PART II. SURVIVAL AFTER RELAPSE DURING UNMAINTAINED REMISSION AND AFTER SECOND CESSATION OF THERAPY

Nygaard, R. and Moe, P. J. (Department of Paediatrics, University Hospital, Trondheim, Norway). Outcome after cessation of therapy in childhood leukemia. A population-based Nordic study of 986 patients. II. Survival after relapse during unmaintained remission and after second cessation of therapy. Acta Paediatr Scand Suppl 354: 20, 1989.
This is the second part of a population-based investigation of 986 patients after discontinuation of therapy for childhood leukemia. Patients who had their first relapse after cessation of therapy ( n =206) were studied for subsequent outcome in terms of survival after relapse. The patients with ALL ( n =191) were also analyzed according to patient variables with possible influence on survival. Fifty-one (26.7%) of the patients with relapse of ALL electively stopped therapy once more, and for them subsequent survival in remission was evaluated.
The overall estimated proportion alive at five years after relapse in unmaintained remission was 0.37 and at ten years 0.28. There was no significant difference in survival after relapse for males vs. females, and this could be attributed to the fact that isolated testicular relapses carried a better chance of subsequent survival than did relapses in other sites. Age at relapse did not have any influence on survival. However, time from cessation of therapy to first relapse was of prognostic value: Patients who relapsed within 6 months had a signifcantly lower survival than did those with relapse after longer periods in unmaintained remission.
Five-year DFS was 0.57 after second cessation of therapy in patients with ALL. Our study confirms that there may be more than one chance of cure.     

Extramedullary recurrence of acute lymphoblastic leukemia 15 years after initial diagnosis

We describe a 19-year-old man with recurrence of a lymphoid malignancy involving the ethmoid sinus 15 years following diagnosis and 10 years after discontinuation of therapy for childhood acute lymphoblastic leukemia (ALL). The cytologic appearance and immunologic phenotype of the tumor cells suggest that this malignancy represents a recurrence of his original tumor. Initial relapse of ALL is unusual after 4 years of continuous remission off therapy. This case illustrates that late relapse can occur and may present with unusual sites of involvement.     

Children cured of acute lymphoid leukemia. Long-term follow-up studies, including progeny

The subject of analysis is a group of 111 children with acute lymphoid leukemia (ALL) whose remission has lasted at least 4 years since stopping treatment. Patients were observed from 4 to 18 years after ALL therapy. No symptoms of disease were observed in 110 children; one child had leukemic infiltration of the testes during the fifth year after stopping treatment. In this group of children no changes in physical development have been recorded, but a growth deficiency is sometimes noted. No symptoms of intrinsic organ lesions have been ascertained in most of the patients. All of the patients, except one with schizophrenia, lead normal lives and either attend school or go to work. Seven patients have healthy children, who were born 6-24 years after the beginning of the disease and 3-16 years after cessation of therapy.     

Asymptomatic leukemic-cell infiltration of the pancreas: US findings

Pancreatic infiltration of leukemic cells is a very rare manifestation at the onset of acute lymphoblastic leukemia (ALL) in childhood. Pancreatic enlargement in this situation is unusual and pancreatic involvement is often associated with biliary obstruction, cholestasis and pancreatitis. We report a 3-month-old girl who presented with asymptomatic leukemic infiltration of the pancreas, demonstrated by US with heterogeneous pancreatic enlargement associated with multiple hypoechogenic lesions, without cholestasis. Although these manifestations are rare, ALL should be considered a cause of pancreatic enlargement.     

Long-term second remission in acute leukemia of childhood (author's transl)

Report on a case of acute childhood leukemia, who presents with the following exceptional features: During complete remission early bilateral leukemic infiltrations of the testes, followed--after an intervall of several months--by a serve, general relapse with ascites. New induction therapy resulted in a second complete remission, persisting for the next 8 years with 6MP as well as after cessation of therapy until up to more than 17 years. Comparable courses are not as yet on record.     

Diabetes Insipidus 9 Years after Cessation of Therapy for Acute Lymphoblastic Leukemia

A case of a 16-year-old who developed diabetes insipidus (DI) 9 years after cessation of therapy for ALL is reported. Because hereditary and traumatic factors are excluded as a cause of DI in this patient, possible explanations may be leukemic CNS relapse, secondary brain tumor, primitive idiopathic DI, and late sequelae of CNS radiochemotherapy.     

儿童急性淋巴细胞白血病184例分析

目的分析2001-2010年在本院住院的初发急性淋巴细胞白血病(ALL)患儿的病历资料,为儿童ALL的防治提供参考依据。方法回顾性分析184例初发ALL患儿的临床资料。结果初发ALL患儿年就诊例数由2001年的8例上升到2010年的28例,平均年增长率为13.3%。男女性别比例为1.75∶1。儿童初发ALL的年龄分布以2～7岁组最多,起病时临床表现各不相同,其中T-ALL 33例(17.9%),伴有髓系抗原表达2例;B-ALL 151例(82.1%),伴有髓系抗原表达11例。染色体异常47例(47/156),融合基因异常9例(9/20)。发病季节上差异无显著性。184例中92例接受治疗,化疗缓解率96.7%。化疗后合并感染率38.8%。结论本院初发儿童ALL的就诊病例数呈逐年上升趋势,加强儿童白血病的防治尤其重要。提高白血病患儿的治疗依从性,亦是目前应高度重视和亟待解决的问题。     

Clinical and cytokinetic aspects of remission induction of childhood acute lymphoblastic leukemia (ALL): addition of an anthracycline to vincristine and prednisone.

Fifty-six untreated patients with childhood with acute lymphoblastic leukemia (ALL) were randomized to receive one of three remission induction regimens: vincristine and prednisone (VP), vincristine, prednisone and daunorubicin (VPD), or vincristine, prednisone and adriamycin (VPA). The complete remission rate was similar for all three groups. Although the anthracycline regimens caused somewhat more rapid leukemic cell reduction than the VP only group, this difference was not significant. Labeling index reduction between study days 1 and 5 was significantly greater (p less than 0.001) with an anthracycline than for the VP group, but there was no difference between the two anthracyclines. Granulocytopenia during induction was significantly increased (p less than 0.05) in both the VPD and VPA groups as compared with VP alone. A significantly higher rate of infectious morbidity (p less than 0.01) was associated with the addition of either anthracycline, but to date no significant differences in remission duration or survival have been observed. The addition of anthracyclines to VP for remission induction in childhood ALL has theoretical advantages, but may be undesirable because of increased morbidity.     

Clinical and cytokinetic aspects of remission induction of childhood acute lymphoblastic leukemia (ALL): Addition of an anthracycline to vincristine and prednisone

Fifty-six untreated patients with childhood with acute lymphoblastic leukemia (ALL) were randomized to receive one of three remission induction regimens: vincristine and prednisone (VP), vincristine, prednisone and daunorubicin (VPD), or vincristine, prednisone and adriamycin (VPA). The complete remission rate was similar for all three groups. Although the anthracycline regimens caused somewhat more rapid leukemic cell reduction than the VP only group, this difference was not significant. Labeling index reduction between study days 1 and 5 was significantly greater (p < 0.001) with an anthracycline than for the VP group, but there was no difference between the two anthracyclines. Granulocytopenia during induction was significantly increased (p < 0.05) in both the VPD and VPA groups as compared with VP alone. A significantly higher rate of infectious morbidity (p < 0.01) was associated with the addition of either anthracycline, but to date no significant differences in remission duration or survival have been observed. The addition of anthracyclines to VP for remission induction in childhood ALL has theoretical advantages, but may be undesirable because of increased morbidity.     

Hodgkin lymphoma as second malignancy during continuing chemotherapy for childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy in most parts of the world with a 5-year survival rate above 70%. Long-term survivors are at risk for treatment-related late effects and second malignant neoplasms (SMNs). SMNs occur with a mean latency of 6-6.7 years after ALL diagnosis but are rarely observed during maintenance chemotherapy (CT). Hodgkin lymphoma (HL) as a complication of ALL is very rare. We report two children with ALL who developed HL while receiving maintenance CT. Both received appropriate chemo- and radiotherapy (CT/RT) and have survived for more than10 years.     

Isolated bone relapse in a child with acute lymphoblastic leukemia off-therapy

Osseous relapse, as distinct from bone marrow relapse, is possible during treatment of childhood leukemia. The authors have observed an isolated leukemic bone lesion in an 8-year-old boy in complete bone marrow remission after a second full course of chemotherapy for a testicular leukemic localization. The radiological signs in our case are peculiar because a small bone of the foot (right talus) showed an increased density instead of rarefaction; histological examination demonstrated leukemic bone infiltration. Local radiotherapy (2400 cGy) was given and multidmg induction and maintenance for one year. Two years after the histological diagnosis the child is still in complete remission. This observation suggests that structural bone may be a sancturay site for leukemic cells.     

INTERMEDIATE DOSE METHOTREXATE (IDM) IN CHILDHOOD ACUTE LYMPHOCYTIC LEUKEMIA IN NORWAY

Abstract. Moe, P. J., Seip, M. and Finne, P. H. (Departments of Paediatrics, Universities of Trondheim and Tromsø, Department of Paediatrics, Rikshospitalet, Oslo and Department of Paediatrics, University of Bergen, Bergen, Norway). Intermediate dose methotrexate (IDM) in childhood acute lymphocytic leukemia in Norway. Acta Paediatr Scand, 70:73, 1981–Preliminary results of a national treatment program. The main objectives of this study were: 1. To determine whether early start of CNS prophylaxis with intrathecal methotrexate during induction treatment, followed by three courses of IDM plus intrathecal methotrexate after remission has been obtained, offers adequate protection against CNS-leukemia. 2. To determine whether the use of IDM with leukovorin rescue as “sanctuary” therapy following remission reduced the incidence of sanctuary relapse and thereby also the incidence of hematological relapse. It has proved possible to institute this program on a national basis with good results, even in small departments treating 0–3 new cases of leukemia a year. Sixty-six children (38 boys, 28 girls) with acute lymphocytic leukemia (ALL), diagnosed in the years 1976-78, had received IDM while they were in complete primary remission. During the same period 13 additional cases of ALL were diagnosed in Norway, 4 (5% of 79 cases) of whom did not achieve complete remission, while 4 died early from infections, one received no treatment, and 4 were treated with other protocols. Life tables of patients in complete continuous remission (CCR) and survival tables are presented for standard risk patients and increased risk patients, respectively, and for all 66 together. Among these 66, 40 had been observed for 2½ years or more by January 1980. Of these 29 (72.5%) were still in CCR, and in 24 antileukemic treatment had been discontinued. So far there has been a total of 7 systemic, 2 CNS and 1 combined systemic and CNS relapses among the 66 cases diagnosed in the period 1976-78. No testicular or other sanctuary relapses have been seen among these 66 cases, nor among the remaining 13 cases with the diagnosis of ALL in childhood in Norway during the years 1976-78. The cessation rate of antileukemic treatment will probably be 70–75 % of all cases receiving IDM while in complete remission, and about 60 % of the total material diagnosed in 1976-78 as ALL in childhood in Norway.     

Fine Needle Aspiration Cytology (FNAC) of the Testes in Childhood Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma: Preliminary Report

Eighteen patients with childhood acute lymphoblastic (ALL) or non-Hodgkin's lymphoma (NHL) in remission and 2 patients with ALL in suspected testicular relapses were studied by testicular fine needle aspiration cytology (FNAC). Well-preserved testicular cells, both singly and in small clusters, were considered indicative of an adequate aspiration. Of 18 patients in remission, 17 had at least one adequate sample from each testis and one showed evidence of leukemic infiltrate. None of these patients experienced a relapse during a median follow up of 4 years. In 2 other patients with clinically suspected testicular relapses, the smears from fine needle aspirates contained numerous malignant lymphoid cells that could be readily distinguished from seminiferous tubular cells. The observations indicate that FNAC is a promising new approach to study testicular conditions in childhood ALL and NHL. A larger prospective study and accumulation of additional follow-up data is required before a definitive evaluation of the technique can be made.     

Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: A 10-year follow-up study

The outcome of 171 children with ALL who relapsed for the first time after elective cessation of therapy (1–86 mo) and followed over 10 years (median 60 mo; range 1–232 mo) has been evaluated. One hundred and three patients relapsed in the bone marrow (BM), 29 in the testis (T), 21 in the central nervous system (CNS), 14 in the BM plus another site and 4 in other sites. Second remission was achieved in 97% of patients (97% BM, 100% T, 90% CNS, respectively) with reinduction schedules including three or more drugs. All but 4 out of 100 patients who relapsed in the BM received cranial reprophylaxis with intrathecal CT alone or CT plus radiotherapy. Seven patients in second CR underwent allogeneic bone marrow transplantation from an HLA matched sibling. The overall survival was 34% and disease-free survival (DFS) probability at 100 years was 22%. A second relapse was observed in 73% of patients. Forty children are alive in second continuous remission and 24 are alive after a second or subsequent relapse. Patients with isolated T relapse showed a significant better outcome than those with BM or CNS involvement. Most patients (62%) with isolated BM relapse showed a further disease recurrence in BM, and DFS was shorter when relapse occurred within 12 months from off-therapy. Eighty-two patients in second CR stopped the treatment a second time and showed a survival and DFS probabilities, respectively, of 69% and 43%. Thus, children with ALL who relapse after cessation of therapy still have a high risk of further late relapses and should be treated with intensive chemotherapy and CNS reprophylaxis. BMT must be considered for all patients relapsing in the BM within 12 months from off-therapy. © 1995 Wiley-Liss, Inc.     

Letter to the editor: Ifosfamide nephrotoxicity in children

An 11-year-old boy with prior bone marrow and testicular relapses of his acute lymphoblastic leukemia (ALL) developed an isolated metatarsal bone relapse during complete hematologic remission 10 months after completion of chemotherapy. Although there was no radiographic or histologic evidence of additional occult leukemia, the polymerase chain reaction (PCR) technique detected a leukemic clone in both his bone marrow and metatarsal. A literature survey revealed only 10 reported cases of isolated bone relapse occurring during complete bone marrow remission in childhood ALL. Most of these patients had prior bone marrow or extramedullary relapses. The majority experienced subsequent relapses after their isolated bone recurrence. We report a case of isolated bone recurrence, review all previously reported cases, and suggest that PCR elucidation of clonal disease may provide a better understanding of these extremely rare extramedullary events. © 1994 Wiley-Liss, Inc.     

Prolonged second remissions in childhood acute lymphocytic leukemia: A report from the childrens cancer study group

To date, median duration of second and subsequent remissions in childhood acute lymphocytic leukemia (ALL) has been short, with most studies reporting median remission duration less than 6 months. In May 1979, the Childrens Cancer Study Group (CCSG) undertook a pilot study to assess the efficacy of a vincristine, methotrexate, and L-asparaginase regimen (modified Capizzi) for maintenance in children with ALL in second or subsequent remission. Thirty patients were treated with this maintenance regimen. By life table analysis, predicted median duration of hematologic remission was 57 weeks. Ten patients (33%) were in continuous hematologic remission at 1 year and three (10%) continue in remission > 2 years from maintenance onset. Major toxicity included leukoencephalopathy in four patients, three of whom had experienced at least one central nervous system relapse prior to study entry. Allergic reactions to Escherichia coli L-asparaginase were common. Nine of 30 patients experienced at least one CNS relapse during therapy. We conclude that a modified Capizzi regimen is the most effective regimen reported to date for maintaining second and subsequent remission in childhood ALL. CCSG is currently utilizing this regimen in an ongoing open study.     

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of relapsed or poor risk childhood acute leukemia

The prognosis of relapsed acute leukemia or chronic leukemia in acute blast crisis is poor and new chemotherapeutic regimens could be useful for these patients. Six relapsed acute lymphoblastic leukemia (ALL), nine relapsed acute myeloblastic leukemia (AML), one chronic myelomonocytic leukemia (CMML) and one chronic myeloid leukemia (CML) in acute blast crisis between three to 18 years (median 10 years) received fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) chemotherapy (CT). Five of the AML relapses were after bone marrow transplantation (BMT) and four were recurrent relapses. At the end of the second course only three patients (2 AML, 1 ALL) were in complete remission (CR). Of the three patients in CR, one patient with AML had her first donor lymphocyte transfusion (DLT) on the 7th day of the second FLAG-IDA course and she is disease-free on the 30th month of the second remission. The remaining two patients were transplanted from unrelated donors in a BMT center abroad on the 5th and 8th month of the last remission and both died with BMT-related complications. Out of 25 courses, seven resulted in fatal infections. The regimen was ineffective in B-cell ALL as in acute blastic crisis of CMML and CML. We could not evaluate the remission-inducing effect accurately in most of the patients due to induction failure. FLAG-IDA appears to be a myelotoxic therapy for relapsed or poor risk leukemia in a developing country. It is not cost-effective; dose modifications or a regimen without IDA may be tried if there is an available marrow donor.     

Growth patterns and final height of survivors of childhood leukemia

Growth patterns of 85 survivors of childhood leukemia were analyzed retrospectively. All patients remained in first remission with no central nervous system involvement. The mean age at diagnosis was 5.8 +/- 3.6 years. The diagnoses were acute lymphoblastic leukemia (ALL) in 68 patients (80%) and acute non-lymphoblastic leukemia (ANLL) in 17 patients (20%). All except two patients received cranial irradiation: 51 patients with 1,800 cGy and 32 patients with 2,400 cGy. Mean height SDS was -0.7 +/- 1.36 at the time of diagnosis, which decreased to -0.92 +/- 1.31 by the end of treatment, and further decreased to -1.14 +/- 1.38 at 6 years after cessation of treatment. Mean weight SDS was -0.55 +/- 1.13 at the time of diagnosis, increasing slightly to -0.39 +/- 1.02 at the end of treatment, and decreasing to -0.46 +/- 1.65 at 6 years after cessation of treatment. Of these survivors, 51 patients (26 boys and 25 girls) reached a final height that was 1.04 SDS or 5.3 cm less than their target height. There was no difference of height and weight SDS between patients with ALL and ANLL. Girls and boys had different growth patterns. Girls had a slightly increased height SDS and gained more weight after cessation of treatment, resulting in less final height deficit and overweight for height, whereas boys had further height and weight reduction resulting in more deficit of final height.     

Acute myelogenous leukemia in children: a preliminary report of combination chemotherapy.

Twenty-four children (2 to 21 years) diagnosed as having AML from 1969 to 1972 were randomized to receive either a single combination (COMP or PRAVD) or sequential combination chemotherapy (alternating POMP and PRAVD). Seventeen achieved complete remission. Patients who received POMP alone had the longest median duration of remission (1,400 days) compared to PRAVD (395 days) or POMP-PRAVD (270 days); interpretation of this difference is uncertain, since the numbers in each group are small. Fifteen patients have relapsed, four initially with CNS involvement. Successful reinduction was achieved almost exclusively for patients who had initially received POMP. Survival after first relapse was short. Patients less than 16 years had a median survival of 632 days, compared to 285 days for patiens greater than 16 (p less than 0.05). The high initial induction rate in these patients is encouraging, but the duration remission is inferior to that seen in childhood ALL. Moreover, the slope of the relapse curve is continuous over a five-year period with no definite plateau where it might appear that patients are no longer at risk of relapse. Improved methods for the treatment of childhood ALL and adult AML suggest possible new approaches to AML in children, with prophylactic treatment of central nervous system, late intensification, and immunotherapy.