CLINICAL NEWS cardiovascular disease and other factors ( i . e ., hypertension , hypercholesterolemia , diabetes , obesity , a history of ischemic disease , non-ischemic cardiac disease , or venous thromboembolism ). Patients with these risk factors were twice as likely to develop serious AOEs as patients without these risk factors ( risk ratio = 2.2 ; 95 % CI 1.5-3.3 ; p value not reported ).
“Considering the extent of prior exposure to multiple TKIs in this patient population , [ the final PACE ] results compare favorably with those of secondgeneration TKIs .”
— JORGE E . CORTES , MD
Twelve patients ( 4 %) died during the study or within 30 days after the end of ponatinib treatment , including four deaths due to disease progression . One patient death ( pneumonia and acute myocardial infarction ) was deemed possibly or probably related to ponatinib .
“ Considering the extent of prior exposure to multiple TKIs in this patient population , [ the final PACE ] results compare favorably with those of second-generation TKIs ,” the researchers concluded , noting that the study was limited by a lack of a comparator arm . However , “ these final results of the PACE study support ponatinib as an effective treatment for patients with CML who have received prior therapies .” ARIAD Pharmaceuticals supported the study .
The corresponding authors report financial support from ARIAD , Bristol-Myers Squibb , Novartis , Pfizer , and Teva . Peloton Advantage and ARIAD provided editorial support .
REFERENCE
Cortes JE , Kim DW , Pinilla-Ibarz J , et al . Ponatinib efficacy and safety in Philadelphia chromosome – positive leukemia : final 5-year results of the phase 2 PACE trial . Blood . 2018 . [ Epub ahead of print ]
Insights From a Pyruvate Kinase Deficiency Registry : Broad Spectrum of Severity , Broad Role for Monitoring
No guidelines exist for the diagnosis , management , and monitoring of patients with red cell pyruvate kinase ( PK ) deficiency – the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia . Clinical features vary widely and the frequency of complications ( e . g ., jaundice , gallstones , iron overload , severe anemia , thrombosis , and osteopenia ) has not been determined .
To characterize the clinical manifestations , complications , and treatment for patients with PK deficiency , Rachael F . Grace , MD , of the Dana-Farber / Boston Children ’ s Cancer and Blood Disorder Center in Massachusetts , and co-authors conducted the retrospective and prospective longitudinal cohort PK Natural History Study ( NHS ). According to an update from the registry published in Blood , PK deficiency manifests a broad spectrum of anemia severity , but there are few early clinical predictors of clinical severity .
“ Together with the absence of predictors for disease severity , the potential for serious complications highlight [ s ] the importance of close monitoring and follow-up of these patients by a hematologist – even in those patients with mild anemia ,” the researchers noted .
The NHS included 254 patients ( median age = 19.0 years ; range = 0.1-69.9 years ) with biochemically or molecularly diagnosed PK deficiency ; people were enrolled between June 2014 and April 2017 from 31 centers in five countries , including 55 patients from the Amish community ( 22 % of total cohort ). Thirty-five percent of the total population was related to another participant in the study .
Medical history and laboratory and radiologic data were retrospectively collected at enrollment . The researchers found that perinatal complications occurred in about one-quarter of participants ( n = 65 / 233 ; 28 %): preterm birth ( 56 %), prenatal anemia requiring in utero transfusions ( 47 %), and preterm labor ( 42 %) were the most common .
“ Most newborns present with significant jaundice ,” the authors noted . However , 10 percent did not have perinatal jaundice . Although “ the diagnosis of PK deficiency should be suspected in patients with perinatal jaundice and hemolysis ,” the absence of this feature does not exclude the possibility of PK deficiency .
Splenectomy was a common treatment approach for PK deficiency ; among the entire cohort , 150 participants ( 59 %) underwent splenectomy . This procedure was observed at a higher rate in the Amish community , compared with the rest of the cohort ( p < 0.0001 ) and in adult patients ( 75 % vs . 42 % of pediatric patients ; p < 0.0001 ). The most common reasons for splenectomy – according to medical record review – were to improve baseline anemia ( 88 %), decrease transfusion burden ( 85 %), improve patient quality of life ( 83 %), and reduce jaundice ( 57 %). In most patients ( 90 %), the transfusion burden was reduced following splenectomy , with a median change in hemoglobin of 1.6 g / dL ( range = – 5.5-4.9 g / dL ; n = 72 ).
Predictors of response to splenectomy included higher pre-splenectomy hemoglobin ( p = 0.007 ), lower indirect bilirubin ( p = 0.005 ), and the presence of missense PKLR mutations ( p = 0.0017 ).
A total of 250 patients had a known transfusion history : 210 ( 84 %) received a blood transfusion in their lifetimes , including 98 percent ( n = 198 / 202 ) of patients older than 5 years . “ Most patients with PK deficiency … received regular transfusions in early childhood ,” the authors noted , adding that the management of PK deficiency in pediatric patients is “ highly variable .” Most patients ( 61 %) delayed splenectomy beyond age 5 but received regular transfusions or transfusions for acute triggers ; six children younger than 5 years ( 12 %) underwent splenectomy and six had never received transfusion ( 12 %). “ This likely reflects both variability in clinical severity and differences in management strategies by hematologists , as the hemoglobin nadirs overlap between transfusion groups ,” they explained .
Among those older than 5 years at the time of enrollment , 79 patients were receiving regular transfusions until the time of splenectomy . Sixty-two ( 78 %) could discontinue transfusions after the procedure , which suggests that splenectomy is effective for most patients in this group . However , the authors noted , “ in young patients who continue to rely on regular transfusions , the risk of transfusions must be balanced with the risks of splenectomy ,” which comes at a higher risk of bacterial infections .
“Together with the absence of predictors for disease severity , the potential for serious complications highlight [ s ] the importance of close monitoring and follow-up ...”
— RACHAEL F . GRACE , MD
Seven percent of patients ( n = 17 / 252 ) had a history of thrombosis , and splenectomized patients had a significantly higher incidence of thrombosis , compared with those with intact spleens ( 11 % vs . 0 %; p = 0.0001 ). “ Although this important potential complication must be considered , the rates of postsplenectomy thrombosis and post-splenectomy pulmonary hypertension are not so elevated that splenectomy should be avoided in this patient population ,” the authors commented .
Gallstones were a frequent complication of PK deficiency across all age groups , occurring in 45 percent of patients ( n = 112 / 248 ) at a median age of 14.3 years ( range = 2.2-60.4
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