Multi-agent combination chemotherapy for adult acute lymphoblastic leukemia--individualized chemotherapy

Eighteen adults with acute lymphoblastic leukemia (ALL) including 14 previously untreated and 4 relapsed cases were treated with individualized and intensified induction and post-remission therapy. CNS prophylaxis was performed with i. th. methotrexate alone and started early during induction. All patients achieved complete remission. In a median follow up of 65 weeks, 2 yr-disease free survival (DFS) rate was 73.5 +/- 13.0% in previously untreated patients. This treatment program has resulted in markedly improved remission rate and DFS in adults with ALL.     

Dose-intensive therapy for adult acute lymphoblastic leukemia

Major challenges remain to be overcome to increase the cure rate for acute lymphoblastic leukemia (ALL), especially for middle-aged and older adults. Despite high rates of complete remission (CR), many patients relapse after chemotherapy alone. Dose-intensive therapy and stem-cell transplantation (SCT) have been able to rescue some of these patients. However, many patients presently are being cured using intensive consolidation chemotherapy during first remission (CRI) and at a lower cost and toxicity than with SCT. The use of SCT in CRI should be governed by an assessment of known risk factors. Among younger adults in the prime transplant age group (< 50 years), there is no advantage to allogeneic (allo)-SCT across the board, but it is recommended for those with Philadelphia chromosome-positive (Ph+) ALL or pro-B ALL with t(4;11) and possibly for those with B-lineage ALL and initial WBC counts > 100,000/microL. There is as yet no evidence that allo-SCT can improve the already high cure rate achieved with chemotherapy alone in favorable subsets such as T-cell ALL. There appears to be no advantage to autologous (auto)-SCT over chemotherapy for consolidation of either high-risk or standard-risk patients in CRI. The argument that early use of auto-SCT shortens the duration of treatment and thereby improves the quality of life is not persuasive, as there is little morbidity from maintenance chemotherapy. Patients who receive a modern, intensive multiagent chemotherapy program for CRI but later relapse are unlikely to be cured with additional chemotherapy alone. High-grade multidrug resistance develops rapidly. These patients should undergo allo-SCT if possible. Unfortunately, allo-SCT is available to only a minority of such patients because of the lack of a donor or insurance coverage, or the presence of comorbid conditions or older age. The use of alternative donors (either matched, unrelated donors or partially human leukocyte antigen [HLA] matched family members) is appropriate in this circumstance. Auto-SCT with or without previously used purging methods is ineffective for patients with advanced ALL.     

成年人急性淋巴细胞白血病方案优化与分层治疗

 儿童急性淋巴细胞白血病（AML）疗效在不断改善,而成年人ALL疗效一直没有大的改观。临床上很多危险因素影响其预后,其中最重要的是早期对治疗的反应。儿童ALL的方案与成年人方案相比采用了更大剂量的左旋门冬酰胺酶、激素和长春碱,采用儿童方案可以改善成年人ALL的预后。对于Ph+ ALL、CD+20 ALL联合靶向治疗有助于提高患者长期生存。异基因造血干细胞移植仅适用于高危、复发难治性ALL。     

成年人急性淋巴细胞白血病方案优化与分层治疗

儿童急性淋巴细胞白血病(AML)疗效在不断改善,而成年人ALL疗效一直没有大的改观.临床上很多危险因素影响其预后,其中最重要的是早期对治疗的反应.儿童ALL的方案与成年人方案相比采用了更大剂量的左旋门冬酰胺酶、激素和长春碱,采用儿童方案可以改善成年人ALL的预后.对于Ph+ALL、CD+20ALL联合靶向治疗有助于提高患者长期生存.异基因造血干细胞移植仅适用于高危、复发难治性ALL.     

Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia.

PURPOSE: To evaluate response and outcome with a front-line intensive multiagent chemotherapy regimen in adults with Burkitt's-type acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS: From September 1992 to June 1997, 26 consecutive adults with newly diagnosed untreated B-ALL received hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD). Their median age was 58 years (range, 17 to 79 years), and 46% were > or = 60 years. Patients received Hyper-CVAD alternated with courses of high-dose methotrexate and cytarabine. Granulocyte colony-stimulating factor and prophylactic antibiotics were administered for all eight planned courses. CNS prophylaxis alternated intrathecal methotrexate and cytarabine on days 2 and 7 of each course. RESULTS: Complete remission (CR) was obtained in 21 patients (81%). There were five induction deaths (19%). The median time to CR was 22 days (range, 15 to 89 days); 70% achieved CR within 4 weeks. The 3-year survival rate was 49% (+/- 11%); the 3-year continuous CR rate was 61% (+/- 11%). Twelve CR patients (57%) were in continuous CR at a median follow-up of 3+ years (range, 13+ months to 6.5+ years). Characteristics predicting for worse survival were age > or = 60 years, poor performance status, anemia, thrombocytopenia, peripheral blasts, and increased lactate dehydrogenase level. The 3-year survival rate was 77% for 14 patients younger than 60 years and 17% for 12 patients > or = 60 years (P <.01). Regression analysis identified older age, anemia, and presence of peripheral blasts as independent factors associated with shorter survival. Patients could be stratified according to (1) no or one adverse feature, (2) two adverse features, and (3) all adverse features. The 3-year survival rates were 89%, 47%, and 0%, respectively (P <.01). CONCLUSION: Hyper-CVAD is effective in adult B-ALL. Identification of patients with high risk for relapse and improved methods to detect residual disease may result in risk-oriented approaches.     

Myeloid surface antigen expression in adult acute lymphoblastic leukemia.

The expression of myeloid surface markers was investigated in 41 cases of untreated adult acute lymphoblastic leukemia (ALL). Nineteen cases (46%) reacted with at least one myeloid monoclonal antibody (CD15 in 16 cases, CD13 in 10 cases, CD14 in five cases, and CD33 in four cases). Double-staining confirmed the coexpression of myeloid and lymphoid markers. In addition, 35 samples were tested for CD34 expression. Fourteen of the 17 myeloid-positive cases tested were positive for CD34 vs. eight of 18 negative cases (p less than 0.05). A t(9;22) translocation was found in eight cases, and a t(4;11) translocation in two cases, all expressing CD34 and myeloid antigens. These findings confirm the high frequency of myeloid markers on the surface of adult ALL blasts, and suggest that these leukemias may originate in a poorly differentiated precursor cell with mixed differentiation capacities.     

Anthracycline dose intensification in adult acute lymphoblastic leukemia

BACKGROUND:

In previous studies of frontline therapy for adult acute lymphoblastic leukemia (ALL), early treatment with higher doses of anthracyclines has been reported to improve outcome. The current study was conducted to evaluate whether addition of anthracycline‐based consolidation chemotherapy (Course 2) with liposomal daunorubicin (150 mg/m² intravenously [IV] on Days 1 and 2) and cytarabine (1.5 g/m² IV on Days 1 and 2) to the standard hyper‐CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and cytarabine) would improve outcome.

METHODS:

Sixty‐eight consecutive adults with de novo ALL or lymphoblastic lymphoma were treated with this modified hyper‐CVAD regimen inclusive of rituximab for CD20 expression ≥20%.

RESULTS:

Sixty‐three (93%) patients achieved complete response (CR). With a median follow‐up of 90 months, the 5‐year CR duration (CRD) and overall survival (OS) rates were 46% and 44%, respectively. Compared with 208 patients treated with standard hyper‐CVAD (rates of 45% and 47%, respectively; P = not significant), outcome with the modified hyper‐CVAD regimen was not improved overall. Outcome was improved by the addition of rituximab for the CD20‐positive subset (rates of CRD and OS of 50% and 53%, respectively), whereas anthracycline intensification worsened outcome for the CD20‐negative subset (rates of CRD and OS of 41% and 35%, respectively; P = .01) compared with standard hyper‐CVAD. A high mortality rate related to infections in CR was noted among patients aged 60 years or older.

CONCLUSIONS:

In the context of the hyper‐CVAD regimen, early anthracycline intensification did not improve outcome for adults with de novo ALL or lymphoblastic lymphoma. Cancer 2010. © 2010 American Cancer Society.     

The biology and therapy of adult acute lymphoblastic leukemia

BACKGROUND: Much progress has been made in understanding the biology of acute lymphoblastic leukemia (ALL). This has translated into the recognition of several subgroups of ALL and the institution of risk-adapted therapies. New therapies are emerging based on the definition of specific cytogenetic-molecular abnormalities. METHODS: A review from the English literature, including original articles and related reviews from Medline (Pubmed) and abstracts based on publication of meeting material, was performed. RESULTS: Changes in the pathologic classification of ALL have led to therapeutic consequences. Adaptation of successful treatment strategies in children with ALL has resulted in similar complete response rates in adults. Prognosis has especially improved in mature-B-cell and T-lineage ALL. The role of tyrosine kinase inhibitors in Philadelphia chromosome-positive ALL was evaluated in the current study. However, regardless of the ALL subgroup, long-term survival of adults is still inferior to that in children. CONCLUSIONS: Intense clinical and laboratory research is attempting to close the gap in outcome between children and adults with ALL. Investigations are focusing on 1) refinement of the basic treatment stratagem of induction, consolidation, and maintenance; 2) expansion of risk-based, subgroup-oriented therapies; 3) assessment of minimal residual disease, its impact on disease recurrence, and its practical implications in clinical practice; 4) salvage strategies; 5) the role of stem cell transplantation in ALL; and 6) the development of new drugs based on a better understanding of disease biology.     

Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) represents the most common cytogenetic abnormality in adult ALL. It is found in 15% to 30% of patients, and its incidence increases with age. As in children, prognosis in Ph-positive adult ALL is poor. No therapeutic approach has had substantial impact on its unfavorable course. We analyzed the characteristics and outcome of newly diagnosed adults with Ph-positive ALL treated at the M. D. Anderson Cancer Center between 1980 and 1997. The diagnosis of patients was based on typical morphological and immunophenotypic criteria of marrow aspirate and biopsy specimens. Cytogenetic and molecular studies were also performed. A total of 67 patients were included in this study. From 1980 until 1991, 38 patients with Ph-positive ALL were treated with vincristine, Adriamycin, and dexamethasone (VAD), or with acute myeloid leukemia (AML)-like induction protocols. Since 1992 a total of 29 patients received induction therapy with an intensified treatment protocol, called "hyper-CVAD". The outcome of patients treated with standard and intensified treatment regimens was compared and results of our institution contrasted with data obtained from other centers. Ph-positive ALL was present in 67 of 498 patients with newly diagnosed ALL (13%). Patients with Ph-positive ALL had a higher median age (44 versus 34, P=0.007), higher median white blood cell (WBC) counts at presentation (25 versus 8, P=0.0002), and higher peripheral median percentage of blast counts (63 versus 40, P=0.023). FAB subtype L2 (70% versus 49%, P=0.001) and CALLA-positive pre-B immunophenotype (75% versus 37%, P<0.001) predominated among Ph-positive ALL. Myeloid marker coexpression was more frequent in Ph-positive ALL when compared with Ph-negative ALL (52% vs. 27% for CD13, P<0.001, and 44% vs. 27% for CD33, P=0.005). Among patients treated with hyper-CVAD, the complete remission (CR) rate was 90% versus 55% (P=0.002) with pre-hyper-CVAD regimens (VAD and AML-like induction protocols), the median CR duration was 43 weeks versus 32 weeks (P>0.5), median disease-free survival (DFS) was 42 weeks versus 29 weeks (P=0.008), and median survival was 66 weeks versus 45 weeks (P>0.5). Patients with hyperdiploid Ph-positive ALL on hyper-CVAD therapy achieved significantly longer CR duration and DFS than hypo- and pseudodiploid cases (59 weeks versus 42 and 31 weeks, P=0.02 and 0.04, respectively). In contrast, patients treated with regimens prior to hyper-CVAD had significantly shorter CR duration (21 weeks versus 33 and 29 weeks, P=0.03) and DFS with hyperdiploid karyotypes when compared to pseudodiploid and hypodiploid cases (16 weeks versus 30 and 13 weeks, P=0.008). In conclusion, our results demonstrate improved response rate and DFS with current intensive regimens (hyper-CVAD) in patients with Ph-positive ALL, but no advantage in overall survival.     

Current therapeutic strategies in adult acute lymphoblastic leukemia

Approximately half of all adults with acute lymphoblastic leukemia now survive long term. This article summarizes the current approaches to treating acute lymphoblastic leukemia in adults, with a focus on a pragmatic approach to decision making. Coupled with a particularly punishing and often complex combination chemotherapy treatment regimen, treatment-related morbidity and mortality are frequent, and this article focuses on these situations. The field will change significantly over the next few years with many ongoing clinical studies and molecular insights which will be translated into providing prognostic information and novel therapeutic targets.     

Expression pattern of hybrid phenotype in adult acute lymphoblastic leukemia.

We examined the expression of hybrid phenotype in 236 adults with acute lymphoblastic leukemia (ALL; 188 B-lineage ALL and 48 T-lineage ALL). In B-lineage ALL, myeloid antigen (mAg) CD15 was concentrated in CD10-CD20- cases (49%); CD13 (42%); and CD33 (43%) in CD10+CD20- cases. This trend had no correlation with the presence of Ph1 or t(4;11) chromosomal abnormality. T-cell antigen CD2, CD4, and CD7 was seen in four, four, and two cases, respectively, and CD4+ and CD7+ cases commonly expressed CD13 and/or CD33 (CD13/CD33). In T-lineage ALL, expression of mAg, CD11b (47%), CD13 (38%), CD15 (28%), and CD33 (51%) was restricted to CD3- cases. B-cell antigen CD19 was found in two cases with CD7 solely as T-cell antigen, and these cases possessed CD13/CD33. CD21 was detected in three cases with CD3. In whole ALL, CD13/CD33 was associated closely with the presence of stem-cell antigen CD34, and in T-lineage ALL, CD13/CD33 had a significant correlation with additional stem-cell features, such as HLA-DR, multidrug resistance 1 (MDR1) and c-kit gene expression. Our results suggest that immature ALL cells frequently express B+M+, T+M+, and occasionally B+T+M+ phenotype; that B+T+M- phenotype is extremely rare; and that mAg expression in B-lineage ALL is complicated as compared to T-lineage ALL.     

Prognostic factors and outcome of therapy in adult acute lymphoblastic leukemia.

We conducted a ten-year review of our patients of adult acute lymphoblastic leukemia. Most patients received vincristine and prednisone for induction. Twenty-four patients additionally received doxorubicin. Serious pretreatment morbidity included intracerebral haemorrhage (8 patients), septicaemia (22 patients), pneumonia (8 patients) and CNS leukemia (3 patients). Our complete remission (CR) rate was 41%, predicted median duration of remission was 20.8 months and predicted median duration of overall survival was 10.4 months. Significantly higher CR rates were observed for lower age, female sex and lesser degrees of haemorrhage and infection. High initial WBC count was the only adverse prognostic factor for remission duration. Survival was significantly inferior for nonresponders, age greater than 20 years, and severe haemorrhage and infection. Remission attainment remains the chief obstacle to enhancing overall survival in adult acute lymphoblastic leukemia. However responders often experience years of good quality life.     

Multiagent chemotherapy in relapsed acute lymphoblastic leukemia in children

Twenty-seven evaluable children with early first bone marrow relapse of acute lymphoblastic leukemia were treated with an intensive induction/consolidation and ongoing maintenance therapy. Induction therapy consisted of a 35-day course of daunomycin, vincristine, and prednisone, immediately followed by teniposide, cytosine arabinoside (Ara-C), and L-asparaginase. Intrathecal methotrexate, hydrocortisone, and Ara-C were given through the induction/consolidation phase. Twenty-three of 27 patients achieved remission by the end of induction/consolidation. Maintenance with the same drugs in a modified dosage schedule continued for approximately 2 years. A small subgroup of patients who were M3 at day 35 but M1 at day 56 (end of induction/consolidation) and had a cumulative event-free survival (EFS) of only 0.40 at 6 months, all had relapsed by 15 months. However, the EFS for M1 patients by day 35 and maintained on chemotherapy was 0.64 at 12 months and 0.32 at 30, 36, and 48 months, respectively. Although good reinduction and remission duration rates at 12 to 24 months were achieved and an apparent plateau in survival occurs at 30 months, fall-off in survival would not be unexpected with probably less than 20% alive after 5 years.     

Recovery of blood B-lymphocytes and serum immunoglobulins after chemotherapy for childhood acute lymphoblastic leukemia.

Recovery of humoral immunity after cessation of chemotherapy for childhood acute lymphoblastic leukemia (ALL) was investigated by determining blood leukocyte, lymphocyte and B-lymphocyte, and serum immunoglobulin (Ig) levels and IgG subclasses at 0, 1, 3, 6, 9, and 12 months after cessation of chemotherapy for ALL in 14 patients. Blood B-lymphocytes were analyzed with the use of flow cytometry and monoclonal CD20 antibody. At cessation of chemotherapy, the amount of blood B-lymphocytes was subnormal in most patients but increased to normal levels in 1 month after therapy was discontinued. The recovery of serum Ig, which reflect B-cell function, was slower, but occurred by 6 months after therapy was discontinued in most patients. The authors conclude that by 6 months after cessation of chemotherapy for ALL, a sufficiently functioning immune system by these parameters is established and that prophylactic antibiotics can be withdrawn and immunizations started.     

Methotrexate and asparaginase combination chemotherapy in refractory acute lymphoblastic leukemia of childhood.

Two groups of children with refractory acute lymphoblastic leukemia were treated with a regimen of methotrexate (MTX) and asparaginase (Asn'ase) based on studies of the effect of MTX in vitro on human lymphoblasts exposed to Asn'ase. Induction therapy in 12 children produced 4 complete remissions, 3 partial remissions, and 5 failures. Responsiveness to Asn'ase seemed necessary for successful induction with the drug combinations. Maintenance therapy in 18 children produced a median hematologic remission of 31 weeks (range 3-85 weeks). During remission, 2 children developed central nervous system leukemia and 2 died of infection. The mean maximally tolerated dose of MTX was 361 mg/m2. The results of this trial suggest therapeutic synergy in maintenance therapy and the capability of Asn'ase to attenuate MTX toxicity.     

改良的德国多中心成年人急性淋巴细胞白血病研究组方案临床应用研究

 目的　分析改良的德国多中心成年人急性淋巴细胞白血病研究组（GMALL）方案治疗成年人急性淋巴细胞白血病（ALL）的疗效和安全性。方法　2005年1月至2009年12月共37例新诊断的ALL患者,接受改良的GMALL方案单纯化疗,对其进行回顾性分析,并与同期接受该院常规方案治疗的44例成年ALL患者进行对比分析。结果　改良GMALL方案的累积完全缓解（CR）率为89.2 %（33／37）,1、2、3及4年累积总生存（OS）率分别为77.5 %、48.0 %、40.0 %和40.0 %。主要不良反应为3～4级血液学毒性和感染,不良反应易于控制,治疗相关死亡率低。改良GMALL方案组的OS优于该院常规方案组。结论　改良的GMALL方案治疗成年人ALL疗效满意,不良反应可以耐受,值得临床推广。