Treatment of relapsing acute lymphoblastic leukemia in childhood. I. Experiences with 82 first bone marrow and 17 isolated central nervous system relapses observed 1968-1980

Of 99 patients with acute lymphoblastic leukemia in first bone marrow or isolated CNS relapse seen between 1968 and 1980, 48 were treated without standardized protocol and 51 according to a relapse protocol. Of 16 patients with bone marrow relapse after cessation of the initial treatment 6 survived 8 1/2 years or more, of 66 with bone marrow relapse while on therapy only 4 survived. All of the latter were low risk patients with an initial WBC of less than 20 x 10(9)/l and no enlargement of the mediastinum. All of the 17 patients with isolated CNS relapse died. The relapse protocols used probably improved the chances of children with first bone marrow but not of those with isolated CNS relapse.     

A population-based study of children with standard risk acute lymphoblastic leukemia in the five Nordic countries. A follow-up of 230 patients

Two hundred and thirty children with standard risk acute lymphoblastic leukemia (ALL) were diagnosed during a period of 3 years from July 1, 1981 to June 30, 1984 in the five Nordic countries. Criteria for standard risk ALL were age above 2.0 and below 10 years, WBC less than or equal to 20 x 10(9)/l, no evidence of CNS-involvement, mediastinal mass or T- or B-cell leukemia. The children were treated without prophylactic CNS irradiation, the majority (200 patients) according to two treatment programs. Follow-up of the entire group after a minimum of 30 months showed 64% of the children living in complete continuous remission with a probability of event-free survival of 0.60. The treatment results are not entirely satisfactory and intensification of therapy is required. A subgroup of patients with WBC between 10 and 20 x 10(9)/l and with adverse prognosis was identified, justifying a change of the present criteria for risk grouping.     

Treatment of relapsing acute lymphoblastic leukemia in childhood. III. Experiences with 54 first bone marrow,nine isolated testicular,and eight isolated central nervous system relapses observed 1985-1989

Of 54 children with acute lymphoblastic leukemia (ALL) and first hematological recurrence observed between 1985 and 1989, 31 relapsed while still on treatment and 23 after cessation of therapy. Of the former, only one survived. Of the latter, 11 children survived after a minimum follow-up of 25 months. During the same period, a first isolated testicular relapse was observed in nine boys, of whom six survived, and an isolated CNS relapse in eight patients, of whom three survived. As a rule, survivors of a bone marrow or testicular relapse were doing well while those surviving a CNS relapse had considerable neuropsychological sequelae. These results, compared with those of two preceding studies, suggest that with intensification of front-line treatments, it becomes more difficult to rescue children who relapse, particularily those with a bone marrow relapse while on therapy. © 1994 Wiley-Liss, Inc.     

Outcome after first relapse in children with acute lymphoblastic leukemia: A population-based study of 315 patients from the nordic society of pediatric hematology and oncology (NOPHO)

This study reports the outcome after relapse of acute lymphoblastic leukemia (ALL) in a population-based study of 809 children over 1 year of age diagnosed July 1981 through June 1986 and with non-B acute lymphoblastic leukemia in the five Nordic countries. By January 1994, 315 children had suffered at least one relapse. The bone marrow was involved in 216 cases. There were 69 isolated CNS relapses, 25 isolated testicular recurrences and five relapses in other extramedullary sites. Of the 315 children with relapse, 94 are still in a second complete remission 12–138 (median: 78) months after relapse. The overall probability of a second event free survival (P-2.EFS) and survival after relapse was 0.28 and 0.33 respectively. The probability of remaining in second remission at 11 years was significantly correlated to the duration of first remission (P < 0.001), the site of relapse (P < 0.001) and gender (P = 0.004). The P-2.EFS for early, intermediate, and late bone marrow involved relapses were 0.08, 0.19, and 0.50 respectively. For early, intermediate and late isolated CNS relapses the P-2.EFS were 0.21, 0.38 and 0.61, respectively. The P-2.EFS for boys with isolated testicular relapses was 0.69. Girls with isolated CNS relapse (P < 0.001) and with bone marrow involved relapse (P = 0.04) had a significantly better prognosis than boys. Children with initial high risk criteria, especially T-ALL and mediastinal mass who relapsed, had a very poor prognosis. Conclusion: In this population-based study, about 30% of children with ALL obtained a long second remission and possible cure. © 1995 Wiley-Liss, Inc.     

High risk acute lymphoblastic leukemia in Denmark

In a retrospective study of acute lymphoblasic leukemia (ALL) in Denmark from 1973 to 1981, 95/267 children below 15 years of age fulfilled at least one of the following high risk (HR) criteria: WBC > 50 × 10⁹/1, mediastinal mass, meningeal leukemia, extramedullary leukemia, T-ALL, B-ALL and congenital leukemia. Significantly more of the children in HR had considerable hepato- and/or splenomegaly compared with children in the standard risk (SR) and intermediate risk (IR) groups. Hemoglobin values above 6.0 mmol/l were found in 35% of HR children and in 9% of children in SR and IR (p < 0.0005). Treatment protocols varied. The percentage achieving complete remission (CR) was 93.7. Median relapse free survival (RFS) was 18 months. Twenty-nine children (32.5%) have been in CCR for 24–114 months as of July 1983. Initial WBC was the only independent prognostic parameter. Of children with initial WBC < 50 × 10⁹/l, 62% remained in CCR compared to 15% with WBC > 50 × 10⁹/l. Treatment protocols employed before July 1977 were significantly inferior to protocols employed during the last half of the study period. Fifty-seven patients relapsed most frequently in the bone marrow. In 38.5% of the relapses, the central nervous system (CNS) was involved. When the CNS prophylaxis was initiated early during induction treatment, significantly fewer CNS recurrences arose than when the CNS prophylaxis was started after remission had been induced. Acute lymphoblastic leukemia, children, high risk, prognosis.     

Central Nervous System Disease in Childhood Acute Lymphoblastic Leukemia: Prognostic Factors and Results of Treatment

(years) revealed that isolated CNS relapse had occurred in 70 children (9.0%). Of these 70 patients, 12 out of 142 children (8.5%) had initially received irradiation and 58 out of 628 children (9.2%) only chemotherapy as CNS-prophylaxis. There was a significant higher risk for boys (12%) than for girls (6%) to relapse in the CNS compartment. Unfavorable prognostic factors for survival after isolated CNS relapse were short duration of first remission and male sex. In high-risk patients after an isolated CNS relapse, there was no difference in prognosis related to treatment with or without irradiation as initial CNS prophylaxis.     

Modified BFM therapy for children with previously untreated acute lymphoblastic leukemia and unfavorable prognostic features. Report of Children's Cancer Study Group Study CCG-193P

The Children's Cancer Study Group's (CCG) clinical trials in acute lymphoblastic leukemia (ALL) prior to 1981 consistently demonstrated that patients presenting with a white blood cell count (WBC) greater than or equal to 50,000/microliter or the "lymphoma syndrome" had a less than 40% 3-year event-free survival (EFS). The Berlin Frankfurt Munster (BFM) 76/79 study suggested that the prognosis of these patients could be improved. Before testing this therapy in a randomized setting, 29 CCG institutions used it for treatment of 209 newly diagnosed children with ALL and an initial WBC greater than or equal to 50,000/microliter or the lymphoma syndrome. In the intensive phases of therapy, 77% of cumulative parenteral doses and 55% of cumulative oral doses were within 10% of protocol requirements or were modified appropriately for reported toxicity. One hundred ninety-five patients achieved remission (93.3%). Eleven patients died in remission (5.6%)--10 during the intensive reinduction/reconsolidation phase. The 4-year EFS (+/- 1 SD) was 62% (+/- 3.7%) with a median follow-up of 40 months. Only one patient has had an isolated CNS relapse. These results appear superior to past CCG studies for high-risk patients and extend observations made from studies of similar therapy.     

Extramedullary infiltration at diagnosis and prognosis in children with acute myelogenous leukemia

BACKGROUND: Extramedullary infiltration (EMI) is an occasional clinical symptom in childhood acute myelogenous leukemia (AML), but there is considerable controversy regarding the prognostic significance of EMI in AML. PROCEDURE: We evaluated the frequency and prognostic significance of EMI at diagnosis of AML in children. RESULTS: Of 240 cases of de novo AML excluding children with Down syndrome and acute promyelocytic leukemia, 56 (23.3%) showed EMI at diagnosis. Patients with EMI had a higher initial WBC count and a higher proportion of M4/M5 morphological variants. The complete remission rate following induction chemotherapy was lower in patients with EMI. However, the overall survival and event-free survival did not differ between patients with and without EMI. A detailed analysis showed that patients with EMI with a WBC count at diagnosis of over 100 x 10(9)/L or infiltration into the central nervous system are likely to have a poor prognosis. CONCLUSIONS: CNS leukemia and EMI together with a WBC count of >100 x 10(9)/L at diagnosis of AML are high risk factors for relapse, and alternative treatment approaches for patients with these characteristics should be explored.     

A Population-Based Study of Children with Standard Risk Acute Lymphoblastic Leukemia in the Five Nordic Countries

ABSTRACT. Two hundred and thirty children with standard risk acute lymphoblastic leukemia (ALL) were diagnosed during a period of 3 years from July 1, 1981 to June 30,1984 in the five Nordic countries. Criteria for standard risk ALL were age above 2.0 and below 10 years, WBC <20×10⁹/l, no evidence of CNS-involvement, mediastinal mass or T- or B-cell leukemia. The children were treated without prophylactic CNS irradiation, the majority (200 patients) according to two treatment programs. Follow-up of the entire group after a minimum of 30 months showed 64% of the children living in complete continuous remission with a probability of event-free survival of 0.60. The treatment results are not entirely satisfactory and intensification of therapy is required. A subgroup of patients with WBC between 10 and 20×10⁹/I and with adverse prognosis was identified, justifying a change of the present criteria for risk grouping.     

A population-based study of childhood acute lymphoblastic leukemia diagnosed from July 1981 through June 1985 in the five Nordic countries. Incidence, patient characteristics and treatment results

Six hundred and fifty-six children with acute lymphoblastic leukemia (ALL) have been diagnosed in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) during the period from July 1981 through June 1985. Annual incidence of ALL was 3.6/100,000 children aged less than 15 years, with an incidence for males of 3.8 and for females of 3.4 respectively. Half of the children were younger than 5 years of age at diagnosis, with a peak incidence between 2-3 years of age. The leukemias were classified as Standard Risk (SR), Intermediate Risk (IR) or High Risk (HR) leukemia according to prognostic criteria at diagnosis. The remission rate was 95%. In children greater than or equal to 1 year of age with non-B-cell ALL at diagnosis, the Event-Free Survival (EFS) was 0.58; 0.65 for SR-children, 0.51 for IR-children and 0.52 for HR-children. WBC count at diagnosis was the most important prognostic factor and a WBC count of 11-20 X 10(9)/l was associated with the worst prognosis of all WBC values (EFS = 0.30), independent of other prognostic factors. Male sex was the second most important adverse prognostic criterion. The follow-up in January 1986 (observation time 6-54 months), showed that 442 of the 656 children (67%) were in complete continuous remission. The total results indicate a possibility to improve the prognosis for most of the risk groups of ALL with a more intensive treatment.     

Acute lymphoblastic leukaemia under 2 years.

Presenting features and natural history were assessed in 48 children with acute lymphoblastic leukaemia less than 2 years of age at diagnosis. Of these, 16 were less than 1 year (group 1) and 32 were between 1 and 2 years (group 2). Results were compared with a group of 348 children between the ages of 2 and 14 years (group 3) diagnosed over the same period. The children in group 1 presented with a higher prevalence of null cell acute lymphoblastic leukaemia, leucocyte counts greater than 100 X 10(9)/l, and hepatosplenomegaly and had a higher central nervous system (CNS) relapse rate and shorter duration of remission than those in the other two groups. Disease free survival and overall survival in group 2 paralleled that of group 3, although children in group 2 had a significantly higher CNS relapse rate. Neurological toxicity resulting from treatment with methotrexate and radiation was common in those under 2 years as a whole. In conclusion, children under 1 year have a particularly poor prognosis, while those between 1 and 2 years have a prognosis similar to that in the older age group. Alternative approaches to CNS prophylaxis are needed to reduce the high prevalence of CNS disease and toxicity.     

Bone marrow relapse occurring as first relapse in children with acute lymphoblastic leukemia

In a retrospective review which covered the whole Dutch childhood population of approximately 3 million children we studied the prognosis in 164 children with acute lymphoblastic leukemia (ALL) who were initially treated between 1973 and 1983, and who had an isolated bone marrow relapse occurring as first relapse. Until their first relapse, the patients were initially treated according to standard protocols, while treatment for relapse was heterogeneous, and not intensive. Second complete remission (CR) was attained by 78% of the patients. The median duration of second CR was 9 months, the median survival 13 months. Multivariate analysis showed that the duration of the first CR was the most significant variable with regard to prognosis. None of the patients who developed their bone marrow relapse during initial treatment, i.e., within 24 months from diagnosis, survived. Among the 73 patients who relapsed after cessation of the initial treatment there were 19 long-term disease-free survivors, 14 of whom had not developed subsequent relapses after 48+-125+ months. From this study we conclude that treatment in children with first bone marrow relapse has to be intensified.     

Lymphocytic leukemia in children: prognostic significance of clinical and laboratory findings at time of diagnosis.

Forty-eight children with untreated acute lymphocytic leukemia were evaluated with regard to their clinical presentation and the surface membrane characteristics, mitogen responsiveness, and cytochemical staining features of their lymphoblasts. The presence at diagnosis of 20% or more bone marrow lymphoblasts possessing T-cell surface markers was associated with the development of early relapse and death. Age, sex, initial peripheral leukocyte count (WBC), lymph node enlargement or the presence of hepato- or splenomegaly bore no statistically significant relationship to the patient's lymphoblast type, and only a WBC in excess of 10(5)/microliter correlated with a poor prognosis. Leukemic T-cells were found to be periodic acid-Schiff negative from nearly all patients, helping to distinguish such patients from the larger group of children whose leukemic cells were PAS positive, but negative for T-cell membrane features. In those patients who had multiple relapses, the surface membrane characteristics, staining features, and mitogen responses of their lymphoblasts remained constant. This suggests that relapse occurs in the same clone of malignant cells present at diagnosis and that the above features may be reliably used to evaluate and classify patients beyond the time of diagnosis.     

Prognostic factors for relapsed childhood acute lymphoblastic leukemia: impact of allogeneic stem cell transplantation--a report from the Kyushu-Yamaguchi Children's Cancer Study Group

BACKGROUND: The treatment results of childhood acute lymphoblastic leukemia (ALL) with a first relapse were retrospectively analyzed to determine prognostic factors. In particular, an attempt was made to clarify whether stem cell transplantation (SCT) had any advantages over chemotherapy. PROCEDURES: Of the 407 children with ALL diagnosed between 1984 and 1996, 117 suffered from a relapse before December 1999. The patients were treated differently according to the protocols of each institution. The potential prognostic factors examined were: the time of initial diagnosis, gender, immunophenotype of leukemic blasts and the NCI-risk classification at initial diagnosis, the site of relapse, the time of relapse (early: within 18 months after diagnosis, intermediate: other than either early or late relapse, late: later than 6 months after the discontinuation of front-line chemotherapy), and the treatment after relapse (chemotherapy alone and SCT). RESULTS: A second complete remission (CR2) was achieved in 90 patients (77%) and thirty of them maintained CR2, thus resulting in an event-free survival rate (EFS) of 25.1% and an overall survival rate of 26.1%. The significant prognostic factors identified by a multivariate analysis included the time of relapse (EFS: early 16.2%, intermediate 23.9%, late 35.1%, P = 0.012) and the treatment after relapse (EFS: SCT 30.3%, chemotherapy 22.0%, P = 0.049). When patients with an isolated bone marrow relapse and continuous CR2 for more than 3 months were analyzed, the treatment in CR2 was the only independent prognostic factor (EFS: SCT 60.2%, chemotherapy 25.7%, P = 0.005). CONCLUSIONS: In children with ALL and a first relapse, the time of relapse and the treatment after relapse were found to be independent prognostic factors. Allogeneic SCT in CR2 showed significantly better results than chemotherapy in patients with an isolated bone marrow relapse.     

Clinical and biologic features predict poor prognosis in acute lymphoid leukemias in children and adolescents: a Pediatric Oncology Group review

Although the prognosis of children with ALL has improved markedly, approximately one-half of children continue to relapse. Clinical and biologic features of ALL have been studied at the time of diagnosis and many of these features have been shown to predict the risk of relapse, permitting tailoring of therapy based on relapse hazard. Results of studies of the Pediatric Oncology Group (POG) detailed here demonstrate that high white blood cell (WBC) count at diagnosis, very young or older age within childhood, and the presence of a mediastinal mass or central nervous system leukemia predict a poor prognosis within the context of certain therapies. However, not only age and WBC count, but immunophenotype of ALL as well, were especially predictive of prognosis in these POG studies. The information reviewed here has special importance for the planning of clinical trials for children with ALL.     

Delayed craniospinal irradiation for a first isolated central nervous relapse of acute lymphoblastic leukemia: report on 14 cases

BACKGROUND: Children developing an isolated central nervous system (CNS) relapse as first recurrence of their acute lymphoblastic leukemia (ALL) are considered to have a systemic relapse as well. They are mostly treated with intensive chemotherapy and craniospinal irradiation. In most treatment schedules, irradiation is given early after induction treatment. Because craniospinal irradiation affects a large portion of hematopoietic bone marrow systemically, treatment is often delayed owing to aplasias. Also, dose reductions are frequently needed. Children receiving simultaneously irradiation and chemotherapy are prone to (often severe) neurotoxicity. This study reports on children with a first isolated CNS relapse of their ALL receiving chemotherapy for 40 weeks. Treatment ends with the administration of irradiation given after cessation of chemotherapy. PROCEDURE: Fourteen children, with blasts and >5 cells/mm(3) in two consecutive samples of cerebrospinal fluid and a blast percentage <5% in their bone marrow were treated according to an intensive systemic and site-specific chemotherapy. Craniospinal irradiation was administered after cessation chemotherapy. RESULTS: Event-free-survival was 57% (confidence interval 35-89%), freedom from relapse was 61.5%; follow-up ranges from 2.0 to 15.1 years (median 11.7 years). One child died from septicemia during induction. Five children experienced a second relapse and died from their malignancy. Two children [with a t(9;22) or a rearranged MLL gene] relapsed prior to radiotherapy. Outcome was related to duration of first remission, age at relapse, and identification as a high-risk patient at initial diagnosis. No neurologic complications were noted during and after treatment. CONCLUSIONS: Delayed irradiation for isolated CNS relapse in children with ALL gives favorable survival rates, without significant toxicity. Neurotoxicity was absent.     

Prognosis after Relapse in Acute Lymphoblastic Leukemia in Childhood

This is a survey of all the 265 relapses occurring in 515 children with ALL diagnosed in Sweden in the years 1973-1980. Two hundred and nineteen relapses occurred on therapy, and 46 after discontinuation of therapy. Bone marrow was involved in the relapse in 71% and 67% of the two groups, respectively. Only 38/265 (14%) children with relapse were still alive at follow-up in January 1985. Of these, 16/219 (7%) had relapsed during therapy (median survival time after relapse 9 months) compared to 22/46 children (48%) with a relapse after cessation of therapy (median 43 months). The prognosis was better if relapse occurred after cessation of therapy and in children with isolated testicular relapse. Thirteen children were bone marrow transplanted, and 6 of these were alive at follow-up. It is concluded that children with ALL relapse have very bad prognosis with cytostatic regimens used today, especially if the bone marrow is involved.     

PROGNOSTIC VALUE OF DAY 14 BLAST PERCENTAGE AND THE ABSOLUTE BLAST INDEX IN BONE MARROW OF CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

This study included all 690 children in Norway diagnosed as having acute lymphocytic leukemia (ALL) from July 1975 till the end of 1997. Relapses and deaths were monitored until the end of 2000. Neuroleukemia prophylaxis was intravenous methotrexate (MTX) infusions as intermediate-dose methotrexate (IDM) or high-dose methotrexate (HDM) combined with intrathecal MTX. From 1992, systemic therapy was considerably intensified, and, in addition, patients in a subgroup of the high-risk and very high-risk groups were given prophylactic cranial irradiation. The overall findings showed that MTX significantly reduced central nervous system (CNS)-related relapses, and, in general, reinforced systemic therapy reduced significantly non-CNS relapses and deaths. The overall crude survival was 75%. During the study period, the crude survival improved for patients on standard protocols from initially 65 to 90%. Forty patients (6%) developed isolated CNS relapse, 27 (4%) had combined CNS relapse, whereas 180 (26%) had non-CNS relapse. When IDM and HDM were compared, the cumulative risk for isolated CNS relapse was significantly lower with HDM, 12 and 5%, respectively. For any relapses that involved the CNS, the risk remained significantly lower for HDM, 8 versus 18%. Of the 40 patients with isolated CNS relapse, 23 survived (58%).     

Methotrexate infusions as central nervous system prophylaxis in children with acute lymphocytic leukemia: the Norwegian experience

This study included all 690 children in Norway diagnosed as having acute lymphocytic leukemia (ALL) from July 1975 till the end of 1997. Relapses and deaths were monitored until the end of 2000. Neuroleukemia prophylaxis was intravenous methotrexate (MTX) infusions as intermediate-dose methotrexate (IDM) or high-dose methotrexate (HDM) combined with intrathecal MTX. From 1992, systemic therapy was considerably intensified, and, in addition, patients in a subgroup of the high-risk and very high-risk groups were given prophylactic cranial irradiation. The overall findings showed that MTX significantly reduced central nervous system (CNS)-related relapses, and, in general, reinforced systemic therapy reduced significantly non-CNS relapses and deaths. The overall crude survival was 75%. During the study period, the crude survival improved for patients on standard protocols from initially 65 to 90%. Forty patients (6%) developed isolated CNS relapse, 27 (4%) had combined CNS relapse, whereas 180 (26%) had non-CNS relapse. When IDM and HDM were compared, the cumulative risk for isolated CNS relapse was significantly lower with HDM, 12 and 5%, respectively. For any relapses that involved the CNS, the risk remained significantly lower for HDM, 8 versus 18%. Of the 40 patients with isolated CNS relapse, 23 survived (58%).     

A Population-Based Study of Childhood Acute Lymphoblastic Leukemia Diagnosed from July 1981 through June 1985 in the Five Nordic Countries

Six hundred and fifty-six children with acute lymphoblastic leukemia (ALL) have been diagnosed in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) during the period from July 1981 through June 1985. Annual incidence of ALL was 3.6/100000 children aged < 15 years, with an incidence for males of 3.8 and for females of 3.4 respectively. Half of the children were younger than 5 years of age at diagnosis, with a peak incidence between 2–3 years of age. The leukemias were classified as Standard Risk (SR), Intermediate Risk (IR) or High Risk (HR) leukemia according to prognostic criteria at diagnosis. The remission rate was 95%. In children 1 year of age with non-B-cell ALL at diagnosis, the Event-Free Survival (EFS) was 0.58; 0.65 for SR-children, 0.51 for IR-children and 0.52 for HR-children. WBC count at diagnosis was the most important prognostic factor and a WBC count of 11-20×10⁹/l was associated with the worst prognosis of all WBC values (EFS=0.30), independent of other prognostic factors. Male sex was the second most important adverse prognostic criterion. The follow-up in January 1986 (observation time 6–54 months), showed that 442 of the 656 children (67%) were in complete continuous remission. The total results indicate a possibility to improve the prognosis for most of the risk groups of ALL with a more intensive treatment.