ABSTRACT
B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) blasts strictly depend on the transport of extra-cellular asparagine (Asn), yielding a rationale for L-asparaginase (ASNase) therapy. However, the carriers used by ALL blasts for Asn transport have not been identified yet. Exploiting RS4;11 cells as BCP-ALL model, we have found that cell Asn is lowered by either silencing or inhibition of the transporters ASCT2 or SNAT5. The inhibitors V-9302 (for ASCT2) and GluγHA (for SNAT5) markedly lower cell proliferation and, when used together, suppress mTOR activity, induce autophagy and cause a severe nutritional stress, leading to a proliferative arrest and a massive cell death in both the ASNase-sensitive RS4;11 cells and the relatively ASNase-insensitive NALM-6 cells. The cytotoxic effect is not prevented by coculturing leukaemic cells with primary mesenchymal stromal cells. Leukaemic blasts of paediatric ALL patients express ASCT2 and SNAT5 at diagnosis and undergo marked cytotoxicity when exposed to the inhibitors. ASCT2 expression is positively correlated with the minimal residual disease at the end of the induction therapy. In conclusion, ASCT2 and SNAT5 are the carriers exploited by ALL cells to transport Asn, and ASCT2 expression is associated with a lower therapeutic response. ASCT2 may thus represent a novel therapeutic target in BCP-ALL.
Subject(s)
Amino Acid Transport System ASC , Asparagine , Cell Survival , Minor Histocompatibility Antigens , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Humans , Amino Acid Transport System ASC/metabolism , Amino Acid Transport System ASC/genetics , Asparagine/metabolism , Minor Histocompatibility Antigens/metabolism , Minor Histocompatibility Antigens/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Cell Survival/drug effects , Amino Acid Transport System A/metabolism , Amino Acid Transport System A/genetics , Cell Line, Tumor , Asparaginase/pharmacology , Asparaginase/therapeutic use , Cell Proliferation/drug effects , ChildABSTRACT
Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status. In the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (4.4%) patients treated with five doses (P<0.001; Odds Ratio 2.86 [95% Confidence Interval 1.99-4.13]). In a multivariate regression model, treatment with additional IT MTX proved to be the strongest risk factor for life-threatening infections (Odds Ratio 2.85 [1.96-4.14]). Fatal infections occurred in 16 (0.3%) and 38 (1.6%) patients treated with three or five IT MTX doses, respectively (P<0.001). As the relevance of additional intrathecal MTX in induction for relapse prevention in CNS2 patients is unclear, doses of intrathecal therapy have been reduced for these patients. (Clinicaltrials.gov identifiers: NCT01117441 and NCT00613457).
Subject(s)
Methotrexate , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Methotrexate/therapeutic use , Induction Chemotherapy/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Combined Modality Therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Osteonecrosis (ON) is a well-known sequela of paediatric acute lymphoblastic leukaemia (ALL) treatment. Incidence differs substantially among studies and the clinical significance of radiological findings is not fully established. We analysed 256 consecutive patients with ALL treated in our Institution between October 2010 and December 2016. Within the cohort, 41 developed ON, with a mean 5-year cumulative incidence of 18.5 (standard error, SE, 5.7)% overall. The mean (SE) 5-year cumulative incidence of ON was 12.7 (2.1)% after censoring upon stem cell transplantation (SCT) and/or relapse. Patients aged ≥10 years and patients allocated to the high-risk stratum had a 10-fold and fivefold higher risk of ON respectively. The risk of ON was more than double in relapsed patients, whereas no significant impact of gender, immunophenotype and SCT was demonstrated. Multiple lesions (median four joints involved per patient) were detected by magnetic resonance imaging in all but one patient, with the knee being the most affected joint. Lesions affecting convex joint surfaces experienced the worst evolution, whereas most lesions on diaphyses and concave surfaces remained radiologically stable or disappeared during follow-up. ON has a high prevalence in paediatric ALL, presenting with multiple lesions. Lesions involving convex surfaces were at higher risk of radiological deterioration.
Subject(s)
Osteonecrosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Incidence , Neoplasm Recurrence, Local , Osteonecrosis/diagnostic imaging , Osteonecrosis/epidemiology , Osteonecrosis/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Risk FactorsABSTRACT
BACKGROUND: l-Asparaginase (ASP) plays a crucial role in the treatment of childhood acute lymphoblastic leukemia (ALL). Currently, different ASP products are available in the market, including both native and pegylated drugs. Several biogeneric Escherichia coli ASP (GEN-ASP) products have been developed in response to shortages and expensiveness of the native E. coli ASP innovator compounds, but some concerns have been raised about their quality. Recently, a number of generic pegylated ASP products (GEN-PEG-ASP) have been marketed to substitute for the innovator product (PEG-ASP). METHODS: Clinical courses and serum asparaginase activity (SAA) levels were monitored in 12 children with ALL, who were treated in our institution with two doses of a GEN-PEG-ASP product, given IV at 2500 IU/m2 during the remission induction phase. Results were compared with those obtained in a reference cohort of 35 patients treated in our institution, who received the innovator PEG-ASP product at same dosage and within the same chemotherapy background. RESULTS: Compared to the reference cohort treated with PEG-ASP, SAA levels were significantly lower in the 12 patients receiving GEN-PEG-ASP (p < .0001); a higher proportion of ASP-associated hypersensitivity reactions (2/12 vs. 0/35; p = .061) and silent inactivation (3/12 vs. 0/35; p = .014) were observed in comparison with the reference cohort. CONCLUSIONS: Our results highlighted different pharmacological profiles and different rates of hypersensitivity reactions and silent inactivation in the GEN-PEG-ASP cohort compared to those treated with the innovator product. Our findings suggest that a rigorous clinical attention and a thorough pharmacological monitoring are advisable in patients treated with GEN-PEG-ASP products.
Subject(s)
Antineoplastic Agents , Asparaginase , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Asparaginase/adverse effects , Asparaginase/therapeutic use , Child , Escherichia coli , Humans , Polyethylene Glycols/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Remission InductionABSTRACT
B-cell acute lymphoblastic leukaemia (B-ALL) reprograms the surrounding bone marrow (BM) stroma to create a leukaemia-supportive niche. To elucidate the contribution of immune cells to the leukaemic microenvironment, we investigated the involvement of monocyte/macrophage compartments, as well as several recruitment pathways in B-ALL development. Immunohistochemistry analyses showed that CD68-expressing macrophages were increased in leukaemic BM biopsies, compared to controls and predominantly expressed the M2-like markers CD163 and CD206. Furthermore, the "non-classical" CD14+ CD16++ monocyte subset, expressing high CX3CR1 levels, was significantly increased in B-ALL patients' peripheral blood. CX3CL1 was shown to be significantly upregulated in leukaemic BM plasma, thus providing an altered migratory pathway possibly guiding NC monocyte recruitment into the BM. Additionally, the monocyte/macrophage chemoattractant chemokine ligand 2 (CCL2) strongly increased in leukaemic BM plasma, possibly because of the interaction of leukaemic cells with mesenchymal stromal cells and vascular cells and due to a stimulatory effect of leukaemia-related inflammatory mediators. C5a, a macrophage chemoattractant and M2-polarizing factor, further appeared to be upregulated in the leukaemic BM, possibly as an effect of PTX3 decrease, that could unleash complement cascade activation. Overall, deregulated monocyte/macrophage compartments are part of the extensive BM microenvironment remodelling at B-ALL diagnosis and could represent valuable targets for novel treatments to be coupled with classical chemotherapy.
Subject(s)
Antigens, CD/metabolism , Macrophages/metabolism , Monocytes/metabolism , Neoplasm Proteins/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Tumor Microenvironment , Adolescent , Adult , Aged , Coculture Techniques , Female , Human Umbilical Vein Endothelial Cells , Humans , Macrophages/pathology , Male , Middle Aged , Monocytes/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
AIM: To evaluate the cumulative prevalence of coeliac disease, systemic lupus erythematosus, autoimmune hyperthyroidism and primary immunodeficiencies in children with either newly diagnosed/persistent or chronic immune thrombocytopenia (ITP). METHODS: Monocentric retrospective analysis of the clinical and biochemical features of 330 consecutive patients with ITP referred to our Pediatric Hematology Unit between January 2009 and December 2018. RESULTS: The prevalence of systemic lupus erythematosus (0.3%), coeliac disease (0.3%) and autoimmune hyperthyroidism (0.6%) was not increased compared to general paediatric population. Of note, the prevalence of underlying primary immunodeficiencies was 2.4%, remarkably higher than the general paediatric population (P = .005). All the patients diagnosed with immunodeficiency developed either bi-/trilinear cytopenia or splenomegaly. CONCLUSION: Whilst autoimmune and immunological screening is already recommended at the onset of immune thrombocytopenia, we recommend that primary immunodeficiencies be regularly screened during follow-up, especially in case of additional cytopenia or lymphoproliferation.
Subject(s)
Celiac Disease , Hyperthyroidism , Lupus Erythematosus, Systemic , Purpura, Thrombocytopenic, Idiopathic , Celiac Disease/complications , Celiac Disease/epidemiology , Child , Humans , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/epidemiology , Purpura, Thrombocytopenic, Idiopathic/epidemiology , Purpura, Thrombocytopenic, Idiopathic/etiology , Retrospective StudiesABSTRACT
Minimal residual disease (MRD) analysis has become a powerful indicator to refine therapy in acute lymphoblastic leukemia (ALL). Here, we present an MRD detection based on the next-generation sequencing of PTEN exon 7 mutations (NGS-PTEN) in 30 pediatric T-cell ALL patients. By comparing the NGS-PTEN results with current quantitative PCR of antigen receptor gene rearrangements (qPCR-Ig/TR), an overall concordance of 80% was found between the two methods. However, the NGS-PTEN qualified a lower number of high-risk patients than qPCR-Ig/TR. These findings suggest that NGS-PTEN is a promising tool that could potentially be used to support current MRD methodologies for T-ALL patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/genetics , Induction Chemotherapy/adverse effects , Mutation , Neoplasm, Residual/diagnosis , PTEN Phosphohydrolase/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , High-Throughput Nucleotide Sequencing , Humans , Neoplasm, Residual/chemically induced , Neoplasm, Residual/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , PrognosisABSTRACT
B-cell precursor-acute lymphoblastic leukemia modulates the bone marrow (BM) niche to become leukemia-supporting and chemo-protective by reprogramming the stromal microenvironment. New therapies targeting the interplay between leukemia and stroma can help improve disease outcome. We identified ActivinA, a TGF-ß family member with a well-described role in promoting several solid malignancies, as a factor favoring leukemia that could represent a new potential target for therapy. ActivinA resulted over-expressed in the leukemic BM and its production was strongly induced in mesenchymal stromal cells after culture with leukemic cells. Moreover, MSCs isolated from BM of leukemic patients showed an intrinsic ability to secrete higher amounts of ActivinA compared to their normal counterparts. The pro-inflammatory leukemic BM microenvironment synergized with leukemic cells to induce stromal-derived ActivinA. Gene expression analysis of ActivinA-treated leukemic cells showed that this protein was able to significantly influence motility-associated pathways. Interestingly, ActivinA promoted random motility and CXCL12-driven migration of leukemic cells, even at suboptimal chemokine concentrations, characterizing the leukemic niche. Conversely, ActivinA severely impaired CXCL12-induced migration of healthy CD34+ cells. This opposite effect can be explained by the ability of ActivinA to increase intracellular calcium only in leukemic cells, boosting cytoskeleton dynamics through a higher rate of actin polymerization. Moreover, by stimulating the invasiveness of the leukemic cells, ActivinA was found to be a leukemia-promoting factor. Importantly, the ability of ActivinA to enhance BM engraftment and the metastatic potential of leukemic cells was confirmed in a xenograft mouse model of the disease. Overall, ActivinA was seen to be a key factor in conferring a migratory advantage to leukemic cells over healthy hematopoiesis within the leukemic niche.
Subject(s)
Activins/genetics , Biomarkers, Tumor , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Activins/metabolism , Animals , Bone Marrow/pathology , Bone Marrow Cells/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cytokines/metabolism , Disease Models, Animal , Gene Expression Regulation, Leukemic , Humans , Inflammation Mediators/metabolism , Mesenchymal Stem Cells/metabolism , Mice , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Stromal Cells/metabolismABSTRACT
Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 µmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 µmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 µmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin-icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT.
Subject(s)
Asparaginase/therapeutic use , Asparagine/cerebrospinal fluid , Polyethylene Glycols/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/cerebrospinal fluid , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Austria , Child , Child, Preschool , Czech Republic , Drug Monitoring , Female , Germany , Humans , Infant , Italy , MaleABSTRACT
Notwithstanding the improvement in treatment results for paediatric T cell acute lymphoblastic leukaemia (T-ALL) it remains important to understand if genetic aberrations influence therapy response. PTEN tumour suppressor gene inactivation is a frequent event in T-ALL but its effect on patient therapy response is debatable. We analysed the effect of the presence of mutated PTEN on outcome in 257 children with T-ALL treated with Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)-Berlin-Frankfürt-Münster (BFM) protocols. PTEN mutations were present in 31 (12·1%) patients and were significantly associated with increased risk of relapse. PTEN mutations also indicate a poor prognosis in T-ALL patients in the absence of NOTCH1 mutations or in the group of patients with co-presence of PTEN mutation and deletions. These results indicate that PTEN genomic aberrations and the biologically consequential PTEN inactivation contribute to adverse therapy response in T-ALL patients; PTEN status as a biomarker may contribute to the development of new molecularly-defined stratification algorithms.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , PTEN Phosphohydrolase/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Asparaginase/therapeutic use , Child , Child, Preschool , Daunorubicin/therapeutic use , Female , Gene Deletion , Humans , Male , Mutation , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prednisone/therapeutic use , Prognosis , Recurrence , Vincristine/therapeutic useABSTRACT
Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Child , Child, Preschool , Combined Modality Therapy , Cranial Irradiation , Dexamethasone/administration & dosage , Dexamethasone/pharmacokinetics , Disease-Free Survival , Female , Hematopoietic Stem Cell Transplantation , Humans , Infant , Kaplan-Meier Estimate , Male , Methotrexate/administration & dosage , Neoplasm, Residual , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prednisone/administration & dosage , Proportional Hazards Models , Remission Induction , Treatment OutcomeSubject(s)
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Benzamides , Humans , Imatinib Mesylate , Nuclear Pore Complex Proteins/genetics , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapyABSTRACT
The outcome of high-risk (HR) acute lymphoblastic leukemia patients enrolled in the AIEOP-BFM ALL 2000 study in Italy is described. HR criteria were minimal residual disease (MRD) levels ≥10(-3) at day 78 (MRD-HR), no complete remission (CR) at day 33, t(4;11) translocation, and prednisone poor response (PPR). Treatment (2 years) included protocol I, 3 polychemotherapy blocks, delayed intensification (protocol IIx2 or IIIx3), cranial radiotherapy, and maintenance. A total of 312 HR patients had a 5-year event-free survival (EFS) of 58.9% (standard error [SE] = 2.8) and an overall survival of 68.9% (SE = 2.6). In hierarchical order, EFS was 45.9% (4.4) in 132 MRD-HR patients, 41.2% (11.9) in 17 patients with no CR at day 33, 36.4% (14.5) in 11 patients with t(4;11), and 74.0% (3.6) in 152 HR patients only for PPR. No statistically significant difference was found for disease-free survival in patients with very HR features [MRD-HR, no CR at day 33, t(4;11) translocation], given hematopoietic stem cell transplantation (HSCT) (n = 66) or chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months). Patients at HR only for PPR have a favorable outcome. MRD-HR is associated with poor outcome despite intensive treatment and/or HSCT and may qualify for innovative therapies. The study was registered at www.clinicaltrials.gov as #NCT00613457.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Combined Modality Therapy , Female , Hematopoietic Stem Cell Transplantation , Humans , Infant , Male , Neoplasm, Residual , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Radiotherapy , Remission Induction , Treatment OutcomeABSTRACT
Eighty-two children and adolescents who underwent allogeneic transplantation for acute lymphoblastic leukaemia in remission (period 2001-2011, median follow-up 4·9 years) had been assessed for minimal residual disease (MRD) by real-time quantitative polymerase chain reaction before and at 1, 3, 6, 9 and 12 months after transplantation. Five-year event-free survival (EFS) and cumulative incidence of relapse were 77·7% [standard error (SE) 5·7] and 11·4% (SE 4·4), respectively, for patients with pre-transplant MRD <1 × 10(-4) (68%), versus 30·8% (SE 9·1; P < 0·001) and 61·5% (SE 9·5; P < 0·001), respectively, for those with MRD ≥1 × 10(-4) (32%). Pre-transplant MRD ≥1 × 10(-4) was associated with a 9·2-fold risk of relapse [95% confidence interval (CI) 3·54-23·88; P < 0·001] compared with patients with MRD <1 × 10(-4). Patients who received additional chemotherapy pre-transplant to reduce MRD had a fivefold reduction of risk of failure (hazard ratio 0·19, CI 0·05-0·70, P = 0·01). Patients who experienced MRD positivity post-transplant did not necessarily relapse (5-year EFS 40·3%, SE 9·3), but had a 2·5-fold risk of failure (CI 1·05-5·75; P = 0·04) if any MRD was detected in the first 100 d, which increased to 7·8-fold (CI 2·2-27·78; P = 0·002) if detected after 6 months. Anticipated immunosuppression-tapering according to MRD may have improved outcome, nevertheless all patients with post-transplant MRD ≥1 × 10(-3) ultimately relapsed, regardless of immunosuppression discontinuation or donor-lymphocyte-infusion. In conclusion, MRD before transplantation had the strongest impact on relapse and MRD positivity after transplantation, mostly if detected early and at low levels, did not necessarily imply relapse. Additional intensified chemotherapy and modulation of immunosuppression may reduce relapse risk and improve ultimate outcome.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/surgery , Adolescent , Child , Child, Preschool , Combined Modality Therapy , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Infant , Male , Neoplasm Recurrence, Local/pathology , Neoplasm, Residual , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prognosis , Treatment OutcomeABSTRACT
BACKGROUND: The aim of this paper is to describe the results of acute lymphoblastic leukemia (ALL) treatment in Nicaragua from 1995 to 2005 in the context of an international cooperation program. PROCEDURES: Patients <18 years with ALL were treated with two consecutive protocols (1995 and 2000). After a steroid prophase, a three-drug induction was administered in protocol 1995, and a four-drug induction, including asparaginase, was administered in protocol 2000. In protocol 2000, a modified BFM phase IB with cyclophosphamide, 6-mercaptopurine and cytosine arabinoside was administered to patients at high risk (HR), who also received IV methotrexate (500 mg/m(2)) in the consolidation phase. Reinduction consisted of dexamethasone, vincristine, doxorubicin, cytosine arabinoside, and 6-thioguanine administered over 7 (protocol 1995) or 4 (protocol 2000) weeks; reinduction was repeated twice for patients at HR. Maintenance consisted of p.o. 6-mercaptopurine and methotrexate, and vincristine and dexamethasone pulses were added in the 2000 study. The total duration of therapy was 24 months. RESULTS: In total, 540 patients were treated. Overall, 7% of patients died during induction, and 9% abandoned treatment. At 5 and 10 years from diagnosis, event-free survival (EFS) rates of 38.1% and 36.6%, respectively, and overall survival rates of 48.0% and 39.6%, respectively, were obtained, considering abandonment as an event. CONCLUSIONS: In our experience, a 10-year EFS of 36.6% was achieved in a country with limited resources. Factors limiting a higher success rate were treatment abandonment and a high relapse rate.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , International Cooperation , Male , Neoplasm Recurrence, Local/mortality , Nicaragua , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Survival Rate , Time FactorsABSTRACT
PURPOSE: The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS: A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS: By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P < .001). CONCLUSION: Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.
Subject(s)
Asparaginase , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Infant , Prednisone/adverse effects , Treatment Outcome , Disease-Free Survival , Neoplasm Recurrence, Local/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Polyethylene Glycols , Recurrence , Randomized Controlled Trials as TopicABSTRACT
New prognostic markers are needed for upfront identification of patients with acute lymphocytic leukemia with a high risk of relapse or who are not likely to respond to the most aggressive chemotherapy. We focused our analysis on Ikaros (IKZF1) gene deletions in a homogeneous cohort of 410 pediatric patients with Philadelphia chromosome-negative, B-cell precursor acute lymphoblastic leukemia enrolled in Italy into the AIEOP-BFM ALL2000 study. We confirm their reported poor prognostic value, although the associated event-free survival was relatively high (approximately 70%). The difference in the cumulative incidence of relapse between patients positive or not for IKZF1 deletions was not marked: 24.2% (5.9) versus 13.1% (1.8) overall and 23.9% (6.6) versus 16.5% (2.5) in the intermediate-risk subgroup. In line with this, IKZF1 deletions were not an independent prognostic factor for the hazard of relapse. Most IKZF1-deleted cases stratified in the high-risk group relapsed, suggesting that once identified, patients with these deletions require an alternative treatment. In conclusion, the need of and benefit from introducing IKZF1 deletions as an additional stratification marker for patients with Philadelphia-negative B-cell precursor acute lymphoblastic leukemia remain questionable.
Subject(s)
Gene Deletion , Genetic Markers/genetics , Ikaros Transcription Factor/genetics , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/diagnosis , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/mortality , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Survival Rate/trendsABSTRACT
The outcome of children and adults with acute lymphoblastic leukemia is markedly different. Since there is limited information on the distribution of clinico-biological variables in different age cohorts, we analyzed 5202 patients with acute lymphoblastic leukemia enrolled in the Italian multicenter AIEOP and GIMEMA protocols and stratified them in nine age cohorts. The highest prevalence of acute lymphoblastic leukemia was observed in children, although a second peak was recorded from the 4(th) decade onwards. Interestingly, the lowest incidence was found in females between 14-40 years. Immunophenotypic characterization showed a B-lineage in 85.8% of patients: a pro-B stage, associated with MLL/AF4 positivity, was more frequent in patients between 10-50 years. T-lineage leukemia (14.2%) was rare among small children and increased in patients aged 10-40 years. The prevalence of the BCR/ABL1 rearrangement increased progressively with age starting from the cohort of patients 10-14 years old and was present in 52.7% of cases in the 6th decade. Similarly, the MLL/AF4 rearrangement constantly increased up to the 5(th) decade, while the ETV6/RUNX1 rearrangement disappeared from the age of 30 onwards. This study shows that acute lymphoblastic leukemia in adolescents and young adults is characterized by a male prevalence, higher percentage of T-lineage cases, an increase of poor prognostic molecular markers with aging compared to cases in children, and conclusively quantified the progressive increase of BCR/ABL(+) cases with age, which are potentially manageable by targeted therapies.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Adolescent , Adult , Age Factors , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Italy/epidemiology , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Retrospective Studies , Young AdultABSTRACT
INTRODUCTION: Venous thromboembolic events (VTEs) are frequent complications of childhood acute lymphoblastic leukemia (ALL) treatment. The aim of the study was to evaluate the rate of symptomatic VTEs in children with ALL and the predictive value of clinical and biological factors and routine monitoring of coagulation parameters in identifying children at a higher risk of this complication. MATERIALS AND METHODS: Between September 2000 and July 2006, 2042 children (≥1 and younger than 18 y) with newly diagnosed ALL were enrolled in Italy in the AIEOP (Italian Association of Pediatric Hematology and Oncology)-BFM (Berlin-Frankfurt-Muenster) ALL 2000 trial. Patients with symptomatic VTEs (deep venous thromboses or cerebral venous thromboses) were identified after a careful review of clinical records. The impact of coagulation derangement at the onset of VTEs was evaluated by a nested case-control study. RESULTS: Forty-eight (2.4%) children presented with a VTE. The rate of VTEs was higher in male patients (P=0.001); patients randomized to receive dexamethasone tended to have a higher rate of VTE compared with those who received prednisone (P=0.10). The coagulation derangement at the onset of VTE was not associated with VTE occurrence. The prevalence of a factor V Leiden G1691A mutation and the prothrombin G20210A variant was higher in children with VTE than that expected in the general population.