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PAPER SPOTLIGHT
Predicting Survival Outcomes for Children With Down Syndrome and AML or MDS
Children with Down syndrome ( DS ) have a higher risk of developing acute lymphocytic leukemia ( ALL ) and acute myeloid leukemia ( AML ) than those without DS . Though these patients typically have a favorable event-free survival ( EFS ), they may experience treatment-related morbidity and mortality , complicating decisions about optimal treatment intensity .
In a report from the Children ’ s Oncology Group ( COG ) AAML0431 trial published in Blood , Jeffrey W . Taub , MD , from the Children ’ s Hospital of Michigan at Wayne State University , and co-authors examined treatment and survival trends , as along with the prognostic significance of minimal residual disease ( MRD ) levels , among patients with DS and AML ( referred to as myeloid leukemia of DS [ ML-DS ]).
The AAML0431 study included 204 children ( age range = 0-4 years ) with a confirmed diagnosis of DS or DS mosaicism ( the presence of typical chromosomes and an extra copy of chromosome 21 ) and AML ( diagnosed according to the French- American-British classification , excluding promyelocytic leukemia ; n = 144 ) or myelodysplastic syndromes ( MDS ; with < 30 % blasts ; n = 60 ). Patients were enrolled
between March 2007 and December 2011 .
Children were excluded if they previously received chemotherapy , radiation , or any antileukemic therapy ( except intrathecal cytarabine administered at diagnosis or as prior therapy for transient myeloproliferative disorders ).
Treatment consisted of four cycles of induction therapy and two cycles of intensification therapy :
• induction cycles 1 , 3 , and 4 : Continuous-infusion cytarabine 6.7 mg / kg per day for 4 days ( 96 hours ), continuousinfusion daunorubicin 0.67 mg / kg for 24 hours every 4 days ( 96 hours ), and oral 6-thioguanine 1.65 mg / kg twice daily for 4 days
• induction cycle 2 : Cytarabine 100 mg / kg administered as a 3-hour infusion every 12 hours for 4 doses on days 1 , 2 , 8 , and 9 with E . coli asparaginase 200 units / kg administered intramuscularly 3 hours after the last dose of cytarabine on days 2 and 9
• intensification cycles 1 and 2 : Continuousinfusion cytarabine 3.3 mg / kg every 24 hours for 7 days ( 168 hours ) and etoposide 4.2 mg / kg administered as a 1-hour infusion for 3 days
Cumulative chemotherapy doses were cytarabine 27,800 mg / m 2 , daunorubicin 240 mg / m 2 , and etoposide 750 mg / m 2 .
At data cutoff ( June 30 , 2016 ) and after a median follow-up of 5.6 years ( range = 0-8.7 years ), 5-year EFS and overall survival were 91 percent and 93 percent , respectively . The cumulative incidence of relapse was 10 percent for patients with AML and 5.1 percent for patients with MDS ( see TABLE 1 for survival outcomes ).
Most adverse events ( AEs ; 27.1 % of total AEs and 66 % of grade ≥3 AEs ) occurred during induction cycle 2 , when high-dose cytarabine was administered . The median time to absolute neutrophil count recovery (> 1,000 / μL ) was also the longest during induction cycle 2 ( median = 37 days ; maximum = 67 days ), and rates of hospitalization in the intensive care unit were highest during induction cycles 1 ( 6.9 %) and 2 ( 7.0 %).
Grade ≥3 febrile neutropenia was the most common AE and
TABLE 1 . Survival Outcomes
All Patients ( n = 240 )
5-year EFS 89.9 % ( 95 % CI 84.8-93.4 )
5-year OS 93.0 % ( 95 % CI 88.5-95.8 )
occurred most frequently during induction cycles 1 ( 27 %) and 2 ( 29.7 %). No life-threatening cardiac toxicities occurred , though seven grade ≥3 cardiac AEs were documented . Treatment failure occurred in 20 patients , related to relapse ( n = 14 ), non-relapse death ( n = 3 ), secondary malignancies ( n = 2 ), and induction failure ( n = 1 ). Thirteen patients were taken off treatment during induction cycle 1 ( n = 4 ), induction cycle 2 ( n = 3 ), induction cycle 4 ( n = 2 ), and intensification cycle 1 ( n = 4 ).
Because MRDpositivity has been identified as a prognostic factor for patients with non-DS AML , Dr . Taub and researchers also assessed whether MRD levels could identify risk groups in patients with ML-DS . MRD data were available for 146 patients ( 71.6 %), and detected in 21 patients ( 14.4 %) following induction cycle 1 . Those patients had significantly worse disease-free survival than those who were MRD-negative ( 76.2 % vs . 92.7 %; p = 0.01 ). Patients who were MRD-positive were more likely to be male ( p < 0.001 ) and have isolated trisomies ( other than trisomy 8 ; p = 0.05 ).
Among MRD-negative patients , 8.3 percent ( n = 10 / 120 ) of those with evaluable response were not in complete response ( CR ) according to morphologic analyses , whereas 68.4 percent of MRD-positive patients ( n = 13 ) achieved CR . A
AML ( n = 144 )
88.6 % ( 95 % CI 82.0-92.8 )
92.2 % ( 95 % CI 86.4-95.6 ) morphologic bone marrow response after induction cycle 1 was associated with CR in 177 patients ( 87.2 %), partial response in 15 ( 7.4 %), and relapsed disease in 10 ( 4.9 %).
“ A comparison of marrow morphology and MRD analysis after induction 1 revealed that 23 of 139 patients ( 16.5 %) classified by morphology would have been reclassified as positive or negative by MRD ,” the authors noted . “ MRD therefore appears to be a more highly sensitive and objective indicator of response .
“ The earlier use of high-dose cytarabine and reduction in daunorubicin dose was associated with better patient outcomes , compared with those seen in past COG trials ,” the authors concluded . “ By identifying the appropriate patient population ( e . g ., MRD-negative after induction 1 ), a reduction in cytarabine dose intensity presents a logical approach to reduce potential toxicity , particularly infectious complications , in ML-DS patients .”
The study is limited by its small patient population , particularly the number of patients with available MRD data , non-randomized design , and lack of validation of prognostic markers in an independent cohort .
REFERENCE
Taub JW , Berman JN , Hitzler JK , et al . Improvement outcomes for myeloid leukemia of Down syndrome : a report from the Children ’ s Oncology Group AAML0431 trial . Blood . 2017 April 7 . [ Epub ahead of print ]
MDS ( n = 60 )
93.2 % ( 95 % CI 82.9-97.4 )
94.9 % ( 95 % CI 85.1-98.3 ) p Value
AML = acute myeloid leukemia ; MDS = myelodysplastic syndromes ; EFS = event-free survival ; OS = overall survival
0.329
0.492
18 ASH Clinical News June 2017