Literature Scan
of immunoglobin M ( IgM ) flare , rituximab was added to the treatment regimen from cycle three onward , with the first dose given intravenously at 375 mg / m 2 and the subsequent doses administered subcutaneously at a dose of 1,400 mg .
Patients with progressive disease after cycle four went off study . After eight cycles , patients with at least minor response ( MR ) continued rituximab maintenance at 400 mg subcutaneously every three months for two years .
The investigators examined the overall response rate ( ORR ) following induction , based on the IgM level . Additional endpoints included rates of complete response , very good partial response ( VGPR ), partial response ( PR ), and MR , time to first and best responses , duration of response ( DOR ), PFS , and overall survival ( OS ).
At baseline , the median age of the population was 69 years ( range = 46-91 ). Patients had undergone a median of two prior treatments ( range = 1-7 ). Approximately 70 % of patients had an intermediate or high International Prognostic Scoring System score for WM .
At the end of eight treatment cycles , the ORR was 71 %, including 14 % with VGPR , 37 % with PR , and 20 % with MR . There was an improvement in depth of response until month 12 , with a best ORR of 85 % ( 15 % VGPR , 46 % PR , and 24 % MR ). The median DOR was 36 months .
Mean hematocrit level significantly increased from 33 % at baseline to 38 % following eight treatment cycles ( p < 0.001 ). Levels of IgM significantly decreased after two cycles of ixazomib , from a median of 3,700 to 2,700 mg / dL ( p < 0.0001 ) and further to 1,200 mg / dL following eight cycles ( p < 0.001 ).
The median time to first response was four months . The median PFS and OS were not reached during the study ; however , PFS was 56 % and OS was 88 % after a median 24-month followup period .
Six patients died during the study as a result of disease progression ( n = 2 ), progressive multifocal leukoencephalopathy ( n = 1 ), graft-versushost disease following allogeneic hematopoietic cell transplantation after disease progression ( n = 1 ), and cardiac comorbidities ( n = 2 ).
In terms of toxicity , most events included grade 2 or 3 cytopenias , grade 1 or 2 neurotoxicity , and grade 2 or 3 infections . There were no infusion-related reactions or IgM flares with subcutaneous rituximab . Patients reported significant improvements in quality of life after induction .
These findings are limited by the study ’ s small sample size and lack of a control group . “ Larger randomized trials need to compare the efficacy of IRD to other regimens for relapsed or refractory WM ,” Dr . Kersten wrote .
Study authors report relationships with Takeda , the manufacturer of ixazomib .
Reference Kersten MJ , Amaador K , Minnema MC , et al . Combining ixazomib with subcutaneous rituximab and dexamethasone in relapsed or refractory Waldenström ’ s macroglobulinemia : Final analysis of the phase I / II HOVON124 / ECWM-R2 study [ published online ahead of print , 2021 Aug 13 ]. J Clin Oncol . doi : 10.1200 / JCO . 21.00105 .
New Prognostic Model Outperforms Established Predictive Models in MDS
In a study published in the Journal of Clinical Oncology , researchers reported that a newly developed personalized prediction model comprising clinical and genomic data performed better than established predictive models in patients with myelodysplastic syndromes ( MDS ). The model predicted both survival and leukemia transformation possibilities unique to each patient , suggesting that it could “ be used as a stand-alone model or in conjunction with the IPSS / IPSS-R scoring systems to improve their accuracy ,” the researchers , led by Aziz Nazha , MD , from Cleveland Clinic , wrote .
The study included a training cohort that consisted of 1,471 patients with MDS who were assessed at Cleveland Clinic and the Munich Leukemia Laboratory in Germany between 2001 and 2018 . Dr . Nazha and colleagues used the training cohort to build the model with a random survival algorithm . The model was later validated in an independent group of patients with MDS who were treated at Moffitt Cancer Center in Tampa , Florida , between 2005 and 2018 . Researchers performed targeted deep sequencing on 38 genes commonly reported in genomic panels that have shown clinical significance in MDS .
In the patients with MDS who were included in the training cohort , the median age was 71 years ( range = 19-99 years ). Based on the revised International Prognostic Scoring System ( IPSS-R ) scores , patients had the following cytogenetic risk :
• very good : 4 % ( n = 65 )
• good : 72 % ( n = 1,060 )
• intermediate : 13 % ( n = 193 )
• poor : 4 % ( n = 60 )
• very poor : 6 % ( n = 93 )
In addition , risk stratification per the IPSS-R revealed that 51 % of patients ( n = 749 ) had very low or low risk MDS , 23 % had intermediate risk ( n = 336 ), and 19 % had high or very high risk ( n = 182 ). Risk was not evaluable for 7 % of patients .
The commonly mutated genes in the overall training cohort were SF3B1 , TET2 , and ASXL1 . Factors identified as having an effect on overall and leukemia-free survival in the algorithm included chromosomal karyotype , platelet , hemoglobin levels , bone marrow blast percentage , age , other clinical variables , and mutation number .
During a median follow-up of 43.6 months , the median overall survival ( OS ) was 32.2 months ( range = 0.03-221.8 ). A total of seven genes were associated with OS in an analysis adjusted for age and IPSS-R score .
A multivariate analysis that included age , IPSS-R risk categories , and significant mutations found that the predictive value of some mutations varied depending on the variables included in the prognostic model . For instance , mutations in ASXL1 , EZH2 , KRAS , NRAS , RAD21 , SF3B1 , and TP53 that were identified as significant in the univariate analysis were included in the multivariate analysis . In contrast , mutations in ASXl1 , CBL , EZH2 , NRAS , RA21 , SF3B1 , TET2 , and TP53 were considered significant when the researchers added 24 genes that were mutated in 30 or more patients .
IPSS-R cytogenetic risk groups were considered the most important variable for survival , while blast percentage was considered the most important variable predicting transformation to acute myeloid leukemia , the authors reported .
The researchers also noted that the model was “ dynamic ” and allowed them to upstage and downstage patients into more appropriate risk categories . For example , patients who had a survival probability of less than 50 % at 18 months were considered “ higher-risk ” after application of the model . Additionally , the new model identified 306 patients ( 20 %) in the training group who were also higher-risk , including 148 patients who were considered lower-risk per IPSS and 107 who were considered lower-risk per IPSS-R . Seventy-three patients ( 16 %) in the validation cohort were classified as higher-risk with the new model , including 28 and 33 who were classified as lower-risk per IPSS and IPSS- R , respectively .
The investigators explained that while the model included age as an important prognostic factor , younger patients with MDS often experience greater loss of life years compared with older patients . “ Thus , including age in prognostic scores may lead to less intensive treatment in younger patients since they have a better OS ,” the researchers wrote .
The authors report no relevant conflicts of interest .
Reference Nazha A , Komrokji R , Meggendorfer M , et al . Personalized prediction model to risk stratify patients with myelodysplastic syndromes [ published online ahead of print , 2021 Aug 18 ]. J Clin Oncol . doi : 10.1200 / JCO . 20.02810 .
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28 ASH Clinical News November 2021