Written in Blood
Does MRD Predict PFS in Patients With CLL on Indefinite Ibrutinib-Based Therapy ?
According to research published in Blood , measurable residual disease ( MRD ) was not associated with improved progression-free survival ( PFS ) in patients with chronic lymphocytic leukemia ( CLL ) who were on indefinite ibrutinib-based therapy or who received six cycles of fludarabine , cyclophosphamide , and rituximab ( FCR ). However , PFS was significantly longer in patients with undetectable MRD .
The study also found that ibrutinib-treated patients with CLL who have detectable MRD levels lower than 10 -1 have longer PFS . “ We have established in this large cooperative group study for upfront therapy of CLL that sequential MRD done with sensitive flow cytometry approaches can be highly informative for the practitioner in predicting clinical outcomes for patients on novel agent-based approaches ,” study author Neil Kay , MD , of Mayo Clinic , told ASH Clinical News .
Lead study author Victoria Wang , PhD , of Dana- Farber Cancer Institute , explained that the utilization of MRD assessment in B-cell CLL has been a source of controversy for some time . Issues with MRD assessment in this condition include finding optimal ways to measure MRD , timing of MRD measurements , and its use as a surrogate for clinical outcomes in CLL .
While MRD status is associated with the survival outcomes of patients with CLL , “ with the advent of novel agents either alone or in combination , the value of MRD testing as a surrogate of outcome has been less obvious most likely because of more infrequent complete remissions ,” said Dr . Wang . There is also limited data on the value of MRD status in patients who receive ibrutinib-based therapies .
The phase III study by Drs . Kay and Wang evaluated the association of PFS and MRD status in patients with CLL . Patients were randomized to the IR treatment group ( indefinite ibrutinib plus six cycles of rituximab ) or the FCR treatment group ( six cycles of fludarabine , cyclophosphamide , and rituximab ).
The MRD levels in peripheral blood were measured using eight-color flow cytometry with a sensitivity of one CLL cell per 104 leukocytes . MRD was estimated by dividing the number of monotypic events by the total number of leukocytes . Samples with an MRD level of < 10 -4 (< 1 CLL cell / 10 4 leukocytes ) had undetectable MRD .
A total of 529 patients were randomized to receive either IR ( n = 354 ) or FCR ( n = 175 ). The undetectable MRD rates for patients in the IR group were significantly lower than those in the FCR group ( p < 0.001 ). Undetectable MRD was associated with longer PFS for patients in the FCR group than in the IR group .
Patients with undetectable MRD in the FCR group had significantly better PFS than those who had detectable MRD at three , 12 , and 24 months . In contrast , patients with MRD in the IR group did not have significantly worse PFS than those with undetectable MRD .
In the IR arm , undetectable MRD was associated with mutated immunoglobin heavy chain ( IGHV , p = 0.001 ), as well as lower CD19 + CD5 + cell counts ( p = 0.020 ) and higher CD49d + cell counts ( p = 0.001 ) at baseline . For the FCR group , undetectable MRD was associated with higher hemoglobin levels ( p = 0.011 ), mutated IGHV ( p = 0.009 ), and higher CD49d + ( p = 0.042 ) cell counts .
While patients in the FCR group with unmutated IGHV at baseline had significantly shorter PFS than those with mutated IGHV , there was no association between IGHV mutation and PFS in the IR group .
Given the small number of deaths in this study ( n = 23 ), the researchers were unable to perform an analysis focused on MRD status and overall survival . The researchers added that future studies are needed to validate these findings , particularly those observed in the continuous IR arm .
“ These findings need to be further assessed with longer follow up and validated in future large phase III trials ,” concluded Dr . Kay . “ However , they set the stage for further use of MRD studies as an important surrogate laboratory tool in assessing responses to novel agents for CLL patients .”
Study authors report relationships with AstraZeneca , the manufacturer of ibrutinib .
Reference Wang VX , Hanson CA , Tschumper RC , et al . Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib [ published online ahead of print , 2021 Aug 18 ].. Blood . doi : 10.1182 / blood . 2020010146 .
Defining Incidence and Mortality Rates of Intracranial Hemorrhage in Patients With Hemophilia
Compared with the general population , intracranial hemorrhage ( ICH ) rates are higher in all patients with hemophilia , according to a study published in Blood . Reported incidences peak in neonates and decline with age . Senior author Karin Fijnvandraat , MD , PhD , of Amsterdam University Medical Centers in the Netherlands , said the increased risk of ICH in this population is concerning and calls for improvements in hemophilia care worldwide , given the overall burden the bleeding disorder places on patients .
“ We hope that this review provides a reference from the era of clotting factor concentrates for studies evaluating effects of novel therapies on ICH in hemophilia ,” Dr . Fijnvandraat told ASH Clinical News .
A systematic review of the literature , led by Anne- Fleur Zwagemaker , PhD-c and Dr . Fijnvandraat , was conducted to identify the rate of ICH in patients with hemophilia . In total , 45 studies with 54,470 patients were included . The hemophilia population comprised 809,151 person-years and 5,326 live births .
The studies spanned up to 60 years , and most of the studies were primarily performed in high-income regions . Data were available for patients with severe hemophilia ( 46 %) and non-severe hemophilia ( 54 %). Patients in the studies were from 43 countries , including those in Europe , East Asia , Southeast Asia , West Asia , Australia , North America , South America , and Africa .
The investigators performed pooled analyses of ICH incidence and mortality rates in the following groups :
• all ages
• < 25 years of age
• neonates
Pooled incidence of ICH and mortality rate in the all ages group was 2.3 ( 95 % CI 1.2-4.8 ) and 0.8 ( 95 % CI 0.5- 1.2 ), respectively , per 1,000 person-years . In children and young adults under the age of 25 , pooled ICH incidence was 7.4 ( 95 % CI 4.9-11.1 ) and the mortality rate was 0.5 ( 95 % CI 0.3-0.9 ), per 1,000 person-years . In neonates , the pooled cumulative incidence of ICH was 2.1 % ( 95 % CI 1.5-2.8 ) per 100 live births .
Across all ages , 52 % of ICH events were considered spontaneous , with a corresponding weighted pooled proportion of 0.58 ( 95 % CI 0.40-0.73 ). In contrast , 35 % of all ICH events in children and young adults were deemed spontaneous , with a corresponding weighted pooled proportion of 0.35 ( 95 % CI 0.28-0.43 ).
According to the researchers , these findings call for increased vigilance in the care of patients with hemophilia , as well as adequate follow-up and monitoring , particularly in those with certain risk factors . However , their review was unable to identify the effect of risk factors on ICH in patients with hemophilia .
The high rate of ICH in infants , as demonstrated in the study , raises a question regarding the appropriate timing of prophylaxis initiation . Long-term studies are required to determine the impact of very early prophylaxis with non-replacement products on the incidence of ICH .
According to the investigators , counseling patients with hemophilia and their families on ICH risks and symptoms may be appropriate . “ In neonates , our data support the need for an active pedigree approach for genetic testing and comprehensive counselling of pregnant carriers ,” the authors added .
The considerable heterogeneity of the study settings and populations is a limitation of the review . Additionally , most studies included in the review were retrospective . ●
This work was supported by a grant from Sobi .
Reference Zwagemaker AF , Gouw SC , Jansen JJ , et al . Incidence and mortality rates of intracranial hemorrhage in hemophilia : a systematic review and meta-analysis [ published online ahead of print , 2021 Aug 19 ]. Blood . doi : 10.1182 / blood . 2021011849 .
36 ASH Clinical News October 2021