CLINICAL NEWS non-splenectomized patients with corticosteroid-resistant and / or relapsed immune thrombocytopenia ( ITP ).
“ Despite decades of research , the treatment of severe , corticosteroid-resistant or relapsed disease remains a great challenge ,” the study authors , led by Fei-Er Feng , from the Peking University Institute of Hematology in Beijing , China , noted .
The steroid danazol has a hematopoietic stimulatory and immunomodulatory effect , the authors noted , and the agent has recently been shown to reverse abnormal telomere function in patients with thrombocytopenia . Previous research suggested that ATRA has an immunomodulatory effect on hematopoiesis and could be a potential treatment for ITP .
In this study , the authors hypothesized that the combination of ATRA and danazol would work synergistically to target both increased platelet destruction and insufficient platelet production associated with ITP .
The investigators enrolled adult patients between 2012 and 2016 from four medical centers in Beijing and one center in Shandong , China . Patients were included if they had a platelet count of < 30 × 10 9 / L , had not achieved a sustained response (> 4 weeks ) to treatment with full-dose corticosteroids , or had relapsed during steroid-tapering or after its discontinuation . Patients with secondary ITP ( e . g ., patients with HIV , hepatitis C virus , H . pylori infection , or systemic lupus erythematosus ) were excluded .
Ninety-three patients were randomized to receive danazol 400 mg twice-daily ( n = 48 ) or danazol 400 mg twice-daily plus ATRA 10 mg twice-daily ( n = 45 ).
Treatment with ATRA plus danazol more than doubled the proportion of patients who responded to therapy : 92.5 percent in the combination group and 42.5 percent in the danazol-alone group ( 92.5 % and 42.5 %). Only 58.3 percent and 11.1 percent of patients who received danazol monotherapy achieved any response and CR , respectively .
After 1 year of follow-up , 71.6 percent of patients in the combination group achieved sustained partial or complete response ( CR ; primary endpoint ), compared with 47.2 percent of patients in the danazol group ( p < 0.001 ).
Among responding patients , those who received both danazol and ATRA appeared to achieve a treatment response more rapidly , and these responses were deeper , compared with the danazol monotherapy group :
• median time to treatment response : 30.5 days vs . 49 days ( p value not provided )
• peak platelet count : 155 × 10 9 / L vs . 69 × 10 9 / L ( p value not provided )
The authors also found that , in multivariate analyses , both initial response at day 28 , and median duration of ITP were potentially associated with a sustained response .
There were no treatment-related deaths , but one patient receiving danazol monotherapy died from an intracranial hemorrhage 4 weeks after study enrollment .
“ Our findings demonstrate that the combination of ATRA and danazol is safe and effective in achieving a rapid and long-lasting response ,” the authors concluded , “ making it a potential promising therapeutic option for patients with non-splenectomized corticosteroidresistant / relapsed ITP .”
These results are limited by the small patient population and , because patients were enrolled mainly from centers in Beijing , the results might not be generalizable . Also , the trial was unblinded , which could potentially introduce bias .
The authors report no relevant conflicts of interest .
REFERENCE
Feng F , Wang M , Feng R , et al . The combination of oral all-trans retinoic acid and danazol vs . danazol as second-line treatment in adult immune thrombocytopenia : a multicenter , randomized , open-label trial . Abstract # S431 . Presented at the 22nd Congress of the European Hematology Association , June 24 , 2017 ; Madrid , Spain .
Evaluating a Risk-Adapted Treatment Approach in Younger Patients With AML
A risk-adapted approach incorporating minimal residual disease ( MRD ) and cytogenetic data could help identify patients with acute myeloid leukemia ( AML ) who would benefit from hematopoietic cell transplantation ( HCT ), or who would be able to avoid autologous HCT ( AHCT ), according to results from a phase II trial presented at the 22nd Congress of the European Hematology Association .
Adriano Venditti , MD , from the University of Rome Tor Vergata in Italy , and researchers evaluated the feasibility of this approach in the GIMEMA AML1310 trial , which assigned risk and post-remission therapy according to patients ’ pre-treatment cytogenetic data and postconsolidation levels of MRD .
Between January 2012 and May 2015 , investigators enrolled 515 patients with previously untreated AML from 55 institutions . At baseline , patients were categorized as low risk ( core binding factor [ CBF ] -positive AML without c-Kit mutations or NPM1-positive , FLT3-negative AML ), intermediate risk ( FLT3-TKD mutated , c-Kit mutated , or CBFpositive AML ), or high risk ( adverse-risk karyotype , FLT3-ITD mutations ).
Dr . Venditti presented results from 500 patients ( median age = 49 years ; range = 18-61 years ) who were evaluable for response at the time of presentation . Most patients ( 73 %) had intermediate-risk disease ; 11 percent had low-risk disease , and 16 percent had high-risk disease . Patients received the following induction therapy :
• intravenous daunorubicin 50 mg / m 2 once-daily on days 1 , 3 , and 5
• intravenous etoposide 50 mg / m 2 once-daily on days 1-5
• intravenous cytarabine 100 mg / m 2 as a once-daily continuous infusion on days 1-10
Those who achieved a complete remission ( CR ) or CR with incomplete platelet recovery ( CRi ) after one or two induction cycles then received consolidation therapy with daunorubicin ( 50 mg / m 2 once-daily on days 4-6 ) and cytarabine ( 500 mg / m 2 twicedaily on days 1-6 ). Patients who did not achieve CR / CRi received salvage therapy with fludarabine , cytarabine , and idarubicin . MRD was assessed by flow cytometry after consolidation therapy , and patients received HCT within 3 months of the end of consolidation therapy . Patients who had high-risk disease and / or were MRD-positive were assigned to receive allogeneic HCT ( alloHCT ), and those who had low-risk disease and / or were MRD-negative were assigned to receive AHCT .
Following induction therapy , 361 of 494 evaluable patients achieved CR ( 73 %); 18 percent had refractory AML and 9 percent died during treatment . Subsequently , 341 patients completed the consolidation phase and were allocated to receive transplant and a total of 232 patients eventually received transplant ( 109 [ 33 %] AHCT and 123 [ 36 %] alloHCT ).
After a median follow-up of 27.9 months ( range not provided ), the cumulative incidence of relapse was 32.9 percent .
The 24-month overall survival ( OS ) and diseasefree survival ( DFS ) rates were 55.9 percent and 54.9 percent , respectively ( 74.8 % and 63.8 % in the lowrisk group ; 42.5 % and 44.8 % in the high-risk group ).
In the intermediate-risk category , rates of OS and DFS were similar , regardless of MRD status :
• MRD-negative : 78.6 % and 61.4 %
• MRD-positive : 69.8 % and 66.6 %
“ In the intermediate-risk category , HCT can be avoided if MRD is not detectable ,” the researchers noted . “ If MRD is positive , HCT can prolong OS and DFS to equalize those of the low-risk category .”
The results suggest that “ a program of riskadapted , MRD-driven therapy is feasible in a multicenter , cooperative setting ,” the authors concluded .
The study ’ s findings are limited by the lack of a comparator arm and that not all patient allocated to a treatment approach received that treatment . ●
The authors report no relevant conflicts of interest .
REFERENCE
Venditti A , Piciocchi A , Candoni A , et al . Risk-adapted , MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia : results of the AML1310 trial of the GIMEMA Group . Abstract # S111 . Presented at the 22nd Congress of the European Hematology Association , June 23 , 2017 ; Madrid , Spain .
ASHClinicalNews . org ASH Clinical News
35