monozygotic twins is estimated to be between 50 and 100%. The leukemic clone is thought to develop in one twin and transfer to the other twin via placental anastamoses. This hypothesis is supported by studies documenting identical, clonal, non-constitutional fusion sequences in concordant leukemias of monozygotic twins. For the ~80% of infant leukemias that are MLL-R+, the twin concordance rate is thought to be 100%, with a very short latency period between the diagnosis of the two twins. This suggests that either the MLL fusion is sufficient to cause leukemia, or it promotes the rapid acquisition of additional mutations required for the development of overt disease.

We report a case of discordance in an infant monozygotic twin pair in which twin A presented with MLL-ENL+ ALL and twin B, who was transiently RT-PCR+ for MLL-ENL in bone marrow (BM) and blood, remains healthy 2.5 years later. Twin A was diagnosed at age 9 months (T=0) with CD10(−) pre-B ALL, cytogenetics t(11;19)(q23;p13.3), FISH+ for MLL-R, RT-PCR+ for MLL-ENL fusion transcript. Twin B was healthy with normal CBC and physical exam (PE). At T+7wks, twin B’s CBC and PE remained normal, but RT-PCR on peripheral blood mononuclear cells (PBMNC) was MLL-ENL+. Three weeks later (T+10wks), BM aspirate was also RT-PCR+ for MLL-ENL. Morphology, FISH and cytogenetics were normal, as were CBC and PE. Two weeks later (T+12wks), twin B developed neutropenia (WBC= 2,880/ml; ANC=461) and thrombocytopenia (29,000/ml) one week after a viral URI (fever, rhinorrhea, cough, diffuse erythematous rash). He had no lymphadenopathy or hepatosplenomegaly on PE. Review of his PB smear confirmed the cytopenias and revealed atypical lymphocytosis and activated monocytes compatible with a viral process, but no lymphoblasts. Large platelets were noted, suggesting a diagnosis of acute ITP. No treatment was given. Repeat CBC 2 days later showed recovery of counts with WBC of 6,390/ml (ANC=1150) and platelets of 117,000/ml. RT-PCR of PBMNC was negative for MLL-ENL; BM aspirate was not performed. One week later, CBC had normalized. Over the next 4 months, monthly CBC and PE were normal, and monthly RT-PCR of PBMNC were negative. Twin B remains healthy with no clinical or laboratory evidence of leukemia at T+2.5yrs.

Twin A was treated according to COG protocol P9407. End-induction BM showed morphologic remission, normal cytogenetics and negative FISH, although RT-PCR remained MLL-ENL+. End-consolidation BM showed continued remission, and was negative for MLL-ENL by cytogenetics, FISH and RT-PCR. At the end of P9407 therapy, an additional 1 year of maintenance therapy was given (total duration of therapy = 2 years). Two months after completion of therapy (26 months from diagnosis), twin A experienced an isolated testicular relapse of CD10(−) pre-B ALL, MLL-ENL+. He received reinduction chemotherapy and testicular radiation and is currently receiving post-induction chemotherapy.

To our knowledge, this is the first report of discordant MLL-R leukemia in infant monozygotic twins, and the first report of documented spontaneous clearance of a detectable preleukemic clone in a healthy “twin B”. There are reports of twins discordant for MLL-R leukemia, but placental status was either unknown, dichorionic, or the leukemia developed in the first twin at 5 years of age and was likely postnatally acquired. The temporal association of the disappearance of the preleukemic clone in twin B with an episode of viral-induced, self-limited thrombocytopenia and neutropenia suggests the possibility that the immune process that mediated the cytopenias may also have been responsible for clearance of the preleukemic clone.

This report confirms prior reports that clonal MLL-R cells are shared between monozygotic twins. However, this case presents evidence against the hypothesis that MLL rearrangements (specifically the MLL-ENL fusion) are sufficient for the development of overt leukemia. It is possible that a viral-induced autoimmune reaction may have aborted the progression of twin B’s MLL-ENL+ preleukemic clone to overt leukemia by eradicating the clone prior to the acquisition of additional mutations. It is also possible that twin B’s preleukemic clone persists at a level beneath the sensitivity of our RT-PCR assay. A less speculative conclusion is that short latency concordance of infant MLL-R leukemia in monozygotic twins is not universal.