Severe congenital neutropenia (SCN) is caused by germline mutations, most commonly in
, impacting neutrophil maturation and leading to high risk of life-threatening infections. Most patients with
...mutant SCN can achieve safe neutrophil counts with chronic Granulocyte-Colony Stimulating Factor (G-CSF). However, up to 10% of patients have neutropenia refractory to G-CSF and require allogeneic stem cell transplant. Traditional conditioning for these patients includes busulfan and cyclophosphamide which is associated with significant toxicities. We present five patients with SCN without myeloid malignancy transplanted using a reduced toxicity regimen of busulfan, fludarabine and thymoglobulin. 5 pediatric patients with SCN underwent matched sibling donor bone marrow transplant (MSD-BMT) between 2014-2022 on or per CHP14BT057 (NCT02928991), a prospective, single center trial testing elimination of cyclophosphamide from conditioning in pediatric patients with single lineage inherited BMF syndromes. All patients had MSDs and no evidence of MDS. Conditioning consisted of PK-adjusted busulfan, fludarabine, and thymoglobulin, with calcineurin inhibitor and mycophenolate mofetil GVHD prophylaxis. With median follow-up of 48.4 months, overall and event-free survival were 100%. There was no acute GVHD and one instance of chronic limited GVHD. Patients exhibited >95% donor myeloid chimerism at 5 years post-BMT. Two patients experienced CMV reactivation without end-organ disease, and no other viral reactivation or significant infections occurred. MSD-BMT with reduced toxicity myeloablation for SCN provides excellent outcomes while minimizing toxicity. These data suggest that busulfan, fludarabine, and ATG can be considered an efficacious, low-toxicity standard of care regimen for patients with SCN undergoing MSD-BMT.
Adjuvant chemotherapy cures only a subset of women with nonmetastatic breast cancer. Genotypes in drug-metabolizing enzymes, including functional polymorphisms in cytochrome P450 (CYP) and ...glutathione S-transferases (GST), may predict treatment-related outcomes.
We examined CYP3A4*1B, CYP3A5*3, and deletions in GST mu (GSTM1) and theta (GSTT1), as well as a priori-defined combinations of polymorphisms in these genes. Using a cohort of 90 node-positive breast cancer patients who received anthracycline-based adjuvant chemotherapy followed by high-dose multiagent chemotherapy with stem-cell rescue, we estimated the effect of genotype and other known prognostic factors on disease-free survival (DFS) and overall survival (OS).
Patients who carried homozygous CYP3A4*1B and CYP3A5*3 variants and did not carry homozygous deletions in both GSTM1 and GSTT1 (denoted low-drug genotype group) had a 4.9-fold poorer DFS (P = .021) and a four-fold poorer OS (P = .031) compared with individuals who did not carry any CYP3A4*1B or CYP3A5*3 variants but had deletions in both GSTT1 and GSTM1 (denoted high-drug genotype group). After adjustment for other significant prognostic factors, the low-drug genotype group retained a significantly poorer DFS (hazard ratio HR = 4.9; 95% CI, 1.7 to 14.6; P = .004) and OS (HR = 4.8; 95% CI, 1.8 to 12.9; P = .002) compared with the high- and intermediate-drug combined genotype group. In the multivariate model, having low-drug genotype group status had a greater impact on clinical outcome than estrogen receptor status.
Combined genotypes at CYP3A4, CYP3A5, GSTM1, and GSTT1 influence the probability of treatment failure after high-dose adjuvant chemotherapy for node-positive breast cancer.
To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen ...receptor T-cell therapy.
Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial.
The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (
< .001), but persistence was not different (
= .73). Event-free and overall survival were worse in the HTBC (
= .004,
< .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (
= .18).
Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.
Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes ...mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1 to 29, 74 (32%) were categorized as high risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall complete remission rate was 94%, with no difference between strata. There was no difference in relapse-free survival (RFS; P = .8112), with 2-year RFS for the high-risk group of 63% (95% confidence interval CI, 52-77). There was similarly no difference seen in overall survival (OS) (P = .5488), with 2-year OS for the high-risk group of 70% (95% CI, 60-82). For patients with KMT2A-rearranged infant ALL (n = 13), 2-year RFS was 67% (95% CI, 45-99), and OS was 62% (95% CI, 40-95), with multivariable analysis demonstrating no increased risk of relapse (hazard ratio, 0.70; 95% CI, 0.21-2.90; P = .7040) but a higher proportion of relapses associated with myeloid lineage switch and a 3.6-fold increased risk of all-cause death (95% CI, 1.04-12.75; P = .0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.
Abstract Genetic variation in drug detoxification pathways may influence outcomes in pediatric acute lymphoblastic leukemia (ALL). We evaluated relapse risk and 24 variants in 17 genes in 714 ...patients in CCG-1961. Three TPMT and 1 MTR variant were associated with increased risks of relapse (rs4712327, OR 3.3, 95%CI 1.2–8.6; rs2842947, OR 2.7, 95%CI 1.1–6.8; rs2842935, OR 2.5, 95%CI 1.1–5.0; rs10925235, OR 4.9, 95%CI 1.1–25.1). One variant in SLC19A1 showed a protective effect (rs4819128, OR 0.5, 95%CI 0.3–0.9). Our study provides data that relapse risk in pediatric ALL is associated with germline variations in TPMT , MTR and SLC19A1.
CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. ...Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed.
We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19.
Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts.
HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.
CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with ...CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 56% male and 85 44% female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity.
Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 97% of 66 vs 121 94% of 129; p=0·74), with no significant difference in relapse-free survival (60% 95% CI 49-74 vs 60% 51-71; p=0·50) or overall survival (83% 75-93 vs 71% 64-79; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% 82-100 vs 71% 64-78; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 41% vs 38 58%; grade 1, 24 19% vs 20 30%; grade 2, 14 11% vs 10 15%; grade 3, 12 9% vs 6 9%, and grade 4, 3 2% vs 2 3%; p=0·20) and cytokine release syndrome (any grade, 110 85% vs 53 80%; grade 1, 12 9% vs 2 3%; grade 2, 61 47% vs 38 58%; grade 3, 18 14% vs 7 11% and grade 4, 19 15% vs 6 9%; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata.
Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
Children's Hospital of Philadelphia Frontier Program.
Children living in poverty experience excessive relapse and death from newly diagnosed acute lymphoblastic leukemia (ALL). The influence of household poverty and neighborhood social determinants on ...outcomes from chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (r/r) leukemia is poorly described. We identified patients with r/r CD19+ ALL/lymphoblastic lymphoma treated on CD19-directed CAR T-cell clinical trials or with commercial tisagenlecleucel from 2012 to 2020. Socioeconomic status (SES) was proxied at the household level, with poverty exposure defined as Medicaid-only insurance. Low-neighborhood opportunity was defined by the Childhood Opportunity Index. Among 206 patients aged 1 to 29, 35.9% were exposed to household poverty, and 24.9% had low-neighborhood opportunity. Patients unexposed to household poverty or low-opportunity neighborhoods were more likely to receive CAR T-cell therapy with a high disease burden (>25%), a disease characteristic associated with inferior outcomes, as compared with less advantaged patients (38% vs 30%; 37% vs 26%). Complete remission (CR) rate was 93%, with no significant differences by household poverty (P = .334) or neighborhood opportunity (P = .504). In multivariate analysis, patients from low-opportunity neighborhoods experienced an increased hazard of relapse as compared with others (P = .006; adjusted hazard ratio HR, 2.3; 95% confidence interval CI, 1.3-4.1). There was no difference in hazard of death (P = .545; adjusted HR, 1.2; 95% CI, 0.6-2.4). Among children who successfully receive CAR T-cell therapy, CR and overall survival are equitable regardless of proxied SES and neighborhood opportunity. Children from more advantaged households and neighborhoods receive CAR T-cell therapy with a higher disease burden. Investigation of multicenter outcomes and access disparities outside of clinical trial settings is warranted.
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