Intermittent chemotherapy and bcg in continuation therapy of children with acute lymphocytic leukemia

Continuation therapy using intermittent chemotherapy and BCG inoculation was commenced in 28 children with acute lymphocytic leukemia (ALL) immediately after remission induction and “CNS prophylaxis.” At a median followup time of 17 months, 71% remain in total remission and 86% in bone marrow remission. Complications of the therapy were minimal. Major infections occurred on two occasions and there were no deaths in remission. Neutropenia, “minor” infections and postponement of chemotherapy occurred most often during the first three courses of treatment. There were no local or systemic BCG infections. Tuberculin sensitivity was tested in 25 patients. It was positive in 17 of 18 patients in total remission and all four patients with only CNS relapse, and was negative prior to relapse in three patients who developed bone marrow disease.     

Relapse rates following cessation of chemotherapy during complete remission of acute lymphocytic leukemia

The therapeutic benefit of maintenance chemotherapy beyond three years for children with acute lymphocytic leukemia (ALL) in continuous complete remission was evaluated by the investigators of Childrens Cancer Study Group (CCSG). Two hundred and twenty leukemic children in first remission for three years or longer and who had received at least three years of continuous chemotherapy were eligible. One hundred and one patients were randomized to either continue chemotherapy for an additional three years or to discontinue therapy, and 119 patients nonrandomly continued or discontinued therapy. The patients had received a variety of chemotherapy regimens. The study period extended from April 1970 until December 1977, with a median follow-up time of 25 months. Relapses occurred in 15 randomized patients (15%). Randomized patients remaining on chemotherapy experienced a statistically significant lower relapse rate than patients randomized to discontinue therapy. Also among randomized patients, bone marrow relapse was signicantly more frequent in males than in females. Considering the total patient group, age and white blood count at diagnosis had no significance in predicting relapse. Of relapse events in males, 21% were isolated testicular relapses, identifying the testicle as a major risk site in males completing three years of continuous complete remission. This study demonstrates that continuing chemotherapy beyond three years results in a significant prolongation of remission in males, although the eventual survival outcome for later discontinuance of therapy will require longer follow-up.     

Relapse rates following cessation of chemotherapy during complete remission of acute lymphocytic leukemia.

The therapeutic benefit of maintenance chemotherapy beyond three years for children with acute lymphocytic leukemia (ALL) in continuous complete remission was evaluated by the investigators of Childrens Cancer Study Group (CCSG). Two hundred and twenty leukemic children in first remission for three years or longer and who had received at least three years of continuous chemotherapy were eligible. One hundred and one patients were randomized to either continue chemotherapy for an additional three years or to discontinue therapy, and 119 patients nonrandomly continued or discontinued therapy. The patients had received a variety of chemotherapy regimens. The study period extended from April 1970 until December 1977, with a median follow-up time of 25 months. Relapses occurred in 15 randomized patients (15%). Randomized patients remaining on chemotherapy experienced a statistically significant lower relapse rate than patients randomized to discontinue therapy. Also among randomized patients, bone marrow relapse was significantly more frequent in males than in females. Considering the total patient group, age and white blood count at diagnosis had no significance in predicting relapse. Of relapse events in males, 21% were isolated testicular relapses, identifying the testicles as a major risk site in males completing three years of continuous complete remission. This study demonstrates that continuing chemotherapy beyond three years results in a significant prolongation of remission in males, although the eventual survival outcome for later discontinuance of therapy will require longer follow-up.     

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.     

Long-term survival in childhood acute leukemia: "late" relapses.

The "late" relapse patterns of childhood acute leukemia were studied in 83 children in their first continuous complete remission for more than three years prior to randomization for stopping therapy (40 patients) or continuing therapy (43 patients) for a total of six years. Twenty of 83 (22.9%) have relapsed: Ten in the bone marrow, one in the central nervous system, and nine in the testes. The testes relapse rate of 41.1% (7/17) in males discontinuing therapy at three years was much higher than that of 8.7% (2/23) in males continuing therapy. This difference is significant at P = 0.01 (Wilcoxon test).     

小儿急性淋巴细胞白血病中枢神经系统白血病诊治现状

中枢神经系统白血病(CNSL)的防治是小儿急性淋巴细胞白血病(ALL)治疗的一部分。诊断时高白细胞计数、T细胞型及分子遗传学为t(4;11)和Ph 是CNS复发的危险因素,脑脊液不同检查结果的预后价值有待明确。头颅放疗已不用于标危ALL患儿,头颅放疗的预防剂量已减为12Gy,鞘内及全身化疗对CNSL的治疗有重要作用。部分小儿CNS复发经挽救治疗可以长期存活,早期CNS复发的患儿应在第2次CR期进行异基因骨髓移植。     

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.     

Use of the Ommaya reservoir in the prevention and treatment of CNS leukemia—an update

The prophylaxis of the CNS in ALL with intraventricular methotrexate therapy via an Ommaya reservoir in 18 patients resulted in a reduction of the CNS relapse rate to 11% with a 6-10+ year follow-up. This procedure proved to be safe and effective in our hands, but with newer, equally effective and less invasive methods of CNS prophylaxis now available, its use is no longer indicated. Intraventricular therapy via the Ommaya reservoir was also evaluated for its role in improving CNS remission duration after a leukemic recurrence in the CSF. The treatment of CNS relapse with intraventricular chemotherapy and low dose (600r) neuraxis radiation is encouraging. Of the ten patients treated for CNS leukemia, three are long-term (8-11+ years) survivors. Isolated CNS relapse occurred in three. The median CNS disease-free survival and the median relapse-free survival are 39 months and 21 months respectively.     

Induction of long-term remission of a relapsed childhood B-acute lymphoblastic leukemia with rituximab chimeric anti-CD20 monoclonal antibody and autologous stem cell transplantation

Childhood B-cell neoplasms account for approximately 2% of childhood acute lymphoblastic leukemia (ALL). The short but intensive chemotherapy yields a currently 75% to 85% event-free survival. The prognosis for children with relapsed disease is considered to be dismal.We report a 12-year old boy diagnosed with B-cell ALL with central nervous system (CNS) involvement. He relapsed in the bone marrow immediately after primary chemotherapy. Rituximab as a single agent achieved a complete morphologic remission. After 4 treatments with rituximab an isolated CNS relapse occurred. CNS remission was reinduced with chemotherapy and the patient received an autologous transplant with rituximab for in vivo purging. He is currently in complete clinical and molecular remission for more than 1 year.     

Localized bone marrow relapse in acute lymphoblastic leukemia.

Localized bone marrow relapse is rare in acute lymphoblastic leukemia. Discordant bone marrow specimens were found in an 11-year-old asymptomatic girl who had been in remission for six years and off chemotherapy for 2 1/2 years. One bone marrow sample showed marked leukemic infiltration, whereas marrow from another site was normal. Three months later, with normal peripheral blood counts, she developed severe back pain and x-ray evidence of vertebral collapse and periosteal changes in the pubic bone. At that time three of the four areas of bone marrow sampled showed leukemic involvement. Reinduction therapy was begun, and she is now in remission on maintenance chemotherapy. At this time, it is unclear whether routine performance of marrow aspirations and biopsies from multiple sites, in periodic follow-up examinations of patients with acute leukemia would allow earlier detection of relapse frequently enough to justify the procedure. The issue of localized bone marrow involvement, if more common than previously reported, should be addressed at the time a decision is being made to discontinue therapy.     

Localized bone marrow relapse in acute lymphoblastic leukemia

Localized bone marrow relapse is rare in acute lymphoblastic leukemia. Discordant bone marrow specimens were found in an 11-year-old asymptomatic girl who had been in remission for six years and off chemotherapy for 2 1/2 years. One bone marrow sample showed marked leukemic infiltration, whereas marrow from another site was normal. Three months later, with normal peripheral blood counts, she developed severe back pain and x-ray evidence of vertebral collapse and periosteal changes in the public bone. At that time three of the four areas of bone marrow sampled showed leukemic involvement. Reinduction therapy was begun, and she is now in remission on maintenance chemotherapy. At this time, it is unclear whether routine performance of marrow aspirations and biopsies from multiple sites, in periodic follow-up examinations of patients with acute leukemia would allow earlier detection of relapse frequently enough to justify the procedure. The issue of localized bone marrow involvement, if more common than previously reported, should be addressed at the time a decision is being made to discontinue therapy.     

Acute lymphoblastic leukemia in children. Results of a protocol including bone marrow transplantation during the first remission in high-risk forms for relapse

Ninety-two previously untreated children with ALL were admitted to the same institution between November 1984 and November 1988. According to early prognostic factors, patients were divided into 3 groups: group 1 at "low risk" for relapse (n = 18), group 2 at "intermediate risk" (n = 62) and group 3 at "high risk" (n = 12). Every patient received an 8 week-long induction chemotherapy; after CNS prophylaxis, groups 1 and 2 children received a consolidation chemotherapy and then a classical maintenance treatment. Group 3 patients were selected to receive a bone-marrow transplantation during their first remission because of the presence, at diagnosis, of at least one of the following criteria: hyperleukocytosis greater than 100,000 (7 cases), translocation t(1;19) and t(4;11) (2 cases), adolescents (2 cases), no remission at day 30 (2 cases). Ninety-one of 92 children achieved a complete remission and none died during induction therapy. Probability of leukemia-free survival at 4 years is 73 +/- 7% for the whole patient population and 95%, 71% and 60% for patients of groups 1, 2, and 3 respectively. Persistence or disappearance of leukaemic cells in bone marrow after the initial 15 days of chemotherapy appears to influence the probability of a leukemia-free survival.     

Long-term survival in childhood acute leukemia: “Late” relapses

The “late” relapse patterns of childhood acute leukemia were studied in 83 children in their first continuous complete remission for more than three years prior to randomization for stopping therapy (40 patients) or continuing therapy (43 patients) for a total of six years. Twenty of 83 (22.9%) have relapsed: Ten in the bone marrow, one in the central nervous system, and nine in the testes. The testes relapse rate of 41.1% (7/17) in males discontinuing therapy at three years was much higher than that of 8.7% (2/23) in males continuing therapy. This difference is significant at P = 0.01 (Wilcoxon test).     

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.     

Treatment of childhood acute lymphoblastic leukemia with intermediate-dose cytosine arabinoside and adriamycin

Eight pediatric patients with acute lymphoblastic leukemia (ALL) were treated with intermediate-dose cytosine arabinoside (ID-AraC, 1 g/m2) in combination with adriamycin except one patient. Of the eight patients, four refractory to the initial induction therapy and one in bone marrow relapse gained complete remission with two to three cycles of this therapy. Four of the five patients have been in continuous remission for 4 to 24 months with the maintenance therapy of monthly administration of ID-AraC. One patient in central nervous system (CNS) relapse has continued in remission from CNS leukemia after two cycles of the therapy. Side effects of ID-AraC and adriamycin were generally mild to moderate and tolerable in all children. These results suggest that the use of ID-AraC and adriamycin might prove effective in the treatment of ALL refractory to other regimens.     

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.     

Evaluation of the LSA2L2 protocol for treatment of childhood non-Hodgkin's lymphoma. A report from the Polish Children's Leukemia/Lymphoma Study Group

From 1979 to 1982, 97 previously untreated children with non-Hodgkin's lymphoma were treated with the LSA2L2 protocol proposed by Wollner. Staging was done according to the criteria proposed by Wollner and re-staged according to Murphy's criteria. Each patient, regardless of clinical stage and histologic group, was given the same chemotherapy. A total of 28 nonrandomized patients received either cranial irradiation or intermediate-dose intravenous methotrexate as CNS prophylaxis. The complete remission rate was 72.6%. The 3-year actuarial estimate of survival was 73% and the disease-free survival rate was 62% for all responders, and was influenced by stage and main clinical features present at the time of initial presentation. The overall survival rate at 3 years is 52%. Of 26 children who failed to achieve complete remission, 21 had presented with disseminated disease. Also, 20/67 patients who entered remission have suffered relapses: four in the bone marrow, seven in the CNS, and nine with local relapses. Only one of 28 children who received CNS prophylaxis developed CNS disease as the site of first relapse, whereas six of those who received only intrathecal chemotherapy did so. This study confirms the improved outlook in comparison with a historical group for children with non-Hodgkin's lymphoma by the use of an intensive multiple-drug regimen and CNS prophylaxis.     

Masked Deficit of Vitamin B12in a Turkish Girl with Thalassemia

A 12-year-old girl with acute promyelocytic leukemia has been treated with conventional chemotherapy. The patient remained in complete remission for a year when the first bone marrow relapse occurred. Since reinduction chemotherapy was rejected by the parents, an alternative treatment with oral all-trans retinoic acid was administered. A second complete remission was achieved within 100 days. After 14 months a second bone marrow relapse occurred. AM-trans retinoic acid and the combination with interferon-a failed.     

All-Trans Retinoic Acid as an Alternative to Chemotherapy in the Treatment of Acute Promyelocyte Leukemia

A 12-year-old girl with acute promyelocytic leukemia has been treated with conventional chemotherapy. The patient remained in complete remission for a year when the first bone marrow relapse occurred. Since reinduction chemotherapy was rejected by the parents, an alternative treatment with oral all-trans retinoic acid was administered. A second complete remission was achieved within 100 days. After 14 months a second bone marrow relapse occurred. AM-trans retinoic acid and the combination with interferon-a failed.     

Successful autologous bone marrow transplant for relapsed Ki-1 lymphoma

We report on a 16 year old girl with relapsed Ki-1 lymphoma and a very poor prognosis. The initial manifestation was multiple bone metastases and lymphadenopathy. The patient achieved remission with modified adriamycin, bleomycin, vincristine, daunomycine therapy. However, 14 months after the completion of therapy, relapse occurred in a new cervical lymph node on the left side. After preparation with chemotherapy and total lymphoid irradiation (TLI) the patient underwent autologous bone marrow transplantation (A-BMT). Ki-1 lymphoma shows clinically diverse symptoms, but hematopoietic stem cell transplantation should be performed in relapsed cases. It may be effective to give TLI followed by A-BMT for patients such as ours who have lymph node involvement without bone marrow metastasis.