Cyclic combination chemotherapy for acute lymphoblastic leukemia recurring after elective cessation of therapy

Cyclic combination chemotherapy was administered to 26 patients with acute lymphoblastic leukemia who had relapsed in the bone marrow greater than or equal to 6 months after elective cessation of therapy. Each patient had been in initial continuous complete remission for 36-111 months (median, 47 months). Prednisone, vincristine, and doxorubicin induced second complete remissions in all patients within 1 month. Continuation therapy consisted of alternating 6-week courses of 6-mercaptopurine/methotrexate and vincristine/cyclophosphamide with intervening reinforcement courses of prednisone/doxorubicin, for a total of 18 months. All patients received 4 weeks of late intensification therapy with the same agents used for remission reinduction. Periodic intrathecal methotrexate was given as reprophylaxis for subclinical central nervous system leukemia. The estimated rate of continuous failure-free survival at 5 years is 31% +/- 17% (2 SE). Eight patients remain free of leukemia for 42 + to 65+ months after completing therapy a second time. Adverse second events included 11 hematologic, 1 testicular, and 3 meningeal relapses. Patients who relapsed at more than 12 months after the completion of initial treatment have had significantly longer second remissions than patients whose first remissions were shorter (p = .04). None of the other six factors we analyzed showed predictive strength. These end results indicate that intensive cyclic continuation chemotherapy, as described here, will secure durable second remissions in approximately one-third of the children with late bone marrow relapses.     

Testicular histology and function following long-term chemotherapy of acute leukemia in children and outcome of the patients who received testicular biopsy

Wedge biopsy of the testis was performed in 46 children who had received long-term chemotherapy for acute lymphoblastic leukemia. Occult testicular infiltration was noted in three children (6.5%). Two of three children with biopsy-proven infiltration died of systemic disease in spite of local irradiation and reinduction chemotherapy. Six of 43 children shown to be negative by testicular biopsy relapsed 11 months to 15 years later, and 3 of 6 patients died of systemic disease, but none of the cases developed testicular disease. Chemotherapy-induced gonadal damage was observed in 30 of 46 children, and tubular damage was occasionally still seen 4 years after cessation of treatment. Although gonadal damage usually depends on the cumulative dosage of cyclophosphamide, intact tubular fertility index was found in several children who had received a greater dose of cyclophosphamide intermittently. Induction and maintenance chemotherapy for acute lymphoblastic leukemia had little influence on hormonal function. Testicular biopsy at the time of cessation of chemotherapy seems to be worthwhile for the subsequent strategy of treatment, and long-term surveillance for gonadal damage of long-term survivors will be required.     

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.     

Normal final height after treatment for acute lymphoblastic leukemia without irradiation

In order to evaluate the influence of chemotherapy on linear growth, 28 children treated for acute lymphoblastic leukemia without irradiation were evaluated before, during and after the end of therapy. Median age at diagnosis was 4.4 years (range 2.2–12.7 years) and treatment was discontinued after a median period of 3.1 years (3.0–5.2 years). We observed a significant decrease in height SDS ( p = 0.006) from diagnosis to the end of chemotherapy, followed by catch-up in height SDS from the end of chemotherapy to final observation. Catch-up growth took place mainly within the first 2 years after cessation of therapy. In 22 patients final height was reached. Final height was normal (median height SDS-0.035) and even significantly higher than mid-parental height SDS ( p = 0.012). In those patients who attained adult stature, the sitting height to standing height ratio was also normal. In conclusion, in children treated for acute lymphoblastic leukemia, chemotherapy exerted a negative influence on growth, but catch-up occurred within 2 years after cessation of therapy, resulting in normal final height and body proportions.     

Late Relapses in Acute Lymphoblastic Leukemia

Two children presented with relapsed acute lymphoblastic leukemia 6 years and 8 years after cessation of maintenance treatment. Relapses this length of time off treatment are unusual, with only 7 previously reported cases. It is often unclear whether the relapse is of the original disease or a second leukemia, and our results in both cases suggest relapse of their primary disease.     

Late Relapses in Acute Lymphoblastic Leukemia

Two children presented with relapsed acute lymphoblastic leukemia 6 years and 8 years after cessation of maintenance treatment. Relapses this length of time off treatment are unusual, with only 7 previously reported cases. It is often unclear whether the relapse is of the original disease or a second leukemia, and our results in both cases suggest relapse of their primary disease.     

CESSATION OF THERAPY IN CHILDHOOD LEUKEMIA A Survey of 160 Cases from the Nordic Countries

ABSTRACT. 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.     

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.     

RELAPSE RATE AFTER CESSATION OF THERAPY IN CHILDHOOD LEUKEMIA

Abstract. Johansen, O. J. & Moe, P. J. (Department of Paediatrics, University of Trondheim, Norway). Relapse rate after cessation of therapy in childhood leukemia. A follow-up report on 277 cases from the five Nordic countries. Acta Paediatr Scand, 69: 663, 1980. —Two hundred and seventy-seven children from the Nordic countries who had their antileukemic therapy stopped before January 1979 were surveyed. The children were in remission when therapy was discontinued. So far 64 (23.1%) have relapsed. Central nervous system (CNS) and testicular leukemia have been a problem, but CNS-prophylaxis has been in common use in the Nordic countries only since 1972–1973. Most of the patients relapsed during the first year after stopping therapy, whereas no patient relapsed later than 4 years after cessation of therapy.     

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

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

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.     

Morphologic changes in blast cells of children with acute lymphoblastic leukemia in relapse

Relapse in children with acute lymphoblastic leukemia (ALL) on therapy may be due to development of a resistant clone of blast cells. Seven children who presented initially with the "common"-type, L1 lymphoblast relapsed with a morphologically different and more undifferentiated blast cell. All were male, with a median age of 12 years at initial presentation. One child who relapsed while off therapy was successfully reinduced and remains in hematologic remission on therapy. The remaining 6 children died within 10 months of relapse. Selection of a resistant clone of lymphoblasts by chemotherapy may be responsible for relapse in children with ALL and should be studied in hopes of controlling the disease.     

Allogeneic bone marrow transplantation in the treatment of acute leukemias of children. Study of 26 patients

Twenty-six children with acute leukemia were treated with allogeneic marrow transplantation from HLA identical siblings after a conditioning regimen with Cyclophosphamide-total body irradiation (19 patients), Melphalan-total body irradiation (6 patients) or Busulfan-cyclophosphamide (1 patient). Eighteen were transplanted in complete remission (4 with acute non lymphoblastic leukemia in first remission, 14 with acute lymphoblastic leukemia: 6 in first, 6 in second and 2 in subsequent remission): 2 died of cytomegalovirus pneumoniae, 1 relapsed and 15 survive in continuous complete remission from 5 to 42 months after transplantation (median = 22 months). Eight were transplanted in relapse, 7 achieve complete remission, 5 of them relapsed, 1 died of G.V.H. and 1 survives in continuous complete remission 46 months after transplantation. Actuarial analysis shows a disease free survival rate at 3 years of 82% for patients transplanted in remission and 12% for patients transplanted in relapse (p less than 0.01).     

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).     

Prognostic significance of primary bone changes in children with acute lymphoblastic leukemia

In a period of 6.5 years, acute leukaemia was diagnosed in 140 children at our hospital: 137 children had long bone radiographs and 45 patients had bone lesions. Eleven of the 115 patients who had skull radiographs had osteolytic lesions and another four had wide sutures. No patients had bone changes at relapse or at cessation of 3 years' successful therapy. In acute lymphoblastic leukemia, the frequency of osseous lesions tended to be higher in patients in sub-groups with a more favourable prognosis. The duration of remission and survival times were higher in patients with “leukemic” long bones than in those without them (p<0.10 and <0.05, respectively). Changes in the skull could not be related to the outcome. We found no abnormalities in the bones of the eight patients with acute non-lymphoblastic leukemia.     

bcr-abl-positive T-cell acute lymphoblastic leukemia associated with parvovirus B19 infection

The authors report an unusual presentation of a Philadelphia chromosome-positive acute lymphoblastic leukemia with two unusual features: a bcr-abl fusion mRNA coding for p210 protein and a T-cell immunophenotype. The patient was a 16-year-old boy who presented with septic shock and pancytopenia, likely precipitated by an acute parvovirus B19 infection. Management consisted of supportive therapy, followed by chemotherapy for T-cell acute lymphoblastic leukemia and stem cell transplantation. He died 8 months after transplant due to idiopathic pneumonia syndrome, but without evidence of relapsed disease.     

Time course of recovery of adrenal function in children treated for leukemia

OBJECTIVE: Many protocols for treating children with early B-cell lineage acute lymphoblastic leukemia use 28 consecutive days of high-dose glucocorticoids during induction therapy. We prospectively studied the effects of this therapy on adrenal function. STUDY DESIGN: Ten children with early B-cell lineage acute lymphoblastic leukemia were evaluated by cosyntropin (corticotropin (1-24)) stimulation testing before initiation of dexamethasone therapy and every 4 weeks thereafter until adrenal function returned to normal. RESULTS: All 10 patients had normal adrenal function before dexamethasone treatment and insufficient adrenal responses 24 hours after completing therapy. Each child felt ill for 2 to 4 weeks after completing therapy. Although 7 patients recovered normal adrenal function after 4 weeks, 3 patients did not have normal adrenal function until 8 weeks after discontinuing therapy. Statistically significant differences in both basal and corticotropin-stimulated cortisol levels were noted when comparing tests performed at baseline, 24 hours after completing therapy, and 4 weeks after completing therapy. CONCLUSION: High-dose dexamethasone therapy, a standard treatment for early B-cell acute lymphoblastic leukemia, can cause adrenal insufficiency lasting more than 4 weeks after cessation of treatment. This problem might be avoided by tapering doses of glucocorticoids and providing supplemental glucocorticoids during periods of increased stress.     

氯法拉滨治疗儿童复发/难治性急性淋巴细胞性白血病的疗效分析

目的：探讨氯法拉滨应用于儿童复发/难治性急性淋巴细胞性白血病的疗效和不良反应。方法：26例复发/难治性急性淋巴细胞性白血病患儿接受氯法拉滨单药治疗,男22例,女4例,中位年龄9.5岁（4~17岁）。患儿均接受连续5 d静脉滴注氯法拉滨（52 mg/m2,每次超过2 h）,其中13例患儿接受连续2次氯法拉滨单药化疗,1例患儿接受连续3次氯法拉滨单药化疗。结果：26例患儿第1次氯法拉滨化疗后11例（42%）获完全缓解,7例（27%）获部分缓解,总有效率69%,8例（31%）未缓解。26例患儿中,13例继续给予第2次氯法拉滨化疗后11例（85%）获完全缓解,1例（8%）部分缓解,1例（8%）未缓解。其中1例患儿接受3次氯法拉滨化疗均获完全缓解。化疗的不良反应主要为中性粒细胞减少、感染、肝功能损害、胃肠道反应,无化疗相关死亡病例。结论：氯法拉滨治疗儿童复发/难治性急性淋巴细胞性白血病有一定疗效,不良反应可以耐受,是一种新的治疗选择。     

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.     

SERIAL DETERMINATIONS OF SERUM FERRITIN IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA Evaluation of its Usefulness as a Prognostic Index

Abstract. Thirty children with acute lymphoblastic leukemia were monitored with serial serum ferritin determinations for up to 17 months. In children with acute lymphoblastic leukemia before initiation of therapy, or in relapse, the mean serum ferritin concentration was 636 μg/l. In children who went into primary remission, the mean serum ferritin concentration fell from 265 μg/l prior to start of treatment, to 161 μg/l after 3 months of treatment. Five patients relapsed. Their serum ferritin levels prior to the relapses ranged from 7 to 135 μg/l. At the time of relapse a further increase in serum ferritin was found in only 2 of the children. Thus, whereas high serum ferritin levels may signal disease activity in acute lymphoblastic leukemia, a normal serum ferritin level does not exclude disease activity or impending relapse.