Mortality and morbidity caused by measles in children with malignant disease attending four major treatment centres: a retrospective review.

Measles is a major cause of mortality and morbidity in children receiving treatment for leukaemia. A review was made of all the documented cases of measles in children in first remission from acute lymphoblastic leukaemia at four major treatment centres in 1974-84. Over the 11 years reviewed 1043 children with acute lymphoblastic leukaemia were referred to these centres. Fifty one (4.9%) died while in first remission and 15 (29.4%) of these deaths were due to measles or its complications: 12 cases of pneumonia, 10 of them fatal; and six cases of encephalitis, five of them fatal and the sixth child left severely handicapped. These children would have had at least a 50% chance of long term survival. The severity of measles in the immunocompromised patient reinforces the need to improve the poor uptake of measles immunisation in Britain.     

Vincristine and Prednisone for the Induction of Remissions in Acute Childhood Leukaemia

A total of 65 children with acute lymphoblastic leukaemia and seven with other types of acute leukaemia received treatment with a combination of vincristine and prednisone. In all 122 courses of treatment were given. Of 22 patients with acute lymphoblastic leukaemia who received this as their first treatment, all achieved complete remission. The complete remission rates were 82% for patients with acute lymphoblastic leukaemia in their first relapse, 63% in the second relapse, and much lower in subsequent relapses and in the patients with other types of acute leukaemia. Alopecia and gastrointestinal and neuromuscular toxicity occurred respectively in 51%, 29%, and 21% of instances, only the last of these side-effects of vincristine being dose-related. Most of the complete remissions were obtained with a total dose of vincristine which carried only a low risk of neurotoxicity.     

Late marrow recurrences in childhood acute lymphoblastic leukaemia.

Thirty children with acute lymphoblastic leukemia had a recurrence in the bone marrow after treatment was stopped electively. A second haematological remission was achieved in 27 (90%), and the median duration of remission was shortest (six months) in those relapsing within six months of stopping treatment. Four of six children relapsing over one year after stopping treatment remained in second haematological remission. Leukaemic infiltration of the central nervous system developed in four patients remaining in marrow remission. It is concluded that conventional chemotherapy is unlikely to be effective in children with acute lymphoblastic leukaemia who relapse soon after stopping treatment, that "reprophylaxis" of the central nervous system probably with long-term intrathecal chemotherapy is essential, and that some patients relapsing after prolonged unmaintained remission may achieve long-term leukaemia-free survival.     

Adriamycin in the Treatment of Acute Leukaemia

In a preliminary study a new antitumour antibiotic, adriamycin, was found to be capable of inducing complete remission in 6 out of 17 patients with acute lymphoblastic leukaemia and in one out of four with lymphoblastic lymphosarcoma despite the fact that these patients had either failed to respond or had relapsed after chemotherapy with agents recognized to be potentially successful in each condition. In five cases of acute lymphoblastic leukaemia adriamycin was used in combination with cytosine arabinoside—three achieved complete remission and two good partial remissions. This combination seems to merit further study in patients who have relapsed on the more conventional chemotherapeutic regimens in acute lymphoblastic leukaemia.In 13 patients with acute myelogenous leukaemia previously treated with daunorubicin and cytosine arabinoside no remissions were obtained with the dose range used.     

Granulocytopoiesis in children with acute lymphoblastic leukaemia.

Numbers, proliferative potential, and differentiative capacity of bone marrow granulocyte-macrophage precursor cells were studied in 130 children with acute lymphoblastic leukaemia (ALL), including 77 children in an acute phase of the disease and 53 in remission. Bone marrow samples from 65 children without haematopoietic abnormalities were used as controls. The numbers of clonogenic precursors were found to be below normal in all phases of ALL, particularly during the acute period when the bone marrow was heavily infiltrated with leukaemic cells. It is shown that the decreases in the numbers and proliferative potential of the precursor cells during the acute phases was associated with the effects of leukaemic blast cells, but that in remission the observed reduction in the precursor cell pool was due to the cytostatic effect of therapy. The differentiative capacity of clonogenic granulocyte and macrophage precursors was not altered in children with ALL.     

Bone-marrow relapse in acute lymphoblastic leukaemia in childhood.

The outcome after bone-marrow relapse was assessed in 53 children with acute lymphoblastic leukaemia (ALL). Twenty-five out of 37 children (67%) whose first remission ended in relapse during treatment (group A) achieved a second remission, as did 15 out of 16 (94%) who relapsed after treatment had been stopped (group B). Nevertheless, the median duration of second remission was only 12 weeks in group A and 35 weeks in group B. The median survival from time of relapse was 32 weeks in group A and 75 weeks in group B. It is concluded that marrow relapse is equally serious whether it occurs during treatment or after treatment has been stopped, and that most children with ALL have a single chance of cure at the time of diagnosis.     

Status of allogeneic bone marrow transplantation in childhood in the GDR

Of 25 HLA-identical, MLC negative transplants 10 patients had acute lymphoblastic leukaemia (ALL), 8 acute nonlymphoblastic leukaemia (ANLL), 3 severe aplastic anaemia, 2 malignant histiocytosis, 1 patients neuroblastoma and 1 Fanconi anaemia. 3 HLA nonidentical, MLC positive transplants were performed, two children had malignant infantile osteopetrosis and 1 child had a severe combined immunodeficiency disease. Patients with ALL and ANLL received cyclophosphamide and single dose total body irradiation. 3 patients received fractionated TBI. The results for the allogeneic group overall indicate that the actuarial disease free survival rate is 0.62. 16 of 25 patients are in continuous complete remission (CCR) periods of 3-78 months posttransplant. All three transplanted children with severe aplastic anaemia alive disease-free for periods of 21-81 months. 10 patients with ALL were transplanted (2 in first remission for high risk ALL, 8 in second remission). 7 of 10 patients are alive and disease-free (CCR rate 0.67). 8 patients underwent BMT for ANNL while in first remission in 7 patients and in third partial remission in 1 patient. 4 of 8 patients are alive and disease-free for periods of 25-56 months (CCR rate 0.50). 1 patient with neuroblastoma stage IV survives 24 months, 1 child with Fanconi anemia died on day +25 of GVHD and septicaemia. 1 of the 2 patients transplanted for malignant histiocytosis relapsed 3 months posttransplant, 1 patient is alive and disease-free 5 months posttransplant. In none of the HLA-nonidentical and MLC positive transplantations T-cell depleted marrow engrafted.     

Risk of acute childhood leukaemia in Sweden after the Chernobyl reactor accident. Swedish Child Leukaemia Group.

OBJECTIVE--To evaluate the risk of acute childhood leukaemia in areas of Sweden contaminated after the Chernobyl reactor accident in April 1986. DESIGN--Population based study of childhood leukaemia diagnosed during 1980-92. SETTING--Coordinates for places of residence of all 1.6 million children aged 0-15 years; aerial mapped areas of Sweden heavily contaminated after the Chernobyl accident. SUBJECTS--888 children aged 0-15 years with acute leukaemia diagnosed in Sweden during 1980-92, identified with place of birth and residence at diagnosis. MAIN OUTCOME MEASURES--Risk of leukaemia in areas contaminated after the Chernobyl accident compared with the rest of Sweden and in the same areas before the accident. RESULTS--During six and a half years of follow up after the accident the odds ratio for acute leukaemia was 0.9 (95% confidence interval 0.6 to 1.4) in highly contaminated areas (> or = 10 kBq/m2) compared with the same areas before the accident. For the subgroup acute lymphoblastic leukaemia in children aged under 5 years at diagnosis the odds ratio was 1.5 (0.8 to 2.6). For all cases diagnosed after May 1986 in highly contaminated areas compared with areas of low contamination the odds ratio was 0.9 (0.7 to 1.3). For acute lymphoblastic leukaemia in children aged under 5 years at diagnosis the odds ratio was 1.2 (0.8 to 1.9) in highly contaminated areas compared with areas of low contamination. Dose-response analysis showed no correlation between the degree of contamination and the incidence of childhood leukaemia. CONCLUSION--There has been no significant increase in the incidence of acute childhood leukaemia in areas of Sweden contaminated after the Chernobyl reactor accident.     

Growth hormone and tumour recurrence.

OBJECTIVE--To determine whether using growth hormone to treat radiation induced growth hormone deficiency causes tumour recurrence. DESIGN--Comparison of tumour recurrence rates in children treated with growth hormone for radiation induced deficiency and an untreated population. Computed tomograms from children with brain tumours were reviewed when starting growth hormone and subsequently. SETTING--North West region. PATIENTS--207 children treated for brain tumour, 47 of whom received growth hormone and 161 children with acute lymphoblastic leukaemia 15 of whom received growth hormone. MAIN OUTCOME MEASURES--Tumour recurrence and changes in appearances on computed tomography. RESULTS--Among children with brain tumour, five (11%) who received growth hormone had recurrences compared with 42 (26%) who did not receive growth hormone. Also adjusting for other variables that might affect tumour recurrence the estimated relative risk of recurrence was 0.82 (95% confidence interval 0.28 to 2.37). The only child with acute lymphoblastic leukaemia who relapsed while taking growth hormone had relapsed previously before starting treatment. Two of the five children with brain tumours who relapsed had abnormal appearances on computed tomography when growth hormone was started. 14 other children who remained relapse free and had follow up computed tomography showed no deterioration in radiological appearance during treatment. CONCLUSIONS--In this population growth hormone did not increase the risk of tumour recurrence but continued surveillance is essential. Abnormal results on computed tomography are not a contraindication to treatment with growth hormone.     

Giant-cell pneumonia caused by measles and methotrexate in childhood leukaemia in remission.

Four children who had acurate lymphoblastic leukaemia in remission and developed pneumonia were studied. Investigations including electron microscopy and immunofluorescence of lung biopsy material disclosed measles, although there was no clinical evidence of the disease. Despite an identical presentation, two types of illness developed: two children died of giant-cell pneumonia, while the other two developed pneumonia indistinguishable from that associated with methotrexate treatment, recovering when treated with steroids and gammaglobulin. Measles infection is easily overlooked in the absence of rash. The diagnosis may be suggested by clinical and radiological features and confirmed by specific immunofluorescence staining of lung biopsy tissue.     

Poor prognosis of acute lymphoblastic leukaemia in Asian children living in the United Kingdom.

A study of the results of treatment of acute lymphoblastic leukaemia in Asian (Indian and Pakistani) children living in the United Kingdom showed that they had a poorer prognosis than native white children due mainly to deaths during remission. Similar proportions of Asian and white children suffered relapse. Lower socioeconomic status, poor nutrition, and difficulties in communication may have contributed to the worse outcome in the Asian children.     

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate

Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m² methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m². Seven days later intravenous methotrexate, 120 mg/m² was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m² with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m² (median 200 mg/m²). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m² caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.     

Analysis of treatment in childhood leukaemia. I. Predisposition to methotrexate-induced neutropenia after craniospinal irradiation. Report to the Medical Research Council of the Working Party on Leukaemia in Childhood.

The degree of drug-induced neutropenia resulting from a controlled trial (UKALL I) of treatment in acute lymphoblastic leukaemia was analysed. The main agent associated with severe neutropenia was methotrexate, and methotrexate-induced neutropenia was significantly greater in patients who had received craniospinal irradiation. The synergistic toxic effect of irradiation followed by methotrexate treatment seems to have contributed to three of the five deaths which occurred in complete remission in this trial; all deaths in remission occurred in patients who had received central nervous system prophylaxis. Analysis of patients who subsequently relapsed compared with those still in remission after 18 months of treatment indicated that the former, on average, had slightly lower neutrophil counts. This suggests that the children who relapsed did not receive any less aggressive treatment than those who remained in remission.     

TFX immunotherapy in children with ALL during remission

The in vivo effect of thymus factor X (TFX) on the E-rosetting capacity, the absolute peripheral blood lymphocytes and T-cell number per microliter, the skin test reactivity to recall antigens, and the immunoglobulin production was evaluated in 20 children with acute lymphoblastic leukaemia. The in vitro effect of TFX was also tested. The mean percentage of E-rosettes in these patients increased from 50 to 64%. Although absolute peripheral blood lymphocyte and T-cell number per microliter rose significantly, the mean values did not reach those in healthy children. The tests with recall antigens were positive in 13% of patients prior to immunotherapy and 32% following the therapy. The influence of immunotherapy on infectious episodes and on the stabilisation of remission was also evaluated. TFX in vivo appears to restore immunocompetence, decrease infections, and prolong remissions in children with ALL in remission.     

L-Asparaginase in Treatment of Acute Leukaemia and Lymphosarcoma

L-Asparaginase was used to treat 40 patients with acute leukaemia or lymphosarcoma. Fifteen with acute lymphoblastic leukaemia either untreated or in relapse after previous therapy were given “Squibb,” “Bayer,” or “Porton” L-asparaginase. Five of these patients had complete remission of their disease, and four had good partial remission. Eleven patients with acute myeloid leukaemia were treated for a short period with L-asparaginase alone. None of them went into remission though a pronounced fall in the numbers of circulating white cells was seen. Six patients with lymphosarcoma received L-asparaginase, two of them having good partial remissions.The toxic side-effects of the L-asparaginase from the three sources seemed to vary, and L-asparaginase from Erwinia carotovora appeared to be antigenically different from the enzyme produced by Escherichia coli.The way in which leukaemic cells become resistant to the action of the enzyme requires further investigation. To overcome this resistance asparaginase should be used in combination with other drugs in the treatment of acute leukaemia.     

Autologous responses to human leukaemic cells in mixed leucocyte culture

Summary Cryopreserved leukaemic blasts and remission non-T cells from 22 patients with acute leukaemia (15 lymphocytic, 7 non-lymphocytic) were tested as stimulators of autologous remission T cells and normal allogeneic T cells in primary and secondary MLC. In most cases the autologous response elicited by leukaemic cells was less than or equal to that elicited by remission non-T cells. However, T cells from 2 patients in long-standing first remission from ANLL displayed greater proliferation in response to leukaemic blasts than to remission non-T cells in both primary and secondary MLC. The results are suggestive of sensitization of these 2 patients to leukaemia-specific antigens, but other possible explanations are discussed. Abbreviations used: MLC, mixed leucocyte culture; ANLL, acute non-lymphocytic leukaemia; ALL, acute lymphoblastic leukaemia; AMLR, autologous mixed lymphocyte reaction; NK cells, natural killer cells; MNC, mononuclear cells     

Combination chemotherapy for acute lymphoblastic leukaemia in adults.

Fifty-one adults with acute lymphoblastic leukaemia were entered into a trial of intense initial chemotherapy and early "prophylaxis" of the central nervous system (CNS). Initial treatment with OPAL (Oncovin (vincristine), prednisolone, adriamycin (doxorubicin), and L-asparaginase (colaspase)) followed by craniospinal or cranial irradiation and intrathecal methotrexate produced remission in 36 patients (71%). Seventeen of these patients relapsed three to 18 months after the start of remission; the remainder had been in remission for 12 to 52 months by the end of the study. The predicted median duration of complete remission was 18.5 months. None of the four patients who initially had clinical evidence of CNS disease, three of whom also had leukaemic cells identical to those found in Burkitt''s lymphoma, achieved remission. Those patients who initially had hepatomegaly or splenomegaly had a shorter remission than those without. The predicted median survival was 27 months in those who achieved complete remission, one month in those who did not, and 21 months overall. The addition of colaspase and doxorubicin to vincristine and prednisolone and the use of early CNS treatment clearly improved the remission rate among adults with acute lymphoblastic leukaemia, though the presence and length of remission was affected by the extent of disease at presentation. Burkitt-like leukaemia, which had a poor prognosis, is probably a separate disease and may benefit from a different therapeutic approach.     

Intrinsic capacity of monocytes to produce cytokines ex vivo in patients with acute lymphoblastic leukaemia

Monocytic cytokine profiles of fifteen children with acute lymphoblastic leukaemia (ALL) were included to determine whether malignancy per se contributes to impaired cytokine profiles in vivo and ex vivo. The ex vivo tumour necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) production was positively correlated with the monocyte number and with the number of intracellular TNF-alpha or IL-1beta positive cells in lipopolysaccharide (LPS)-stimulated MNC cultures. The mean ex vivo TNF-alpha and IL-1beta production per 1x10(4)monocytes in these cultures was not significantly different in children at diagnosis of ALL, at remission or in controls. High IL-10 plasma levels at diagnosis of ALL had no effect on the ex vivo TNF-alpha and IL-1beta production of monocytes in LPS stimulated MNC cultures. These results show that monocytes of ALL patients have a normal intrinsic capacity to produce cytokines ex vivo. However, the decreased monocyte number is responsible for the lower TNF-alpha and IL-1beta concentrations ex vivo upon LPS stimulation.     

Bone marrow transplantation in childhood leukaemia--experience and strategies in the Federal Republic of Germany

BMT has gained its place in the treatment of childhood leukaemia. Nevertheless, there are still many questions open. In acute lymphoblastic leukaemia children should normally be grafted in 2nd remission (CR). Some high risk cases, however, should probably be grafted in 1st CR. It is not clear whether children with late relapses benefit more from BMT than from renewed chemotherapy. Children with a relapse during maintenance therapy, however, have a better survival rate with BMT. In acute nonlymphoblastic leukaemia certain high risk patients should be grafted in 1st CR but it has still to be shown that BMT is superior to chemotherapy in such cases. It is not clear whether children with a relapse following intensive chemotherapy (such as the BFM-protocols) will benefit from BMT at all. In chronic myelocytic leukaemia, BMT in chronic phase should be performed. Thus, for the first time cure has become possible for this disease. Waiting for acceleration or even the occurrence of a blast crisis decreases the chance of survival after BMT dramatically. Since complications of BMT such as graft-versus-host reaction or severe infections are less frequent in children, relapses remain the main problem after BMT in childhood leukaemia.     

Remission-induction of acute lymphoblastic transformation of chronic myeloid leukaemia, followed by long-term maintenance therapy

Acute lymphoblastic transformation of chronic myeloid leukaemia (LT-CML) of 7 consecutive patients was treated according to a remission-induction and maintenance therapy used for de novo acute lymphoblastic leukaemia (ALL). All 7 patients achieved a second chronic phase with a median remission duration of 15 months. Two patients showed an isolated central nervous system (CNS) relapse. This did not occur in the 4 patients, who received prophylactic therapy with intrathecal methotrexate. The second transformation was nonlymphoblastic in nature in 4 out of the 5 patients. A treatment protocol similar to that of a bad risk ALL, including long-term maintenance therapy and CNS-prophylaxis is indicated in lymphoblastic transformation of CML.