Long-term survival in acute lymphoblastic leukaemia in adults

Abstract: Between November 1983 and January 1987, 51 consecutive previously untreated adults below 65 years of age were treated for acute lymphoblastic leukaemia with LI or L2 morphology. Induction regimen for the first 15 patients consisted of 4 weekly doses of doxorubicin and vincristine, and of asparaginase and prednisolone. Two more doses of doxorubicin and vincristine were given for refractory disease. Next 36 patients received in addition cyclophosphamide on day 1. Consolidation comprised 17 rotating cycles of three regimens. Three intensification cycles were given, and maintenance treatment lasted until 3 years, or relapse. Median follow-up time for living patients is 62 months. 82% of the patients achieved remission. Median relapse-free survival (RFS) was 13 months, and 17% of the patients are in remission at 54 + to 80 + months. Age over 25 yr, a low white blood cell (WBC) count, and a low blast cell count were associated with a longer RFS. Median survival was 24 months, and 33% of the patients lived for 4 yr. Adverse prognostic factors were: age ≤25 of >45 yr, a high WBC count, and a high blast cell count. The results support the policy of concentrating more effort on the initial chemotherapy.     

E-rosette positive acute lymphoblastic leukaemia in adolescents and adults

E-rosetting of leukaemic blast cells is one of the markers of T-cell acute lymphoblastic leukaemia (ALL). In children, E⁺ ALL has a bad prognosis. In adults, data are scarce. This report provides information on 25 E⁺ ALL adult patients who have a minimum follow-up time of 36 months. Twenty-two of 25 patients (88%) achieved complete remission (CR) (median duration 16 months), and six of them were alive, relapse-free, and off therapy after 36–81 months, with a 26% projected 6-year relapse-free survival. In 97 patients with E⁻SmIg⁻ ALL, who were treated at the same Institutions, over the same period of time, and by the same modalities, the outcome of therapy was almost identical: CR 80%, median duration of first CR 15 months, projected 6-year relapse-free survival 15%. The white blood cell (WBC) count at presentation influenced significantly and to the same degree first CR length in both E⁺ and E⁻ cases. In this adult series, WBC count was not as high as in children. Moreover, a high Hb concentration, a very high WBC count, lymphadenomegaly, and mediastinal involvement, were found more frequently in adolescents and young adults than in adults. Based on these data, it is suggested that in adults E-rosetting as such is not a marker of a poorer prognosis, that some of the typical features of children E⁺ ALL weaken with age, and that in adults the disease can have a less aggressive character.     

Treatment of acute lymphoblastic leukemia in adults

Acute lymphoblastic leukemia (ALL) in adults is an uncommon but devastating malignant proliferation of lymphoid precursors. Treatment programs for adult patients are largely based on pediatric regimens. However, cure rates in adults have been limited to 30-40% for the past several decades as opposed to the 80% cure rate in children. Treatment of adolescents and young adults is evolving with the adoption of more aggressive “pediatric-inspired” treatment programs. The role of allogeneic stem cell transplant is first remission remains controversial in spite of recent data suggesting improved outcomes in patients younger than 35. Kinase inhibitors in combination with standard chemotherapy have significantly improved outcomes in ALL associated with the Philadelphia chromosome. The treatment of ALL in the elderly remains challenging. Promising new agents such as nelarabine and clofarabine may improve the outlook. This article reviews the current state of the art for the treatment of ALL in adults.     

Treatment of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified paediatric regimen

Between 2000 and 2006, 85 adult BCR-ABL negative acute lymphoblastic leukaemia (ALL) patients between 18 and 60 years of age were treated using a modified paediatric regimen, which included high doses of asparaginase delivered weekly for 30 weeks during intensification. The complete response rate with induction therapy was 89%, and decreased with increasing age, mainly due to higher induction mortality. All post-induction treatments were delivered on an outpatient basis. The most common complications during intensification were infections (47%), osteonecrosis (32%), venous thromboembolism (23%) and neuropathy (22%). At a median follow-up of 4 years, the 5-year overall survival (OS) and relapse-free survival (RFS) were 63% and 71%, respectively. Significant adverse predictors for OS were age >35 years, high white blood cell count, MLL rearrangement, allogeneic stem cell transplantation in first complete remission and <80% of the planned asparaginase dose delivered during intensification. Patients aged ≤35 years had a 3 year OS of 83%, as compared to 52% for patients aged >35 years. We conclude that the administration of this paediatric regimen is feasible and has considerable activity in adult ALL, particularly in younger patients. Effective delivery of asparaginase dosing appears to be important in achieving an optimal antileukaemic effect.     

Treatment of acute lymphoblastic leukaemia (ALL).

Forty-six consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 23 years (range 14 to 64), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard central nervous system (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate, and monthly intrathecal chemotherapy, with drug intensification comprising either vincristine, adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was achieved in 36 patients (78%) and only the FAB L1 morphology was a significant predictive factor (Chi-squared = 3.91: p < 0.05). Eight of the 10 non-responders had significant drug resistance and 3 deaths were associated with marrow hypoplasia. Median follow-up is 52 months. Median duration of CR is 28 months, median survival of all patients is 16 months, and for those who achieved CR is 44 months. There was no difference between the two maintenance arms. Significant prognostic factors for survival are French-American-British (FAB) subtype, in which the L1 is better than L2 (p = 0.05), and age (p = 0.035). Nineteen patients have experienced medullary relapse and 7 (37%) achieved subsequent CR; this is durable in a single patient who underwent allogeneic bone marrow transplantation. Eight patients (17%) had CNS disease at diagnosis; 5 achieved CR and 1 is alive and disease-free at 65+ months. There has been 1 CNS relapse. These results demonstrate that prolonged remissions and survival can be achieved with this protocol and many patients possibly cured. The level of toxicity is acceptable and the pattern of induction failure indicates that a margin exists for intensifying chemotherapy and thereby possibly further improving results.     

Granular common acute lymphoblastic leukaemia in adults: a morphological study

2 cases of acute lymphoblastic leukaemia characterised by the presence of cytoplasmic inclusions morphologically similar to azurophil granules are described. Azurophil granulation of blasts is one of the cardinal features which differentiate acute myeloid from acute lymphoblastic leukaemia. Although such granulation of lymphoblasts has caused diagnostic confusion in the past, we found that the granules could be distinguished from myeloid azurophil granules both morphologically and by their characteristic cytochemical staining reactions. They were negative for peroxidase/sudan black and chloroacetate esterase, but gave coarse scattered granular positivity for both acid phosphatase and alpha-naphthyl acetate esterase. Both the electron microscopic appearance of the granules and their cytochemical staining reactions suggested that they were lysosomes. Granular ALL does not appear to be associated with any morphological subtype or karyotype; but is strongly associated with the common ALL phenotype. Its prognostic significance remains uncertain. It occurs more frequently than the small number of previous reports might suggest and, given the potential for misdiagnosis, should be more widely recognised.     

Management of osteonecrosis in children and young adults with acute lymphoblastic leukaemia

Osteonecrosis is a disabling complication in children and young adults with acute lymphoblastic leukaemia. It can affect any or multiple joints but the hip and knee are most frequently involved and a cause of long-term disability. The problem is almost exclusively that of older children and young adults of whom over 70% have asymptomatic changes on screening magnetic resonance imaging and 15-20% have resulting symptoms. Dexamethasone is associated with a higher risk than prednisolone in US but not European or UK trials and alternate week scheduling of dexamethasone in the intensification course is associated with a lower risk than a continuous 3-week schedule in US trials. Genetic factors and obesity contribute to the risk, as do metabolic abnormalities caused by drugs, such as asparaginase, which increase tissue exposure to steroids. Management is primarily supportive but a minority of patients require surgical intervention including replacement of the affected joint. A variety of surgical techniques and, latterly, bisphophonates, have been tried to prevent progression but their efficacy remains uncertain. Whether patients should continue to receive steroids after diagnosis of osteonecrosis is uncertain but most trial investigators recommend stopping them after completion of the intensification phase of treatment.     

Adult acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia (ALL) in adults is a relatively rare neoplasm with a curability rate around 30% at 5 years. This consideration makes it imperative to dissect further the biological mechanisms of disease, in order to selectively implement an hitherto unsatisfactory success rate. The recognition of discrete ALL subtypes (some of which deserve specific therapeutic approaches, like T-lineage ALL (T-ALL) and mature B-lineage ALL (B-ALL)) is possible through an accurate combination of cytomorphology, immunophenotytpe and cytogenetic assays and has been a major result of clinical research studies conducted over the past 20 years. Two–three major prognostic groups are now easily identifiable, with a survival probability ranging from <10 to 20% (Philadelphia-positive ALL) to about 50–60% (low-risk T-ALL and selected patients with B-lineage ALL). These issues are extensively reviewed and form the basis of current knowledge. The second major point relates to the emerging importance of studies that reveal a dysregulated gene activity and its clinical counterpart. It is now clear that prognostication is a complex matter ranging from patient-related issues to cytogenetics to molecular biology, including the evaluation of minimal residual disease (MRD) and possibly gene array tests. On these bases, the role of a correct, highly personalised therapeutic choice will soon become fundamental. Therapeutic progress may be obtainable through a careful integration of chemotherapy, stem cell transplantation, and the new targeted treatments with highly specific metabolic inhibitors and humanised monoclonal antibodies.     

Treatment of older adults with acute promyelocytic leukaemia

Only 15 to 20% of acute promyelocytic leukaemia (APL) patients are older than 60 years, and the characteristics and outcome of APL in that age range are not well known. Published studies show that APL in elderly patients has haematological features similar to those of APL in younger patients. However, using the current combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy, the outcome for these patients, although it has much improved, remains less favourable than that for younger patients. This is due to a higher incidence of early deaths and deaths in complete remission (CR), during consolidation chemotherapy courses, whereas the relapse rate appears similar in older and younger adults.Treatment approaches with more limited myelosuppression, especially consolidation chemotherapy with an anthracycline alone (without Ara-C), low-dose maintenance treatment with 6-mercaptopurine, methotrexate and ATRA, and consolidation with arsenic trioxide, should be tested especially in elderly patients in order to replace more toxic 'classical' anthracycline-Ara-C consolidation treatment, after achieving CR with ATRA.     

Thrombosis and acute lymphoblastic leukaemia

Venous thrombosis is more frequent in patients treated for acute lymphoblastic leukaemia (ALL) than other malignancies and has distinctive causes, clinical features and remedies. The reported incidence varies from 1% to 36%, depending on the chemotherapy protocol and whether the reported cases are symptomatic or detected on screening radiography. The risk is thought to arise from increased thrombin generation at diagnosis combined with reduced thrombin inhibitory capacity due to depletion of circulating anti-thrombin (AT) by asparaginase. A number of patient and treatment variables have been reported to influence the risk of thrombosis including hereditary thrombophilia, early insertion of central venous catheters and exposure to a combination of steroids and asparaginase during induction. Erwinia asparaginase is associated with a lower risk of thrombosis compared with Escherichia coli asparaginase. The majority of symptomatic thromboses are related to central venous catheters and involve the upper venous system. Central nervous system thrombosis involving the cerebral venous sinuses is a unique feature of asparaginase-related thrombosis and is reported to occur in 1-3% of patients. Conclusive evidence to support the use of anti-coagulant treatment or AT concentrates for primary prevention is lacking, as is evidence for the efficacy of AT concentrates in the management of established thrombosis. Preventative strategies are hampered by conflicting data on factors that would enable identification of those at highest risk of thrombosis.     

Children and adults with acute lymphoblastic leukaemia have similar gene expression profiles

OBJECTIVES: To compare the gene expression pattern in children and adults with acute lymphoblastic leukaemia (ALL) in order to improve our understanding of the difference in disease biology and prognosis. METHODS: The gene expression profiles in diagnostic samples from 29 children and 15 adults with ALL were analysed using the oligonucleotide chip Hu95ver2a, produced by Affymetrix. RESULTS: Unsupervised hierarchical cluster analysis revealed that, in spite of differences in outcome, patients clustered irrespective of age, first by T-cell or B-precursor immunophenotype, and second by cytogenetic changes within the B-precursor group. The expression pattern analysis allowed the reclassification of some samples into the proper cytogenetic group. We also showed that separate clustering of samples with the BCR/ABL translocation could be explained by different breakpoint regions in the BCR. No significant difference in gene expression was observed between samples with and without CDKN2A deletion within the B-precursor group. Analysis of different age groups revealed a similarity in expression profiles when infants with the MLL translocation and adults over 40 yr of age were compared irrespective of karyotype. CONCLUSIONS: In spite of the difference in clinical outcome, the gene expression pattern in children and adults with ALL is very similar and is primarily dependent on immunophenotype and cytogenetic aberrations. However, when age groups are compared, the expression patterns of infants and adults over 40 show a remarkable similarity.     

Morphological and cytochemical findings in 150 cases of T-lineage acute lymphoblastic leukaemia in adults

We evaluated the morphological findings in 150 consecutive cases of T-lineage acute lymphocytic leukaemia (T-ALL). Cytochemistry including PAS staining and acid phosphatase reaction proved of limited value for the diagnosis of ALL.
The diagnosis of acute leukaemia was easy to establish in most instances. However, in a few cases the leukaemic cells were difficult to recognize as blasts. The nuclei of such cells showed condensed chromatin and nucleoli were lacking, and was encountered particularly in thymic ALL.
Basophilic cytoplasm combined with prominent vacuolization suggestive of mature B-ALL (ALL-L3 type), was observed in 16 cases. Other features, however, such as cell size, polymorphism, chromatin structure, sparse cytoplasm or focal positivity for acid phosphatase, excluded a diagnosis of ALL-L3 in those cases.
Distinction from hybrid leukaemia was difficult in 20 cases, because of a low percentage of peroxidase-positive blasts or other features which suggested a separate myeloid leukaemia component. In nine of these the hybrid nature of the leukaemia was considered as certain on the basis of morphology. Seven cases had been diagnosed as biphenotypic with coexpression of myeloid and lymphoid markers by immunological techniques.
In conclusion, our analysis showed some serious pitfalls of the morphology in T-ALL, clearly indicating the need for immunological analysis of the leukaemic cells. However, morphology remains an essential component of the diagnostic repertoire, especially when the marrow is difficult to aspirate and in cases with equivocal immunological findings. Furthermore, recognition of a separate myeloid leukaemic component in addition to the lymphatic one requires a morphological analysis.     

Treatment of relapsed/refractory acute myeloid leukaemia in adults

The prognosis of relapsed acute myeloid leukaemia (AML) is poor and treatment is challenging. While the most potent treatment modality for patients who achieve a complete remission after relapse is still allogeneic haematopoietic cell transplantation (allo‐HCT), both transplant‐related mortality and relapse rates are high and many patients are not candidates for this approach. After a few decades of relative stasis in this field, a large number of novel approaches have become available to tackle this highly fatal disease. This is mostly due to our improved understanding of disease pathogenesis (including targetable mutations) and the anti‐leukaemia potential of the immune system. Several small‐molecule inhibitors and immunotherapeutic options are being explored in clinical trials and many more are in pre‐clinical phase. Future studies will focus on novel and mechanistically driven combinations, sequential treatments, and low‐toxicity maintenance strategies. While cure of relapsed/refractory AML without allo‐HCT is currently unlikely, treatments are becoming less toxic and remissions are lasting longer.     

Long-term outcome of ph-negative acute lymphoblastic leukaemia in adults: a single centre experience

BACKGROUND AND OBJECTIVES: In adult acute lymphoblastic leukaemia (ALL), unlike in childhood ALL, the percentage of long-term remitters and survivors has not improved significantly over the last decades. In the present analysis, we describe a series of adult ALL patients consecutively treated with the same regimen in order to analyse prognostic factors and treatment outcome as well as to define new risk-oriented strategies. DESIGN AND METHODS: From 1990 to 1998, 102 newly diagnosed ALL patients were referred to our division, 83 of them were eligible for the present study. Median age was 31 years (range 13-76); 77.1% had B-lineage ALL and 22.9% T-lineage ALL; 36.1% showed associated myeloid markers. All patients received an induction phase treatment, consisting of a 4-week cycle with vincristine, daunorubicin, L-asparaginase and desametasone; the consolidation phase included cyclophosphamide, cytarabine, 6-mercaptopurine and central nervous system (CNS) prophylaxis, followed by three of months maintenance (methotrexate + 6-mercaptopurine), re-induction (4-week cycle with vincristine, adriamicin, desametasone), and 2-year maintenance with methotrexate + 6-mercaptopurine. RESULTS: Complete remission (CR) was achieved in 66 patients (79.5%); 20.5% of patients were resistant. The relapse rate was 60.2%. There were 10 CNS relapses (accounting for 12% of all patients, 15% of all CRs and 20% of all relapses). One patient had an ovarian and 2 had a breast relapse. Eleven patients remained in first continuous CR after chemotherapy. Median overall survival (OS) and disease-free survival (DFS) were 1.8 and 1.0 years, respectively, with a median follow-up of 5.6 years (range 0.3-12.1). Initial white blood cell count 相似文献