Outcomes of Down-Syndrome Associated Acute Lymphoblastic Leukemia in Adults: A Single Center Retrospective Review

Background:

Children and adults with Down Syndrome (DS) have an approximately 20-fold increased risk of developing acute lymphoblastic leukemia, which in the majority of cases is of the B-cell precursor  (BCP) type , and have significantly inferior outcomes due to both higher relapse rates and increased treatment-related mortality. During treatment for ALL, children with DS are at a higher risk of complications such as prolonged neutropenia, severe mucositis and longer hospitalizations. In view of the significant barriers to successful treatment for pediatric DS-ALL and the absence of outcome data for DS-ALL in adults, we retrospectively reviewed the outcomes of adult patients with DS-ALL treated at our center.

Methods:

All patients greater than 18 years of age diagnosed with DS-ALL who were followed at Princess Margaret Cancer Center/University Health Network (PMH/UHN) between January 1, 2000 and June 30, 2014 were identified using the institutional leukemia database.

Diagnosis of ALL was established by standard FAB WHO Criteria using multiparameter flow cytometry for immunophenotyping according to ISCN guidelines. Treatment of adult DS patients with de novo ALL and those with relapsed ALL who had not previously received intensive asaparaginas therapy, were treated according to a modified Dana Farber Cancer Institute (DFCI) ALL regimen; reduced doses of methotrexate were used due to the increased risk of mucositis reported in children with DS.  This regimen includes an at least four fold higher total dose of E. coli derived asparaginase compared to other adult regimens.

Results:

Seven adult patients with DS-ALL were treated at our center from 2000 to 2014.    Four of these were diagnosed with de novo DS-ALL (after age of 18 years) and three patients developed a late isolated bone marrow relapse of DS-ALL as adults after previous treatment for childhood DS-ALL.  Approximately half of our patients had favourable cytogenetics and half had intermediate risk cytogenetics .  Treatment was not altered based on cytogenetics.

The median age of 4 patients, with de novo adult DS-ALL, was 26 years (range 21-42 years).  75% achieved a CR after initial induction; one patient died during induction from sepsis. Two of the four de novo adult DS-ALL patients relapsed after CR1 durations of 11 and 35 mon.. One patient received palliative chemotherapy.  At the time of last follow up, 3 of these patients have died.  The one remaining patient is alive in continuous CR at 41 mos.

The three adult DS patients with relapsed ALL had a median age of 14 years (7-15 years) at diagnosis of primary DS-ALL and 29 years (21-36) at the diagnosis of relapse.  Two of these received DFCI as re-induction while the third received Hyper-CVAD. Despite achieving an initial remission all patients with relapsed DS-ALL died , two from subsequent relapsed  and one from an invasive aspergillosis. One patient relapsed while on therapy at 4.7 months. The other patient relapsed while off therapy at 15.2 months.

The overall and relapsed-free survival of adult patients with DS and de novo ALL at 3 years was 50% and 33.3%, respectively, and thus markedly inferior to results of a similarly treated population of adults (aged 18-35 years) without DS ( 3-year OS 83%, 3-year RFS 77%) at our center.

Conclusions:

The results of our series of adult patients with DS and ALL suggest that the barriers to successful treatment of ALL in adults with DS are similar to those observed in children. Although the rarity of adult ALL in general, and that of adult DS-ALL in particular, limits sample size and conclusions, this report is to our knowledge the first describing survival outcomes of adults with DS and ALL and highlights that treatment of primary adult DS-ALL is feasible but significantly less successful compared to adults without DS. As in children,  subsequent relapse and treatment–related mortality impacting outcome are  equally problematic.