Hybrid Email and Outpatient Clinics to Optimize Maintenance Therapy in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia treatment includes an outpatient (OP)-based 2-year maintenance therapy (MT). Over an 8-year period, patients were transited from only OP to a hybrid e-clinic/OP-clinic model. Electronic and patient-held medical records of acute lymphoblastic leukemia patients 1 to 18 years old during MT were used to analyze demographics, drug doses, treatment response and cost. A survey evaluated family satisfaction with the hybrid service. Four hundred and seventy-eight children, all with at least 1 year of MT from March 13, 2014 to March 24, 2022 were grouped into 4 treatment eras, representing the transition from all OP (era 1) to the current hybrid MT practice (era 4). Cohort demographics were similar across all eras. With transition to era 4, OP visits decreased to a third (16 to 18/48 visits). Practice optimization in era 2 resulted in higher MT dose intensity in subsequent eras (era 1: median 82% [interquartile range, 63 to 97]; era 2: 93% [73 to 108]; era 3: 88% [68 to 106]; era 4: 90% [74 to 114], P <0·0001), with no differences in absolute neutrophil count or neutropenia-related toxicity ( P =0.8). The hybrid service reduced MT expenses by ~50% and families (133/156, 85%) reported being very satisfied. Our experience indicates that a hybrid model is feasible, effective and less burdensome for patients and families.

A Bayesian quantile joint modeling of multivariate longitudinal and time-to-event data.

Linear mixed models are traditionally used for jointly modeling (multivariate) longitudinal outcomes and event-time(s). However, when the outcomes are non-Gaussian a quantile regression model is more appropriate. In addition, in the presence of some time-varying covariates, it might be of interest to see how the effects of different covariates vary from one quantile level (of outcomes) to the other, and consequently how the event-time changes across different quantiles. For such analyses linear quantile mixed models can be used, and an efficient computational algorithm can be developed. We analyze a dataset from the Acute Lymphocytic Leukemia (ALL) maintenance study conducted by Tata Medical Center, Kolkata. In this study, the patients suffering from ALL were treated with two standard drugs (6MP and MTx) for the first two years, and three biomarkers (e.g. lymphocyte count, neutrophil count and platelet count) were longitudinally measured. After treatment the patients were followed nearly for the next three years, and the relapse-time (if any) for each patient was recorded. For this dataset we develop a Bayesian quantile joint model for the three longitudinal biomarkers and time-to-relapse. We consider an Asymmetric Laplace Distribution (ALD) for each outcome, and exploit the mixture representation of the ALD for developing a Gibbs sampler algorithm to estimate the regression coefficients. Our proposed model allows different quantile levels for different biomarkers, but still simultaneously estimates the regression coefficients corresponding to a particular quantile combination. We infer that a higher lymphocyte count accelerates the chance of a relapse while a higher neutrophil count and a higher platelet count (jointly) reduce it. Also, we infer that across (almost) all quantiles 6MP reduces the lymphocyte count, while MTx increases the neutrophil count. Simulation studies are performed to assess the effectiveness of the proposed approach.

Activity and toxicity of intramuscular 1000 iu/m2 polyethylene glycol-E. coli L-asparaginase in the UKALL 2003 and UKALL 2011 clinical trials.

In successive UK clinical trials (UKALL 2003, UKALL 2011) for paediatric acute lymphoblastic leukaemia (ALL), polyethylene glycol-conjugated E. coli L-asparaginase (PEG-EcASNase) 1000 iu/m2 was administered intramuscularly with risk-stratified treatment. In induction, patients received two PEG-EcASNase doses, 14 days apart. Post-induction, non-high-risk patients (Regimens A, B) received 1-2 doses in delayed intensification (DI) while high-risk Regimen C patients received 6-10 PEG-EcASNase doses, including two in DI. Trial substudies monitored asparaginase (ASNase) activity, ASNase-related toxicity and ASNase-associated antibodies (total, 1112 patients). Median (interquartile range) trough plasma ASNase activity (14 ± 2 days post dose) following first and second induction doses and first DI dose was respectively 217 iu/l (144-307 iu/l), 265 iu/l (165-401 iu/l) and 292 iu/l (194-386 iu/l); 15% (138/910) samples showed subthreshold ASNase activity (<100 iu/l) at any trough time point. Older age was associated with lower (regression coefficient -9.5; p < 0.0001) and DI time point with higher ASNase activity (regression coefficient 29.9; p < 0.0001). Clinical hypersensitivity was observed in 3.8% (UKALL 2003) and 6% (UKALL 2011) of patients, and in 90% or more in Regimen C. A 7% (10/149) silent inactivation rate was observed in UKALL 2003. PEG-EcASNase schedule in UKALL paediatric trials is associated with low toxicity but wide interpatient variability. Therapeutic drug monitoring potentially permits optimisation through individualised asparaginase dosing.

Unsatisfactory quality of E. coli asparaginase biogenerics in India: Implications for clinical outcomes in acute lymphoblastic leukaemia.

BACKGROUND: The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli-derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low-middle-income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. PROCEDURE: Seven biogeneric EcASNases (P1-P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m2 /dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug-related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). RESULTS: In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high-risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch-to-batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory. CONCLUSIONS: Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high-quality asparaginases remains an unmet therapeutic need.

Efficacy and safety of a bortezomib and reduced-intensity cytarabine-based protocol, TMC ALLR1, for relapsed childhood ALL in India.

The feasibility of bortezomib (BZB) in induction and reduced cytarabine doses in intensification was evaluated in children with relapsed acute lymphoblastic leukaemia (rALL) at a single centre in India. Of 55 children with rALL, 23 received supportive care and 7 refused treatment, with a median survival of 2 (interquartile range 1-6) months. Twenty-two (88%) of 25 children who were treated achieved second remission and 9 (69%) of 13 had end-of-induction minimal residual disease of <10-4 . The lower cytarabine dose was associated with decreased hospitalisation. One-year event-free and overall survival for the treated group was 74·7% (95% confidence interval 52-88) and 79·6% (58-91) respectively.

A triple-probe FISH screening strategy for risk-stratified therapy of acute lymphoblastic leukaemia in low-resource settings.

Karyotyping along with a 3-probe fluorescence in situ hybridization (FISH) strategy was used to risk stratify therapy in 303 children with B-cell precursor acute lymphoblastic leukaemia. Of the 166 patients risk stratified, karyotype identified 91 (55%). FISH identified all karyotypes accurately, with the exception of hypodiploidy, and risk stratified an additional 75 patients. The frequency of ETV6-RUNX1 is lower and high hyperdiploidy, higher than reported in the west. An adapted 3-probe FISH strategy identified two patients with ETV6-ABL1 fusion who received imatinib. In limited-resource settings, a 3-probe FISH approach provides a practical approach for risk-stratified therapy in childhood ALL.

Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia.

Outcome in childhood acute lymphoblastic leukemia is prognosticated from levels of minimal residual disease after remission induction therapy. Higher levels of minimal residual disease are associated with inferior results even with intensification of therapy, thus suggesting that identification and targeting of minimal residual disease cells could be a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient-derived xenografts from patients with high, post-induction levels of minimal residual disease. 5T4-positive cells showed preferential ability to overcome the NOD-scidIL2Rγnull mouse xenograft barrier, migrated in vitro on a CXCL12 gradient, preferentially localized to bone marrow in vivo and displayed the ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (a 5T4-antibody drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4-positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4-positive patient-derived xenograft cells were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD-scidIL2Rγnull mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (P=0.0006) over either monotherapy. These data show that specifically targeting minimal residual disease cells improved outcomes and support further investigation of A1mcMMAF in patients with high-risk B-cell precursor acute lymphoblastic leukemia identified by 5T4 expression at diagnosis.

Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li-Fraumeni cancer predisposition syndrome.

The Li-Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. To address the genetic basis of phenotypic disparities of LFS/LFL, we performed whole-genome sequencing (WGS) of 13 subjects from two generations of an LFS kindred. Neither de novo CNV nor significant difference in total CNV was detected in relation with successive generations or with age at cancer onset. These observations were consistent with an experimental mouse model system showing that trp53 deficiency in the germ line of father or mother did not increase CNV occurrence in the offspring. On the other hand, individual records on 1,771 TP53 mutation carriers from 294 pedigrees were compiled to assess genetic anticipation patterns (International Agency for Research on Cancer TP53 database). No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset.

Pediatric Vaginal Yolk Sac Tumor: Reappraisal of Treatment Strategy in a Rare Tumor at a Unique Location.

Review of the management of 6 young girls with vaginal yolk sac tumor over 25 years showed that the α-fetoprotein levels normalized in 5/6 within 4 cycles of primary cisplatin, bleomycin, etoposide (PEB)/carboplatin, etoposide, bleomycin (JEB)/cisplatin, vinblastine, bleomycin (PVB) chemotherapy. Radioimaging revealed residual tissue but viable tumor was found in only 1 of 2 biopsied. Resection/biopsy is necessary to avoid giving additional primary chemotherapy or to identify patients who need different treatment. If markers do not decay appropriately, PEB/JEB/PVB chemotherapy should not be continued. Taxol-containing salvage chemotherapy regimens, adjuvant modern radiotherapeutic treatment, and fertility-saving curative surgery should then be considered. Despite having mostly advanced disease, 5/6 patients were cured, 2 with chemotherapy alone.