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A clinical trial of chemoimmunotherapy using cell-wall skeleton of BCG (BCG-CWS) was conducted in 28 patients with acute leukemia in complete remission. Chemotherapy consisted of monthly intensification therapy for 2 months and bimonthly therafter. Immunotherapy with 200 microgram of oil-attached BCG-CWS mixed with 10(7) autochthonous leukemic cells was given intradermally at either of upper or lower extremities every week, except when the patients were on maintenance therapy. No serious systemic side effect attributable to BCG-CWS was noted. Six patients developed mild and transient temparature elevation. Most importnat side effect was local skin reaction. Indulated papules developed in all patients, resulting in draining ulcerations in 26 patients. Increase of immunological reactivity of the patients receiving BCG-CWS was noted. Skin test response to PPD, Varidase, and candida extract showed definite increase. In vitro lymphocyte blastogenic response to PPD, concanavalin-A, and pokeweed mitogen revealed significant increase.

A long-term survival study was carried out in a group of 28 adult patients with acute lymphathic leukemia. The complete remission rate was 67.8%, the 50% survival rate is 21.5 months and 41 months in those with complete remissions. Six of 28 patients are long-term survivors and are living at least 5 years after diagnosis. There was a significant majority of female patients among the long-term survivors, with a female to male ratio of 4:2. The 50% survival rate of female patients (n = 11) was 42.5 months and thus considerably higher compared with the corresponding male patients (n = 17, 50% survival rate 7 months). No further clinical or hematological parameters of prognostic relevance were found as a common feature of the long-term survivor group.

Twenty-two patients with chronic lymphocytic leukemia, score 2 according to Rai et al. (10), who received only a course of splenic irradiation are reviewed. Splenic doses ranged from 420 to 1080 rad. Response to splenic irradiation was rated by evaluating peripheral lymphocytosis, hepatosplenomegaly, adenomegaly and disease-related symptoms. Following splenic irradiation, 8 patients showed a significant reduction in splenomegaly; 7 patients showed a significant reduction in peripheral lymphocytosis (less than 10,000/mm3), which has lasted from 15-42 months without any other treatment. In 14 patients, response to splenic irradiation was partial, and it has successively been necessary to treat 12 patients with chemotherapy. Methods of splenic irradiation, survival, clinical and hematologic behavior are discussed in detail.

Between 1972 and 1982, 112 consecutive previously untreated adults (aged 15-69 years, median 26) commenced therapy for acute lymphoblastic leukaemia (ALL) at St Bartholomew's Hospital. The first 63 patients entered into the study received initial treatment which comprised four cycles of adriamycin and vincristine, prednisolone and L-asparaginase with the first cycle (OPAL). In 1978, six cycles were given, with escalating doses of adriamycin and cyclophosphamide from cycle 3 (HEAV'D). Central nervous system (CNS) prophylaxis incorporated intrathecal methotrexate and cytosine arabinoside with cranial irradiation. Maintenance chemotherapy consisted of 6-mercaptopurine, cyclophosphamide and methotrexate for 3 years. Results obtained with the OPAL and HEAV'D regimens were not significantly different. The overall complete remission (CR) rate was 66% (73/111), factors correlating unfavourably with achievement of CR being advanced age (P less than 0.001) and L3 morphology/B-ALL immunophenotype (P less than 0.01). Fifty-three patients have relapsed, the bone marrow being the primary site in 43. Extramedullary relapse alone occurred in 10 (seven CNS, two testicular and one skin). Only three of the 64 patients who had complete CNS prophylaxis subsequently relapsed in the CNS as an isolated site. One patient died in CR, 19 remain in continuous CR between 2.5 and 10.5 years. The median duration of remission of the 73 patients who achieved CR was 18.5 months, factors correlating favourably with duration of CR being low blast cell count at presentation (P less than 0.002) and common ALL immunophenotype (P less than 0.04). Twenty-four patients remain alive, with a median survival of all patients of 18 months. Long-term survival is possible for approximately 20% of adults with ALL treated relatively intensively.

The causes of 37 deaths among 100 Finnish children with ALL were analyzed after a median follow-up of 5 years. Five children died during primary induction, 9 in complete remission, and 23 in hematological relapse. Infections were responsible for 17 deaths, and four deaths were due to toxicity of chemotherapy. In 16 cases ALL relapse was the major cause of death. Ten of the deaths were defined as "avoidable" because they occurred in potentially curable children, i.e., during induction or primary remission. Critical analysis revealed that 5 out of the 10 "avoidable" deaths might indeed have been prevented by appropriate diagnosis and therapy. We want to emphasize the need for continuous education of all pediatricians involved in the care of ALL patients, as well as the importance of best available clinical expertise and centralization of medical therapy in the efforts to diminish the mortality in childhood ALL.

We have treated 37 adults with acute lymphoblastic leukemia (ALL), who have relapsed on previous intensive chemotherapy, with a combination of L-asparaginase and methotrexate (MTX) +/- ifosfamide. The initial study included 26 patients who received the two-drug combination of L-asparaginase and MTX given sequentially. Of the 26 patients, 15 (58%) achieved complete remission (CR), while 3 patients had a partial remission (PR), resulting in an overall response rate of 69%. The median duration of CR was 17.5 weeks. The median survival of complete responders was 39 weeks compared with 10 weeks for failures (P=0.001). The regimen was generally well tolerated and it was possible to give MTX doses of up to 400 mg/m2 with minimal myelosuppression, and severe stomatitis was infrequent. A further study involved the use of this regimen combined with ifosfamide in 11 patients. In this continuing study, there were six CR's (55%) and two PR's, with an overall response rate of 73%. The median duration of CR was 14+ weeks, and the median survival was 40+ weeks. Combination chemotherapy with asparaginase and MTX is effective in inducing remission in adults with ALL in relapse. It should now be considered for inclusion as part of induction therapy of previously untreated adults with ALL.

The identification of important prognostic factors at diagnosis of childhood leukemia has been very useful in explaining the marked differences in disease outcome. After a complete remission is achieved, it is interesting to determine whether the ability to maintain a complete remission and the patient's survival continue to be influenced by the prognostic factors identified at diagnosis. If the maintenance of complete remission and survival continue to be influenced, it is important to determine the magnitude of this effect and its variations with time. Data from a study population of 936 children with newly diagnosed acute lymphoblastic leukemia were analyzed to determine the duration of effect for three variables showing strong prognostic influence: WBC, age at diagnosis, and sex. The strongest of these, WBC, showed a gradual attenuation of effect for children in progressively longer periods of complete continuous remission to a virtual disappearance at 24 months. Age and sex showed a similar reduction in prognostic effect with a negligible contribution at 15 months of continuous complete remission. However, sex becomes an important variables again with a late effect on recurrence results in patients who experience long periods of remission.

Bone marrow smears from 72 consecutive children with a recent diagnosis of acute lymphoblastic leukaemia (ALL) have been morphologically analyzed. A high incidence of lymphoid cells with amoeboid movement configuration (AMC) seems to indicate a more favorable prognosis independently of other prognostic factors e.g. age, WBC or sex. A positive correlation between the AMC and the mitotic indices (MI) of the lymphoblasts indicates some connection between the motility and the proliferative activity of the leukaemic cell clone.

Among 164 patients with acute lymphoblastic leukemia (ALL) (age greater than 11 years) induced into complete remission at four hospitals in Italy and The Netherlands between 1971-1977, 49 survived for more than three years in continuous complete remission. Features at diagnosis of the 49 long-term survivors were compared with those of the parent group. The long-term survivors presented with significantly lower leukocyte counts and were slightly younger. Late relapses occurred in nine patients after 37-91 months from remission. Of the 45 patients who had all treatment stopped after 24-60 months of continuous remission, seven have relapsed. Relapses, mainly in the marrow, occurred 4-32 months after cessation of therapy, the risk of relapse being greatest in the first year and dropping to zero by the fourth year. ALL appears curable in approximately one fifth of adolescents and adults entering complete remission with adequate chemotherapy.

As long as the aetiology of acute lymphatic leukaemia of children is not known its therapy is based on clinical experience. Among the values of experience those factors will play a part, the evidence of which during the ALL initial stage will be a risk for successful therapy and survival rate. This results in a choice of more aggressive variants of modern therapy schemes. In a cytogenetic study made in 35 children with ALL it was tested, whether even leukaemic chromosome clones will be a risk for the course of acute leukaemia. The duration of the first remission and survival rate were considered as criteria. The evidence of a leukaemic chromosome clone could be shown to be followed by a short survival rate, irrespective of the stage of the disease where the clone had been observed first. Thus, cytostatic therapy in those ALL patients who are affected with luekaemic chromosome aberration of stem line character should be aimed at the complete annihilation of the clone, irrespective of other remission criteria. The failure of blood and bone-marrow cultures as early as during the untreated initial stage indicated a primary cellular immuno-insufficiency. This combination of cell immuno-depression with high peripheral leukocytes connts and a primary mediastinal tumour or a generalizing lymphosarcoma respectively, was the highest risk up till now for the course of the disease. Judging from the duration of the first remission and the survival rates, the consecutive schemes of therapy did not differ in their effect on leukaemia with pathological stem lines. On the basis of the present study the impression could not be excluded that up till now long term survival rates could be attributed rather to individual manners of response than to the modern therapy scheme.

In Essen 142 bone marrow transplantations were carried out between December 1975 and February 1985. In 74 cases the indication was acute leukemia in relapse (n = 23) or in first or consecutive remission (n = 51). The conditioning regimen consisted of cyclophosphamide or the combination of cyclophosphamide and total body irradiation. All patients were treated under strict gnotobiotic care. To mitigate the risk of CMV infections, intravenous CMV-hyperimmune globulin and CMV-negative blood products have been applied routinely for 2 years. MTX was used as prophylaxis against GvHD. In the prognostically unfavorable group of acute leukemia in relapse, only one patient showed long-term survival. In this patient, leukemic relapse occurred 6 years after transplantation. The survival rate of AML patients grafted during the first remission is 55% (16/29) with a median observation time of 41 months. For patients grafted in first or consecutive remission of acute lymphoblastic leukemia, the survival rate is 50% (7/14) with a maximal observation time of 34 months. The overall incidence of GvHD in patients at risk was 28% in aplastic anemia, 26% in AML, 9% in ALL, and 63% in CML. In aplastic anemia, no patient developed an interstitial pneumonia. In leukemia, the risk of fatal interstitial pneumonia was 34%.

In vitro incorporation of tritiated thymidine was measured in blast cells from 33 unselected and untreated patients with lymphoblastic leukaemia (ALL) both when autologous plasma was present and also when it was substituted by pooled normal plasma. A similar procedure was carried out on 19 patients with acute non-lymphoblastic leukaemia (AnonLL). Plasma from the patients with ALL was variably found to reduce the uptake of the radiolabelled DNA-precursor by their own blasts, with the most marked effect apparent in those with shorter survival times (P < 0.02). This phenomenon was not observed in AnonLL. The amount of plasma-mediated inhibition shown by the ALL patients also correlated overall with their WBC, a known feature of a poor outlook, but even in the 21 patients with WBC below 20.0 x 10(9)/l there was still a significant association between plasma effect and survival (P < 0.01). The demonstration of such inhibitory plasma may be a useful prognostic marker in otherwise 'standard risk' ALL, and also may indicate a large tumour mass where this is not reflected by the height of the circulating WBC.

The clinical features and diagnostic evaluation of six patients affected by prolymphocytic leukemia (PLL), are described. Some of the cases deviate from a relatively uniform and aggressive clinical course of the disease entity. An actuarial survival analysis of 60 cases gathered from the literature and the authors' experience indicate that the cases showing the most prolongated evolution may reach 30% of the total. The different aggressiveness in the clinical course of these patients does not depend on the efficiency of the therapies applied. The percentage of prolymphocytes (PL) in peripheral blood throughout the clinical course was variable and not depending on the treatments used. This fact, in conjunction with (1) the presence of cellular types deviated from the typical PL and detected both at optical and ultrastructural levels and (2) the existence of cases of PL with minimal splenomegaly and leukocyte counts of less than 50 X 10(9)/liter, could lead to an underdiagnosis of PLL and hinder the actual cognition of the natural medical history of the disease.

Thirty eight patients with acute lymphoblastic leukemia were treated protocol 0171 (VCR, PRED, MTX, cyclophosphamide +/- +/- 6-MP) and protocol 0276/A (VRC, PRED, L-ASP, MTX, 6-MP, cyclophosphamide). Overall complete remission rate in both studies was 84--85%, and additional treatment in protocol 0171 resulted in complete remission rate of 92%. Median duration of complete remission in protocol 0171 was 23 months and median survival of all patients was 33 months. Six patients randomized to regimen "A" (without 6-MP in intensification) had median duration of complete remission 8 months and media survival was 13 months. Seventeen patients treated with regimen "B" (with 6-MP in intensification) had median duration of complete remission 25 months and median survival was 39 months. Median survival of patients allocated on protocol 0276/A in 21+ months and median duration of complete remission is 23 months at present. Twelve percent of patients treated with the best regimen have survived more than 66 months in continuous complete remission. The incidence of drug related death in complete responders was 6%. The relapses were most frequent during the first two years of remission. Extramedullary leukemia as the initial site of relapse was observed in 9% of patients.

The clinical course of a two-year-old girl with acute lymphocytic leukemia (ALL) who inadvertently received intrathecal vincristine is presented. Despite aggressive treatment with parenteral folinic acid and extensive central nervous system washout, the outcome was fatal. The pharmacologic aspects of vincristine and folinic acid that may explain why treatment was unsuccessful, are reviewed.

Nested case-control studies of non-Hodgkin's lymphoma (52 cases), multiple myeloma (20 cases), nonlymphocytic leukemia (39 cases), and lymphocytic leukemia (18 cases) were conducted within a cohort of employed men from two chemical manufacturing facilities and a research and development center. Exposure odds ratios were examined in relation to 111 work areas, 21 specific chemicals, and 52 chemical activity groups. Associations were observed for a maintenance and construction subgroup (non-Hodgkin's lymphoma) and a chlorohydrin production unit (nonlymphocytic leukemia). The odds ratio for the association of "foremen and others" with non-Hodgkin's lymphoma was 3.2 (CI95 = 1.47-7.2) based on 11 cases. A duration-response trend was observed for the chlorohydrin unit with three of four cases assigned 5+ years to that unit. An association between non-Hodgkin's lymphoma and assignment to strong acid alcohol production units (OR = 8.3; CI95 = 2.3-30.7) was not supported by a duration-response trend. Two highly correlated chemical groups, antioxidants (five cases) and nitriles (four cases), were over-represented among multiple myeloma cases. A duration effect was observed. However, examination of work histories did not reveal common jobs or departments among these cases.

Mediastinal involvement was found in 11 (group A) of 43 patients affected with acute lymphatic leukemia when early thoracic roentgenograms of these patients were reviewed. Several clinicobiological characteristics of these patients were compared with those with a normal mediastinum as shown in their roentgenograms (group B). Statistically significant differences were observed between group A and group B not only as far as age was concerned (13 years group A, 7.4 years group B) but also in the ratio males/females (10:1 group A, 10:20 group B) and with regard to the leukocyte counts (266 x 10(9)/liter group A, 20 x 10(9)/liter group B). In addition, patients from group A showed a greater 'tumoral mass' and a more prominent extrahematological involvement (45% group A, 15% group B). In these cases 'convoluted' cells were frequently discovered and the blastic cells exhibited significantly lower scores of PAS-positivity and more marked acid phosphatase activity than those in group B. Although the rate of complete remissions (CR) obtained in both groups was similar (80% group A, 93% group B), marked differences were observed not only in the duration of CR but in the period of survival after CR as well, both factors being more prolonged in group B patients. 50% of patients with mediastinal involvement (group A) relapsed in the first 6 months of the evolution of the disease.

A complete national material of children with acute lymphoblastic leukemia diagnosed in the years 1973-1980 was analyzed with regard to prognostic differences between males and females. In accordance with international criteria (age, WBC, CNS involvement, and mediastinal mass), the children were classified as standard risk (SR) and increased risk (IR). Thirty-eight percent of the males and 32% of the females fulfilled criteria for assignment to the group with an increased risk. A linear multiple regression analysis on the material showed that WBC was the most important prognostic criterion, followed by sex, age, and mediastinal mass. The prognosis was significantly poorer for males in the standard risk (p less than 0.03) and in the increased risk group (p less than 0.0001). The IR criteria were more valid for males than for females. Serious complications resulting from therapy were more frequently reported for females than for males. These studies suggest that sex is of significance both for the prognosis and for the efficacy of treatment.

Burkitt's-type leukemias have specific cytologic, immunologic, and cytogenetic characteristics. Initial symptomatology frequently includes abdominal tumors and initial CNS involvement. Despite intensive treatment including high-dose cyclophosphamide, prognosis remains poor in most patients because of failures to achieve complete remission (CR) or because of early relapses, especially CNS relapses. Class III acute lymphoblastic leukemia in children is defined by the presence of two or more unfavorable parameters and recent progress has been achieved by intensive therapy. Cox's multifactorial analysis allows improved discrimination. A phase I protocol for increased-risk leukemias, including testis preventive irradiation and monthly reinductions without continuous maintenance for the first 6 months of CR, seems promising.

We hypothesized that the sister chromatid exchanges assay in acute leukemia long-term survivors may detect: (a) long-term effects of combined chemo- and radiotherapy; and possibly (b) those individuals with inherently deficient DNA repair. Accordingly, we determined the sister chromatid exchanges frequency in 26 blood specimens from 24 acute leukemia long-term survivors (patients) and 14 blood specimens from 13 control subjects (controls). The patients consisted of 23 children with acute lymphocytic and one child with acute myelocytic leukemia. The median length of chemotherapy was 5 years. Eighteen of the 24 patients also received prophylactic fractional central nervous system irradiation for the first 3 years of treatment, and one patient received therapeutic irradiation to the central nervous system. The median off-therapy period at the time of study was 2.5 years with a range of 0 to 7.5 years. The controls consisted of the parents of the patients and laboratory personnel. A mean exchange score per cell was established for each specimen (25 to 30 cells/specimen were scored), and it ranged from 3.0 to 9.7 in the patients and from 3.0 to 11.5 in the controls. A mean +/- S.D. calculated from those means was 6.0 +/- 1.8 for the patients and 6.9 +/- 2.8 for the controls. They were not significantly different. We conclude that chemo- and radiotherapy produced no persistent DNA alterations detectable by this method.

We examined the results of stopping therapy in children with acute lymphocytic leukemia. Of 639 patients in eight consecutive "total therapy" studies, 278 (44 per cent) had all treatment stopped, usually after 2 1/2 years of complete remission. About one fifth (55 of 278) of this group have relapsed, mainly in the bone marrow. The relapse rate for the first year off therapy was higher than that for the next three years (0.16 vs. 0.04, P less than 0.01). The life-table estimates of the four-year relapse rates were 0.24 for all patients and 0.22 for patients receiving adequate central-nervous system prophylaxis. Boys had a higher relapse rate than girls (0.33 vs. 0.15 P less than 0.01). None of the 79 patients who remained in complete remission for at least four years off therapy have yet relapsed. Acute lymphocytic leukemia appears curable in over one third of all newly diagnosed patients who receive treatment for approximately 2 1/2 years.

Of 111 patients presenting with acute forms of leukemia, 44% had a chromosomally abnormal cell line in the bone marrow at diagnosis. In each of the acute leukemia forms (myeloid, lymphatic, stem-cell), patients with karyotypic abnormalities showed mean and median survival times like those with normal chromosomes. Both groups showed a wide range of survival times. The mean and median survival times of patients with mixed populations of chromosomally normal and abnormal cells did not differ from those of patients with exclusively abnormal cells in the bone marrow. The karyotypic abnormalities associated with acute leukemia, as well as having no etiologic significance, probably do not determine the subsequent course of the leukemia.

The Children's Cancer Study Group investigated the relative efficacies of four treatments directed at the central nervous system (CNS) and other sanctuary areas in 724 children with acute lymphoblastic leukaemia (ALL). The results show that CNS relapse rates are lower in patients receiving effective treatment before CNS symptoms arise, but the bone marrow relapse rate was not significantly affected by prophylactic therapy. In patients with an initial white blood count of 50000/microliter or more, multiple CNS relapses resulted in a lower survival rate. The data from the group receiving the least effective CNS prophylaxis indicate that CNS leukaemia is not necessarily followed by bone marrow relapse and death. These observations suggest that reseeding of the bone marrow by leukaemic cells from the CNS is not a major factor in the evolution of ALL. CNS prophylaxis is of value in averting the CNS complications of ALL and those associated with its therapy, but the improved survival in childhood ALL during the past decade is probably not due to the successful prevention of CNS leukaemia. Improvements in survival are probably the result of more effective systemic chemotherapy and better general management.

21 patients, 18 with chronic lymphocytic leukaemia (CLL) and 3 with prolymphocytic leukaemia (PLL), all B-lymphocyte origin and with progressive disease, were treated with a regime of low-dose splenic irradiation (SI). All patients experienced a rapid relief of disease-related symptoms. Following SI the total lymphocyte count (TLC) was markedly reduced in 18 patients. Partial to complete regression of splenomegaly occurred in 9 patients. Pre-existing anaemia of production failure type improved in 6 patients and as a result the haemoglobin rose to normal or near normal levels. SI caused the loss of T-, B- and Null-lymphocytes, but the loss of B-lymphocytes predominated. CLL/PLL became quiescent for long periods in 9 patients (CLL = 8; PLL = 1) but remained progressive in the other 9, all CLL. SI had no demonstrable effects on TLC, splenomegaly or anaemia in the 3 remaining patients (2 CLL, 1 PLL). The treatment was well tolerated by all, and side effects were almost absent. Transient reduction of neutrophils and platelets occurred commonly. No patient with initially normal neutrophil and platelet counts developed irreversible neutropenia or thrombocytopenia. In view of these effects, the ease of administration and the lack of side effects, further evaluation of low-dose SI, particularly in comparison with other regimes, seems worthwhile.

One hundred fifty-three children with ALL were diagnosed in Norway in the period August 1975-December 1980. One hundred thirty-two of them received 3 infusions of methotrexate as consolidation therapy combined with methotrexate intrathecally as CNS prophylaxis. Eleven (44%) of the total 25 methotrexate cases with WBC above 50 X 10(9)/L were in CCR after 4 1/2-10 years. Two more cases had discontinued therapy, while in second remission. The event-free survival of all diagnosed 32 children in Norway with WBC above 50 X 10(9)/L was 37%. Seven infants below the age of 1 year are included in the 32 cases.

The aim of this study was to find out whether the time required for disappearance of peripheral blast cells, or blast clearance, could be used to identify patients with a slow response to treatment associated with a poor prognosis of acute lymphoblastic leukemia (ALL). Our series consisted of 158 children with newly diagnosed ALL. The mean follow-up time was 69 months (range 22 to 140 months). Blast clearance was significantly associated with length of event-free survival. Only two of nine children with blast clearance greater than or equal to 2 weeks and 4 of 11 children with blast clearance of 11 to 13 days were in remission at the time of analysis as compared with 86 of 138 of the children with more rapid blast clearance. The respective 5-year event-free survivals were 17%, 36%, and 60% (P = .003). Multivariate analysis showed that the relative risk of death or relapse in patients with blast clearance of greater than 10 days was 5.2-fold (95% confidence limits 2.1 to 13.1) as compared with the others (P less than .001). Our results indicate that patients with a slow response to treatment can be identified by simple differential peripheral cell counts during the early induction phase well before or even instead of performance of a more invasive bone marrow aspiration.

Five weekly doses of triple intrathecal (IT) chemotherapy (methotrexate, hydrocortisone, cytosine arabinoside) starting on day 1 of treatment were added to systemic induction therapy in a regimen (Arm 3) that was compared to three other regimens (Arms 1, 2, and 4) in which central nervous system (CNS) prophylaxis was initiated after complete marrow remission (CR) was attained. The CR rate for Arm 3 was only 83% as compared to 91-92% for other Arms. The lower CR rate was the result of a significantly higher death rate during induction for patients receiving early CNS prophylaxis (10.6 vs 0.9-3.5%). These differences were only observed in high risk patients as defined in the study. The early death rate was especially high (30%) in Arm 3 for children who were less than 2 years of age. Infection was the primary cause of morbidity and mortality. Severe infection following the initiation of induction therapy was found in 16.7% of patients on Arm 3 vs 1.8-6% on other regimens. Immediate triple IT chemoprophylaxis during induction therapy of acute lymphoblastic leukemia as used in this study appears to be associated with increased susceptibility to infection and this form of CNS prophylaxis has increased hazards of morbidity and mortality in infants and other high risk patients.