t(17;19) in Children with Acute Lymphocytic Leukemia: A Report of 3 Cases and a Review of the Literature

Several cytogenetic abnormalities identified in patients with childhood acute lymphocytic leukemia (ALL) have been associated with a poor prognosis. There are several case reports in the literature describing t(17;19) in children with ALL. This translocation has been associated with hypercalcemia, coagulopathy, and poor outcome. We present three cases of ALL with t(17;19) treated at our institution and review the outcome of children reported in the medical literature.


Introduction
Over the past 2 decades, the outcome of children with acute lymphocytic leukemia has exceeded 80% in patients treated in developed countries [1]. Cytogenetic abnormalities, iden-ti�ed in �y percent of all ALL patients, have long been identi�ed as factors that can in�uence the risk of relapse. Some of the identi�ed high risk cytogenetic abnormalities include hypodiploidy, t(4;11), and t(9;22)(q34;q11.2) [1,2]. In current treatment protocols, patients with high risk features are strati�ed to a more intensive therapy and/or an allogeneic stem cell transplant.
e chromosomal rearrangement t(17;19), observed in less than 1% of precursor B ALL, has been identi�ed as a poor prognostic indicator. is translocation, which juxtaposes the E2A and HLF genes, results in the creation of a mutant fusion protein that is thought to play a role in pathogenesis. Furthermore, this translocation results in the disruption of the E2A gene which plays an important role in lymphopoiesis [3,4]. ALL with t(17;19) have been associated with hypercalcemia and coagulopathy, although the mechanism of these �ndings is unclear [5,6]. We report on 3 children with t(17;19) ALL and review the outcome of children with this translocation reported in the medical literature.

Discussion
e chromosomal rearrangement t(17:19) in childhood ALL is rare but is increasingly recognized as a clinically signi�cant cytogenetic abnormality. We report three cases to contribute to the growing body of the literature about this translocation and the associated clinical features [4]. Eighteen cases of t(17;19) associated ALL had been previously reported in the English literature (Table 1) [4][5][6][7][8][9][10][11][12][13][14]. ere are a number of common clinical features, which are demonstrated in these cases. Some of the �rst described cases presented with disseminated intravascular coagulation (DIC), a rare �nding in childhood ALL [13]. Of the 17 cases with available data, 8 had evidence of DIC either at diagnosis or at relapse. Case 2 reported here presented with a prolonged PTT and hypo�brinogenemia consistent with DIC.
Another clinical feature commonly seen with t(17;19) ALL is hypercalcemia. is was demonstrated in ten of thirteen previously reported cases with available data. Two of the three cases reported here (Cases 1 and 3) were associated with signi�cant hypercalcemia. It has been suggested based upon previous cases that hypercalcemia in t(17;19) patients is partly parathyroid hormone-related protein (PTHrP) mediated [5]. However, this association was not observed in our patients as both had normal levels of PTHrP.
Perhaps most notably, this translocation has been thought to be a poor prognostic indicator with patients having poor response to initial therapy and early relapse. Of the twentyone reported cases, all patients have died of progressive disease with the exception of one who was alive on therapy at 1-year aer diagnosis with no long-term follow-up data [6]. Two cases presented here were rapidly progressive with poor response to standard therapy leading to early relapse in Case 1 and failure to achieve remission in Case 3. Case 2 underwent allogeneic bone marrow transplant in �rst complete remission but still went on to relapse 8 months aer transplant. ere is one previously reported case of a patient undergoing stem cell transplant in �rst complete remission with eventual relapse and death [8]. It should be noted that both patients died aer relapse and not from complications of transplant. Recently Glover et al. reported on in vitro sensitivity of leukemia blasts from a patient with t (17;19) to dasatinib a tyrosine kinase inhibitor [9]. e patient had a transient clinical response to combination of dasatinib and chemotherapy although he eventually relapsed and died during the re-induction therapy.
e cases reported here are consistent with previous evidence linking t(17;19) ALL with DIC, hypercalcemia, and a poor prognosis. In the current Children's Oncology Group studies, these patients are not classi�ed as very high risk. Based upon previous cases and our experience, we conclude that t(17;19) in ALL should be considered a very highrisk indicator and treated as such. Novel and more aggressive therapies including tyrosine kinase inhibitors, targeted immune therapies, and allogeneic stem cell transplant should be considered in these patients.