Refractory Pediatric Acute Lymphoblastic Leukemia Research Articles

Targeting pediatric leukemia-propagating cells with anti-CD200 antibody therapy

AbstractTreating refractory pediatric acute lymphoblastic leukemia (ALL) remains a challenge despite impressive remission rates (>90%) achieved in the last decade. The use of innovative immunotherapeutic approaches such as anti-CD19 chimeric antigen receptor T cells does not ensure durable remissions, because leukemia-propagating cells (LPCs) that lack expression of CD19 can cause relapse, which signifies the need to identify new markers of ALL. Here we investigated expression of CD58, CD97, and CD200, which were previously shown to be overexpressed in B-cell precursor ALL (BCP-ALL) in CD34+/CD19+, CD34+/CD19–, CD34–/CD19+, and CD34–/CD19– LPCs, to assess their potential as therapeutic targets. Whole-genome microarray and flow cytometric analyses showed significant overexpression of these molecules compared with normal controls. CD58 and CD97 were mainly co-expressed with CD19 and were not a prerequisite for leukemia engraftment in immune deficient mice. In contrast, expression of CD200 was essential for engraftment and serial transplantation of cells in measurable residual disease (MRD) low-risk patients. Moreover, these CD200+ LPCs could be targeted by using the monoclonal antibody TTI-CD200 in vitro and in vivo. Treating mice with established disease significantly reduced disease burden and extended survival. These findings demonstrate that CD200 could be an attractive target for treating low-risk ALL, with minimal off-tumor effects that beset current immunotherapeutic approaches.

Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada

Tisagenlecleucel, a chimeric antigen receptor T-cell therapy for relapsed or refractory pediatric acute lymphoblastic leukemia, has been approved for use in multiple jurisdictions. The public list price is US $475 000, or more than CaD $600 000. Assessing the cost-effectiveness of tisagenlecleucel is necessary to inform policy makers on the economic value of this treatment. To assess the value for money of tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible pediatric patients with acute lymphoblastic leukemia under unknown long-term effectiveness. A cost-utility analysis of tisagenlecleucel compared with current standard care using a Canadian population-based registry of pediatric patients with acute lymphoblastic leukemia was performed. Results from 3 pooled single-arm tisagenlecleucel clinical trials and a provincial pediatric cancer registry were combined to create treatment and control arms, respectively. The population-based control arm consisted of patients meeting clinical trial inclusion and exclusion criteria, starting at second relapse. Multistate and individual-level simulation modeling were combined to predict patient lifetime health trajectories by treatment strategy. Tisagenlecleucel efficacy was modeled across long-term cure rates, from 10% to 40%, to account for limited information on its long-term effectiveness. Uncertainty was tested with 1-way and probabilistic sensitivity analysis. Data were collected in September 2017, and analysis began in December 2017. Tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible patients. Relative health care costs, survival gains, and quality-adjusted life-years (QALYs) between tisagenlecleucel and current standard care. The treatment and control arms were modeled on 192 and 118 patients, respectively. The mean (SD) age of control individuals was 10 (4.25) years, and the mean (SD) age of the pooled clinical trial sample was 11 (6) years. The control individuals had 78 boys (66%), and the pooled clinical trial sample had 102 boys (53%). Treatment with tisagenlecleucel was associated with an additional 2.14 to 9.85 life years or 1.68 to 6.61 QALYs, compared with current care. The average additional cost of tisagenlecleucel was CaD $470 013 (US $357 031). Accounting for the total discounted cost over the patient lifetime resulted in an incremental cost of CaD $71 000 (US $53 933) to CaD $281 000 (US $213 453) per QALY gain. To our knowledge, this study offers the first cost-effectiveness analysis of tisagenlecleucel compared with current standard care for pediatric patients with acute lymphoblastic leukemia using a constructed population-based control arm. At a willingness-to-pay threshold of $150 000/QALY, tisagenlecleucel had a 32% likelihood of being cost-effective. Tisagenlecleucel cost-effectiveness would fall below $50 000/QALY with a long-term cure rate of over 0.40 or a price discount of 49% at its currently known effectiveness.

Treatment of children with relapsed and refractory acute lymphoblastic leukemia with mitoxantrone, vincristine, pegaspargase, dexamethasone, and bortezomib.

The treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in children is challenging and new treatment options are needed. Bortezomib is a proteasome inhibitor with activity in pediatric acute lymphoblastic leukemia. Adding bortezomib to standard reinduction chemotherapy in relapsed and refractory pediatric ALL has produced very good response rates in prior studies. We evaluated bortezomib in combination with reinduction therapy (ALL R3) in 10 children with relapsed or refractory ALL. Bortezomib (1.3mg/m2 /dose) was administered to patients on days 1, 4, 8, and 11. In addition, patients received mitoxantrone, dexamethasone, pegaspargase, vincristine, and intrathecal methotrexate over 4weeks. Of the 10 patients, eight (80%) achieved a complete remission (CR) or complete remission with incomplete recovery (CRi). Of the patients in CR, two had undetectable minimal residual disease by flow cytometry(<0.01%). Five patients were subsequently treated with a stem cell transplant. All eight patients that achieved CR or CRi eventually relapsed. One patient remains alive following treatment with tisagenlecleucel after relapse. Grade 3 or higher infections occurred in four out of 10 patients, and other toxicities commonly associated with bortezomib were not seen. In children with relapsed or refractory ALL, the addition of bortezomib to reinduction chemotherapy that includes mitoxantrone produces a complete response in the majority of cases and does not lead to excessive toxicity.

Hematopoietic Stem Cell Transplantation in Children with Refractory Acute Lymphoblastic Leukemia

▪PurposeIt is difficult to decide whether children with leukemia who could not achieve complete remission (CR) after relapse or primary induction failure should undergo transplantation. Nonetheless, allogeneic hematopoietic stem cell transplantation (HSCT) is a possible approach for refractory acute leukemia including acute lymphoblastic leukemia (ALL). Even after refractory to conventional chemotherapy, a graft versus leukemia (GVL) effect could be expected to some extent. This approach is considered to be experimental because the mortality rate of HSCT is extremely high. A previously conducted large-scale study showed that age younger than 10 years was a factor of good prognosis; however, the details in children are unclear. The purpose of this retrospective analysis was to describe the outcomes and risk factors of HSCT for children with refractory ALL.Patients and MethodsThe data was collected through the Transplant Registry Unified Management Program (TRUMP) system, the registry of The Japan Society for Hematopoietic Cell Transplantation. In total, 325 patients with ALL younger than 21 years old when HSCT was performed between January 2001 and December 2015 and who harbored blasts in peripheral blood and/or bone marrow were analyzed. Both myeloablative regimens and reduced-intensity conditioning regimens were analyzed. Patients were classified as having poor-risk cytogenetics with either t(4;11), t(9;22), t(8;14), hypodiploidy or near triploidy, or more than 5 cytogenetic abnormalities. Other ALL cytogenetic findings were classified as other abnormalities or normal. Myeloablative conditioning was defined as total body irradiation (TBI) of >8 Gy and the administration of 8 mg/kg of busulfan (BU), >140 mg/m2 of melphalan, or >10 mg/kg of thiotepa. All other regimens were analyzed as reduced-intensity conditioning HSCT, including low-dose TBI (≤8 Gy) and low-dose BU (≤8 mg/kg). The graft included bone marrow, peripheral blood stem cells, or cord blood. Overall survival (OS) was used as a primary outcome because for HSCT during relapse, post-HSCT CR was not always achieved or reliably documented.ResultsThe median follow-up time of survivors was 1145 days (range 110-3710). The median age was 11 years. Thirty-five percent of patients had a pre-HSCT performance status (PS) of 0, which corresponds to a Karnofsky PS of ≥90. The rate of pre-HSCT fungal infection was 14%. Fifty-nine patients had more than 25% marrow blasts when HSCT was performed. When HSCT was performed, 10%, 60%, and 30% of patients exhibited primary induction failure, first relapse, and second or later relapse, respectively. Ninety-one percent of patients had neutrophils and 67% exhibited platelet recovery by day 100. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) on day 100 was 43%. The cumulative incidence of chronic GVHD (cGVHD) at 3 years after HSCT was 19%. Two hundred and forty-seven patients died. The causes of death were leukemia progression (57%), followed by graft failure (11%), GVHD (10%), hemorrhage (6%), and infection (5%). The 3-year OS rate in all the patients was 22% (95% confidence interval (CI), 18-27). Age, white blood cell count at diagnosis, prior history of central nervous disease, disease status, conditioning regimens, donor-recipient human leukocyte antigen match, graft type, or year in which HSCT was performed did not affect the OS. Grade ≥2 aGVHD did not affect OS. Whereas Patients with chronic GVHD had better 3-year OS (49%, 95% CI 35-61%) compared to that in patients without chronic GVHD (22%, 95% CI 16-29%) (p = 0.001) (Figure 1). Multivariate analysis showed that other than cGVHD, low PS (relative risk (RR): 2.53), blasts in bone marrow greater than 25% (RR: 1.43), T cell phenotype (RR: 1.86), high-risk or normal cytogenetics (RR: 1.42), and a history of HSCT (RR: 1.90) were significant adverse pre-HSCT variables (Table 1). Patients who had 0 or 1 (n = 113), 2 (n = 113), and 3-5 pre-HSCT variables (n = 99) had 42% (95% CI, 32-51), 17% (95% CI, 10-25), and 6% (95% CI, 2-13) 3-year OS, respectively (Figure 2).ConclusionSome patients with refractory pediatric ALL achieved relatively long survival following HSCT in the relapsed period, especially when a GVL effect was obtained. A scoring system using pre-HSCT variables should help decide whether HSCT should be performed or not. HSCT is worth considering for children who have undergone ≤2 pre-HSCTs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Pediatric B-Cell Acute Lymphoblastic Leukemia.

The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel was recently approved to treat relapsed or refractory pediatric acute lymphoblastic leukemia. With a one-time infusion cost of $475,000, tisagenlecleucel is currently the most expensive oncologic therapy. We aimed to determine whether tisagenlecleucel is cost effective compared with currently available treatments. Markov modeling was used to evaluate tisagenlecleucel in pediatric relapsed or refractory acute lymphoblastic leukemia from a US health payer perspective over a lifetime horizon. The model was informed by recent multicenter, single-arm clinical trials. Tisagenlecleucel (under a range of plausible long-term effectiveness) was compared with blinatumomab, clofarabine combination therapy (clofarabine, etoposide, and cyclophosphamide), and clofarabine monotherapy. Scenario and probabilistic sensitivity analyses were used to explore uncertainty. Main outcomes were life-years, discounted lifetime costs, discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (3% discount rate). With an assumption of a 40% 5-year relapse-free survival rate, tisagenlecleucel increased life expectancies by 12.1 years and cost $61,000/QALY gained. However, at a 20% 5-year relapse-free survival rate, life-expectancies were more modest (3.8 years) and expensive ($151,000/QALY gained). At a 0% 5-year relapse-free survival rate and with use as a bridge to transplant, tisagenlecleucel increased life expectancies by 5.7 years and cost $184,000/QALY gained. Reduction of the price of tisagenlecleucel to $200,000 or $350,000 would allow it to meet a $100,000/QALY or $150,000/QALY willingness-to-pay threshold in all scenarios. The long-term effectiveness of tisagenlecleucel is a critical but uncertain determinant of its cost effectiveness. At its current price, tisagenlecleucel represents reasonable value if it can keep a substantial fraction of patients in remission without transplantation; however, if all patients ultimately require a transplantation to remain in remission, it will not be cost effective at generally accepted thresholds. Price reductions would favorably influence cost effectiveness even if long-term clinical outcomes are modest.

The social value of tisagenlecleucel, a CAR-T cell therapy, for the treatment of relapsed or refractory pediatric acute lymphoblastic leukemia in the United States: What are consequences of treatment delays?

10529Background: Despite the recent approval of tisagenlecleucel, a CAR-T cell therapy, to treat pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (pALL) i...

Epratuzumab and Blinatumomab as Therapeutic Antibodies for Treatment of Pediatric Acute Lymphoblastic Leukemia: Current Status and Future Perspectives.

More than 85% of children affected by acute lymphoblastic leukemia (ALL) are successfully treated; however relapse remains a remarkable clinical concern, with 50-60% of relapsing patients facing a fatal outcome. Management of relapsed patients includes standardized intensive risk-adapted regimens based on conventional drugs, and hematopoietic stem cells transplantation for patients with unfavourable features. Biological drugs, in particular the monoclonal antibody epratuzumab and the bi-functional recombinant single chain peptide blinatumomab, have been recently recognized as novel potential agents to be integrated in salvage ALL therapy to further improve rescue outcome. A systematic search of peer-reviewed scientific literature and clinical trials in public databases has been carried out. Both clinical and pre-clinical studies have been included to summarize recent evidence on epratuzumab and blinatumomab for salvage ALL therapy. Sixty-two papers and 25 clinical trials were included. Although not all patients responded properly to these agents, their use in relapsed and refractory pediatric ALL seems promising. Phase 3 studies have recently begun and more consistent results about epratuzumab and blinatumomab safety and efficacy in comparison to conventional therapies are expected in the next years. Epratuzumab seems safe in the dosing scheme proposed in ALL, but its efficacy over the conventional chemotherapy is still questionable. Blinatumomab has shown promising results in high risk cases such as elder adult patients and conclusive studies on pediatric ALL are needed. Patient inter-individual variability to these agents has not been investigated in depth, but this issue needs to be addressed, in particular for blinatumomab.

Phase II Study on Bortezomib (BTZ) in Multiple Relapsed or Refractory Pediatric Acute Lymphoblastic Leukemia (rALL): High Response Rate with a Modestly Intensive Regimen Including BTZ, Not Related to Pharmacokinetics

BTZ is a proteasome inhibitor and could improve the poor prognosis of rALL (Messinger 2012). We developed a European phase II study in pediatric rALL, in which patients were randomised for 'early' or 'late' BTZ, in compliance with the Declaration of Helsinki. BTZ was given as iv push for 4 doses at 1.3 mg/m2/dose, in group 'early' on days 1, 4, 8 and 11 and in group 'late' on days 8, 11, 15 and 18. All patients also received DXM (10 mg/m2/day in 3 doses for 2 weeks) and VCR (1.5 mg/m2/dose (maximum 2 mg) as 1-hour infusion on days 8 and 15), plus intrathecal methotrexate (i.t. MTX, dose age-adjusted) on day 1. Cycles could be repeated in case of a good response. The number of 12 patients in each group provides a power of 80% to detect a statistically significantly lower absolute number of circulating leukemic blasts on day 8 of treatment in patients exposed to 'BTZ early' as compared to patients not yet exposed to BTZ ('BTZ late') of at least 30% (2-sided test, alpha <0.05).Between October 2010 and September 2014, 29 patients with information on response and/or toxicity after cycle 1 enrolled, 17 boys and 12 girls, median 9.7 years of age (range, 1 - 17.5). Most had second or subsequent rALL (n=16). The primary endpoint, day 8 absolute blast count, was evaluable in 26 patients (n=2 not eligible for the primary endpoint in retrospect, n=1 no material received), and was not different between 'BTZ early' (n=13) and 'BTZ late' (n=13). Absolute blast count had decreased at day 8 in both 'BTZ early' (p =0.017) and 'BTZ late' (p =0.046) compared to day 1 blast count, but to the same extent (median 85-86% decrease).Regarding response after cycle 1, 25 patients were evaluable (n=2 discontinued treatment due to toxicity, n=2 no material received). Nine patients (36%) achieved a complete remission with incomplete blood count recovery (CRi), 6 (24%) a partial remission (PR), and 10 had a treatment failure (TF), for a total response rate of 60%. There was no relation between remission status and the administration of BTZ being early or late (p =0.7). There was no association between response and disease status, although numbers were small (p =0.8). Four patients with a relapse after allo-SCT achieved CRi, as well as 5 patients with a second or subsequent relapse.Grade 3 or 4 hematological toxicities were thrombopenia (n=29), leukopenia (n=23), neutropenia (n=25), and anemia (n=21). Most common grade 2-4 neurotoxicities were pain (n=9) and peripheral neuropathy (PN) (n=5). Thirteen patients received a second cycle, when one patient developed grade 2 PN and one patient with PN advanced from grade 2 to 3.There was remarkable intra- and inter-individual variability in peak plasma concentrations 15 min after the first administration of BTZ, ranging from 0.7 to 715 ug/L (median 12 ug/L, excluding 2 outliers above limit of quantification (2500 ug/L)). The area-under the plasma concentration curve (AUC) had a 25-fold interindividual variation: median 0.27 ug.h/L (range 0.07 - 1.77). Mean clearance in plasma was 1.1 L/h, with a interindividual variability of 95%. Median bone marrow concentrations of BTZ were 49 ug/kg (range: 1.6 - 106 ug/kg). In most patients, no BTZ was detected in the CSF, with a lower detection limit of 0.05 ng/ml. In 9 patients BTZ was detected at 0.07 - 5.2 ug/L. No correlation between AUC and concentration in CSF was found (r2 = 0.11). The 50% inhibitory concentration (IC50) of 20S activity in plasma was 10.7 ug/L. Plasma pharmacokinetic and pharmacodynamic parameters did not correlate with response to treatment.In conclusion, BTZ in combination with VCR and DXM and i.t. MTX is effective in a significant subset of pediatric rALL, with 60% of patients achieving PR or CRi. Because administration of BTZ early or late showed similar early treatment responses, randomized studies with more patients are necessary to determine the additive value of BTZ to conventional chemotherapy. Repetitive cycles could be given in several children without undue toxicity. In view of the observed toxicity, it might be wise to give these patients subcutaneous BTZ or novel proteasome inhibitors. BTZ does not or hardly penetrate the cerebrospinal fluid.This research is financially supported by the Dutch Foundation Children Cancer-free (clinical research support) and by Janssen Pharmaceuticals (clinical research support and free drug). DisclosuresKaspers:Janssen-Cilag: Research Funding. Off Label Use: Bortezomib off-label for pediatric ALL. Zwaan:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding.

The Anti-CD19 Antibody–Drug Conjugate SAR3419 Prevents Hematolymphoid Relapse Postinduction Therapy in Preclinical Models of Pediatric Acute Lymphoblastic Leukemia

Relapsed or refractory pediatric acute lymphoblastic leukemia (ALL) remains a major cause of death from cancer in children. In this study, we evaluated the efficacy of SAR3419, an antibody-drug conjugate of the maytansinoid DM4 and a humanized anti-CD19 antibody, against B-cell precursor (BCP)-ALL and infant mixed lineage leukemia (MLL) xenografts. ALL xenografts were established as systemic disease in immunodeficient (NOD/SCID) mice from direct patient explants. SAR3419 was administered as a single agent and in combination with an induction-type regimen of vincristine/dexamethasone/l-asparaginase (VXL). Leukemia progression and response to treatment were assessed in real-time, and responses were evaluated using strict criteria modeled after the clinical setting. SAR3419 significantly delayed the progression of 4 of 4 CD19(+) BCP-ALL and 3 of 3 MLL-ALL xenografts, induced objective responses in all but one xenograft but was ineffective against T-lineage ALL xenografts. Relative surface CD19 expression across the xenograft panel significantly correlated with leukemia progression delay and objective response measure scores. SAR3419 also exerted significant efficacy against chemoresistant BCP-ALL xenografts over a large (10-fold) dose range and significantly enhanced VXL-induced leukemia progression delay in two highly chemoresistant xenografts by up to 82 days. When administered as protracted therapy following remission induction with VXL, SAR3419 prevented disease recurrence into hematolymphoid and other major organs with the notable exception of central nervous system involvement. These results suggest that incorporation of SAR3419 into remission induction protocols may improve the outcome for high-risk pediatric and adult CD19(+) ALL.

Spectrum of HLA associations: the case of medically refractory pediatric acute lymphoblastic leukemia.

Although studies of HLA and disease now date back some 50 years, a principled understanding of that relationship has been slow to emerge. Here, we examine the associations of three HLA loci with medically refractory pediatric acute lymphoblastic leukemia (pALL) patients in a case–control study involving 2,438 cases and 41,750 controls. An analysis of alleles from the class I loci, HLA-A and HLA-B, and the class II locus DRB1 illuminates a spectrum of extremely significant allelic associations conferring both predisposition and protection. Genotypes constructed from predisposing, protective, and neutral allelic categories point to an additive mode of disease causation. For all three loci, genotypes homozygous for predisposing alleles are at highest disease risk while the favorable effect of homozygous protective genotypes is less striking. Analysis of A–B and B–DRB1 haplotypes reveals locus-specific differences in disease effects, while that all three loci influence pALL; the influence of HLA-B is greater than that of HLA-A, and the predisposing effect of DRB1 exceeds that of HLA-B. We propose that the continuum in disease susceptibility suggests a system in which many alleles take part in disease predisposition based on differences in binding affinity to one or a few peptides of exogenous origin. This work provides evidence that an immune response mediated by alleles from several HLA loci plays a critical role in the pathogenesis of pALL, adding to the numerous studies pointing to a role for an infectious origin in pALL.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-012-0605-5) contains supplementary material, which is available to authorized users.

Enzymology of Purine and Pyrimidine Antimetabolites Used in the Treatment of Cancer

Enzymology of Purine and Pyrimidine Antimetabolites Used in the Treatment of Cancer

Little patients, losing patience: pediatric cancer drug development

The December 2004 Food and Drug Administration (FDA) approval of clofarabine (Clolar, Genzyme) for refractory pediatric acute lymphoblastic leukemia was a milestone in the history of pediatric cancer drug development. A rare occurrence, it represented approval of a new cancer drug for a pediatric