Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
2016; Elsevier BV; Volume: 27; Linguagem: Inglês
10.1093/annonc/mdw025
ISSN1569-8041
AutoresD. Hoelzer, Renato Bassan, Hervé Dombret, Adele K. Fielding, Josep‐María Ribera, Christian Buske,
Tópico(s)Acute Myeloid Leukemia Research
ResumoThe estimated overall incidence of acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma in Europe is 1.28 per 100 000 individuals annually, with significant age-related variations (0.53 at 45–54 years, ∼1.0 at 55–74 years and 1.45 at 75–99 years) and that of Burkitt leukaemia/lymphoma is between 0.17 and 0.33 in the same age groups [1.Sant M. Allemani C. Tereanu C. et al.Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project.Blood. 2010; 116: 3724-3734Google Scholar]. These figures qualify ALL as a rare disease in adults, making assessment and care at qualified centres highly desirable. Predisposing risk factors for adult ALL are not known, contrary to childhood ALL [2.Inaba H. Greaves M. Mullighan C.G. Acute lymphoblastic leukaemia.Lancet. 2013; 381: 1943-1955Google Scholar]. Therapeutic progress is undeniable as shown by large registry data. In Europe, 5-year overall survival (OS) improved from 29.8% in the years 1997–1999 to 41.1% in 2006–2008 (P < 0.0001), still as a function of age. Compared with the reference group (age 15–54 years: OS >50%), OS was <30% in the 55–64 years age group (hazard ratio 2.05) and 20% (CD3, CD79a >10%)–B-lineage ALL:Pro-B/B-I (CD19/CD79a/cCD22+)Common/B-II (CD10+/cIgM-)Pre-B/B-III (cIgM+/sIg-)Mature-B/B-IV (sIg+)–T-lineage ALL:Pro-T/T-I (cCD3/CD7+)Pre-T/T-II (CD2/CD5)Cortical-T/T-III (CD1a+)Mature-T/T-IV (CD3+/CD1a-)MandatoryMandatoryMandatoryCytogenetics/genetics–Cytogenetics/FISH/RT-PCR–ALL with adverse clinico-biological features:Ph+ ALL (rapid detection, to TKI therapy)t(4;11)+ ALLt(1;19)+ ALLother high-risk cytogeneticsMandatory–CGH/SNP/GEP/NGS–ALL with adverse clinico-biological features:Ph-like ALLETP ALLNOTCH1/FBW7-unmutated/RAS/PTEN-altered T-ALLIKZF1, CLRF2, MLL, TP53, CREBBP, RAS alterationsRecommended for new clinical trialsMRD study–MRD marker(s): LAIP (immunophenotype)/molecular probe (PCR)–MRD-based risk classificationMandatoryStorage of diagnostic material–Cell banking/storage of DNA/RNA/protein lysates–Additional/future studiesHighly recommendedHLA typing–Patient/siblings–Early application of SCT if requiredRecommendedALL, acute lymphoblastic leukaemia; CNS, central nervous system; MPO, myeloperoxidase; AML, acute myelogenous leukaemia; c, cytoplasmic; IgM, immunoglobulin M; s, surface; Ig, immunoglobulin; FISH, fluorescence in situ hybridisation; RT-PCR, reverse transcriptase polymerase chain reaction; Ph+, Philadelphia-positive; TKI, tyrosine kinase inhibitor; CGH, comparative genomic hybridisation; SNP, single nucleotide polymorphism; GEP, gene expression profiling; NGS, next-generation sequencing; Ph, Philadelphia; ETP, early T-cell precursor; T-ALL, T-cell ALL; MRD, minimal residual disease; LAIP, leukaemia-associated immunophenotype; PCR, polymerase chain reaction; HLA, human leucocyte antigen; SCT, stem-cell transplantation. Open table in a new tab ALL, acute lymphoblastic leukaemia; CNS, central nervous system; MPO, myeloperoxidase; AML, acute myelogenous leukaemia; c, cytoplasmic; IgM, immunoglobulin M; s, surface; Ig, immunoglobulin; FISH, fluorescence in situ hybridisation; RT-PCR, reverse transcriptase polymerase chain reaction; Ph+, Philadelphia-positive; TKI, tyrosine kinase inhibitor; CGH, comparative genomic hybridisation; SNP, single nucleotide polymorphism; GEP, gene expression profiling; NGS, next-generation sequencing; Ph, Philadelphia; ETP, early T-cell precursor; T-ALL, T-cell ALL; MRD, minimal residual disease; LAIP, leukaemia-associated immunophenotype; PCR, polymerase chain reaction; HLA, human leucocyte antigen; SCT, stem-cell transplantation. Aspiration of bone marrow is a standard procedure, with a core marrow biopsy being necessary only in case of insufficient cell yield. The bone marrow must contain at least 20% blast cells, as a criterion to differentiate ALL from lymphoblastic lymphoma with/without marrow involvement, even if therapeutic consequences are very limited. The proportion of circulating blasts is highly variable. ALL blasts are atypical lymphoid or undifferentiated cells. Once minimally differentiated acute myelogenous leukaemia (AML) has been ruled out, the morphological analysis is uninformative in ALL, if not for the common association between FAB L3 morphology and B-ALL [7.Bennett J.M. Catovsky D. Daniel M.T. et al.The morphological classification of acute lymphoblastic leukaemia: concordance among observers and clinical correlations.Br J Haematol. 1981; 47: 553-561Google Scholar]. The immunophenotype study plays the key diagnostic role, demonstrating commitment of the blast cell population to the B- or T-cell lineage. The European Group for the Immunological Characterization of Leukemias (EGIL) recognised distinct BCP/T-ALL subsets, providing a rational immunological classification along with criteria for differential diagnosis [8.Béné M.C. Castoldi G. Knapp W. et al.Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL).Leukemia. 1995; 9: 1783-1786Google Scholar]. Original EGIL standards and definitions of mixed-lineage leukaemias (MLLs) variously expressing B-, T- and myeloid-associated antigens were updated and improved [9.Béné M.C. Nebe T. Bettelheim P. et al.Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10.Leukemia. 2011; 25: 567-574Google Scholar, 10.Matutes E. Pickl W.F. van't Veer M. et al.Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification.Blood. 2011; 117: 3163-3171Google Scholar]. Further indications on how to best perform diagnostic flow cytometry were presented by a panel of experts [11.van Dongen J.M. Lhermitte L. Böttcher S. et al.EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes.Leukemia. 2012; 26: 1908-1975Google Scholar]. The early diagnostic step is completed by a rapid molecular screening by means of reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescence in situ hybridisation (FISH) assays primarily for the detection of BCR-ABL1 gene rearrangements, denoting an underlying t(9;22)(q34;q11)/BCR-ABL1 chromosomal translocation typical of Ph+ ALL and sensitive to targeted therapy with tyrosine kinase inhibitors (TKIs) [I, A] [12.Gleissner B. Gökbuget N. Bartram C.R. et al.Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis.Blood. 2002; 99: 1536-1543Google Scholar]. Results from cytogenetics, genetics and genomics are available at a later stage, allowing the recognition of several ALL syndromes with prognostic and/or therapeutic implications (reviewed in references [2.Inaba H. Greaves M. Mullighan C.G. Acute lymphoblastic leukaemia.Lancet. 2013; 381: 1943-1955Google Scholar] and [6.Chiaretti S. Zini G. Bassan R. Diagnosis and subclassification of acute lymphoblastic leukemia.Mediterr J Hematol Infect Dis. 2014; 6: e2014073Google Scholar]). Standard cytogenetics/FISH and especially RT-PCR are routinely performed to obtain a rapid diagnosis of Ph+ ALL and identify other intermediate/high- and high-risk karyotypes/gene rearrangements, mainly:•t(4;11)(q21;q23)/MLL-AFA4, abn11q23/MLL, t(1;19)(q23;p13)/PBX-E2A, t(8;14) or other abn14q32 in non-Burkitt ALL,•del(6q), del(7p), del(17p), -7, +8, low hypodiploidy, i.e. with 30–39 chromosomes/near triploidy with 60–78 chromosomes,•complex (≥5 unrelated clonal abnormalities), and•T-ALL lacking NOTCH1/FBXW7 mutations and/or with RAS/PTEN abnormalities [I, A] [13.Moorman A.V. Harrison C.J. Buck G.A. et al.Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial.Blood. 2007; 109: 3189-3197Google Scholar, 14.Pullarkat V. Slovak M.L. Kopecky K.J. et al.Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study.Blood. 2008; 111: 2563-2572Google Scholar, 15.Mancini M. Scappaticci D. Cimino G. et al.A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA0496 protocol.Blood. 2005; 105: 3434-3441Google Scholar, 16.Roberts K.G. Li Y. Payne-Turner D. et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.N Engl J Med. 2014; 371: 1005-1015Google Scholar, 17.Trinquand A. Tanguy-Schmidt A. Ben Abdelali R. et al.Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.J Clin Oncol. 2013; 31: 4333-4342Google Scholar]. The more prognostically favourable cytogenetic/genetic subsets are t(12;21)(p13;q22)/TEL-AML1 + ALL (rare in adults) and hyperdiploid ALL, and NOTCH-1/FBXW7-mutated T-ALL. The integration of above studies with new genetics/genomics, i.e. array-comparative genomic hybridisation, gene expression profiling, single-nucleotide polymorphism array analysis and next-generation sequencing, led to the recognition of highly specific poor-risk conditions, whose global incidence is ∼30%. These are: Ph-like ALL, characterised by a gene expression profile similar to Ph+ ALL and associated with IKZF1 deletion, CLRF2 overexpression and tyrosine kinase-activating rearrangements involving ABL1, JAK2, PDGFRB and several other genes [16.Roberts K.G. Li Y. Payne-Turner D. et al.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.N Engl J Med. 2014; 371: 1005-1015Google Scholar]; and early T-cell precursor (ETP) ALL, characterised by lack of CD1a and CD8, weak CD5 expression, at least one myeloid/stem cell marker, a specific transcriptional profile and the possible involvement of several critical genes [18.Coustan-Smith E. Mullighan C.G. Onciu M. et al.Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.Lancet Oncol. 2009; 10: 147-156Google Scholar]. Other genetic aberrations that impart an inferior outlook are other MLL gene rearrangements, TP53 and CREBBP mutations, and deregulation of RAS signalling components (NRAS, KRAS, FLT3, NF1). Although these assays are still investigational and not regularly carried out in the clinical practice, they are recommended for new clinical trials to improve the risk classification and support targeted therapies [III, B]. The diagnostic phase is completed by the search for a sensitive molecular marker or an aberrant leukaemia-associated immunophenotype (LAIP) for the detection and monitoring of minimal residual disease (MRD) [III, B] [19.Brüggemann M. Raff T. Kneba M. Has MRD monitoring superseded other prognostic factors in adult ALL?.Blood. 2012; 120: 4470-4481Google Scholar]. Human leucocyte antigen (HLA) typing of patients and relatives is recommended at this stage, to facilitate subsequent application of an early stem-cell transplantation (SCT), according to study/treatment indications [V, B]. While the suggested diagnostic work-up permits the identification of some high-risk (HR) subsets, clinical risk groups are further defined by several disease-related factors and some host-related factors [20.Hoelzer D. Thiel E. Löffler H. et al.Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults.Blood. 1988; 71: 123-131Google Scholar, 21.Rowe J.M. Prognostic factors in adult acute lymphoblastic leukaemia.Br J Haematol. 2010; 150: 389-405Google Scholar], and the individual prognosis is highly refined by ALL response dynamics (Table 2). Patients presenting with no risk factors are defined as standard risk (SR). Older age, reduced tolerability to treatments and higher white blood cell (WBC) count on presentation (reflecting higher tumoural burden) are universally recognised as independent risk variables predicting for lower complete remission (CR) rate and shorter CR duration. The kinetics of response to early treatment steps is also well recognised and increasingly sought-for prognostic information. This can be obtained through different methodologies and at different treatment times, ranging from pre-phase therapy (prednisone response) to induction day 8–15 (marrow blast cell clearance), end of induction (time to CR, MRD) and post-induction phase (MRD) [III, A].Table 2High-risk factors in adult ALLRisk factorsRisk subsets (notes)RecommendationsPatient-related–Age (years)–Performance status (ECOG score)– >40/55/65– >1MandatoryHighly recommendedDisease-related–WBC (×109/l)–Immunophenotype (B-T-subsets)–Cytogenetics (karyotype)–Genetics–Miscellaneous– >30 (B-lineage)/>100 (T-lineage)– Pro-B/early and mature-T– Ph+/t(4;11)+/other adverse– BCR-ABL1+/MLL+/PBX-E2A+/ Ph-like/IKZF1del/ETP/unmutated NOTCH1– Central nervous system involvementMandatoryMandatoryMandatoryMandatoryRecommended for new clinical trialsMandatoryResponse dynamics–corticosteroid sensitivity (blast count after pre-phase)–early blast cell response (BM morphology)–time to CR (no. of courses)–MRD (molecular/LAIP)– Poor prednisone response (≥1 × 109/l)– Day 8–15 blasts ≥5%– >1 cycle (late CR)– MRD+ (post-induction)RecommendedRecommendedMandatoryMandatoryALL, acute lymphoblastic leukaemia; ECOG, Eastern Cooperative Oncology Group; WBC, white blood cells; Ph+, Philadelphia-positive; Ph, Philadelphia; ETP, early T-cell precursor; BM, bone marrow; CR, complete remission; MRD, minimal residual disease; LAIP, leukaemia-associated immunophenotype. Open table in a new tab ALL, acute lymphoblastic leukaemia; ECOG, Eastern Cooperative Oncology Group; WBC, white blood cells; Ph+, Philadelphia-positive; Ph, Philadelphia; ETP, early T-cell precursor; BM, bone marrow; CR, complete remission; MRD, minimal residual disease; LAIP, leukaemia-associated immunophenotype. Quantification of MRD is a major and well-established risk factor and should be obtained whenever possible for all patients also outside of clinical trials. Methods for MRD evaluation and standardisation of MRD quantifıcation have been intensively described [22.MBrüggemann, ASchrauder, TRaffet al. Standardized MRD quantification in European ALL trials. In: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. Leukemia 2010; 24: 521–535.Google Scholar, 23.Campana D. Minimal residual disease in acute lymphoblastic leukemia.Hematology Am Soc Hematol Educ Program. 2010; 2010: 7-12Google Scholar, 24.Garand R. Beldjord K. Cavé H. et al.Flow cytometry and IG/TCR quantitative PCR for minimal residual disease quantitation in acute lymphoblastic leukemia: a French multicenter prospective study on behalf of the FRALLE, EORTC and GRAALL.Leukemia. 2013; 27: 370-376Google Scholar]. Molecular response can be evaluated only for patients in complete cytologic remission (Table 3), with one marker or more for MRD analysis and samples available at the respective time points. Definition of responses are summarised in Table 3. If MRD is measured by flow cytometry, a good MRD response is often defıned as less than 10-3, although MRD levels less than 10-4 can be achieved with the 8–12 colour flow cytometers.Table 3Response parameters according to MRDTerminologyDefinitionsCR (complete haematological remission)–Leukaemic cells not detectable by light microscopy in BM/PB/CSF (BM < 5% blasts)MolCR (complete molecular remission/MRD negativity)–Patient in CR–MRD not detectable by sensitive molecular probe(s) (sensitivity ≥10-4)MolR (molecular/MRD response, less than molCR)–Patient in CR, not in molCR–Low-level non-quantifiable MRD (<10-4/0.01%, i.e. 1 leukaemic cell in 10 000)–Assessable by MFC (lower detection limit, between 10-3 and 10-4)Relapse–Loss of CR status–Haematological relapse (BM ALL blasts >5%)–Extramedullary relapse (CNS, other site)MRD, minimal residual disease; BM/PB/CSF, bone marrow/peripheral blood/cerebro-spinal fluid; MFC, multiparameter flow cytometry; ALL, acute lymphoblastic leukaemia; CNS, central nervous system. Open table in a new tab MRD, minimal residual disease; BM/PB/CSF, bone marrow/peripheral blood/cerebro-spinal fluid; MFC, multiparameter flow cytometry; ALL, acute lymphoblastic leukaemia; CNS, central nervous system. Achievement of complete molecular remission (molCR)/molecular remission is the most relevant independent prognostic factor for disease-free survival (DFS) and OS. Patients with molCR after induction therapy in several studies had significantly superior outcomes, with a DFS of 54%–74%, compared with 17%–40% for MRD-positive patients [25.Holowiecki J. Krawczyk-Kulis M. Giebel S. et al.Status of minimal residual disease after induction predicts outcome in both standard and high-risk Ph-negative adult acute lymphoblastic leukaemia: the Polish Adult Leukemia Group ALL 4-2002 MRD Study.Br J Haematol. 2008; 142: 227-237Google Scholar, 26.Patel B. Rai L. Buck G. et al.Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993.Br J Haematol. 2010; 148: 80-89Google Scholar, 27.Beldjord K. Chevret S. Asnafi V. et al.Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.Blood. 2014; 123: 3739-3749Google Scholar, 28.Brüggemann M. Raff T. Flohr T. et al.Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia.Blood. 2006; 107: 1116-1123Google Scholar, 29.Gökbuget N. Kneba M. Raff T. et al.Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies.Blood. 2012; 120: 1868-1876Google Scholar, 30.Bassan R. Spinelli O. Oldani E. et al.Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL).Blood. 2009; 113: 4153-4162Google Scholar, 31.Ribera J.M. Oriol A. Morgades M. et al.Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial.J Clin Oncol. 2014; 32: 1595-1604Google Scholar]. Patients with molecular failure (molFail) after induction proceeded to allogeneic haematopoietic SCT, and their outcome was thereby substantially improved, compared with the chemotherapy-only arm [29.Gökbuget N. Kneba M. Raff T. et al.Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies.Blood. 2012; 120: 1868-1876Google Scholar, 32.Bassan R. Spinelli O. Oldani E. et al.Different molecular levels of post-induction minimal residual disease may predict hematopoietic stem cell transplantation outcome in adult Philadelphia-negative acute lymphoblastic leukemia.Blood Cancer J. 2014; 4: e225Google Scholar, 33.Dhédin N. Huynh A. Maury S. et al.Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.Blood. 2015; 125: 2486-2496Google Scholar]. The question arises as to whether the evaluation of MRD overcomes all of the pre-therapeutic risk factors, or whether MRD should be combined with the pre-therapeutic factors [27.Beldjord K. Chevret S. Asnafi V. et al.Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.Blood. 2014; 123: 3739-3749Google Scholar, 34.Hoelzer D. Gökbuget N. Change in prognostic factors.Leukemia. 2012; 1: S1-S2Google Scholar, 35.Bassan R. Hoelzer D. Modern therapy of acute lymphoblastic leukemia.J Clin Oncol. 2011; 29: 532-543Google Scholar]. A practical approach is to bring the conventional prognostic factors and MRD into a decision algorithm. At diagnosis, patients are stratifıed into SR and HR groups, since HR patients are potential candidates for SCT in first complete remission (CR1), and an early donor search is warranted. However, it is not clear how to proceed with HR patients in molCR/molecular remission, although some studies suggest a lack of benefit from SCT in these patients. Also, MRD is not available for all patients, and the risk stratification in those patients should rely on conventional risk factors. Overall, a rapid yet comprehensive diagnostic approach is essential for accurate risk definitions and appropriate risk-related treatment choices (Figure 1). When the diagnosis is established, treatment should start immediately, preferably in a specialised hospital; that is, physicians with experience in the treatment of acute leukaemia, a well-trained nursing staff, sufficient supportive care (e.g. platelet substitution) and access to an intensive care unit. A pre-phase therapy with corticosteroids (usually prednisone 20–60 mg/day or dexamethasone 6–16 mg/day, both i.v. or p.o.) alone, or in combination with another drug (e.g. vincristine, cyclophosphamide), is often given together with allopurinol and hydration for ∼5–7 days. The first intra-thecal therapy for central nervous system (CNS) prophylaxis is administered in this period in some studies. The pre-phase therapy allows a safe tumour reduction, avoiding in most cases a tumour lysis syndrome (TLS) [35.Bassan R. Hoelzer D. Modern therapy of acute lymphoblastic leukemia.J Clin Oncol. 2011; 29: 532-543Google Scholar]. In some cases, rasburicase may be given to prevent TLS. In cases with a very high WBC count (e.g. >100 000/µl), either measure is sufficient, and a leukapheresis is needed only in very rare cases. The time needed for pre-phase therapy will also allow to obtain the results of the diagnostic work-up, e.g. cytogenetics, molecular genetics. The response to pre-phase therapy defines the chemosensitivity of the disease, and is included in some studies for risk assessment, since good responders to prednisone may have a better outcome [36.Annino L. Vegna M.L. Camera A. et al.Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study.Blood. 2002; 99: 863-871Google Scholar]. Supportive therapy should be initiated whenever necessary early on, e.g. to treat infections or to substitute platelets/erythrocytes. Severe neutropaenia ( 80%) during induction therapy, causing infections and infection-related death. A joint analysis of five randomised trials revealed a shorter duration of neutropaenia, and reduction in the rate of febrile neutropaenia in some but not all cases [37.Gökbuget N. Bassan R. Dombret H. et al.Recommendations of the European Working Group for Adult ALL (EWALL).1st edition. UNI-MED Science Verlag,, Bremen2011Google Scholar], and based on that, prophylactic granulocyte colony-stimulating factor should be considered during induction therapy [II, B]. The goal of induction therapy is the achievement of a CR, or even better, a molCR/good molecular response, usually evaluated within 6–16 weeks from start of chemotherapy, after which time the achievement of molCR is rather uncommon. Most regimens are centred on vincristine, corticosteroids, and anthracycline (daunorubicin, doxorubicin, rubidazone, idarubicin), with or without cyclophosphamide or cytarabine. l-Asparaginase is the only ALL-specific drug that depletes the asparagine levels and has been particularly explored in paediatric trials. It is now more intensively used in adults. Pegylated asparaginase (PEG-Asp) has the advantage of a significantly longer period of asparagine depletion. Dexamethasone is often preferred to prednisone, since it penetrates the blood–brain barrier and also acts on resting leukaemic blast cells (LBCs). There are no randomised trials comparing different induction regimens; however, there is a substantial number of large (>100 patients) prospective non-randomised trials. In 6617 patients from 14 studies, the weighted mean for the CR rate was 83% (62%–92%) [35.Bassan R. Hoelzer D. Modern therapy of acute lymphoblastic leukemia.J Clin Oncol. 2011; 29: 532-543Google Scholar]. Using current approaches, the CR rate had increased to 80%–90%, higher for SR patients at ≥90%, and less in HR patients at ∼75%. There is only one randomised study for induction therapy; this compares prednisone to dexamethasone [38.Labar B. Suciu S. Willemze R. et al.Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group.Haematologica. 2010; 95: 1489-1495Google Scholar], demonstrating equal outcome [I, C]. There are two chemotherapy regimens; one is a widespread schema patterned after the paediatric BFM (Berlin–Frankfurt–Münster) protocols with Induction I, Induction II, Consolidation cycles, sometimes an intermittent re-induction cycle, and is mostly used in European adult ALL trials. A schematic treatment algorithm in adult ALL, including diagnosis and risk assessment for achievement of CR and risk-oriented post-remission therapy, is given in Figure 1. Another approach is to repeat two different alternating intensive chemotherapy cycles, identical for Induction and Consolidation, accounting for a total of eight cycles, such as the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) protocol, preferentially used in the United States, but also in other parts of the world. The rationale to use systemic high-dose (HD) therapy is particularly to reach sufficient drug levels in sanctuary sites, such as the CNS. Most protocols employ 6–8 courses which contain either HD methotrexate or HD cytarabine ± asparaginase. HD cytarabine is usually administered for 4–12 doses at 1–3 g/m2 and methotrexate at 1–1.5 g/m2 and up to 3 g/m2. Maintenance therapy usually consists of daily 6-mercaptopurine and weekly methotrexate. In some treatment regimens, repeated cycles of vincristine, dexamethasone or other drugs in monthly or longer intervals are given. In one randomised study, the maintenance arm with reinforcement cycles was not superior to conventional maintenance therapy (37% versus 38% at 8 years) [36.Annino L. Vegna M.L. Camera A. et al.Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study.Blood. 2002; 99: 863-871Google Scholar]. A treatment duration of 2.5–3 years is optimal and is usually recommended. Omission of maintenance worsens outcome s
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