Application of a Non-Mixture Cure Rate Model for Analyzing Survival of Patients with Breast Cancer

Background: As a result of significant progress made in treatment of many types of cancers during the lastfew decades, there have been an increased number of patients who do not experience mortality. We refer to theseobservations as cure or immune and models for survival data which include cure fraction are known as cure ratemodels or long-term survival models. Materials and Methods: In this study we used the data collected from 438female patients with breast cancer registered in the Cancer Research Center in Shahid Beheshti University ofMedical Sciences, Tehran, Iran. The patients had been diagnosed from 1992 to 2012 and were followed up untilOctober 2014. We had to exclude some because of incomplete information. Phone calls were made to confirmwhether the patients were still alive or not. Deaths due to breast cancer were regarded as failure. To identifyclinical, pathological, and biological characteristics of patients that might have had an effect on survival of thepatients we used a non-mixture cure rate model; in addition, a Weibull distribution was proposed for the survivaltime. Analyses were performed using STATA version 14. The significance level was set at P ≤ 0.05. Results: Atotal of 75 patients (17.1%) died due to breast cancer during the study, up to the last follow-up. Numbers ofmetastatic lymph nodes and histologic grade were significant factors. The cure fraction was estimated to be58%. Conclusions: When a cure fraction is not available, the analysis will be changed to standard approachesof survival analysis; however when the data indicate that the cure fraction is available, we suggest analysis ofsurvival data via cure models.     

Indication and results of bone marrow transplantation in acute leukemia

The indication and results of bone marrow transplantation (BMT) for acute leukemia were discussed focusing on data obtained by the BMT study group of the Ministry of Health and Welfare, Japan. With regard to the indication of BMT, the following factors were selected as significantly favorable: young age, in remission, no infection, complete HLA-matched marrow donor, no previous radiation treatment of the brain or lung, fractionated TBI, low dose rate, platelet transfusion from anti-CMV antibody-negative donor. Recently, the incidence of such favorable patients has increased in BMT, reflecting the improvement of results with this procedure. The long-term survival rates were 75% for ALL and 50% for ANLL when BMT was performed during the patients' first remission. These data reveal the merit of BMT as a treatment with a high rate of complete cure.     

Utilization of a Mixture Cure Rate Model based on the Generalized Modified Weibull Distribution for the Analysis of Leukemia Patients

Objective: Cure rate models are survival models, commonly applied to model survival data with a cured fraction. In the existence of a cure rate, if the distribution of survival times for susceptible patients is specified, researchers usually prefer cure models to parametric models. Different distributions can be assumed for the survival times, for instance, generalized modified Weibull (GMW), exponentiated Weibull (EW), and log-beta Weibull. The purpose of this study is to select the best distribution for uncured patients’ survival times by comparing the mixture cure models based on the GMW distribution and its particular cases. Materials and Methods: A data set of 91 patients with high-risk acute lymphoblastic leukemia (ALL) followed for five years from 1982 to 1987 was chosen for fitting the mixture cure model. We used the maximum likelihood estimation technique via R software 3.6.2 to obtain the estimates for parameters of the proposed model in the existence of cure rate, censored data, and covariates. For the best model choice, the Akaike information criterion (AIC) was implemented. Results: After comparing different parametric models fitted to the data, including or excluding cure fraction, without covariates, the smallest AIC values were obtained by the EW and the GMW distributions, (953.31/969.35) and (955.84/975.99), respectively. Besides, assuming a mixture cure model based on GMW with covariates, an estimated ratio between cure fractions for allogeneic and autologous bone marrow transplant groups (and its 95% confidence intervals) were 1.42972 (95% CI: 1.18614 - 1.72955). Conclusion: The results of this study reveal that the EW and the GMW distributions are the best choices for the survival times of Leukemia patients.     

Allogeneic marrow transplantation for acute nonlymphoblastic leukemia

Bone marrow transplantation (BMT) from an HLA-matched sibling donor can cure 15% of end-stage patients with refractory acute leukemia. Failures are largely due to acute or chronic graft-versus-host disease, idiopathic or cytomegalovirus-associated interstitial pneumonitis, veno-occlusive disease of the liver, opportunistic infections, and leukemia relapse. The post-BMT leukemia relapse rate has been reduced from 65% to 20-40% by performing BMT in first complete remission (CR). Overall, about 50% of such patients become long-term tumor-free survivors. Younger patients do far better than older ones. A prospective comparative trial for acute nonlymphoblastic leukemia (ANL) in first CR revealed that BMT was more likely than chemotherapy to be fatal within the first 6 months after induction but that the probability of long-term tumor-free survival thereafter was significantly greater after BMT than after chemotherapy. It is recommended that patients less than 30 years old with ANL should undergo BMT while in first CR, whereas those patients over 30 years old should postpone BMT to the earliest sign of relapse.     

Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation

At the present time, there is limited information on the outcome of patients with acute lymphoblastic leukemia (ALL) who relapse after bone marrow transplantation (BMT). Intuitively, it might be expected that leukemia recurring after BMT would be refractory to further treatment. In an attempt to improve survival in patients with ALL who relapse after BMT, we used standard chemotherapy for reinduction and maintenance. Of 65 patients who relapsed following allogeneic, autologous, or syngeneic BMT, 12 elected to receive no further chemotherapy, and their median survival from relapse was 36 days (range 13 to 167 days). The 53 patients who received therapy had a significantly longer median survival of 168 days (range 18 days to 4.7 years). With multidrug induction regimens there were 29 of 52 (56%) complete remissions. Six patients are currently alive, with two off therapy. In the patients who received therapy, the following factors were independent predictors of prolonged survival: longer time from BMT to relapse; younger age at diagnosis; and the use of a preparative regimen containing fractionated total body irradiation. In conclusion, leukemia recurring after BMT remains sensitive to standard therapy in many patients. We recommend that patients with ALL who relapse after BMT receive reinduction and maintenance therapy as additional good quality survival time is achieved in patients who attain a remission.     

Allogeneic marrow transplantation for chronic granulocytic leukemia

A retrospective analysis is presented of results obtained with allogeneic bone marrow transplantation (BMT) in three phases of Philadelphia chromosome-positive chronic granulocytic leukemia. At BMT, 23 patients were in blastic phase (BP), 33 were in accelerated phase (AP), and 45 were in chronic phase (CP). With a follow-up time of 1-8 years after BMT, the probability of long-term survival was 14, 10, and 58%, respectively, for patients transplanted in BP, AP, or CP. The probability of cytogenetic relapse with or without clinical hematologic relapse at 3 years after BMT was 80, 38, and 31%, respectively, for patients transplanted in BP, AP, or CP. Splenectomy did not influence posttransplant survival. Given the dismal prognosis on conventional therapy, patients younger than 50 in BP or AP should be considered for BMT. For the patient in CP, BMT offers the possibility of cure but with a significant risk of early death. Patients under 40 who fully understand the risks and potential benefits of BMT should be offered BMT early in CP before any change to AP occurs.     

Factors Affecting Long-Survival of Patients with Breast Cancer by Non-Mixture and Mixture Cure Models Using the Weibull,Log-logistic and Dagum Distributions: A Bayesian Approach

Background: Breast cancer is a top biomedical research priority, and it is a major health problem. Therefore, the present study aimed to determine the prognostic factors of breast cancer survival using cure models. Methods: In this retrospective cohort analytic study, data of 140 breast cancer patients were collected from Ali Ibn Abi Taleb hospital, Rafsanjan, Southeastern Iran. Since in this study, a part of the population had long-term survival, cure models were used and evaluated using DIC index. The data were analyzed using Openbugs Software. Results: In this study, of 140 breast cancer patients, 23 (16.4%) cases died of breast cancer. Based on the findings, the Bayesian nonmixture cure model, with type I Dagum distribution, was the best fitted model. The variables of BMI, number of children, number of natural deliveries, tumor size, metastasis, consumption of canned food, tobacco use, and breastfeeding affected patients’ survival based on type I Dagum distribution. Conclusion: The results of the present study demonstrated that the Bayesian nonmixture cure model, with type I Dagum distribution, can be a good model to determine factors affecting the survival of patients when there is the possibility of a fraction of cure. In this study, it was found that adapting a healthy lifestyle (eg, avoiding canned foods and smoking) can improve the survival of breast cancer patients.     

Estimation of the Cure Rate in Iranian Breast Cancer Patients

Background: Although the Cox’s proportional hazard model is the popular approach for survival analysis to investigate significant risk factors of cancer patient survival, it is not appropriate in the case of log-term disease free survival. Recently, cure rate models have been introduced to distinguish between clinical determinants of cure and variables associated with the time to event of interest. The aim of this study was to use a cure rate model to determine the clinical associated factors for cure rates of patients with breast cancer (BC). Materialsand Methods: This prospective cohort study covered 305 patients with BC, admitted at Shahid Faiazbakhsh Hospital, Tehran, during 2006 to 2008 and followed until April 2012. Cases of patient death were confirmed by telephone contact. For data analysis, a non-mixed cure rate model with Poisson distribution and negative binomial distribution were employed. All analyses were carried out using a developed Macro in WinBugs. Deviance information criteria (DIC) were employed to find the best model. Results: The overall 1-year, 3-year and 5-year relative survival rates were 97%, 89% and 74%. Metastasis and stage of BC were the significant factors, but age was significant only in negative binomial model. The DIC also showed that the negative binomial model had a better fit. Conclusions: This study indicated that, metastasis and stage of BC were identified as the clinical criteria for cure rates. There are limited studies on BC survival which employed these cure rate models to identify the clinical factors associated with cure. These models are better than Cox, in the case of long-termsurvival.     

Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits.

PURPOSE: Allogeneic bone marrow transplantation (BMT) is an option for some patients with chronic myelogenous leukemia (CML). We retrospectively evaluated the effect of various risk factors observed at diagnosis and at transplantation on survival, event-free survival (EFS), and relapse after BMT. PATIENTS AND METHODS: Seventy-nine patients with CML in chronic phase (CP) were treated with cyclophosphamide and total body irradiation followed by BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) in most instances or CsA plus the use of lymphocyte-depleted bone marrow (BM). RESULTS: Survival at 4.5 years was 52%. Stratified by age and GVHD prophylaxis, the actuarial survival was 65% (95% confidence interval [CI], 47% to 78%) in patients aged less than 30 years receiving unmanipulated BM, 33% (95% CI, 12% to 56%) in patients greater than or equal to 30 years old receiving unmanipulated BM, and 38% (95% CI, 14% to 63%) in patients greater than or equal to 30 years old receiving lymphocyte-depleted BM. In univariate analysis, patient age (greater than or equal to 30 years) and the use of lymphocyte-depleted BM negatively influenced EFS. When stratified by age and GVHD prophylaxis, however, ABO incompatibility, cytomegalovirus (CMV) seropositivity, and chronic GVHD significantly reduced the probability of EFS. Factors that have been associated with early death in nontransplanted patients (ie, sex, spleen size, blast and platelet counts at presentation) were not predictive of long-term survival outcome after BMT. CONCLUSIONS: The data suggest that (1) BMT should be offered early after diagnosis to all patients with CML in CP who have compatible sibling donors regardless of prognostic factors at presentation, (2) GVHD remains the principal cause of mortality after BMT in patients receiving CsA, and (3) T-cell depletion by the physical separation method of counterflow elutriation (CE) is associated with a significant risk of relapse.     

Improved survival time: What can survival cure models tell us about population‐based survival improvements in late‐stage colorectal,ovarian, and testicular cancer?

BACKGROUND: The objective of the current study was to investigate the long-term impact of treatment advances on the survival of patients with late-stage ovarian, colorectal (American Joint Committee on Cancer stage III, men), and testicular cancers by estimating the increase in the percentage cured from their disease and the change in survival time of uncured patients. METHODS: Cause-specific survival data from 1973 to 2000 were obtained from the Surveillance, Epidemiology, and End Results Program. Survival cure models were fit and were used to estimate the gain in life expectancy (GLE) attributed to an increase in the fraction of cured patients and to prolonged survival among noncured patients. RESULTS: Treatment improvement for ovarian cancer resulted in a total GLE of 2 years, and 80% of that GLE was because of an extension of survival time in uncured patients (from 0.9 years to 2.1 years) rather than an increased cure fraction (from 12% to 14%). In contrast, the cure rate rose from 29% to 47% for colorectal cancer, representing 82% of a 2.8-year GLE, and from 23% to 81% for testicular cancer, representing 100% of a 24-year GLE. CONCLUSIONS: The current results suggested that treatment benefits for testicular and colorectal cancer in men with late-stage disease primarily are the result of increases in cure fraction, whereas survival gains for ovarian cancer occur despite persisting disease. Cure models, in combination with population-level data, provide insight into how treatment advances are changing survival and ultimately impacting mortality. Survival patterns reflect the underlying biology of response to cancer treatment and suggest promising directions for future research.     

Cure Models for Estimating Hospital-Based Breast CancerSurvival

Objective: Research on cancer survival is enriched by development and application of innovative analyticalapproaches in relation to standard methods. The aim of the present paper is to document the utility of a mixturemodel to estimate the cure fraction and compare it with other approaches. Methods: The data were for 1,107patients with locally advanced breast cancer, who completed the neo-adjuvant treatment protocol during 1990-99at the Cancer Institute (WIA), Chennai, India. Tumour stage, post-operative pathological node (PN) and tumourresidue (TR) status were studied. Event free survival probability was estimated using the Kaplan-Meier method.Cure models under proportional and non-proportional hazard assumptions following log normal distribution forsurvival time were used to estimate both the cure fraction and the survival function for the uncured. Results:Event free survival at 5 and 10 years were 64.2% and 52.6% respectively and cure fraction was 47.5% forall cases together. Follow up ranged between 0-15 years and survival probabilities showed minimal changesafter 7 years of follow up. TR and PN emerged as independent prognostic factors using Cox and proportionalhazard (PH) cure models. Proportionality condition was violated when tumour stage was considered and it wasstatistically significant only under PH and not under non PH cure models. However, TR and PN continued tobe independent prognostic factors after adjusting for tumour stage using the non PH cure model. A consistentordering of cure fractions with respect to factors of PN and TR was forthcoming across tumour stages using PHand non PH cure models, but perceptible differences in survival were observed between the two. Conclusion: IfPH conditions are violated, analysis using a non PH model is advocated and mixture cure models are useful inestimating the cure fraction and constructing survival curves for non-cures.     

Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia

The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by allogeneic bone marrow transplantation (BMT) has been shown to be effective therapy for patients with acute and chronic leukemia. Therefore, we determined the long-term disease-free survival of patients who did not achieve a remission and were then treated with high-dose therapy and bone marrow allografting from matched sibling donors. Twenty-one patients (median age, 28 years) who did not achieve a remission with induction chemotherapy were subsequently treated with allogeneic BMT. After BMT, 90% achieved a complete remission. Six died of complications of the therapy, and six patients relapsed between 27 and 448 days after BMT. Nine patients (43%; median age, 25 years) are alive between 556 and 4,174 days after BMT. The cumulative probability of disease-free survival at 10 years is 43%. This study suggests that allogeneic BMT can be an effective therapy to achieve long-term control of acute leukemia, even in those patients who do not achieve a remission with primary therapy.     

Factors Affecting Long-Survival of Patients with Esophageal Cancer Using Non-Mixture Cure Fraction Model

Objective: Esophageal cancer (EC) is one of the gastrointestinal malignancies with a very high morbidity andmortality rate due to poor prognosis. This study aims to assess the effects of risk factors on survival and cure fraction ofpatients with EC in a population of Iranian patients using a non-mixture cure fraction model. Methods: This retrospectivecohort study was conducted on 127 patients with EC who were diagnosed during 2009-2010 and were followedup for 5 years in East-Azarbaijan, Iran. Stepwise selection and non-mixture cure fraction model were used to findthe risk factors of EC survival patients. Results: The mean (±standard deviation) diagnosis age of the EC was66.92(±11.95). One, three and five-year survival probabilities were 0.44 (95% confidence interval (CI): 0.36-0.54),0.2 (95% CI: 0.14-0.28) and 0.13 (95% CI: 0.08-0.2) respectively. Female sex (Estimate=-0.99; 95% confidence interval(CI): -1.41,-0.58; p-value<0.001), low level socioeconomic status (Estimate=0.39; 95%CI: 0.12,0.66; p-value=0.043),the group who did not do esophagectomy surgery (Estimate=0.58; 95%CI: 0.17,0.99; p-value=0.005) and unmarriedgroup (Estimate=0.58; 95%CI: 0.11-1.05; p-value=0.015) were found as the significant predictor of survival andcure fraction of the EC patients. Population cure rate was 0.11 (95%CI: 0.07-0.19) and Cure fraction was estimated5.11 percent. Conclusion: This study found gender, socioeconomic status, Esophagectomy surgery and marital statusas the potential risk factors for survival and cure fraction of Iranian EC patients. Moreover, non- mixture cure fractionprovides more accurate and more reliable insight into long-term advantages of EC therapy compared to standard classicsurvival analysis alternatives.     

Treatment of Acute Promyelocytic Leukemia in Patients Presenting at Vancouver General Hospital from 1983 to 1992

Between 6/83 and 8/92, 23 of 361 patients (6.4%) presenting at Vancouver General Hospital with acute myelogenous leukemia had acute promyelocytic leukemia (APL). Treatment plan was: 1) induction with high-dose cytosine arabinoside and an intercalator; and 2) consolidation with allogeneic bone marrow transplantation (BMT) for those aged ≤ 50 years with a sibling donor or repeat of induction for the others. Complete remission (CR) was achieved in 20 patients (87%). Eleven patients in CR were eligible for allogeneic BMT; 4 were considered unsuitable, 2 refused, and 5 underwent this treatment-1 died of acute graft-versus-host disease, 1 relapsed and 3 are leukemia-free and well 1.6, 3.3 and 3.9 years after diagnosis. Fifteen patients did not undergo allogeneic BMT in CR; 4 received no further treatment and all died, 2 relapsed before consolidation therapy and both died, 1 underwent autologous BMT and died of complications, and 8 received consolidation treatment as planned--1 died of sepsis, 2 relapsed and 5 are leukemia-free and well 1.0, 3.8, 4.5, 4.9 and 8.5 years after diagnosis. The actuarial overall survival for all 23 patients was 38% (95% confidence interval [CI] 18-57%). The actuarial 2-year leukemia-free survival was 60% (95% CI 20-85%) for the 8 patients who underwent consolidation chemotherapy as planned and 53% (95% CI 68-86%) for the 5 patients who underwent allogeneic BMT in CR. These results suggest that patients with APL who are able to undergo consolidation chemotherapy have a relatively good prognosis and allogeneic BMT may reasonably be held in reserve for salvage therapy.     

Acute Monocytic Leukemia: A Single Institution Experience

Using strict FAB criteria, 39 cases of monocytic leukemia were identified in 463 consecutive cases of AML. Patients had a median age of 49 with no sex predominance. Extramedullary disease and hyperleukocytosis were common (54% and 36% of patients respectively). Cytogenetic analysis was successful in 38 of 39 patients; 71% had a cytogenetic abnormality and 42% of these involved chromosome 11; 14 of 16 chromosome 11 abnormalities involved the region of 11q23. Non-chromosome 11 abnormalities tended to occur in older patients and to be associated with a lower platelet count; patients with the translocation 9;11 tended to have a lower white count and a higher incidence of therapy-related leukemia. 35 patients were treated with induction therapy including intensive chemotherapy (n = 33) and allogeneic BMT at presentation (n = 2). Patients who entered remission underwent consolidation chemotherapy, autologous BMT, or allogeneic BMT depending on policies at the time of diagnosis. Of 6 patients who underwent further intensive chemotherapy there is 1 long-term disease-free survivor. 3 of 8 patients undergoing autologous BMT and 2 of 3 patients undergoing allogeneic BMT are long-term disease-free survivors. We conclude that this specific subtype of AML, relatively rare when strict criteria are applied, is associated with unique biologic and clinical features and that the high relapse rate associated with conventional therapy makes new treatment approaches involving stem cell transplantation or immunomodulation necessary.     

Fitting Cure Rate Model to Breast Cancer Data of Cancer Research Center

Background: The Cox PH model is one of the most significant statistical models in studying survival of patients. But, in the case of patients with long-term survival, it may not be the most appropriate. In such cases, a cure rate model seems more suitable. The purpose of this study was to determine clinical factors associated with cure rate of patients with breast cancer. Materials and Methods: In order to find factors affecting cure rate (response), a non-mixed cure rate model with negative binomial distribution for latent variable was used. Variables selected were recurrence cancer, status for HER2, estrogen receptor (ER) and progesterone receptor (PR), size of tumor, grade of cancer, stage of cancer, type of surgery, age at the diagnosis time and number of removed positive lymph nodes. All analyses were performed using PROC MCMC processes in the SAS 9.2 program. Results: The mean (SD) age of patients was equal to 48.9 (11.1) months. For these patients, 1, 5 and 10-year survival rates were 95, 79 and 50 percent respectively. All of the mentioned variables were effective in cure fraction. Kaplan-Meier curve showed cure model’s use competence. Conclusions: Unlike other variables, existence of ER and PR positivity will increase probability of cure in patients. In the present study, Weibull distribution was used for the purpose of analysing survival times. Model fitness with other distributions such as log-N and log-logistic and other distributions for latent variable is recommended.     

Comparison of the survivals between bone marrow transplantation and chemotherapy for acute leukemia in first remission--a Japanese single institution study.

The outcome of sixty-four patients with acute leukemia in first remission who had been treated with either bone marrow transplantation (BMT) or conventional chemotherapy was retrospectively evaluated (a median follow-up of 37 months). Among them, 26 patients (age range; 14-42 years) received allogeneic BMT from HLA-identical siblings and 38 patients (age range; 13-43 years) who had no HLA-identical donors undertook the continued combination chemotherapy. Kaplan-Meier product-limit estimate of actuarial survival of acute myelogenous leukemia (AML) patients was 48.9% for the BMT group and 15.7% for the chemotherapy group (p = not significant, NS). For acute lymphoblastic leukemia (ALL) patients, the survival following BMT was 80.2% and was significantly higher than that of the chemotherapy group of 33.3% (p < 0.05). The disease-free survival of AML and ALL for the BMT group was 34.3% and 36.5%, respectively, which was higher than that of the chemotherapy group (16.7% and 23.4%, respectively (p = NS)). These findings in our Japanese single institution study suggested that BMT may be the treatment of choice for adult patients with acute leukemia in first remission if they had suitable donors and that more effective therapeutic regimens were necessary for patients without compatible donors in order to obtain the longer remission duration.     

Autologous bone marrow transplantation in hematologic malignancies

Autologous bone marrow transplantation (BMT) has become effective therapy for high-risk hematologic leukemias with long-term disease-free survivals and apparent cure in a substantial fraction of patients with relapsed aggressive non-Hodgkin's lymphoma, relapsed Hodgkin's disease, and the acute leukemias. Preliminary reports suggest autologous BMT may also be useful treatment for low-grade non-Hodgkin's lymphomas, chronic myelogenous leukemia, and multiple myeloma. Recent studies have begun to address the role autologous BMT should play in these diseases, especially relative to conventional-dose therapy and allogeneic BMT. Relapse remains the major cause for failure following autologous BMT. Novel approaches that can increase the antitumor effect of this treatment without increasing toxicity are being investigated.     

Management of advanced acute lymphoblastic leukemia in children and adults: results of the ALL R-87 protocol. AIEOP and GIMEMA Cooperative Groups

Fifty-seven patients aged < 55 years with acute lymphoblastic leukemia (ALL) in second or third bone marrow (BM) relapse or refractory to first-line therapy were enrolled in an Italian cooperative study. The ALL R-87 protocol included idarubicin (IDA) plus intermediate dose cytarabine (IDARA-C) and Prednisone (PDN) as induction, followed by a consolidation phase and BMT. Complete remission (CR) was achieved in 41/57 patients (72%). The CR rate was significantly higher in patients aged < 15 years at diagnosis and at time of treatment compared to those aged > or = 15 (84% vs 50%, p=0.01 and 85% vs 54%, p = 0.02, respectively). Nineteen of 41 responders (46.3%) underwent bone marrow transplant (BMT) (10 autologous and 9 allogeneic). The estimated probabilities of event free survival (EFS +/- SE) and survival +/- SE at 6 years were 0.13 +/- 0.05 and 0.20 +/- 0.06, respectively, for all enrolled patients. Univariate analysis showed that children had a better EFS rate compared to adults (0.16 +/- 0.07 vs 0.08 +/- 0.07, p = 0.014). The estimated probability of disease free survival (DFS +/- SE) at 6 years was 0.18 +/- 0.07 for all responders. No differences in DFS were observed between patients submitted to allogeneic or autologous BMT (0.33 +/- 0.16 vs 0.25 +/- 0.15). Among patients treated in second or third relapse, a first CR length > or = 48 months favorably influenced both DFS (p = 0.014) and EFS (p = 0.018). Our results show the efficacy of the intermediate dose ARA-C plus IDA schedule for high risk adult and childhood ALL patients. No differences in disease outcome were observed between allogeneic and autologous BMT.     

Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group.

PURPOSE: We report the first large prospective study of children with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) treated in a uniform fashion on Children's Cancer Group protocol 2891. PATIENTS AND METHODS: Ninety children with JMML, various forms of MDS, or acute myeloid leukemia (AML) with antecedent MDS were treated with a five-drug induction regimen (standard or intensive timing). Patients achieving remission were allocated to allogeneic bone marrow transplantation (BMT) if a matched family donor was available. All other patients were randomized between autologous BMT and aggressive nonmyeloablative chemotherapy. Results were compared with patients with de novo AML. RESULTS: Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAEB) exhibited high induction failure rates and overall remission of 58% and 48%, respectively. Remission rates for patients with RAEB in transformation (RAEB-T) (69%) or antecedent MDS (81%) were similar to de novo AML (77%). Actuarial survival rates at 6 years were as follows: JMML, 31% +/- 26%; RA and RAEB, 29% +/- 16%; RAEB-T, 30% +/- 18%; antecedent MDS, 50% +/- 25%; and de novo AML, 45% +/- 3%. For patients achieving remission, long-term survivors were found in those receiving either allogeneic BMT or chemotherapy. The presence of monosomy 7 had no additional adverse effect on MDS and JMML. CONCLUSION: Childhood subtypes of MDS and JMML represent distinct entities with distinct clinical outcomes. Children with a history of MDS who present with AML do well with AML-type therapy. Patients with RA or RAEB respond poorly to AML induction therapy. The optimum treatment for JMML remains unknown.