Monitoring Of High-Dose Methotrexate (Mtx)-Related Toxicity and Mtx Levels in Children with Acute Lymphoblastic Leukemia: A Pilot-Study in Indonesia

The administration of high-dose methotrexate (HD-MTX) requires an accurate monitoring of blood MTX levels to determine the regimen of leucovorin rescue and urine alkalinization to prevent toxicity. However, it is technically and logistically challenging to screen patients routinely in limited-resource settings. This study aimed to evaluate blood MTX levels at 24- and 48-hours from start of infusion in relation to clinical toxicity in childhood ALL. Methods: A prospective cohort study was conducted on 32 consecutive children with acute lymphoblastic leukemia (ALL) who had received at least one cycle of 1 g/m2 HD-MTX intravenous infusion as a part of consolidation treatment based on the 2013 Indonesian ALL Protocol. In total, 68 cycles were evaluated. Serum MTX concentrations were measured using enzyme immunoassay. MTX toxicity was categorized using common toxicity criteria (CTCAE) 3.0 version. The association between MTX level and clinical toxicity was assessed by non-parametric analysis. Results: The 24-hours MTX level was median 29.8 ng/mL (0.065 µmol/L) (IQR 8.1–390.6) with a modest decrease in 48-hours MTX serum level in all cycles (median 28.3 ng/mL and 0.062 µmol/L; IQR 0.35–28.7; p <0.05). The two most common toxicities were hepatotoxicity (32.2%) and neutropenia (30.9%). Nephrotoxicity and febrile neutropenia occurred in 8.8% and 5.8% of patients, respectively, with low percentage of mucositis (4.3%) and thrombocytopenia (5.6%) recorded.  No statistically significant association was found between MTX levels and clinical toxicity, except for liver toxicity.Conclusion: Serum MTX levels at 24-hours and 48-hours are low, followed by only 4.4% grade III/IV hepatotoxicity and 26,4% grade III/IV neutropenia. There is no significant association between the clinical toxicity and MTX levels at the two points of measurement. An attempt to increase the MTX dose and/or to introduce a loading dose should be considered in subsequent ALL protocol as supported by further pharmacokinetic MTX studies in the Indonesian population.     

Treatment of isolated testicular relapse in childhood acute lymphoblastic leukemia: an Italian multicenter study. Associazione Italiana Ematologia ed Oncologia Pediatrica

Between May 1980 and April 1987, 49 children with acute lymphoblastic leukemia (ALL) in isolated testicular and first leukemia relapse (ITR) were enrolled in the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) multicenter study REC80-ITR. According to the Rome Workshop criteria, 77% were at standard and 23% at high initial prognostic risk. In 33% of the cases, ITR occurred during first treatment. The REC80-ITR protocol consisted of an induction phase regimen of vincristine (VCR), cytarabine (ARA-C), methotrexate (MTX), and asparaginase (L-asp), and bilateral testicular irradiation, and CNS prophylaxis with intrathecal MTX and a maintenance phase with a multidrug rotating regimen. Total treatment duration was 30 months. The median time of observation after ITR was 51 months. The Kaplan-Meier estimates of survival and disease-free survival (DFS) at 4 years were 67.7% and 41%, respectively. Patients who had an ITR on therapy or within the first off-therapy year showed the poorest outcome. The DFS at 3 years was 20%, 47.6%, and 100%, respectively, for children who had an ITR on treatment (n = 16), within the first year of treatment withdrawal (n = 22), or later (n = 10) (P = .001). Patients with an asymptomatic occult testicular infiltrate at treatment discontinuation had a very unfavorable prognosis. Eighty-one percent of second relapses involved the bone marrow. In our experience, children presenting an early ITR (ie, within 6 months of treatment withdrawal) need a very aggressive treatment because of the high probability of an underlying systemic disease. On the other hand, patients with a late ITR seem to have a truly local recurrence and can apparently be cured by standard protocols, as shown in protocol REC80-ITR.     

Treatment of adults with acute lymphoblastic leukemia: Do the specifics of the regimen matter?

BACKGROUND:

Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m² daily for 5 days with mitoxantrone 80 mg/m² (the ALL‐2 regimen) as a novel induction regimen. Compared with historic controls, the ALL‐2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)‐positive ALL.

METHODS:

The authors conducted a multicenter, prospective, randomized trial of the ALL‐2 regimen compared with a standard 4‐drug induction (the L‐20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004.

RESULTS:

The median follow‐up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL‐2 regimen versus the L‐20 regimen was 83% versus 71% (P = .06). More patients on the L‐20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL‐2) versus 7% (L‐20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL‐2 arm versus 27% on the L‐20.

CONCLUSIONS:

Despite superior results of induction therapy with the ALL‐2 regimen, this treatment did not improve long‐term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.     

Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.     

Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organization for Research and Treatment of Cancer 58881 randomized phase III trial.

PURPOSE: The European Organization for Research and Treatment of Cancer 58881 study was designed to test in a prospective multicentric randomized trial the value of high-dose (HD) intravenous (IV) cytarabine (Ara-C) added to HD IV methotrexate (MTX) to reduce the incidence of CNS and systemic relapses in children with increased-risk acute lymphoblastic leukemia (ALL) or stage III and IV lymphoblastic lymphoma treated with a Berlin-Frankfurt-Munster (BFM)-based regimen. PATIENTS AND METHODS: After completion of induction-consolidation phase, children with increased-risk (risk factor > 0.8 or T-lineage) ALL or stage III and IV lymphoblastic lymphoma were randomized to receive four courses of HD MTX (5 g/m(2) over 24 hours every 2 weeks) and four intrathecal administrations of MTX (Arm A) or the same treatment schedule with additional HD IV Ara-C (1 g/m(2) in bolus injection 12 and 24 hours after the start of each MTX infusion) (Arm B). RESULTS: Between January 1990 and January 1996, 653 patients with ALL (593 patients) or lymphoblastic lymphoma (60 patients) were randomized: 323 were assigned to Arm A (without Ara-C) and 330 to Arm B (with Ara-C). A total of 190 events (177 relapses and 13 deaths without relapse) were reported, and the median follow up was 6.5 years (range, 2 to 10 years). The incidence rates of CNS relapse were similar in both arms whether isolated (5.6% and 3.3%, respectively) or combined (5.3% and 4.6%, respectively). The estimated 6-year disease-free survival (DFS) rate was similar (log-rank P =.67) in the two treatment groups: 70.4% (SE = 2.6%) in Arm A and 71.0% (SE = 2.5%) in Arm B. The 6-year DFS rate was similar for ALL and LL patients: 70.2% (SE = 1.9%) versus 76.3% (SE = 5.6%). CONCLUSION: Prevention of CNS relapse was satisfactorily achieved with HD IV MTX and intrathecal injections of MTX in children with increased-risk ALL or stage III and IV lymphoblastic lymphoma treated with our BFM-based treatment protocol in which cranial irradiation was omitted. Disappointingly, with the dose schedule used in this protocol, HD Ara-C added to HD MTX, although well tolerated, failed to further decrease the incidence of CNS relapse or to improve the overall DFS.     

Outcome of treatment with Hyper-CVAD regimen in Chinese patients with acute lymphocytic leukemia

Modern intensive chemotherapy regimens have improved the prognosis for adult patients with acute lymphocytic leukemia (ALL). With these regimens, the complete response (CR) rates are approximately 75% and long-term disease-free survival (DFS) rates are about 20-35%. For patients with high-risk ALL, DFS rates are only 20% or less. Hyper-CVAD regimen is effective in ALL and aggressive non-Hodgkin lymphomas (NHL) with increased CR rates and DFS rates. Between June 2002 and October 2006, 53 consecutive adult patients with newly diagnosed adult ALL were treated with Hyper-CVAD regimen for six to eight cycles. The alternating courses were given every 3-4 weeks or earlier if count recovery occurred. CR rates of 73.6% were achieved in 39 patients, the estimated 2-year survival rate was 82.9% and the estimated 2-year event-free survival (EFS) rate was 87.3%. Side effects were as expected, mostly attributed to myelosuppression. Analysis of prognostic factors suggested that some previously well-established poor prognostic factors such as the degree of leukocytosis and central nervous system (CNS) or testicular involvement were less important with this dose-intensive regimen. However, patients with mediastinal disease had lower CR rates (P<0.05), with the presence of hepatomegaly and t(9;22) abnormalities had poor survival (P<0.05). Compared with other established adult ALL regimens, Hyper-CVAD regimen was associated with significantly better CR rates, overall survival and EFS rates. The long-term follow-up results of Hyper-CVAD were favorable.     

The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with the M-BACOD regimen.

One hundred thirty-four assessable patients with stage II-IV large-cell lymphoma (LCL) were treated with the combination chemotherapy regimen methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) between July 1981 and May 1986. The m-BACOD regimen substituted moderate-dose methotrexate (200 mg/m2 x 2) for the high-dose methotrexate used in the preceding M-BACOD regimen; all other drugs were administered as with m-BACOD. Eighty-two patients (61%) in the completed m-BACOD trial achieved a complete response (CR). With a median follow-up of 3.6 years, 62 patients (76%) continue in CR. Predicted survivals of 1, 3, and 5 years for the entire m-BACOD group are 80%, 63%, and 60%, respectively, with a 5-year disease-free survival (DFS) of 74% for the patients who achieve CR. The results obtained with m-BACOD are comparable with those obtained in the preceding M-BACOD trial, which now has a median follow-up of 8.0 years. The reduction in methotrexate dosage in m-BACOD patients was not associated with an increased incidence of CNS relapse. Long-term follow-up of the 215 M/m-BACOD patients indicates that the regimens are not associated with an increased incidence of secondary malignancy. Prolonged follow-up also indicates that advanced-stage patients have a persistent rate of late relapse of about 7.0% per year for years 2 to 5 of their follow-up and that stage II patients have an approximate 2.1% per year rate of late relapse. Application of the previously described prognostic factor model to the 215 M/m-BACOD patients from the completed trials identifies a high-risk group of patients with a CR rate and predicted 5-year survival (38% and 24%, respectively) that are significantly worse than those of the group as a whole (65% and 57%, respectively).     

The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer

The importance of the interval between methotrexate (MTX) and fluorouracil (5-FU) was studied in 168 patients with previously untreated, measurable, advanced colorectal cancer. They were randomized to receive MTX 200 mg/m2, followed by 5-FU 600 mg/m2 either 24 hours (arm A) or 1 hour (arm B) after MTX. All patients received leucovorin (LV) 24 hours after MTX, 10 mg/m2 orally every 6 hours for six doses. The regimen was repeated every 2 weeks, with 5-FU escalation as tolerated. Arm A was significantly better than arm B with respect to overall response rate (29% v 14.5%, P = .026), time to progression (TTP; median, 9.9 months v 5.9 months, P = .009), and survival (median, 15.3 months v 11.4 months, P = .003). Significant differences between arms were not found in response rate, median TTP, or median survival for the subgroup of patients with rectal primaries who comprised 20% of the patients in each arm. Significant factors prognostic for survival were performance status and number of metastases, as well as treatment. Age did not influence survival. Toxicity was similar in both arms and was primarily gastrointestinal. More mucositis was seen in arm A. There were four toxic deaths secondary to neutropenia and infection (one from arm A and three from arm B) and three other deaths (two from arm A and one from arm B) that were possibly drug-related. The combination of MTX with LV rescue and 5-FU is an active regimen in advanced colorectal cancer; its efficacy is increased in colon, but not rectal cancer, when the interval between MTX and 5-FU is long (24 hours) rather than short (1 hour).     

大剂量甲氨蝶呤治疗成人急性淋巴细胞白血病的药物代谢研究

目的：研究大剂量甲氨蝶呤（HD-MTX）治疗成人急性淋巴细胞白血病时的药物代谢作用及不同解救方案的价值。方法回顾性分析2003至2010年收治的124例成人患者（共190例次 HD-MTX 治疗）的临床和实验室资料。结果190例次患者的甲氨蝶呤血药浓度降至0.1μmol/L 以下的中位时间是72 h（48～342 h）,76例次（40%）发生延迟排泄;延迟排泄组患者的不良反应显著增高（P＜0.05）,其体质指数和甲氨蝶呤治疗第7日的血清肌酐水平均显著高于正常排泄组（分别为 P=0.046和 P＜0.001）。甲酰四氢叶酸钙联合左旋门冬酰胺酶解救不优于单用亚叶酸钙（P=0.849）。缩短甲氨蝶呤输注时间并提前亚叶酸钙的解救时机不能改善甲氨蝶呤的延迟排泄,但可减轻血液学不良反应。结论体质指数、血清肌酐水平影响甲氨蝶呤的代谢。适度缩短甲氨蝶呤输注时间和提前亚叶酸钙的解救时机或能改善甲氨蝶呤的排泄和不良反应。     

Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia.

PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS: Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy. CONCLUSION: Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.     

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.     

Hyper-CVAD方案治疗淋巴母细胞淋巴瘤

 目的　观察Hyper-CVAD方案对淋巴母细胞淋巴瘤（LBL）的疗效及其毒副作用。方法　2003年11月至2006年12月收治LBL患者40例,其中20例接受Hyper-CVAD／MA方案交替治疗8个疗程;另20例予常规急性淋巴细胞白血病方案,包括VDCLP、CAT、HD-MTX、EA等方案交替治疗,后予维持治疗。结果　Hyper-CVAD方案组：诱导化疗结束后CR18例（90 ％）,PR2例（10 ％）,总有效率100 ％,3年无病生存率（DFS）55 ％,总体生存率（OS）66 ％。常规急淋方案组：诱导化疗结束后CR17例（85 ％）PR1例（5 ％）,PD2例（10 ％）,总有效率90 ％,3年DFS 35 ％,OS 52 ％。两组患者在诱导期的CR率和有效率差异无统计学意义。3年DFS和3年OS的差异均有统计学意义（P＜0.05）。结论　Hyper-CVAD方案可以提高LBL患者的长期无病生存率,可作为LBL一线治疗方案之一。     

High-dose methotrexate as part of remission maintenance therapy for childhood acute lymphocytic leukemia: a Pediatric Oncology Group pilot study

Seventeen children with acute lymphocytic leukemia (ALL) in remission were treated with parenteral high-dose methotrexate (HDM) pulses every eight weeks during standard 6-mercaptopurine and methotrexate (MTX) oral maintenance therapy. MTX (1,000 mg/m2) was infused over one hour followed by one hour of intravenous hydration for the purpose of achieving plasma and cerebrospinal fluid (CSF) levels greater than 10(-6) M for a period of 24 hours. Leucovorin (15 mg/m2) was administered orally six, 12, and 18 hours after completion of the HDM. Plasma and CSF concentrations of MTX were evaluated serially in the first 48 hours. During the first 24 hours, the plasma MTX level was maintained at greater than 10(-6) M. The patients receiving intrathecal MTX at a dose of 15 mg/m2 had an adequate, sustained MTX level in the CSF, but when no intrathecal MTX was administered, the CSF levels were less than 10(-6) M. For that reason, intrathecal MTX in a low dose (6 mg/m2) was injected intrathecally one hour after the HDM infusion, allowing the MTX level in CSF to approximate 10(-6) M over the 24 hours. The toxicity of this therapy was minimal. Due to the facts that the plasma and CSF MTX levels could be sustained above the desired concentrations and this regimen could be given in the outpatient clinic, this program has been incorporated into an ongoing study in an effort to prolong complete remissions.     

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) accounts for 25% of childhood cancer. Clinical and biological parameters define prognostic categories and therapeutic approaches. For the majority of children with B-progenitor ALL, age (1-9 yrs) and white blood count (WBC<50,000) indicate standard risk disease; WBC>50,000 and age>9 yrs. define eligibility for high-risk protocols. Infants (<1 yr. old) are high-risk, frequently associated with chromosomal t(4;11) translocation and extramedullary disease. T-cell immunophenotype is usually associated with clinical high-risk features, including older age, high WBC, and extramedullary disease. T-cell immunophenotype is usually associated with clinical high-risk features, including older age, high WBC, and extramedullary disease. Current regimens include induction chemotherapy, consolidation (often including high-dose systemic methotrexate, MTX), and continuation phases; intensification or reinduction is incorporated for high-risk disease. Preventive CNS therapy is a critical component of therapy. Intrathecal (IT) chemotherapy (MTX +/- cytosine-arabinoside and hydrocortisone) and systemic agents provide adequate CNS therapy in standard risk patients. The "threshold" for using preventive cranial irradiation (Crl, 18 Gy) varies among protocols, but systematically includes those with T-cell ALL and WBS>50,000; other criteria may include B-progenitor ALL with WBC>100,000,philadelphia chromosome positive ALL, residual marrow disease at day 7, or male gender, For the 5% of children with CNS leukemia at diagnosis (defined as CSF with 5 or greater WBC/uL and positive cytology), Crl is administered at does of 18 to 24 Gy. Recent series show a CNS relapse rate approximating 5% Reinduction chemotherapy, IT therapy, and subsequent craniospinal irradiation ( typically 24, Gy Crl, 15 Gy spine) achieve durable secondary disease control in greater than 60% of cases with isolated CNS relapse. High-dose systemic MTX has virtually eliminated testicular relapse. CNS toxicities (including leukoencephalopathy) relate to systemic and IT MTX as well as Crl. Late neuropsychologicral data following Crl at 18 Gy show little intellectual deficit compared with children receiving MTX- based preventive therapy alone. Neuroendocrine dysfunction is apparent in long-term survivors following Crl at 24 Gy. The relative efficacy and toxicities of Crl versus more intensive MTX-based regimens are yet controversial. Overall disease-free survival in ALL approximates 70% in contemporary series.     

A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial.

A prospective, randomized multicenter study was performed to evaluate the relative efficacy of two different concepts for early intensive therapy in a randomized trial of children with B-precursor acute lymphoblastic leukemia (ALL) at high risk (HR) for relapse. Four hundred and ninety eligible children with HR-ALL were randomized on the Pediatric Oncology Group (POG) 9006 phase III trial between 7 January 1991 and 12 January 1994. After prednisone (PDN), vincristine (VCR), asparaginase (ASP) and daunorubicin (DNR) induction, 470 patients received either 12 intensive parenteral treatments of intermediate dose (1 g/m2 each) methotrexate (MTX) and mercaptopurine (MP) over 24 weeks (regimen A) or 12 intensive course of alternating myelosuppressive drug combinations given over 30 weeks (regimen B). These drug combinations included MTX/MP, teniposide (VM-26)/cytosine arabinoside (AC) and VCR/PDN/DNR/AC/ASP. Central nervous system (CNS) prophylaxis was age-adjusted triple intrathecal chemotherapy. Patients with CNS disease at diagnosis were treated with craniospinal irradiation after the intensive phase. Continuation was standard doses of MTX and MP for 2 years. This trial was closed early because of an apparent early difference favoring regimen B. Results show that 470 patients achieved remission (97%). Two hundred and thirty two were randomized to regimen A and 238 to regimen B. The estimated 4-year event-free survival (EFS) for patients treated with regimen A is 61.6 % (s.e. = 3.3%) and with regimen B is 69.4% (s.e. = 3.1%), P = 0.091. Toxicities were more frequent on regimen B. In conclusion, for children with B-precursor ALL at high risk to relapse, early intensification with myelosuppressive combination chemotherapy was more toxic but produced no significant difference in EFS when compared to those treated with parenteral methotrexate and mercaptopurine.     

Red blood cell methotrexate and folate levels in children with acute lymphoblastic leukemia undergoing therapy: a Pediatric Oncology Group pilot study

Summary We enrolled children with acute lymphoblastic leukemia (ALL) in a Pediatric Oncology Group (POG) pilot study to monitor erythrocyte (RBC) methotrexate (MTX) and folate (F) levels before and during treatment. The mean value for RBCF at diagnosis was 0.86±0.46 nmol/ml RBC in the 214 patients who achieved remission and 1.21±0.74 nmol/ml RBC in the 10 patients who did not (P=0.020). Folate levels tended to increase during remission induction, but they dropped following an intensive consolidation with methotrexate to levels that were sustained throughout chemotherapy treatment. Methotrexate levels reached mean values of approximately 0.15 nmol/ml RBC at the end of an intensive methotrexate consolidation, then fell to levels that were sustained throughout maintenance therapy. There was a weak correlation between improved event-free survival and higher RBCMTX levels after consolidation, but no correlation was found between improved survival and the level of RBCMTX or RBCF during maintenance therapy. A larger study with more complete data is needed to determine whether RBCMTX or RBCF might be useful in predicting event-free survival in patients with ALL.This work was supported in part by grants from the National Cancer Institute and the National Institute of Health (CA-30969, CA-28476, CA29139, CA-159-89, and CA-33587)     

Combination therapy with methotrexate, vincristine, polyethylene-glycol conjugated-asparaginase, and prednisone in the treatment of patients with refractory or recurrent acute lymphoblastic leukemia.

BACKGROUND: L-asparaginase in combination with methotrexate has synergistic antileukemic activity in a schedule-dependent fashion. A new preparation of L-asparaginase, polyethylene-glycol conjugated (PEG)-asparaginase, is a pharmacologically different formulation of L-asparaginase with distinct properties including a longer half-life and less immunogenic properties. METHODS: Patients with refractory or recurrent acute lymphoblastic leukemia (ALL) were treated with a combination of methotrexate (MTX), vincristine, PEG-asparaginase, and prednisone (MOAP). The treatment was comprised of MTX, 100 mg/m(2) intravenously (i.v.), over 15 minutes on Days 1 and 14; PEG-asparaginase, 2500 IU/m(2), with a maximum dose of 3750 IU i.v. approximately 4-6 hours after MTX on Days 1 and 14; vincristine, 1.4 mg/m(2) (maximum dose, 2 mg) i.v., over 15 minutes on Days 1, 7, and 14; and prednisone, 200 mg daily orally, on Days 1-5 and 14-19. RESULTS: Thirty-two patients with a median age of 34 years (range, 20-74 years) were treated. Eight patients (25%) had ALL that was refractory to prior therapy and 24 patients (75%) had recurrent disease. Seven patients (22%) achieved a complete remission (CR). Five patients (16%) died early due to infections. Features associated with a poor response were high pretreatment lactate dehydrogenase levels and Philadelphia chromosome positive disease. The median duration of CR was 16 weeks and the overall median survival after MOAP therapy was 12 weeks. Anaphylactic reactions were not observed during MOAP combination therapy. CONCLUSIONS: MOAP is an active regimen in patients with refractory or recurrent ALL. This regimen is well tolerated and is not associated with allergic reactions. However, further studies regarding the pharmacologic interaction of MTX with PEG-asparaginase are needed to optimize this regimen.     

Adjuvant methotrexate escalated to toxicity for resectable stage III and IV squamous head and neck carcinomas--a prospective, randomized study

To determine if adjuvant methotrexate (MTX), escalated weekly to toxicity, could improve disease-free survival (DFS) and overall survival by preventing recurrent disease, 60 patients with potentially resectable stage III or IV squamous head and neck carcinomas were stratified by primary site, stage, and nutritional status, then randomized by pairs to receive or not receive adjuvant MTX. All received standard surgery and postoperative radiation therapy. Five patients were taken off study because of unresectability at the time of surgery, leaving 55 evaluable patients. There were no statistically significant imbalances in known prognostic factors between the two treatment arms. MTX was begun at 40 mg/m2 and escalated 10 mg/m2 weekly (four doses preoperatively; four doses postoperatively, preradiation therapy; eight doses postradiation therapy) to mucosal or hematologic toxicity. The median peak MTX dose achieved was 80 mg/m2. Although three patients were hospitalized with MTX toxicity, none died of MTX toxicity. No patient receiving MTX had disease progression during treatment, and there was no increase in postoperative complications. Thirty-two patients died (median survival, 19 months); 23 patients are alive with median follow-up of 43 months. There was no statistically significant difference in actuarial DFS (P = 1.0) or overall survival (P = .61). Although patients on the MTX arm appeared to have less local and regional recurrences at first recurrence (thus more distant metastases), this did not reach statistical significance (P = .06). There was no significant difference between the sites of recurrence at death or last follow-up (P = .38).     

Central nervous system (CNS) prophylaxis in children with low risk acute lymphoblastic leukemia (ALL)

Five hundred four children with low risk acute lymphocytic leukemia (previously untreated, age 3 to 6 years with white blood counts less than 10,000/mm3 at diagnosis) were randomized into two different central nervous system prophylaxis regimens. One regimen (250 patients) consisted of cranial radiation and intrathecal methotrexate (IT MTX). The second regimen (254 patients) consisted of IT MTX only. Median follow-up time for surviving patients is currently 54 months from randomization. Life table analysis of central nervous relapse, marrow relapse, disease-free survival, and survival shows very similar outcome for both treatment groups. The results indicate that maintenance IT MTX as described in this report can be substituted for cranial radiation in children with low risk ALL.     

Unexpectedly severe toxicity from intensive early treatment of childhood lymphoblastic leukemia

In early 1984, we treated 13 consecutive patients with acute lymphoblastic leukemia (ALL) using an induction regimen of rapidly rotated combinations of prednisone, vincristine, asparaginase, teniposide (VM-26), cytosine arabinoside, and high-dose methotrexate (MTX) followed by leucovorin rescue. The intent of this clinical trial, designated Total Therapy Study XI, is to test the hypothesis that greater initial leukemia cell kill will decrease opportunities for the development of drug-resistant mutants, with resultant improvement in the length of disease-free survival. Five patients experienced life-threatening gastrointestinal toxicity within three weeks of the start of treatment. One died. Three other patients had severe abdominal pain, abdominal distention, diarrhea, and weight loss, but not gastrointestinal bleeding. In the remaining five patients, toxicity was rapidly reversible, and each child was able to complete the planned course of chemotherapy. The study was then amended to switch high-dose MTX from the induction phase to the consolidation phase, allowing at least one week for mucosal recovery. Among the next 28 patients who were treated, none showed evidence of severe gastrointestinal toxicity. Patients now receive high-dose MTX alone as consolidation therapy and are tolerating it adequately. Drug timing should be examined critically when intensified multiple-agent regimens are being devised for initial treatment of ALL.