Relapses after termination of therapy of acute lymphoblastic leukemia in children

In the past 16 years, 2004 children with acute lymphoblastic leukemia (ALL) have been treated in the Polish Pediatric Group centers. Eight hundred and eighty-seven (44.3%) of these patients discontinued treatment after the first remission. Acute lymphoblastic leukemia relapse occurred in 180 patients (20.3%). This group was analyzed for the method of treatment and its influence on long-term survival, the time between cessation of treatment and relapse, the character and localization of relapse and later follow-up. It was shown that the patients with the best chance of a second remission are those with late testicular relapse. The most frequent and prognostically poor are bone marrow (BM) relapses which warrant intensive chemotherapy with BM transplantation. Patients with ALL relapse still have the possibility of a second remission and long-term survival.     

Long-term survivors of acute lymphoblastic leukemia — risk of relapse after cessation of therapy

The results of cessation of therapy (COT) in 64 long-term survivors (disease-free survival of five years or more) of acute lymphoblastic leukemia (ALL) were analyzed to determine the incidence of relapse off therapy. Thirty-seven of the patients had intermittent central nervous system (CNS) prophylaxis. Total follow-up from diagnosis varied from 5.75 to 27.75 years. The median time off therapy was three years (range, 8 months to 26 years). Eighty-six percent (55/64) of the patients continue in their initial remission. Eight patients had relapse, and one patient had a morphologically different leukemia at recurrence. All the relapses occurred between five to eight years from diagnosis and the cumulative rate of relapse for this period was 0.14. There was no significant difference in the rate of relapse for those receiving CNS prophylaxis (0.08) versus those not receiving CNS prophylaxis (0.19). The difference in the relapse rates for boys (0.24) versus girls (0.04) was statistically significant (P=0.04). Isolated testicular relapse (ITR) was not seen in any of the 34 boys. The present study confirms the earlier observations by others that relapse is uncommon in ALL patients remaining in remission longer than seven to eight years. ALL patients treated with intermittent CNS prophylaxis administered throughout the period of maintenance chemotherapy appear to be at no greater risk for relapse off therapy than those treated with high-dose initial cranial irradiation and intrathecal methotrexate. The longer duration of therapy and the use of a repetitive reinduction regimen for maintainance seem to be associated with a decreased risk of ITR after discontinuation of therapy for boys and men. There appears to be a small but definite risk of “second” leukemia in the long-term survivors of leukemia.     

Relapse in childhood acute lymphoblastic leukemia after elective cessation of initial treatment: Failure of subsequent treatment with cyclophosphamide,cytosine arabinoside,vincristine and prednisone (COAP)

Although the majority of children with acute lymphoblastic leukemia (ALL) can electively stop treatment after 21/2–5 years of continuous disease-free remission, 20–25% of those patients relapse after discontinuation of therapy. We treated 15 patients whose disease recurred after stopping treatment. Fourteen of them attained complete remission, but the median duration of disease-free survival was only 11 months. In this population, the site of initial relapse, bone marrow or testicle, did not influence subsequent outcome. Patients who relapsed within six months of stopping initial therapy had shorter second remissions than those who relapsed after six months. We conclude that the combination chemotherapy utilized in this study was inadequte for the control of relapsed ALL. Future programs will have to use different drug combinations or bone marrow transplantation.     

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.     

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.     

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.     

Isolated breast relapse after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia

Unusual sites of relapses following bone marrow transplantation (BMT) for childhood acute lymphoblastic leukemia (ALL) are rarely reported. We report the case of a 16-year-old girl who presented with an isolated right breast relapse 8 months after allogeneic BMT for ALL in second remission. Biopsy showed an ALL infiltrate. Bone marrow and CSF were normal. The girl never showed before extramedullary involvement. She was treated with local radiotherapy and mild systemic chemotherapy. Nine months after breast relapse, she presented an isolated central nervous system relapse. The treatment of isolated extramedullary relapses following BMT is still controversial.     

Isolated breast relapse after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia.

Unusual sites of relapses following bone marrow transplantation (BMT) for childhood acute lymphoblastic leukemia (ALL) are rarely reported. We report the case of a 16-year-old girl who presented with an isolated right breast relapse 8 months after allogeneic BMT for ALL in second remission. Biopsy showed an ALL infiltrate. Bone marrow and CSF were normal. The girl never showed before extramedullary involvement. She was treated with local radiotherapy and mild systemic chemotherapy. Nine months after breast relapse, she presented an isolated central nervous system relapse. The treatment of isolated extramedullary relapses following BMT is still controversial.     

高频度强化治疗儿童ALL远期疗效报道

为了提高ＡＬＬ的最终疗效,我们使用高频度强化治疗了我科收治的５例在经济上有能力承受的初治ＡＬＬ病人。方法：第一个化疗年内每个月一次强化治疗;第二化疗年每两个月一次强化治疗;第三个化疗年内每三个月一次强化治疗;第四个化疗年内每四个月一次强化治疗;第五个化疗年内半年一次强化治疗。强化化疗方案以ＣＯＤＰ（Ｌ）、ＣＯＡＰ、Ｖｍ２６＋ＡＲＡ－Ｃ、ＨＤＭＴＸ、ＡＲＡ－Ｃ＋Ｖｍ２６＋Ｃａｒｂｏ＋ＣＴＸ为主。结果：３例病人停药两年和１例停药一年以上,获得长期无病生存;两例髓外复发后骨髓复发,经再诱导化疗获完全缓解。总结：我们的结果表明：高频度强化治疗对获得ＬＴＤＦＳ是有益的,并没有导致耐药性的产生;疗程的缩短（２－３年）并没有影响疗效;本组病例数欠少,进一步扩大试验是必须的。     

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.     

Very late recurrence of childhood acute lymphoblastic leukemia treated with chemoimmunotherapy: a report of three cases occurring 19, 11, and 9 years after discontinuation of chemotherapy

Current therapeutic modalities for childhood acute lymphoblastic leukemia (ALL) are associated with a high cure rate, and recurrences more than 4 years after therapy cessation are very unusual. We report three cases of exceptionally late recurrences of childhood ALL after cessation of chemotherapy (CT) given for respective periods of 8, 7, and 24 months. CT was followed by maintenance immunotherapy (IMT) with Bacillus Calmette-Guérin (BCG) and allogeneic leukemic lymphoblasts pretreated with formaldehyde or irradiated in vitro. Leukemic recurrences were observed 19, 11, and 9 years after cessation of CT and appeared morphologically similar to the original blasts. A second complete remission was easily achieved in all three patients, but two went on to repeated relapse (one has died following the fourth recurrence). We speculate that some residual leukemic cells, remaining after the inadequate, short-term CT, were responsible for these unusual evolutions, and we question a possible delaying role of IMT in prolonging remission. Other possible etiologies are discussed.     

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.     

Lack of benefit of early detection of relapse after completion of therapy for acute lymphoblastic leukemia

BACKGROUND: Although most pediatric oncologists obtain routine blood counts in patients who have completed treatment for acute lymphoblastic leukemia (ALL), the value of this practice is unproven. We therefore sought to determine if detection of relapse by blood counts before the onset of symptoms provided any clinical benefit. PROCEDURES: We performed a retrospective review of 72 patients with ALL who suffered isolated or combined hematologic relapses after the completion of therapy. We compared attainment of second remission and survival after relapse among patients who were asymptomatic and diagnosed by routine blood count, those who had symptoms suggestive of relapse and were diagnosed at the time of a scheduled follow-up, and those whose relapse was diagnosed because of the appearance of symptoms. RESULTS: Only 11% of patients who suffered a relapse were asymptomatic at the time of relapse and diagnosed solely by routine blood counts. There were no significant differences in the survival distributions for the three groups of patients. CONCLUSIONS: In this cohort of patients with relapsed ALL, we found no evidence that detection of relapse by routine blood counts before the onset of symptoms leads to a better outcome.     

RALLE pilot: response-guided therapy for marrow relapse in acute lymphoblastic leukemia in children

Despite improved treatment results of childhood acute lymphoblastic leukemia (ALL), 20% to 30% have a relapse, and then the outcome is very poor. We studied 40 children with ALL marrow relapse piloting an ALL relapse protocol with well-known drugs and drug combinations by using a concept of response-guided design. We also measured response in logarithmic fashion. Our primary end points were achievement of M1 marrow status, minimal residual disease status below 10, and second remission. The remission induction rate was 90% with 10% induction mortality. After the A blocks (dexamethasone, vincristine, idarubicin and pegylated L-asparaginase), 85% had M1 status, 39% had minimal residual disease ≤1×10, and 66% had 2 to 3 log response. After B1 block (cyclo, VP-16) the figures were 92%, 58%, and 83%, respectively. Twenty-five of 40 patients received allogeneic stem cell transplantation. Three-year event-free survival of the whole cohort was 37%, and the relapse rate was 38%. Three-year event-free survival by risk group was 53% for late, 34% for early, and 21% for very early relapses. An ALL marrow relapse nonresponsive to steroids, vincristine, asparaginase, anthracyclines, and alkylating agents is uncommon, and these classic drugs can still be advocated for induction of ALL relapse. The problems lie in creating a consolidation capable of preventing particularly posttransplant relapses.     

Late relapses after treatment for acute lymphoblastic leukemia in childhood: a population-based study from the Nordic countries

Seven late relapses of acute lymphoblastic leukemia occurring 5.5 to 12.3 years after cessation of therapy are reported in 986 patients who had discontinued treatment for leukemia acquired before the age of 15. The study covers patients from the five Nordic countries. Of the 434 patients with ALL who had passed 5 years of follow-up without recurrence, seven have subsequently relapsed so far; an estimated cumulative proportion of 6.9% within the 10 years. In addition, we report a girl 15.9 years old at diagnosis who relapsed 7.3 years after cessation of therapy. These findings confirm that "cure" of acute lymphoblastic leukemia treated in the 1970s cannot be considered definite, even 5 years after discontinuation of therapy.     

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.     

High-dose chemotherapy and blood stem cell autografts for children with first relapsed acute lymphoblastic leukemia: A pilot study of the children's cancer and leukemia study group of Japan (CCLSG)

This study was performed to determine the value of high-dose chemotherapy and peripheral blood stem cell autografts (PBSCT) in the treatment of children with first relapsed acute lymphoblastic leukemia (ALL). Eighteen children underwent PBSCT during the second complete remission (CR) and had a minimum 10 month follow-up. The median age of the patients was 11 yr (range, 2–17 yr). Fifteen patients received the “MCVAC” regimen, one received high-dose MCNU + busulfan therapy, one received high-dose melphalan + VP-16, and one received melphalan + carboplatin + cytosine arabinoside + MCNU. None of these regimens included total body irradiation. Eight patients developed recurrence of the disease at 1 to 19 mo (median, 3 mo) after PBSCT. Patients in whom the first relapse occurred sooner, that is, within 16 mo of initial therapy, tended to have a better survival rate than those who developed relapse after 30 mo (six of seven survived versus four of 11; not significant). Although the preliminary data provided little conclusive information, it did suggest that incorporation of PBSCT in the salvage protocol of relapsed childhood ALL can be justified. © 1994 Wiley-Liss, Inc.     

Allogeneic bone marrow transplantation versus chemotherapy in children with acute leukemia in Sweden

All children in Sweden who underwent bone marrow transplantation (BMT) with an HLA-identical sibling during a 5-year period were compared to those who were treated with chemotherapy and survived at least 3 months after remission. All patients were observed for more than 2 years after diagnosis or relapse. All 11 children with acute myeloid leukemia in first remission who underwent BMT survived compared to only 1 of 15 treated with chemotherapy (p less than 0.001). In children with acute lymphoblastic leukemia (ALL), those relapsing while on chemotherapy and treated with BMT in second to fourth remission (n = 16) had a 5-year survival of 43% compared to 16% for those treated with chemotherapy (n = 53, p less than 0.05). In children with ALL relapsing after cessation of therapy, 4-year survival was 33% for BMT (n = 6) and 55% for chemotherapy (n = 15), p = 0.05).     

Lack of prognostic value of T-, B- and null-lymphocytes in adult acute leukemia

The distribution of T-, B- and null-lymphocytes was studied in the peripheral blood of 38 adult patients with acute nonlymphocytic leukemia (ANLL) and 15 with acute lymphocytic leukemia (ALL) at first diagnosis, during induction treatment, and in remission. Thirteen ANLL and 9 ALL patients were followed until relapse and during reinduction therapy. T- and B-cells were detected by specific membrane marker. The pre- and posttreatment pattern of lymphocyte subpopulations was analyzed to determine their prognostic significance for remission incidence, remission duration, and survival. It was observed that in both types of leukemia, T-cells are more affected by the leukemic process and cytostatic drugs than B-cells. Nonresponding patients possibly have a reduced potential for recruiting precursor T- and B-cells. At first diagnosis, no significant correlation was found between pre- or posttreatment variables and prognosis. At relapse, ANLL patients had a longer second remission when a high proportion of B-cells was found; ALL patients with a high lymphocyte count before and after treatment, experienced longer survival.     

CCLG-97方案治疗标危型急性淋巴细胞性白血病患儿疗效的随访分析

目的 对119例儿童标危型(SR)急性淋巴细胞性白血病(ALL)治疗的效果进行随访分析,探讨如何提高其生存率。方法 119例SR-ALL采用CCLG-97方案进行治疗。结果 4周诱导治疗完全缓解(CR)率为97．4％;21例失访：1998年、1999年、2000年、2001年、2002年各年失访率为63％、14％、10％、8％、5％;1年、2年、3年、4年、5年、6年生存率分别为93．3％、90．2％、88．0％、85．0％、85．0％、85．0％;13例复发,总复发率为13．8％,9例单独骨髓复发中有5例与不规则治疗有关,占56％;2例为4周未CR者于2年内复发;2例为正规疗程中复发,1例为亚二倍体,1例免疫分型示T淋巴系表达;4例为单独中枢神经系统(CNSL)复发,复发率为4．3％;全部患儿无睾丸白血病(TL)发生,无第二肿瘤发生。死亡15例,病死率为12．6％,化疗相关死亡5例,占4．2％。结论 加强管理与正规治疗是提高我国儿童ALL长期存活率的重要措施之一;须在提高检测手段的基础上调整临床分型标准,CCLG-97方案在减少标危型ALL骨髓复发的同时,并未增加化疗相关死亡率;应积极开展大剂量氨甲蝶呤(HD-MTX)的治疗,进一步探索其剂量、用法及个体化的应用。