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.     

Treatment of relapsing acute lymphoblastic leukemia in childhood. II. Experiences with 45 first bone marrow and 24 isolated central nervous system relapses observed 1981-1984

Of 45 children with ALL who had a first hematological recurrence between 1981 and 1984, 33 relapsed while still on treatment and 12 after cessation of therapy. Of the former 1 of 16 high risk (initial WBC greater than or equal to 20 x 10(9)/l and/or enlargement of the mediastinum) and 5 of 17 low risk patients (initial WBC less than 20 x 10(9)/l and no enlargement of the mediastinum), of the latter 6 patients survived after a minimum follow-up of 20 months. During the same time period, a first isolated CNS relapse was observed in 24 children of whom 16 survived. These results suggest that at the time of evaluation 1. the prognosis of children with ALL in first hematological relapse during the years 1981-1984 was not significantly different from that of similar children treated earlier; and 2. the prognosis of children with isolated CNS relapse had improved.     

Hypofractionated moderate dose radiation, intrathecal chemotherapy, and repetitive reinduction/reconsolidation systemic therapy for central nervous system relapse of acute lymphoblastic leukemia in children

BACKGROUND: We assessed efficacy and morbidity of chemotherapy and 1, 800 cGy of hypofractionated craniospinal irradiation (CSI) in children with central nervous system (CNS) relapse following first remisssion of acute lymphoblastic leukemia (ALL). PROCEDURE: Nineteen patients with isolated CNS relapse and 4 with combined CNS/marrow or CNS/testicular relapse received treatment according to Children's Hospital of Philadelphia (CHOP) protocols CHP-449 and CHP-497. CNS treatment included intrathecal methotrexate, cytarabine, and hydrocortisone and 1,800 cGy CSI in 16 fractions over 12 months. Systemic therapy consisted of reinductions with vincristine, prednisone, and daunorubicin and reconsolidations with cytarabine, etoposide, and L-asparaginase every 56 days for 2 years. Outcome measures were event-free survival (EFS), survival, growth, and neuropsychologic assessment or school performance. RESULTS: Follow-up of survivors from first relapse ranges from 52 to 133 months(median 91 months). Actuarial survival and EFSat 10 years are 58% (CI95 = 38-78%) and 54% (CI95 = 32-76%). Events include 2 second CNS, 4 marrow, 1 testicular, and 2 testicular/marrow relapses and 1 secondary leukemia. EFS is 100% (CI95 = 93-100%) in 9 patients with recurrence more than 26 months from diagnosis. Three patients have significant treatment-related reduction in stature. Median full-scale IQs of 6 patients tested were 112 pretreatment and 111 posttreatment among surviving patients. All 17 survivors attend regular school, but 2 receive supplementary special services. CONCLUSIONS: Lower dose, hypofractionated CSI, intrathecal chemotherapy, and moderately intensive systemic chemotherapy provide excellent disease control for patients with late isolated CNS or combined marrow and CNS relapse. Children with brief first remissions remain at substantial risk of subsequent relapse with this therapy, especially in the marrow and testes.     

The clinical indications for identical pathogenesis of isolated and non-isolated testicular relapses in acute lymphoblastic leukaemia

In the present population-based study, we compared the clinical data of testicular relapses with and without concurrent bone marrow relapse and clinical data of the relapses in other locations among boys with acute lymphoblastic leukaemia (ALL), in order to study the possible evidence of early sequestration and local regulation of leukaemic lymphoblast in the testis of humans. The results suggest that the pathogenesis of isolated testicular relapse (T) and testicular relapse with a concurrent bone marrow relapse (T+BM) is likely to be similar. Isolated and non-isolated testicular relapses appeared late after the achievement of remission (T 34±16 months, T+BM 32±15 months) in ALL compared to relapses in other locations (CNS 23±11 months, BM 25±19 months). The better prognosis after testicular relapses (estimated second event free survival probability, 2-EFS: T 0.63, T+BM 0.32) compared to bone marrow relapse (2-EFS: BM 0.13) further suggests that testicular relapse with a concurrent bone marrow relapse possibly originates from the isolated testicular relapse, and that the isolated testicular relapse is a separate entity and not a manifestation of systemic recurrence. Higher frequencies of isolated and non-isolated testicular relapses (T 9%, T+BM 5%) were observed among boys with onset of ALL in early puberty (10-12y) compared to those among younger (T 4%, T+BM 2%) and older (T 0%, T+BM 0%) boys. The late occurrence, the possible association with hormonal maturation and the good prognosis after testicular relapses suggest a possible local regulation of the residual leukaemic lymphoblast in human testis.     

Isolated testicular leukemia following bone marrow transplant for acute lymphocytic leukemia. The need for pretransplant testicular biopsies

Bone marrow transplantation has become an accepted mode of treatment for children with acute myelocytic leukemia in their first remission and acute lymphocytic leukemia after their first bone marrow relapse. Two-year survival rates of 50% can be achieved in patients undergoing transplant during remission, in contrast to a 2-year survival of 15% in those undergoing transplant while still in marrow relapse. Recurrence of bone marrow leukemia relapse is a significant cause of marrow transplant failure. Overt or occult testicular relapse occurs in 10-15% of males with acute lymphocytic leukemia receiving or having completed standard therapy regimens for control of their disease and frequently leads to a subsequent bone marrow relapse. This paper describes a child with acute lymphocytic leukemia who received a successful marrow transplant following bone marrow relapse and developed testicular leukemia relapse approximately 20 months after transplant. The experience with this child suggests that bilateral testicular biopsies should be a mandatory part of the routine evaluation to screen for residual leukemia before bone marrow transplantation.     

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.     

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.     

Long-term control of central nervous system leukaemia.

Seventy-four children with acute lymphoblastic leukaemia had one or more episodes of central nervous system (CNS) leukaemia. 5 children had CNS involvement at diagnosis; 4 survived for less than one year. In 35 children who had not had a previous bone marrow relapse on treatment and who received combination chemotherapy, the median duration of haematological remission from the time of first CNS relapse was almost 3 years. 5 children received full dose (2400 rads) craniospinal irradiation after their first CNS relapse; 4 have remained in CNS and haematological remission for 2 1/2 years or more. 18 children who had a CNS relapse after irradiation received 4-weekly intrathecal methotrexate; in 8 children this was given via an intraventricular reservoir. The median duration of CNS remission in children receiving intrathecal methotrexate was 2 years. Systemic and intrathecal treatment was stopped in 7 children after 2 1/2 years in continuous remission and in 2 children after 2 years. 4 of these 9 children remain in remission at intervals from 41 to 69 weeks off treatment but one is severely retarded. These results show that CNS disease is compatible with prolonged survival, but illustrate the difficulties of eradicating established CNS leukaemia.     

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.     

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.     

Isolated central nervous system relapse of testicular cancer.

Central nervous system involvement with testicular cancer usually occurs with advanced systemic disease. Isolated CNS disease at relapse is rare. We report a patient who developed a solitary brain metastasis with no other systemic disease after having achieved a complete response to frontline therapy. After combined modality therapy for the CNS disease, the patient has remained disease-free for more than 3 years. The literature regarding brain metastases in relapsed testicular cancer is reviewed, including nine cases of isolated brain metastases. The CNS can be a "sanctuary" site for testicular cancer, and in the unusual subset of patients with isolated brain relapse, long-term remission is possible with aggressive therapy.     

Extramedullary Relapse in Childhood Leukemia

As long-term survival of children with leukemia is increasing, the prophylaxis of extramedullary leukemia has become a more important part of treatment. We studied the pattern of occurrence of extramedullary leukemia in a retrospective review. This review included a total of 2317 childhood leukemia patients aged 15 years or less who had been treated at 38 institutes in Japan between 1976 and 1985. Extramedullary leukemia developed in 386 of 1,724 ALL patients (22.4%) and 63 of 544 patients with ANLL (163%). Among the ALL patients, CNS-L was the most common form and was observed in 315 cases (81.6%), followed by testicular leukemia in 89 (23.0%). In the case of ANLL, the most common form of extramedullary leukemia was CNS-L (45 cases, 71.4%), followed by cutaneous leukemia in 10 cases (15.9%). In addition, leukemia of the lymph nodes, ovaries, bones, kidneys and eyes was observed in 7, 5, 5, 4 and 4 cases, respectively. The survival rate of ALL patients with CNS-L was 40.1% for isolated relapse and 2.7% for bone marrow relapse, and no more deaths occurred after 6 years from relapse. The survival rate of patients with testicular leukemia was 40.1% for isolated relapse and 5.9% for complicating bone marrow relapse, and no deaths occurred after 7 years from relapse. Cutaneous leukemia tended to occur late in older children with ALL and early in infants with ANLL, and all these patients died. Infiltration into the kidney was observed in 4 patients, all of whom died. More than 75% of patients died after isolated relapse of leukemia of the bones, ovaries, lymph nodes and eyes. Prophylactic extramedullary leukemia therapy, of CNS-L in particular, has played an important role in the treatment of childhood leukemia. Careful development of more effective therapy and close observation of late effects are required when monitoring affected children who are still growing.     

Marrow transplant experience in children with acute lymphoblastic leukemia: an analysis of factors associated with survival, relapse, and graft-versus-host disease

One hundred fourteen children with acute lymphoblastic leukemia were treated with allogeneic marrow transplantation from HLA-identical siblings after conditioning with cyclophosphamide and total body irradiation. Methotrexate was given posttransplantation for prophylaxis of graft-versus-host disease. The minimum follow-up after transplantation was 2 years. Sixteen of 51 patients transplanted in marrow remission survive from 2.1 to 8.9 years (median 2.7), 13 in continuous remission, one in remission following testicular relapse, and two after marrow relapse. Sixty-three were transplanted in relapse and eight survived 3-10 years (median 5.7), five in continuous remission, and three in remission following testicular relapse. In a multivariate analysis, factors significantly related to increased survival were marrow remission at transplant (p less than 0.007) and chronic graft-versus-host disease (p less than 0.005). Factors associated with increased relapse were marrow relapse at transplant (p less than 0.002) and absence of significant graft-versus-host disease (p less than 0.004). The development of acute graft-versus-host disease was associated with high marrow cell doses (p less than 0.04). These data suggest that some children with acute lymphoblastic leukemia and a poor prognosis with conventional chemotherapy may be cured with marrow transplantation.     

Relapse in acute lymphoblastic leukemia of childhood--treatment and results (author's transl)]

Twelve children with their first relapse of acute lymphoblastic leukemia who had the same initial therapy were treated on an out-patient basis. After 28 days all entered second remission. Medium remission duration was 11 months. At the end of the study seven patients were in continuous complete remission. Of the twelve children seven suffered bone marrow, two meningeal, two testicular relapses and one a combined bone marrow and meningeal relapse. Side effects were compatible with an out-patient treatment.     

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).     

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.     

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.     

The influence of traumatic lumbar puncture and timing of intrathecal therapy on outcome of pediatric acute lymphoblastic leukemia

The CNS is a frequent site of relapse of childhood acute lymphoblastic leukemia (ALL). Traumatic lumbar puncture (TLP) is thought to increase the risk of CNS relapse. The authors examined whether TLP at the time of diagnosis affected outcome and whether this effect was influenced by the timing of intrathecal therapy (IT) in 77 patients with newly diagnosed ALL. IT was instilled at the time of either the diagnostic LP (early) or a second LP 24-48 h later (delayed). Of the 19 patients who had a TLP at diagnosis and received late IT therapy, 6 had isolated CNS relapse and 2 had combined CNS and bone marrow (BM) relapse. Of the 9 patients who had TLP and received early IT therapy, 1 had a CNS relapse (p = .20). In an analysis stratified according to risk of relapse, the odds ratio (OR) for relapse was 0.8 among patients at low and standard risk who had delayed IT therapy after TLP (p = .99) vs. 0.17 for those who had early IT (p = .47). Importantly, among patients with high-risk ALL, the OR for relapse was 21.0 for delayed IT therapy (p = .09) and only 1.5 for early IT therapy after TLP (p = .99). The results indicate that TLP at diagnosis appears to increase the risk of CNS relapse markedly in patients with high-risk ALL, and the use of early IT therapy appears to reduce this risk. These findings need to be confirmed by prospective, randomized studies.     

Cessation of therapy in childhood leukemia. A survey of 160 cases from the Nordic Countries.

A survey is presented of 160 children from the Nordic countries who had their antileukemic therapy discontinued prior to November 1976. Twenty-seven of the 160 cases (17%) had suffered a relapse before May, 1977. Sixty-nine cases had their therapy stopped in the first ten months of 1976. All cases have been reported as acute lymphocytic leukemia. Different types of therapy schedules have been used. Thirty-five cases in sustained remission for more than 3 years without cessation of therapy are also included in the report, seventeen of whom had relapsed while still on therapy. Central nervous system or testicular relapse occurred in 21 of the total 44 cases who relapsed after three or more years of continuous remission, and whether they were on therapy or not.     

Isolated central nervous system relapse of testicular cancer

Central nervous system involvement with testicular cancer usually occurs with advanced systemic disease. Isolated CNS disease at relapse is rare. We report a patient who developed a solitary brain metastasis with no other systemic disease after having achieved a complete response to frontline therapy. After combined modality therapy for the CNS disease, the patient has remained disease-free for more than 3 years. The literature regarding brain metastases in relapsed testicular cancer is reviewed, including nine cases of isolated brain metastases. The CNS can be a “sanctuary” site for testicular cancer, and in the unusual subset of patients with isolated brain relapse, long-term remission is possible with aggressive therapy.