SOHO State of the Art Updates and Next Questions: Management of Asparaginase Toxicity in Adolescents and Young Adults with Acute Lymphoblastic Leukemia

A wider use of L-asparaginase in the treatment of children with acute lymphoblastic leukemia has improved cure rates during recent decades and hence led to introduction of pediatric-inspired treatment protocols for adolescents and young adults. In parallel, a range of burdensome, often severe and occasionally life-threatening toxicities have become frequent, including hypersensitivity, hepatotoxicity, hypertriglyceridemia, thromboembolism, pancreatitis, and osteonecrosis. This often leads to truncation of asparaginase therapy, which at least in the pediatric population has been clearly associated with a higher risk of leukemic relapse. Many of the asparaginase induced toxicities are far more common in older patients, but since their relapse rate is still unsatisfactory, the decision to discontinue asparaginase therapy should balance the risk of toxicity with continued asparaginase therapy against the risk of relapse in the individual patient. The underlying mechanisms of most of the asparaginase induced side effects are still unclear. In this review we address the individual toxicities, known risk factors, and their clinical management.     

SOHO State of the Art Updates and Next Questions | Asparaginase—Understanding and Overcoming Toxicities in Adults with ALL

The adoption of pediatric-inspired regimens in young adults with newly diagnosed acute lymphoblastic leukemia (ALL) has significantly improved their survival outcomes. Pediatric-inspired regimens in ALL rely profoundly on delivering adequate dosing of non-myelosuppressive drugs of which asparaginase, a bacterial derived agent, is a key component. Asparaginase therapy is associated with a spectrum of unique toxicities that are observed more frequently in adult patients compared to children with ALL, and this observation has contributed to the reluctance of adult oncologists to administer the drug to their patients. Understanding the breadth of asparaginase toxicity and the associated risk factors may help in preventing severe manifestations and allow safer treatment for adults with ALL. In this review, we will discuss the different formulations of asparaginase and the appropriate dosing in adults with ALL. We will further discuss the frequency and risk factors for individual toxicities of asparaginase along with strategies for their prevention and management.     

Successful challenges using native E. coli asparaginase after hypersensitivity reactions to PEGylated E. coli asparaginase

Purpose

Asparaginase is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. However, asparaginase-induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Here, we report successful challenges using native Escherichia coli asparaginase after previous hypersensitivity reactions to both PEGylated E. coli asparaginase and Erwinia asparaginase.

Patients and methods

The two patients included in this case report were diagnosed with B-precursor ALL at St. Jude Children’s Research Hospital and were treated with a common regimen. Both patients developed hypersensitivity reactions to PEGylated E. coli asparaginase and Erwinia asparaginase early in treatment, and they were challenged with native E. coli asparaginase. Serum samples were collected for estimating the pharmacokinetic parameters of each patient during native E. coli asparaginase therapy.

Results

Challenges with native E. coli asparaginase were successful, and asparaginase serum concentrations above therapeutic levels were attained in both patients.

Conclusions

These two cases suggest that some patients can be given native E. coli asparaginase after hypersensitivity reactions to PEGylated asparaginase and achieve therapeutic concentrations of the drug in serum.     

L‐asparaginase treatment in acute lymphoblastic leukemia

Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG‐asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG‐asparaginase for first‐line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second‐ or third‐line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL. Cancer 2011. © 2010 American Cancer Society.     

Allergic reactions to Erwinia asparaginase in children with acute lymphoblastic leukemia who had previous allergic reactions to Escherichia coli asparaginase.

BACKGROUND. Escherichia coli asparaginase is an active antileukemia agent in the treatment of childhood acute lymphoblastic leukemia. Allergic reactions occurred in 31 of 125 patients (24.8%) treated with weekly high-dose (25,000 IU/m2) intramuscular E. coli asparaginase and necessitated discontinuation of the drug. METHODS. The authors evaluated the toxic effects of Erwinia asparaginase in the 31 children who had allergic reactions to the E. coli preparation. RESULTS. Subsequent allergic reactions to Erwinia asparaginase occurred in 7 of the 31 children (22.6%). In contrast to previous reports with intravenous administration, most allergic reactions to both asparaginase preparations were characterized by mild urticaria that responded to use of diphenhydramine; none of the reactions was life-threatening. CONCLUSIONS. In summary, the authors found Erwinia asparaginase to be an acceptable substitute for E. coli asparaginase for most children who had allergic reactions. Through the use of both E. coli and Erwinia asparaginase, 94% of children could receive their intended asparaginase.     

门冬酰胺酶在急性淋巴细胞白血病治疗中的副作用及其对策

门冬酰胺酶(L-ASP)是治疗成人和儿童急性淋巴细胞白血病的有效药物,几乎包含在所有的ALL治疗方案中。尽管该药耗竭天冬氨酸的独特作用机理使其对肿瘤细胞具有相对物异性,但部分病人仍在治疗过程中出现各种副反应。L-ASP治疗的严重并发症主要有过敏反应、急性胰腺炎和血栓形成。为预防和早期诊断各种并发症,在L-ASP治疗过程中或治疗后需进行密切的临床和相关实验指标如抗凝血酶和血清淀粉酶观察。     

Correlation between high vascular endothelial growth factor-A serum levels and treatment outcome in patients with standard-risk acute lymphoblastic leukemia: a report from Children's Oncology Group Study CCG-1962.

PURPOSE: Many molecular pathways, including cell cycle control, angiogenesis, and drug resistance, mediate tumor growth and survival. Vascular endothelial growth factor-A (VEGF-A) serum levels <40 and >100 pg/mL have been associated with good and poor prognoses, respectively. EXPERIMENTAL DESIGN: The hypothesis was that serum VEGF-A levels in standard-risk acute lymphoblastic leukemia pediatric patients at induction are predictive of event-free survival (EFS). One hundred seventeen patients were entered in CCG-1962 study and randomized into the native and polyethylene glycolated asparaginase arms. VEGF-A levels were quantified by an ELISA assay. RESULTS: All patients had a decrease in VEGF-A levels by day 14 of induction, but they later dichotomized; EFS group levels remained low and event group levels increased. A correlation exists between high VEGF-A levels at entry to induction and time to event. Moreover, 6-year EFS patients have lower end of induction VEGF-A levels (28 +/- 6 pg/mL) than event patients (>100 pg/mL; P < 0.01). Kaplan-Meier curves using various VEGF-A values were produced; with < or =30 at entry into induction (day 0) and < or =60 pg/mL at the end of induction (day 28), patients with low VEGF-A levels had superior EFS (P < 1e-4). Furthermore, patients who had an increase in VEGF-A during induction (DeltaVEGF-positive, days 0-28) were more likely to have an event (P < 1e-4). Bifurcation by asparaginase treatment arm did not alter these results. CONCLUSIONS: These observations strongly support that high VEGF-A levels in induction are an asparaginase treatment-independent predictive marker for EFS. Hence, an anti-VEGF-A therapy should be tested in acute lymphoblastic leukemia.     

Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free ALL Regimen

Background: venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL), especially in patients treated with asparaginase (ASNase)-including regiments. However, VTE risk in adult Philadelphia-positive ALL (Ph+ve ALL) patients treated with non-hyperCVAD chemotherapy is unclear. In this study, we examined VTE incidence in adult Ph+ve ALL patients treated with imatinib plus a pediatric-inspired asparaginase (ASNase)-free regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol. Methods: a single centre retrospective review of Ph+ve ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008–2019 with imatinib plus modified DFCI protocol was conducted. Results: of the 123 patients included, 30 (24.3%) had at least 1 radiology confirmed VTE event from diagnosis to the end of maintenance therapy. 86.7% (26/30) of the VTE events occurred during active treatment. Of all VTE events, the majority (53.3%) were DVT and/or PE while another significant portion were catheter-related (40.0%). Major bleeding was observed in 1 patient on VTE treatment with low molecular weight heparin (LMWH). Conclusion: a high VTE incidence (24.3%) was observed in adults Ph+ve ALL patients treated with imatinib plus an ASNase-free modified DFCI pediatric ALL protocol, suggesting prophylactic anticoagulation should be considered for all adult Ph+ve ALL patients including those treated with ASNase-free regimens.     

Toxicity Profile of PEG-Asparaginase in Adult Patients With Acute Lymphoblastic Leukemia in Brazil: A Multicenter Cross-Sectional Study

BackgroundCurrently, pediatric-inspired regimens are commonly applied to adults with acute lymphoblastic leukemia (ALL) after the recent recognition that these protocols improve survival. While asparaginase in whatever available formulation is a key component of modern treatment of ALL, many adult oncologists and hematologists struggle to deal with its particular toxicities in clinical practice. We reviewed toxicity outcomes of pegylated asparaginase (PEG-ASP) in adults with ALL treated in 3 reference centers in Brazil.Patients and MethodsThis was a cross-sectional retrospective chart-review study encompassing patients aged 15 years and older diagnosed with ALL or ambiguous-lineage leukemia who received at least one dose of PEG-ASP, regardless of the adopted regimen.ResultsA total of 57 patients were included (age range, 15-57 years). Most patients (70%) received 2000 IU/m² as the initial dose, by intravenous route (72%). The incidence of thromboembolic events was 17.5%, and the main site was cerebral venous sinus (4/10). Thrombosis was more frequent in patients receiving second-line treatment. In obese patients, grade 3 hepatotoxicity and hyperbilirubinemia were more common. Clinical pancreatitis (grade 3 or higher) was found in 2 of 57 cases. PEG-ASP had to be discontinued in 19.3% of exposed patients (11/57).ConclusionBy reviewing the medical charts of adult patients with ALL from 3 reference centers, we found that our incidence of thrombotic and hepatic adverse events is similar to those reported in other trials involving PEG-ASP. Usually these effects should not preclude further use of the drug because most events are manageable in routine clinical practice.     

Asparaginase in the management of adult acute lymphoblastic leukaemia: Is it used appropriately?

Background

Whereas the disease free survival (DFS) continues to improve in paediatric acute lymphoblastic leukaemia (ALL), the prognosis of adult ALL has not altered significantly for last 2-3 decades. About 85% of children with ALL are leukaemia free at 5 years, but at best, only about 40% adults with ‘standard risk’ ALL remain in remission at that time. This is in spite of almost an equal proportion of adult patients achieving a complete remission as their much younger counterparts. Current data supports the efficacy of asparaginase in the treatment of ALL.

Purpose

This review focuses on the role of asparaginase in the management of adult acute lymphoblastic leukaemia (ALL). It examines the current use of this agent in this disease and the potential for optimising its application and monitoring of efficacy in treatment regimens.

Conclusion

Use of l-asparaginase has revolutionised the anti-leukaemia therapy in ALL. Early and sustained asparagine depletion, at least up to the first 30 weeks of therapy, appears to be crucial. Given the clear correlation between the depth of asparagine depletion and the patient outcome, asparaginase therapy should be monitored for adequate asparagine depletion for achievement of optimum results.     

Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study.

This study was designed to test the hypothesis that high-dose asparaginase consolidation therapy improves survival in pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma. Five hundred and fifty-two patients (357 patients with T cell acute lymphoblastic leukemia (ALL) and 195 patients with advanced stage lymphoblastic lymphoma) were enrolled in POG study 8704 (T-3). Treatment included rotating combinations of high-dose myelosuppressive chemotherapy agents proven to be effective in T cell ALL in other POG group-wide or local institutional protocols (including vincristine, doxorubicin, cyclophosphamide, prednisone, asparaginase, teniposide, cytarabine and mercaptopurine). After achieving a complete remission (CR), patients were randomized to receive or not receive high-dose intensive asparaginase consolidation (25,000 IU/m2) given weekly for 20 weeks by intramuscular injection. Intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine) was given to prevent CNS disease, and CNS irradiation was used only for patients with leukemia and an initial WBC of >50,000/microl or patients with active CNS disease at diagnosis. CR was achieved in 96% of patients. The high-dose asparaginase regimen was significantly superior to the control regimen for both the leukemia and lymphoma subgroups. Four-year continuous complete remission rate (CCR) for the leukemia patients was 68% (s.e. 4%) with asparaginase as compared to 55% (s.e. 4%) without. For the lymphoma patients, 4-year CCR was 78% (s.e. 5%) with asparaginase and 64% (s.e. 6%) in the controls. The overall one-sided logrank test had a P value <0.001 favoring asparaginase, while corresponding values were P = 0.002 for ALL and P = 0.048 lymphoblastic lymphoma. Toxicities were tolerable, but there were 18 failures due to secondary malignancies (16 with non-lymphocytic leukemia or myelodysplasia). Neither WBC at diagnosis (leukemia patients) nor lymphoma stage were major prognostic factors. We conclude that when added to a backbone of effective rotating agents, repeated doses of asparaginase during early treatment improve the outcome for patients with T cell leukemia and advanced stage lymphoblastic lymphoma.     

Medication safety in the ambulatory chemotherapy setting

BACKGROUND: Little is known concerning the safety of the outpatient chemotherapy process. In the current study, the authors sought to identify medication error and potential adverse drug event (ADE) rates in the outpatient chemotherapy setting. METHODS: A prospective cohort study of two adult and one pediatric outpatient chemotherapy infusion units at one cancer institute was performed, involving the review of orders for patients receiving medication and/or chemotherapy and chart reviews. The adult infusion units used a computerized order entry writing system, whereas the pediatric infusion unit used handwritten orders. Data were collected between March and December 2000. RESULTS: The authors reviewed 10,112 medication orders (8008 adult unit orders and 2104 pediatric unit orders) from 1606 patients (1380 adults and 226 pediatric patients). The medication error rate was 3% (306 of 10,112 orders). Of these errors, 82% occurring in adults (203 of 249 orders) had the potential for harm and were potential ADEs, compared with 60% of orders occurring in pediatric patients (34 of 57 orders). Among these, approximately one-third were potentially serious. Pharmacists and nurses intercepted 45% of potential ADEs before they reached the patient. Several changes were implemented in the adult and pediatric settings as a result of these findings. CONCLUSIONS: In the current study, the authors found an ambulatory medication error rate of 3%, including 2% of orders with the potential to cause harm. Although these rates are relatively low, there is clearly the potential for serious patient harm. The current study identified strategies for prevention.     

Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia

Between June 1977 and December 1979, 72 evaluable patients with childhood non-T-cell acute lymphoblastic leukemia were induced into complete remission using vincristine, prednisone, and doxorubicin. All received asparaginase consolidation and central nervous system prophylaxis with cranial irradiation and intrathecal methotrexate. All patients then received prolonged intensification with vincristine, prednisone, and doxorubicin, and half of them were randomized to receive weekly high-dose asparaginase. Continuation therapy was with vincristine, prednisone, methotrexate, and 6-mercaptopurine. After a median follow-up of 57 months, there were four remission deaths and 25 relapses. Central nervous system relapse was the first event in 4% of patients. There were fewer treatment failures in the asparaginase-treated group [2-sided, p = 0.04 (0.07 controlling for standard and high-risk groups)]. Asparaginase toxicity occurred in six patients (8%) and was self-limited, but it precluded further use of the drug in those patients. The major toxicity of this treatment program was drug-induced cardiomyopathy which occurred in 10 patients (14%) and was fatal in three of them. In summary, we conclude that the intensive use of high-dose asparaginase has an important role in the treatment of children with acute lymphoblastic leukemia. The morbidity of multiple doses of doxorubicin outweighed its antileukemic advantage in standard-risk patients.     

Clinical impact of in vitro cellular drug resistance on childhood acute lymphoblastic leukemia in Taiwan

Despite the successful treatment of childhood acute lymphoblastic leukemia (ALL), the resistance to chemotherapy in ALL cells continues to play an important role in treatment failure. In vitro drug resistance determined using an MTT [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was carried out in 16 children with newly diagnosed ALL between November 2009 and December 2010. The in vitro therapeutic effects of asparaginase, vincristine, prednisolone, dexamethasone, epirubicin and cytarabine were examined. Although there was no significant association between in vitro drug resistance of leukemic cells and ALL subtypes, ETV6-RUNX1 ALL tended to be more sensitive to asparaginase, vincristine and prednisolone. Leukemic cells from girls were significantly more sensitive to epirubicin compared with boys (p = 0.008). Higher leukocyte count at diagnosis was correlated with in vitro resistance to asparaginase and prednisolone (p = 0.03 and 0.05, respectively). Relapse or death occurred in five patients. The leukemic cells from these five patients demonstrated increased in vitro resistance to asparaginase compared to those from the other 11 patients (p = 0.009). From the present case series, the demonstrated in vitro resistance to chemotherapeutic agents may have a prognostic value in children with ALL before comprehensive minimal residual disease measurement is available.     

Alternatives thérapeutiques à la L-asparaginase native dans le traitement de la leucémie aiguë lymphoblastique de l'adulte

L-asparaginase is an effective antineoplastic agent, which is an integral part of combination chemotherapy protocols for adult acute lymphoblastic leukemia. Its antitumor effect results from the depletion of asparagine, an amino acid essential to leukemia cells, and subsequent inhibition of protein synthesis leading to cytotoxicity. However, its use has been limited by a high rate of hypersensitivity reactions and development of neutrolizing anti-asparaginase antibodies, and by the need of frequent administration. To overcome these limitations modified versions of L-asparaginase (such as asparaginase from other sources, pegylated formulations, and asparaginase loaded into erythrocytes) have been recently proposed. Advantages of these therapeutic alternatives to native L-asparaginase and their results as part of preliminary clinical trials in adults have been outlined in this review.     

Asparaginase in the treatment of non-ALL hematologic malignancies

Asparaginases are among the most effective agents against acute lymphoblastic leukemia (ALL) and are Food and Drug Administration-approved for the treatment of pediatric and adult ALL. However, the efficacy of these drugs for the treatment of other hematologic malignancies particularly acute myeloid leukemia is not well established. The mechanism of action of asparaginases has thought to be related to a swift and sustained reduction in serum l-asparagine, which is required for rapid proliferation of metabolically demanding leukemic cells. However, asparagine depletion alone appears not to be sufficient for effective cytotoxic activity of asparaginase against leukemia cells, because glutamine can rescue asparagine-deprived cells by regeneration of asparagine via a transamidation chemical reaction. For this reason, glutamine reduction is also necessary for full anti-leukemic activity of asparaginase. Indeed, both Escherichia coli and Erwinia chrysanthemi asparaginases possess glutaminase enzymatic activity, and their administrations have shown to reduce serum glutamine level by deamidating glutamine to glutamate and ammonia. Emerging data have provided evidence that several types of neoplastic cells require glutamine for the synthesis of proteins, nucleic acids, and lipids. This fundamental role of glutamine and its metabolic pathways for growth and proliferation of individual malignant cells may identify a special group of patients whose solid or hematologic neoplasms may benefit significantly from interruption of glutamine metabolism. To this end, asparaginase products deserve a second look particularly in non-ALL malignant blood disorders. Here, we review mechanisms of anti-tumor activity of asparaginase focusing on importance of glutamine reduction, pharmacology of asparaginase products, in vitro activities as well as clinical experience of incorporating asparaginase in therapeutic regimens for non-ALL hematologic malignancies.     

A Decade of Experience of Management of Thyroglossal Duct Cyst in a Tertiary Care Hospital: Differentiation Between Children and Adults

Variations in thyroglossal duct cysts (TGDCs) between children and adult are mentioned very little in literature. The lesion mostly found in children but adult population also possesses this anomaly. The aim of this study was to determine the differences in clinical presentations and surgical outcomes of TGDC between children and adults. A retrospective chart review of all patients with TGDCs managed in our hospital from July 2004 to June 2014. All records were reviewed for age, sex, location of cyst in neck and with relation to hyoid bone, size, postoperative complication and recurrence rates. Differences between children and adults were assessed. A total of 39 patients (21 children and 18 adults) were treated for TGDC. Of the pediatric group, 71.4% were male and 28.5% were female, whereas 72.2% of the adults were male and 27.7% were female. Adults were more likely to develop other complaints like neck pain, dysphagia and dyspnea. Position was almost similar in both age groups with midline and infrahyoid location while laterality was seen in adult only. Size of Cyst was found to be larger in adults. The recurrence and post operative complication rates between children and adults were not significantly different. TGDC has male predominance. Clinical presentations were almost similar in both age groups. Although lateral deviation, increase size of cyst and recurrences were seen in adults only, Sistrunk procedure is recommended as a safe and standard surgical treatment in both age groups.     

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia.

Polyethylene glycol-conjugated (PEG) asparaginase is approved for use in patients who develop allergy to other forms of asparaginase, although its ability to deplete asparagine systemically in patients with hypersensitivity has not been well elucidated. In 53 children with newly diagnosed acute lymphoblastic leukemia, we serially assessed asparagine concentrations in cerebrospinal fluid (CSF) and plasma as well as serum anti-asparaginase antibodies. All patients received native Escherichia coli (Elspar) asparaginase during induction therapy; patients received PEG asparaginase during reinductions when available, and those who developed allergy received Erwinia asparaginase. All eight patients who developed clinical evidence of allergy to asparaginase had anti-asparaginase antibodies. Among patients who had no antibodies, those who received E. coli had lower mean (+/-s.d.) CSF asparagine (0.29+/-0.63, n=9) than those who received PEG (0.77+/-0.82, n=4) (P=0.007). Results were similar for plasma asparagine. There was no situation where asparagine concentrations were more effectively depleted by PEG than by other preparations. None of the five patients who developed thrombosis had an allergy or antibodies to asparaginase at the time of the thrombosis. We conclude that asparagine concentrations were less effectively depleted by PEG than by E. coli asparaginase at the doses commonly used. The risk of thrombosis may be affected by the intensity of asparaginase exposure.     

Treatment advances in adult Burkitt lymphoma and leukemia

PURPOSE OF REVIEW: Despite significant improvements in the treatment of Burkitt lymphoma, outcomes of adults are generally inferior to those of children. This review summarizes the most recent developments in the management of Burkitt lymphoma and leukemia in adults. RECENT FINDINGS: Current regimens have largely been derived from pediatric protocols. High complete remission rates are typically achieved, but relapse remains a problem. Recent trials have validated or built upon findings from older studies. SUMMARY: The adoption of aggressive, multiagent, short-course therapy has markedly improved outcomes, but relapse rates remain relatively high in poorer-risk cohorts. New approaches are particularly needed in older patients to improve survival rates while minimizing toxicities.     

Pediatric-Like Therapy for Adults with ALL

Ten years ago, the first studies comparing the results of adult versus pediatric protocols in adolescents with acute lymphoblastic leukemia (ALL) clearly showed that differences in ALL genetics and treatment tolerance could not be the only reasons for the worse outcome observed in adults with this disease as compared to children. It became evident that intensified pediatric chemotherapy regimens could be associated with better response rates and longer survival in adults as well. During the last decade, the use of pediatric-like or pediatric-inspired protocols in adults allowed markedly improving the outcome of young adult patients aged up from 40 years to 60 years, confirming this initial observation. Administration of pediatric-like therapy in adults is now associated with estimated 5-year overall survival comprised between 60 % and 70 %. In this new context, the risk factors and the place of stem cell transplantation need to be reassessed.