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.     

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.     

RELAPSE RATE AFTER CESSATION OF THERAPY IN CHILDHOOD LEUKEMIA

ABSTRACT. The experience of four hundred and ninety children from the Nordic countries who had their antileukemic therapy stopped prior to January 1981 is presented. The observation times after stopping therapy were between 1 month and 19 years. One hundred and five children (21.4%) relapsed before January 1981. No children relapsed later than four years after cessation of therapy. The calculated long term relapse rate is 28%.     

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.     

Immune status in children with acute lymphocytic leukemia. Observations in 67 cases.

67 children affected with acute lympocytic leukemia were immunologically evaluated for lymphocytic markers, serum immunoglobulins and delayed hypersensitivity skin tests at the onset, in remission and after cessation of therapy. E, EA rosettes and surface Ig assayed significantly lower in leukemic children than in matched controls, except for three cases of T-cell leukemia in which E rosettes were very high. After cessation of therapy almost normal results were obtained. As for serum Ig, the only abnormal finding was that of low IgM during therapy. The skin tests with Varidase, Candidine, Mumps antigen and DNCB were not significantly different at onset and in remission. As for DNCB test, the negative responses at onset often became positive in remission, but only when the test was performed before any treatment (anamnestic-like response?). One of the three patients with T-cell leukemia relapsed after 8 months: strangely enough, no surface marker could be detected on that occasion. We could not find any relationship between various immunological tests, or between these tests and prognosis; chemotherapy proved active in suppressing cellular immunity, especially the primary cellular response.     

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.     

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.     

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

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

A Population-Based Study of Children with Standard Risk Acute Lymphoblastic Leukemia in the Five Nordic Countries

ABSTRACT. Two hundred and thirty children with standard risk acute lymphoblastic leukemia (ALL) were diagnosed during a period of 3 years from July 1, 1981 to June 30,1984 in the five Nordic countries. Criteria for standard risk ALL were age above 2.0 and below 10 years, WBC <20×10⁹/l, no evidence of CNS-involvement, mediastinal mass or T- or B-cell leukemia. The children were treated without prophylactic CNS irradiation, the majority (200 patients) according to two treatment programs. Follow-up of the entire group after a minimum of 30 months showed 64% of the children living in complete continuous remission with a probability of event-free survival of 0.60. The treatment results are not entirely satisfactory and intensification of therapy is required. A subgroup of patients with WBC between 10 and 20×10⁹/I and with adverse prognosis was identified, justifying a change of the present criteria for risk grouping.     

A population-based study of children with standard risk acute lymphoblastic leukemia in the five Nordic countries. A follow-up of 230 patients

Two hundred and thirty children with standard risk acute lymphoblastic leukemia (ALL) were diagnosed during a period of 3 years from July 1, 1981 to June 30, 1984 in the five Nordic countries. Criteria for standard risk ALL were age above 2.0 and below 10 years, WBC less than or equal to 20 x 10(9)/l, no evidence of CNS-involvement, mediastinal mass or T- or B-cell leukemia. The children were treated without prophylactic CNS irradiation, the majority (200 patients) according to two treatment programs. Follow-up of the entire group after a minimum of 30 months showed 64% of the children living in complete continuous remission with a probability of event-free survival of 0.60. The treatment results are not entirely satisfactory and intensification of therapy is required. A subgroup of patients with WBC between 10 and 20 x 10(9)/l and with adverse prognosis was identified, justifying a change of the present criteria for risk grouping.     

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.     

Lung scintigraphy after tumor therapy in childhood

Cytostatics- and radiation-induced alterations of the lung were investigated in 18 children after tumour-therapy by means of lung perfusion scintigraphy. 13 patients (Hodgkin- and non Hodgkin lymphoma, acute lymphocytic leukemia with mediastinal tumour, Ewing-sarcoma, and intrathoracal neuroblastoma) received epidiaphragmatical radiation and cytostatics. All 32 lung-scintigrams of these children 1-23 months after cessation of therapy were pathological. 5 patients (acute lymphocytic leukemia, Histiocytosis X) received cytostatics only. 1-6 months after cessation of therapy in these children 6 lung-scintigrams were pathological, one was normal. After cessation of tumour-treatment scintigraphical improvement of disturbed perfusion occurred in 9/18 patients only. In 6 children a deterioration of lung-perfusion was registered. Lung-scintigraphy is a method for testing pulmonary perfusion in diagnosis and therapy control in childhood malignancies. The results of this study indicate that prophylactic provisions against pulmonary damage during oncologic therapy are necessary.     

Intermediate-dose methotrexate versus cranial irradiation in childhood acute lymphoblastic leukemia: A ten-year follow-up

The cure rate of childhood acute lymphoblastic leukemia (ALL) has improved dramatically. Still there is a paucity of long-term data. With the improving cure rate, the quality of life and avoidance of second cancers have become important concerns. We evaluated 596 children and adolescents with ALL on Cancer and Leukemia Group B 7611 (CALGB 7611) who were randomized between 1976 and 1979 to receive intermediate-dose methotrexate (IDM) plus intrathecal methotrexate (IT MTX) or cranial radiation (CRT) plus IT MTX. After 10 additional years of follow-up, the pattern and significance of the results reported in 1983 are confirmed. IDM offered better hematologic protection (P < 0.0006), better testicular protection (P = 0.002), but CRT offered better central nervous system (CNS) protection (P < 0.0001). The retrieval rate for the 231 patients who relapsed while on therapy or within 6 months of elective cessation of therapy is 20 ± 5%. For the 33 patients who relapsed more than 6 months after cessation of therapy, the retrieval rate is 49 ± 10%. For all patients, the 12-year event-free survival was 37 ± 3.6% and the overall survival was 49 ± 3.5%. There were two cases of second malignancies reported in 3,502 person-years of survival. Both occurred following salvage therapy. There was no evidence of an excessive number of second primaries over the general population of children. There were no reported instances of clinical cardiopathy. After a median follow-up of 11 years, there have been no reports of cardiopathy and no evidence of an increased risk of second cancers in children treated on CALGB 7611. While the overall outcome is not what would be expected with modern therapy, one can conclude that CRT offered better CNS protection, but IDM offered better systemic and testicular protection. A small risk of second cancers or cardiac dysfunction may be acceptable with therapies which produce long-term documented survival benefits. Med. Pediatr. Oncol. 28:98–107 © 1997 Wiley-Liss, Inc.     

Value of Routine Bone Marrow Examination for Detection of Bone Marrow Relapse in Children with Standard Risk Acute Lymphoblastic Leukemia

The value of routine bone marrow examination (RBME) in children during and after treatment for standard risk acute lymphoblastic leukemia (SR-ALL) was Investigated. The clinical symptoms and peripheral blood findings at the time of bone marrow relapse of 28 children were reviewed and compared with those of 28 matched controls in continuous complete remission. Five (45%) children with bone marrow relapse during maintenance therapy and six (35%) after cessation of cytostatic treatment were asymptomatic at the time of relapse. Signs indicative of relapse duriny treatment were lymphoblast cells in the peripheral blood, thromhocytopenia, hepatomegaly, anemia, or leukopenia in decreasing order of frequency. Afer cessation of treatment these signs were lymphoblasts in the peripheral blood, hepatomegab, splenomegaly, thrombocytopenia, or leukocytosis. Except for one case with thrombocytopenia, no signs suspicious for relapse were found in the control groups. When each sign was evaluated separately only the presence of lymphoblasts in peripheral blood and hepatomegaly were significant symptoms for relapse after cessation of treatment. The mean percentage of lymphoblasts in the bone marrow at the time of relapse was significant& lower for patients with an unpredicted relapse (46.8%) than patients with clinical and/or laboratory evidence of relapse (79.5 %). When lymphoblasts were present in the peripheral blood the percentage of lymphoblasts in the bone marrow was always more than 40%, both during and after cessation of treatment. These data suggest a relation between clinical and laboratory symptom and progression of the disease. It is concluded that 467% of relapses are detected by RBME in the absence of clinical or laboratory symptoms. This early detection may have a positive prognostic influence with more effective treatment for relapsed ALL.     

Computed tomography scans of the brain in acute leukemia and lymphoblastic lymphoma. Follow-up of children receiving prophylactic central nervous system irradiation

Twenty-seven long-term survivors diagnosed between 1971 and 1977 as having acute lymphoblastic leukemia (23 children), acute myeloblastic leukemia (1 child), and lymphoblastic lymphoma (3 children) have been studied using CT scans of the brain. None of the children had ever had symptoms or signs of CNS involvement. CT scanning was performed in 19 cases at the cessation of therapy; in the other eight cases, CT scanning was performed 24 to 49 months after the end of therapy. In all children, CNS prophylaxis included cranial irradiation with 24 Gy. Six children were also given spinaJ radiation, while in the remaining 21 cases intrathecal Methotrexate was given 5-6 times. CT scans of the brain showed slight abnormalities with increased ventricular size in only two cases. No differences in attenuation or intracranial calcifications were found. (CT = Computed Tomography, ALL = Acute Lymphoblastic Leukemia, AML = Acute Myeloblastic Leukemia, CNS = Central Nervous System). Acute leukemia, brain, children, CT scan, lymphoma.     

Computed tomography scans of the brain in acute leukemia and lymphoblastic lymphoma. Follow-up of children receiving prophylactic central nervous system irradiation

Twenty-seven long-term survivors diagnosed between 1971 and 1977 as having acute lymphoblastic leukemia (23 children), acute myeloblastic leukemia (1 child), and lymphoblastic lymphoma (3 children) have been studied using CT scans of the brain. None of the children had ever had symptoms or signs of CNS involvement. CT scanning was performed in 19 cases at the cessation of therapy; in the other eight cases, CT scanning was performed 24 to 49 months after the end of therapy. In all children, CNS prophylaxis included cranial irradiation with 24 Gy. Six children were also given spinaJ radiation, while in the remaining 21 cases intrathecal Methotrexate was given 5–6 times. CT scans of the brain showed slight abnormalities with increased ventricular size in only two cases. No differences in attenuation or intracranial calcifications were found. (CT = Computed Tomography, ALL = Acute Lymphoblastic Leukemia, AML = Acute Myeloblastic Leukemia, CNS = Central Nervous System). Acute leukemia, brain, children, CT scan, lymphoma.     

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.     

Reduced upper airway nitric oxide in cystic fibrosis

PURPOSE: Incidence data for severe aplastic anaemia (SAA) in children are scanty and vary. Few population based studies have been reported. A retrospective and prospective study was conducted to determine the incidence and course of SAA. PATIENTS AND METHODS: All children with a diagnosis of SAA in the Nordic countries from 1982 through 1993 were registered and have been followed up since 1987. RESULTS: A total of 101 children were diagnosed with SAA. The mean annual child population was 4.31 million. A constant incidence of 1.95/million children/year was found: 2.4 for boys and 1.5 for girls. A non-significant increase of cases occurred from November to March. Possible aetiological agents were noted in 29%. The actuarial survival was 79% after one year and 68% after five years without significant difference between boys and girls. CONCLUSION: The incidence of SAA in the Nordic countries remains stable with a preponderance among boys. SAA has still a high initial mortality and a risk of late deaths.     

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.