Induction therapy for adults with acute lymphoblastic leukemia

Conclusions The authors believe this therapy is comparable with or better than that used in other studies for adult leukemia, with a higher CR rate and excellent survival. They continue to enroll patients in anticipation of answering questions regarding the relative efficacy of allogeneic and autologous transplant and intensive consolidation maintenance.     

TAD-induction therapy for 175 adults with acute myeloid leukemia, followed by consolidation and maintenance therapy. The joint study of Ulm and Tübingen

175 patients with acute myeloid leukemia were treated between February 1980 and March 1985 with a TAD-induction therapy, three intensified consolidation cycles (COAP, COAP, AD), and a two-year mild maintenance therapy. The median age of the patients was 44 years, range 15-68 years. 62.3% of all patients attained complete remission and 13.7% partial remission. The median duration of remission was 10 months and the median survival time of patients in complete remission was 20 months. Patients older than 50 years had a higher early death rate (17.6) than younger patients (8.9%), but no difference was found in remission rates or in the median duration of remission and of survival. These results are in line with those of comparable studies.     

Nation-wide randomized comparative study of doxorubicin,vincristine and prednisolone combination therapy with and without L-asparaginase for adult acute lymphoblastic leukemia

A randomized clinical trial of combination chemotherapy for adult acute lymphoblastic leukemia (ALL) with doxorubicin, vincristine and prednisolone with and withoutL-asparaginase (AdVP vs L-AdVP) was conducted, involving 58 institutions throughout Japan. After reaching complete remission (CR), patients were treated with the same regimen for more than 2 years. Among 166 evaluable cases of the 198 cases enrolled, CR rates were 63.1% (53/84) with AdVP and 64.6% (53/82) with L-AdVP (P=0.837). Median survival times and 7-year survival rates were 12.7 months and 21.2% with AdVP, and 16.0 months and 22.3% with L-AdVP (P=0.955 by generalized Wilcoxon test [GW],P=0.952 by log-rank test [LR]). Median diseasefree survival times and 7-year survival rates were 13.5 months and 23.8% with AdVP and 17.0 months and 30.6% with L-AdVP, showing some increments for L-AdVP but no statistical significance (P=0.141 by GW,P=0.300 by LR). Among the cases of extramurally confirmed FAB subtypes, CR rates were 75.9% (63/83) for the L1 subtype and 51.3% (39/76) for the L2 subtype (P=0.001). As to adverse effects, pancreatitis was complicated more frequently in L-AdVP than in AdVP (P=0.039). Other side effects such as hyperbilirubinemia, diabetes mellitus, diarrhea and hypofibrinogenemia were observed more frequently with L-AdVP, but with no statistical significance. Thus, addition of a single course of L-asparaginase in the induction phase of combination chemotherapy with doxorubicin, vincristine and prednisolone did not significantly enhance the effect of antileukemic treatment of adult ALL.This work was supported by a grant-in-aid from the Japanese Foundation for Multidisciplinary Treatment of Cancer (Co-operative Project no. 2)     

Induction of acute lymphocytic leukemia differentiation by maintenance therapy.

Despite extensive study in many malignancies, maintenance therapy has clinically benefited only two diseases: acute lymphocytic leukemia (ALL) and acute promyelocytic leukemia (APL). ALL maintenance therapy utilizes low-dose 6-mercaptopurine (6MP) and methotrexate (MTX), while maintenance in APL primarily consists of all-trans-retinoic acid (ATRA). 6MP and MTX as used in ALL are also now usually added to maintenance ATRA for APL, based on data suggesting an improved disease-free survival. Although the mechanism of action of MTX and 6MP as maintenance is unknown, low-dose cytotoxic agents are potent inducers of differentiation in vitro. Thus, we studied whether maintenance therapy in ALL, like ATRA in APL, may be inducing terminal differentiation of ALL progenitors. The APL cell line NB4, the ALL cell lines REH and RS4;11, and patients' ALL blasts were incubated with ATRA, 6MP, and MTX in vitro. All three drugs inhibited the clonogenic growth of the APL and ALL cell lines without inducing immediate apoptosis, but associated with induction of phenotypic differentiation. The three drugs similarly upregulated lymphoid antigen expression, while decreasing CD34 expression, on patients' ALL blasts. These data suggest that induction of leukemia progenitor differentiation plays an important role in the mechanism of action of maintenance therapy in ALL.     

The Münster study of intensive induction and consolidation therapy without maintenance therapy of acute myeloid leukemia. Results of 93 patients--cellular determinants for response and length of remission

A 9-day high-dose 3-drug induction regimen including ARA-C, DNR, and TG at special time sequencing was given to 93 patients with AML, 15-74 (median 52) years old. After 1-2 courses for remission induction and, if possible, 2 identical courses of consolidation, no further therapy was applied during remission. Complete remission (CR) was achieved in 71% of all patients and in 74% of responders by 1 course only. Median remission duration is at 1 year with 13 patients in continuous CR for 13-38 (median 24) months. Patients completing consolidation reached a median remission duration of 22 months and those with rapid response to 1 induction course and with complete consolidation 38+ months. Patients monitoring included bone marrow DNA-histograms by flow cytometry, blood counts, percentage, and absolute number of blasts in bone marrow and LDH in serum. Among pretherapeutic parameters only LDH (inversely) correlated with CR duration. In contrast during early therapy rapid blast reduction, decrease of S-phase-index and of LDH as well as short recovery time of platelets and neutrophils predicted for low risk (when high risk included non-response and early relapse). Thus, monitoring of early cellular response parameters reflecting cellularity and proliferation seems to provide important individual determinants of therapeutic outcome.     

Long-term follow-up of intensive ara-C-based chemotherapy followed by bone marrow transplantation for adult acute lymphoblastic leukemia: impact of induction Ara-C dose and post-remission therapy

We report single institution outcome of brief, intensive ara-C-based chemotherapy using bone marrow transplantation as primary intensification for untreated adult patients with acute lymphoblastic leukemia (ALL). Overall disease-free and overall survival were inferior to those reported with prolonged chemotherapy modeled on pediatric protocols. Survival and disease-free survival were superior for patients receiving allogeneic BMT compared with chemopurged autologous transplant or maintenance chemotherapy (patients ineligible for or declining BMT). In multivariate analysis, non-L2-FAB, higher ara-C dose, absence of CNS disease, non-Ph1+ karyotype, allogeneic BMT, T cell phenotype, and younger age were associated with improved disease-free survival. Autologous BMT was not superior to chemotherapy, and appears unlikely to provide adequate curative treatment for most adult ALL patients if not followed by maintenance.     

Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia.

PURPOSE: Cross-sectional studies show that cardiac abnormalities are common in long-term survivors of doxorubicin-treated childhood malignancies. Longitudinal data, however, are rare. METHODS: Serial echocardiograms (N = 499) were obtained from 115 doxorubicin-treated long-term survivors of childhood acute lymphoblastic leukemia (median age at diagnosis, 4.8 years; median follow-up after completion of doxorubicin, 11.8 years). Results were expressed as z scores to indicate the number of standard deviations (SDs) above (+) or below (-) the normal predicted value. Median individual and cumulative doxorubicin doses were 30 mg/m2 per dose and 352 mg/m2, respectively. RESULTS: Left ventricular fractional shortening was significantly reduced after doxorubicin therapy, and the reduction was related to cumulative dose. z scores for fractional shortening transiently improved before falling to -2.76 more than 12 years after diagnosis. Reduced fractional shortening was related to impaired contractility and increasing afterload, consequences of a progressive reduction of ventricular mass, and wall thickness relative to body-surface area. Left ventricular contractility fell significantly over time and was depressed at last follow-up in patients receiving more than 300 mg/m2 of doxorubicin. Systolic and diastolic blood pressures were below normal more than 9 years after diagnosis. Even patients receiving lower cumulative doxorubicin doses experienced reduced mass and dimension. Fractional shortening and dimension at the end of therapy predicted these parameters 11.8 years later. CONCLUSION: Cardiac abnormalities were persistent and progressive after doxorubicin therapy. Inadequate ventricular mass with chronic afterload excess was associated with progressive contractile deficit and possibly reduced cardiac output and restrictive cardiomyopathy. The deficits were worst after highest cumulative doses of doxorubicin, but appeared even after low doses.     

Short intensive sequential therapy followed by autologous stem cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma.

The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15-64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50-116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81% and partial response (PR) 11% for BL/BLL, CR 73% and PR 20% for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73% for BL/BLL vs 46 and 40% for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.     

An outpatient approach to the delivery of intensive consolidation chemotherapy to adults with acute lymphoblastic leukemia

Consolidation chemotherapy (CT) is important in the curative treatment of acute lymphoblastic leukemia (ALL). This therapy is intensive and toxic. Usually, more than 50% of the treatment period is spent in the hospital. To determine if CT could be given safely as outpatient (OP) treatment, this demonstration project included strict patient selection criteria, a multidisciplinary team, and protocols for teaching, symptom management, and transfusion support. Patients were hospitalized for the first course of CT. A right atrial catheter was placed, and patients were taught use of an ambulatory infusion pump and CT administration. Two patients treated on Southwest Oncology Group protocol 8417/19 have completed CT. No infections occurred, and patients had minimal CT side effects. Both patients experienced neutropenia, an expected complication, for 80 and 56 days. With careful patient selection and expert nursing support, intensive outpatient CT is possible with decreased hospitalizations and morbidity, and possible increased quality of life.     

Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia.

PURPOSE: Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia. EXPERIMENTAL DESIGN: Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification. RESULTS: Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91-100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients. CONCLUSIONS: Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.     

Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy.

BACKGROUND: Relapses continue to be problematic for adults with acute lymphoblastic leukemia (ALL). New therapies generally are first tested in the salvage setting prior to incorporation into frontline regimens. Defining the prognosis at relapse (or at failure of induction) and subsequently predicting outcome would be useful to select the population in whom to test new strategies, rather than attempting traditional reinduction therapy. METHODS: Between March 1980 and March 1997, 314 eligible adults with primary refractory (24%) or primary relapsed (76%) ALL were treated with various chemotherapy or stem cell transplantation (SCT) regimens. The Cox proportional hazards model was used to assess biologic factors and disease history in relation to survival. RESULTS: A complete remission (CR) was achieved in 97 patients (31%), 21% died prior to a response, and 49% were refractory to salvage therapy. Of the 76 patients refractory to induction therapy for their de novo ALL, 26 patients (34%) achieved a CR with salvage therapy. The median overall CR duration was 6 months. The median overall survival was 5 months; 24% of the patients were alive at 1 year, and the projected survival at 5 years was 3%. Nineteen patients were alive at the time of last follow-up, 10 with 6 weeks to 10 years of continuous CR from the time of their first salvage therapy. SCT consolidation in second CR was performed in 25% of patients; 28% of those who received allogeneic SCT remain in continuous CR at 4 months, 2(1/2) years, 3(1/2) years, and 10 years, whereas all 8 who received autologous SCT have relapsed. Favorable factors for longer survival by multivariate analysis were age <40 years, absence of circulating blasts, and first CR duration longer than 1 year. Patients were stratified into 4 risk groups: Group 1, with no unfavorable features or only short initial CR duration; Group 2, with only increased age or peripheral blasts; Group 3, with any 2 unfavorable features; and Group 4, with all 3 unfavorable features. The median survival times for each group were 11, 6, 4, and 2 months, respectively; 1-year survival rates were 44%, 25%, 12%, and 9%, respectively (P < 0.01). The resulting model was also predictive for CR rates; the corresponding CR rates were 47%, 35%, 14%, and 9%, respectively (P < 0.01). CONCLUSIONS: Salvage therapy for adult ALL patients continues to yield poor results, but it is an area of research where it may be possible to discover new agents or strategies to be incorporated into frontline therapy. The prognostic model derived will be utilized prospectively to select patients for new therapeutic strategies involving such novel agents as liposomal compounds, purine nucleoside phosphorylase inhibitors, and monoclonal antibodies.     

A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus three courses of standard-dose consolidation with maintenance therapy in adults with acute myeloid leukemia: the Japan Adult Leukemia Study Group AML 97 Study

BACKGROUND: A major concern in the treatment of patients with acute myeloid leukemia (AML) is how to prevent disease recurrences. Although intensive consolidation therapy has proven useful, the effectiveness of maintenance therapy remains controversial. METHODS: Seven hundred eighty-nine patients ages 15-64 (median: 45 yrs) with de novo AML received induction therapy, which consisted of cytosine arabinoside (at a dose of 100 mg/m(2) on Days 1-7) and idarubicin (at a dose of 12 mg/m(2) on Days 1-3). The patients who achieved complete remission (CR) were then randomized into groups that received either four courses of standard-dose consolidation therapy without maintenance (Arm A) or three courses of standard-dose consolidation and six courses of maintenance therapy (Arm B). RESULTS: In total, 78.7% of patients achieved CR. The 5-year overall survival (OS) rate for the 789 eligible patients was 46.9%, and the disease-free survival (DFS) rate for the 621 patients who achieved CR was 32.9%. The 5-year OS rate for Arm A was 52.4%, and 58.4% for Arm B (P = 0.599). The 5-year DFS rate for the patients who achieved CR was 35.8% in Arm A and 30.4% in Arm B (P = 0.543). In analyzing the data according to the risk groups, no statistical difference was observed either in the 5-year OS rate or in the 5-year DFS rate between the 2 arms. CONCLUSIONS: In the current study, the Japan Adult Leukemia Study Group's conventional postremission therapy (three courses of standard-dose consolidation and six courses of maintenance therapy) was replaced successfully by a shorter duration of four courses of standard-dose consolidation therapy without the need for additional maintenance therapy.     

Reinforced HEAV'D therapy for adult acute lymphoblastic leukemia: Improved results and revised prognostic criteria

Thirty-six adults with acute lymphoblastic leukemia (ALL) were treated with adriamycin, vincristine. prednisolone, and asparaginase for remission induction, followed by vincristine-adriamycin-cyclophosphamide consolidation courses, cranial irradiation, a short ara-C plus VM-26 pulse, and vincristine plus cyclophosphamide rotating weekly with ara-C plus VM-26 for three months (reinforced HEAV'D). Thirty-one patients achieved a complete remission (86 per cent). Compared with historical results from a prior study, age >30 years, absolute blast count >15 × 10⁹/1, and CD10-negative immunophenotype were not associated with higher relapse rate and shorter survival, suggesting a positive effect from intensification therapy with ara-C and VM-26 in these poor prognostic categories. However, patients with an abnormal karyotypic pattern or a positive molecular study for BCR-ABL rearrangement detecting t(9;22) had a far greater likelihood of treatment failure (probability of remission at 3 years 0·10) than those with normal karyotype or negative molecular study (probability 0·70), and those not studied or with insufficient methaphases (probability 0·50) (p<0·05 by log-rank test). These results underline the prognostic importance of chromosomal abnormalities and the usefulness of ara-C and VM-26 in the management of adult ALL.     

Treatment of acute myeloid leukemia with a combination of intensive induction chemotherapy, early consolidation, splenectomy and long-term maintenance chemotherapy

The authors developed a therapeutic regimen in which 33 patients aged 11 to 61 years (mean +/- SE, 35.9 +/- 2.3 years) with acute myeloid leukemia (AML) were given intensive induction chemotherapy with Adriamycin (doxorubicin) (ADM), vincristine (VCR) and cytosine arabinoside (ARA-C). Twenty-nine of these patients (88%) attained a complete remission (CR) after 1, 2, or 3 courses and were then subjected to an early consolidation course of chemotherapy, identical to that for induction. After consolidation, all patients in CR received a long-term continuous maintenance therapy in which 6-mercaptopurine (6-MP) and methotrexate (MTX) were alternated, associated with periodic reinforcements with daunorubicin (DNR) and VCR. Twenty-five of the 29 patients who achieved a CR were splenectomized soon after the consolidation course. Histologic sections of the spleens, liver biopsy specimens, and lymph nodes, stained routinely and with the naphthol AS-D chloroacetate esterase (NCA) method, showed mature granulocytes and a few NCA positive mononuclear cells, but no proved leukemic infiltrates. For the 25 splenectomized patients, the probability of remaining in CR at 36 and 54 months was 75% and 66%, respectively; the probability of survival at 36 and 54 months was 85% and 75%, respectively. Age older than 40 years and evidence of extramedullary involvement at presentation appeared to carry a bad prognosis for disease-free survival.     

达沙替尼一线治疗费城染色体阳性急性淋巴细胞白血病四例并文献复习

目的 探讨二代酪氨酸激酶抑制剂（TKI）达沙替尼一线治疗费城染色体阳性急性淋巴细胞白血病（Ph^＋ALL）的临床疗效.方法 应用达沙替尼一线治疗4例Ph^＋ ALL患者并进行文献复习.结果 4例患者用达沙替尼一线治疗4～6周后均获完全血液学反应（CHR）,其中1例患者已达完全细胞遗传学反应（CCyR）;治疗10～12周后均获完全分子生物学反应（CMR）.1例化疗3个周期未缓解的难治性Ph^＋ALL患者用单药达沙替尼治疗6周后达CHR及部分细胞遗传学反应（PCyR）.4例患者的无进展生存期（PFS）分别为10.5、24.0、8.5、10.0个月.结论 达沙替尼治疗Ph^＋ALL临床疗效显著,可获得深度分子生物学反应,同时耐受性良好,可考虑作为Ph^＋ALL的一线治疗.     

Allogeneic bone marrow transplantation for adult acute lymphoblastic leukemia: a single-centre experience.

Between 1990 and 1997, we performed 29 allogeneic BMTs for acute lymphoblastic leukemia (ALL) patients with HLA-identical sibs. Their median age was 31 years (range 15 to 43); there were 15 males and 14 females. The conditioning protocol was Cy-TBI (n = 15), VP16-Cy-TBI(n = 12), CBV (n = 1) and Bu-Cy (n = 1). Cyclosporin and methotrexate were used for GVHD prophylaxis. The median disease-free survival (DFS) was 12 months (range 1 to 92) with an actuarial 4-years DFS of 42.3 per cent. Three patients died of transplant-related complications before 100 days. Relapse occurred in 11 cases at a median time of 5 months (range 3 to 14). All nine patients relapsing within one year died form resistant leukemia. Three patients died of late treatment-related complications. There were 13 survivors (median follow-up 38 months, range 12-98), with 12 in remission. Only four had limited cGVHD, and all had 100 per cent performance scores. One patient also cleared her chronic hepatitis B carrier status due to acquired immunity. The DFS rates amongst CR1 cases and R1/CR2 cases were comparable (p = 0.39). No long-term DFS is obtained from patients with resistant disease (n = 4). The survival results for BMT at CR1 were superior to those using intensive chemotherapy consolidation (p = 0.29), mainly due to poor late results in the chemotherapy arm. For young ALL patients with HLA-matched siblings, the option of BMT should be considered in light of local consolidation survival 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.