ACN_7.13_Full Issue | Page 42

Blood Advances in a Different Vein

Research from recent issues of Blood Advances

Modified EASIX Score Predicts CRS and ICANS Before Severe Symptoms in B-Cell Malignancies

A modified version of the EASIX ( Endothelial Activation and Stress Index ) score , when calculated prior to and soon after chimeric antigen receptor ( CAR ) T-cell infusion , predicted severe cytokine release syndrome ( CRS ) and immune effector cell – associated neurotoxicity syndrome ( ICANS ) before their occurrence . This is according to study findings published in Blood Advances .
The study ’ s corresponding author Miguel- Angel Perales , MD , of Memorial Sloan Kettering Cancer Center ( MSKCC ) in New York , explained that the EASIX score represents a reliable endothelial damage marker that is correlated with allogeneic hematopoietic cell transplantation outcomes . The formula for calculating the EAS- IX score includes lactate dehydrogenase ( LDH ) multiplied by creatinine , the product of which is divided by platelet count . “ We know from prior studies that elevated LDH and low platelets have been associated with severe CRS and ICANS as has C-reactive protein ( CRP ),” Dr . Perales told ASH Clinical News . “ As a result , we were interested in exploring the EASIX in patients treated with CAR T-cell therapies .”
To explore the role of EASIX in predicting outcomes in CAR T-cell recipients , Dr . Perales and colleagues developed a modified EASIX formula , which replaces creatinine with CRP . The researchers applied this modified formula in 53 patients with B-cell acute lymphocytic leukemia ( B-ALL ) and 65 patients with diffuse large B-cell lymphoma ( DLBCL ). Patients with B-ALL in the retrospective study were enrolled at MSKCC in a phase I trial of 1928z CAR T-cell therapy from
2010 through 2016 . Patients with DLBCL were consecutively treated at the same center with axicabtagene ciloleucel or tisagenlecleucel from 2018 through 2019 .
The overall median age of the study population was 58 years ( 44 years for patients with B-ALL and 64 years for patients with DLBCL ). Pre-infusion Eastern Cooperative Oncology Group scores were 0 to 1 in 100 % of patients with B-ALL and 86 % of patients with lymphoma . Approximately 66 % of the study population presented with a high disease burden prior to CAR T-cell infusion , as evidenced by bone marrow blasts percentage > 5 % in patients with B-ALL ( 62 %) and stage 3 to 4 and / or bulky disease in patients with DLBCL ( 69 %).
The primary objective of the study was to evaluate the modified EASIX formula ’ s ability to predict either severe CRS or ICANS . Secondary objectives included exploring the association between the modified EASIX and rates of complete response and best overall response rate to CAR T-cell therapy .
Both the original and modified EASIX formulas demonstrated similar predictive power for severe CRS and ICANS , Dr . Perales and colleagues reported . Low platelets and higher CRP values , however , were the only variables individually correlated with CRS and ICANS . Higher platelet counts were significantly associated with lower odds of severe CRS ( odds ratio [ OR ] = 0.87 ; 95 % CI 0.80-0.94 ; p < 0.001 ) and of severe ICANS ( OR = 0.85 ; 95 % CI 0.78-0.92 ; p < 0.001 ). However , there was no association between levels of LDH or creatinine and severe CRS and ICANS .
Only the modified EASIX significantly predicted disease response and was able to predict severe CRS prior to the onset of severe symptoms ( area under the curve [ AUC ] at lymphodepletion = 80.4 %; day – 1 = 73.0 %; day + 1 = 75.4 %). At day + 3 , the modified scoring system also demonstrated ability to identify risk for severe ICANS ( AUC = 73 %).
“ From a very practical point of view , we now have a tool that is readily accessible at all centers and that allows the clinician to predict severe CAR T-cell – associated toxicity before it occurs ,” said Dr . Perales . “ This may determine whether the patient should be treated outpatient or inpatient , or when the patient should be admitted after infusion of the cells .” He suggested that the modified score may also be useful in designing pre-emptive trials that seek to mitigate severe toxicity based on risk stratification .
A limitation of the study included its singlecenter , retrospective design . “ We are currently working on addressing this limitation with a consortium of centers in the United States ,” explained Dr . Perales . “ In addition , we will need to design prospective clinical trials that stratify patients based on their modified EASIX score to demonstrate the utility in the setting of pre-emptive interventions to reduce severe CRS and ICANS .”
The authors report no relevant conflicts of interest .
Reference Pennisi M , Sanchez-Escamilla M , Flynn JR , et al . Modified EASIX predicts severe cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells . Blood Adv . 2021 ; 5 ( 17 ): 3397-3406 .

Germline Variants in DNA Repair Pathway Genes May Trigger Familial MPNs

Germline variants in DNA repair pathway genes , such as BRCA1 / 2 , may trigger familial myeloproliferative neoplasms ( MPNs ), suggesting these variants should be incorporated in diagnostic workups , according to study findings published in Blood Advances .
“ The occurrence of a rare cancer subtype in more than a single family member suggests that genetic factors play an important role in the pathogenesis of such a malignancy ,” said corresponding study author Steffen Koschmieder , MD , PhD , of the RWTH Aachen University in Aachen , Germany .
Dr . Koschmieder and colleagues designed their study to identify additional predisposing germline variables in familial MPNs . To accomplish this goal , the researchers conducted whole-exome sequencing ( WES ) in a total of five families who were affected by MPNs and whose members carried a somatic JAK2 V617F ( c . 1849G . T ) mutation .
The investigators carried out WES by evaluating DNA of peripheral blood samples . Target regions were enriched using a probe-based capture method , and an in-house method was used for alignment to the reference genome ( hg19 or hg38 ) and variant calling . Sanger sequencing was used to confirm variants of interest .
Rare heterozygous germline variants were detected in known tumor predisposition genes of the DNA repair pathway in four families . These DNA repair pathway genes included the highly penetrant BRCA1 and BRCA2 genes . According to the investigators , the germline variants are associated with hereditary cancer predisposition syndromes , particularly hereditary breast and ovarian carcinomas .
In the first family , a brother and sister who had prefibrotic myelofibrosis both carried a heterozygous loss-of-function mutation in the BRCA1 gene . The sister , who received an index MPN diagnosis at 53 years of age , subsequently developed uterine cancer at age 61 . Two family members died from colorectal cancer : the mother at age 65 and a brother at age 77 . Additionally , one sister died from ovarian cancer at age 52 and one brother died from leukemia at age 5 .
40 ASH Clinical News November 2021