Immunoreactive calcitonin in leukaemia.

A radioimmunoassay was used to measure concentrations of immunoreactive human calcitonin (HCT) in plasma and leucocytes from patients with various leukaemic and myeloproliferative disorders. Plasma immunoreactive HCT concentrations were increased in 32 out of 33 patients with chronic granulocytic leukaemia (CGL) and in all eight patients with acute myeloid leukamia (AML) at presentation or in relapse. Out of 11 patients with other myeloproliferative disorders, eight had increased plasma immunoreactive HCT concentrations. Buffy-coat-cell extracts and culture media from peripheral leucocytes of patients with CGL also contained increased immunoreactive HCT concentrations. In contrast, plasma from patients with chronic lymphocytic leukaemia, acute lymphoblastic leukaemia, and AML in remission had low or undetectable immunoreactive HCT concentrations. Increased plasma and cellular concentrations of immunoreactive HCT may be a consequence of abnormal proliferation of myeloid cells and might prove to be valuable in predicting relapse in patients with myeloid leukaemias.     

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.     

Cytogenetic analysis and clinical significance of chromosome 7 aberrations in acute leukaemia

The analysis was performed on bone marrow cells derived from 96 patients with acute leukaemia (AL): 76 with acute myelogenous leukaemia (AML) and 20 with acute lymphoblastic leukaemia (ALL). Aberrations of chromosome 7 were revealed in 20 (21%) of 96 analysed cases: in 14 (18%) with AML and in six (30%) with ALL. Structural aberrations, present in 13 patients (eight with AML and five with ALL), were unbalanced and led to partial monosomy (12 cases) or trisomy (four cases) of chromosome 7. Twelve (86%) out of 14 AML and all the ALL patients with chromosome 7 aberrations had complex karyotypes in their bone marrow cells. Monosomy 7 and 7q losses were frequently observed in the AML group, whereas, in the ALL group, gains in 7q and losses in the short arms constituted most chromosome 7 aberrations. The occurrence of monosomy, or of losses in 7q, results in a worse response to induction therapy in AML patients. The complete remission (CR) rate was significantly lower in this group in comparison to the group of AML patients with a normal karyotype (p = 0.01) in bone marrow cells.     

Acute leukaemia after busulphan.

During a double-blind study of two years'' cytotoxic chemotherapy with busulphan or cyclophosphamide in patients who had had resection of carcinoma of the bronchus the long-term effects of these two drugs were also studied. Four of the 243 patients treated with busulphan developed leukaemia compared with none of the 234 treated with cyclophosphamide and none of the 249 on placebo. None of these four patients received radiotherapy or other cytotoxic chemotherapy before leukaemia was diagnosed, and all four were among the 19 patients who developed pancytopenia while taking busulphan, five to eight years before leukaemia became clinically apparent. These findings suggest that busulphan is leukaemogenic, though its mode of action is uncertain.     

Bone Marrow Graft in Man after Conditioning by Antilymphocytic Serum

Allogeneic bone marrow grafts carried out after previous administration of antilymphocytic serum alone were attempted in 16 patients. Of these, six had acute myeloblastic leukaemia, four acute lymphoblastic leukaemia, and one a blast cell crisis in polycythaemia vera. Ten of these patients were in an overt phase of the disease and resistant to chemotherapy, while nine had complete agranulocytosis. In five of these patients erythrocyte and leucocyte antigenic markers demonstrated the establishment of the graft. One patient had thalassaemia major, and four others had aplasia of the bone marrow, in one case due to chloramphenicol poisoning and in another to virus hepatitis. The grafts were successful in the last two patients and transformed their clinical condition.No signs of early acute secondary disease were noted in any of the patients, either when the donor had been given antilymphocytic serum or when he was untreated. The grafts had no adoptive immunotherapeutic effect on the acute leukaemia. These observations have clearly shown that antilymphocytic serum has an immunosuppressive effect in man when it is used alone.     

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.     

Chronic Granulocytic Leukaemia: Multiple-drug Chemotherapy for Acute Transformation

The response to 60 trials of therapy in 50 patients with chronic granulocytic leukaemia (C.G.L.) in acute transformation is reported. None of the 13 patients who received single-agent chemotherapy had a satisfactory response. The use of two drugs in combination produced only one satisfactory response in 30 patients. Various types of multiple-drug treatments in eight patients achieved one good response which lasted four months. In contrast when nine patients with rapidly progressive acute transformation of C.G.L. received a regimen—TRAMPCO(L)—incorporating seven or eight drugs (thioguanine, daunorubicin, cytarabine, methotrexate, prednisolone, cyclophosphamide, and vincristine, with or without L-asparaginase colaspase) five improved significantly. Four patients had a good clinical and haematological response with survival for over three, eight, over 12, and 14 and a half months; and one patient had a partial response. Toxicity was not extreme and maintenance therapy with the same regimen was given on an outpatient basis. TRAMPCO(L) seems superior to previously reported regimens and should be considered for rapidly progressive transformation of C.G.L. especially when simpler treatments have failed.     

Bacterial glutaminase in treatment of acute leukaemia.

A glutaminase-asparaginase enzyme from Achromobacter sp has antitumour activity in vitro and in animals. Glutaminase was administered in doses of 3500-20 000 IU/m2 body surface area/day to six patients with acute lymphoblastic leukaemia (ALL) and three patients with acute myeloid leukaemia (AML). The enzyme had a blood half life of 80 minutes but depletion of blood glutamine persisted for 12 hours after single doses. Seven patients, including four (two with AML and two with ALL) resistant to asparaginase, received repeated doses of glutaminase. Antileukaemic effects were observed in all seven; one elderly patient developed metabolic acidosis. Study of this new antileukaemic agent in patients with acute leukaemia at an earlier stage of their disease is now justified.     

Epipodophyllotoxin VP 16213 in Treatment of Acute Leukaemia—Haematosarcoma and Solid Tumours

Epipodophyllotoxin VP 16213 (4-demethyl-epipodophyllotoxin-β-D-ethylidene glucoside), given to 250 patients with various types of malignant disease, induced apparently complete remissions in four out of eight cases of acute monocytoid and acute myelomonocytoid leukaemia but only one complete regression and six incomplete remissions in 21 cases of reticulosarcoma. Incomplete regressions occurred in patients with Hodgkin''s disease, lymphosarcoma, melanoma, and carcinoma of the breast, ovary, testis, bladder, kidney, and thyroid. Seemingly complete regressions of malignant pleural effusion occurred when the drug was given systemically. Toxic side effects interfered with treatment in 40 patients but stopped it in only nine. No signs of toxicity were seen in 114 patients and in 85 the side effects were negligible. VP 16213 represents an advance in the treatment of acute monocytoid leukaemia, which has been up till now insensitive to any drug.     

Further characterization of a non-T,non-B acute lymphoblastic leukaemia cell line (Reh)

Summary The ability of human sera reactive with human leukaemia cells to lyse cells from the Reh line, a tissue culture line of non-T, non-B acute lymphoblastic leukaemia, in a complement-dependent cytotoxicity assay was investigated. Among the ten sera selected for this study, which had been previously shown to be relatively specific for acute lymphoblastic leukaemia cells, four were repeatedly found reactive (MOR, MOU, NAE, and LAN) and one (DRO)reacted occasionally. None of the sera reacted with cells from three EBV-carrying lymphoblastoid cell lines of normal B-lymphocyte origin. Absorption experiments of sera MOR and MOU suggested that the antigens thus demonstrated on Reh cells were identical with those expressed by uncultured cells from acute lymphoblastic leukaemias. At least two distinct antigenic specificities may be expressed by Reh cells. Repeated testing over a period of eight months yielded consistent results.Thus, the Reh line, which can be traced to its leukaemic origin through chromosomal marker, kinetic data, and possibly through its antigenic properties, may be of great value in the study of human sera with anti-leukaemia activity.This work was supported by INSERM, DGRST and CNRS (grants 75.7.1369, 76.7.1681, ATP 31-44, ATP 77-79, AU 155)     

Effects of varying radiation schedule,cyclophosphamide treatment,and duration of treatment in acute lymphoblastic leukaemia. Report to the Medical Research Council by the Working Party on Leukaemia in Childhood.

In a multicentre trial of treatment for acute lymphoblastic leukaemia the effects of three types of central nervous system prophylaxis, the inclusion of cyclophosphamide, and the total duration of chemotherapy were assessed. A schedule with a high dose of spinal irradiation (2400 rads) without intrathecal methotrexate was inferior to schedules with some (1000 rads) or no spinal irradiation but with intrathecal methotrexate. The addition of cyclophosphamide 600 mg/m2 given intravenously every 12 weeks was of no benefit and was possibly deleterious. There was no advantage in adding four 12-week courses of chemotherapy after eight courses (total duration two years) had been given. Girls fared significantly better than boys, the difference being only partly due to the occurrence of testicular relapse.     

Clinicopathological aspects of Richter's syndrome

Richter's syndrome represents an acute transformation of chronic lymphocytic leukaemia or other type of low-grade malignant non-Hodgkin lymphoma to highly malignant anaplastic large-cell lymphoma. The prognosis of this complication is highly unfavourable. The authors report on eight cases of Richter's syndrome observed in a series of 198 patients with the clinical diagnosis of chronic lymphocytic leukaemia and evaluate some clinicopathological and immunological peculiarities of this disease.     

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.     

Recognition of Leukaemia Cells as Foreign before and after Autoimmunization

Leukaemia cells in the peripheral blood of nine patients with acute leukaemia were removed and stored. When the patients had been brought into haematological remission these leukaemia cells were cultured with autologous lymphocytes both before and after the patients had been autoimmunized with their own irradiated leukaemia cells. The extent to which the leukaemia cells stimulated the “normal lymphocytes” was increased as the result of autoimmunization.The implications of the use of this test for determining the best regimen for “immunotherapy” in acute leukaemia are discussed.     

Disturbances in iron utilization in acute leukemia and preleukemia]

With Prussian blue reaction nonhaemoglobin iron in the erythroblasts is demonstrable. Three pathological sideroblast types are recorded separately: abnormal intermediate type I and II sideroblasts and ring sideroblasts, representing increasing levels of sideroachrestic disturbance. This permits the classification of sideroachrestic disturbances into four degrees of seriousness. The frequency of a sideroachrestic disturbance in 47 untreated patients with acute myeloid leukaemia was 87%. Among 11 patients with preleukaemic condition, 8 had a disturbance of iron utilisation. In both preleukaemia and leukaemia mainly intermediate sideroblasts were present. All patients with preleukaemia developed leukaemia within 1-20 months. In the course of preleukaemic condition a slight increase of iron misutilisation was obvious when terminating in overt leukaemia. This could be of prognostic importance. After treatment, pathological sideroblasts disappeared only in 2 out of 15 patients with complete remission. There was no correlation between effect of therapy and course of iron misutilisation.     

Hodgkin's Disease in Patients with Previous Infectious Mononucleosis: 30 Years' Experience

Seventeen out of 17,073 people in Denmark who had had a positive reaction to a Paul-Bunnell test between the years 1940 and 1969 developed Hodgkin''s disease after an interval of at least 12 months. This number was significantly (P < 0·0002) greater than the expected number of two women and four men. Sixteen of those developing Hodgkin''s disease were men. Case records, which were available for 12 of them, confirmed that they had had infectious mononucleosis. The number of cases of leukaemia that developed in the sample population was no greater than expected.     

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.     

Long survival in acute myelogenous leukaemia: an international collaborative study.

A group of 82 adult patients with acute myelogenous leukaemia had survived in continuous first remission for more than three years was studied. These long-surviving patients were being treated at 12 referral centres in Europe and the USA, and they were compared with other patients with acute myelogenous leukaemia from 10 of these centres. There was no clear difference in the amount of induction chemotherapy or the time taken to achieve remission. Immunotherapy was not found to improve chances of long-term survival. The 82 patients were also compared with a group of 115 patients who had no appreciable difference in the number of blood or marrow myeloblasts between these two groups at presentation, but the long survivors had significantly higher initial platelet counts and were slightly younger. The long survivors also tended to have a lower total white cell count at presentation and lower granulocyte counts; there was no obvious explanation for these differences. Eight of the 82 patients relapsed from three to four years after remission and two (of 69 patients) after four to five year. Thereafter relapse was rare, and it seems likely that some of the 40 patients who have survived for five years or more are cured.     

Associations between the two serum proteins haptoglobin and transferrin and leukaemia

Haptoglobin and transferrin (TF) types were determined for 134 patients with leukaemia of the four most common types: acute lymphocytic (ALL), chronic lymphocytic (CLL), acute myelocytic (AML) and chronic myelocytic leukaemia (CML). The phenotype HP1 was found to have an increased incidence in the total patient group due to an increased incidence in those with AML, ALL and CML compared with controls, but not in those with CLL. Although tests of association applied to each of the samples of the four common types of leukaemia produced no significant chi 2 values, they did indicate that the relative incidence (RI) was just under 2 for the groupings of the acute forms ALL and AML, the myelocytic forms AML and CML and for the combination of ALL, AML and CML, respectively. All these associations were statistically significant (p less than 0.05). Analysis of TF subtypes and leukaemia indicated a significantly increased frequency of TF C1C1 among leukaemia patients compared with controls (p less than 0.005). Analysis of the samples of each of the four common types suggested that while the RI was raised in all but ALL patients, the association was significant only in AML patients (p less than 0.05). However, when the two myelocytic types were combined the RI was 2.3 and the association was highly significant (p less than 0.005). No such association could be detected in the lymphocytic forms.     

Active Immunotherapy Used Alone for Maintenance of Patients with Acute Myeloid Leukaemia

A total of 32 patients suffering from acute myeloid leukaemia were initially treated with daunorubicin and cytosine arabinoside, and eight who achieved full remission were given a brief cytoreduction course of cyclophosphamide and thioguanine. Of these eight patients seven were then actively immunized with 10 irradiated allogeneic acute myeloid leukaemia cells and B.C.G. at weekly intervals. Six of these patients have survived in apparent good health for more than one year. Bone marrow changes suggestive of relapse were used as an indication for further short courses of chemotherapy, and except on single occasions in two different patients clinical relapse has been prevented. The average duration of first (bone marrow) remission appears to be comparable with the best achieved in trials using regular chemotherapy for maintenance, though criteria for determining relapse may be different. The rate of reinduction of remissions (bone marrow) in this series was high, with a subsequent increase in overall survival time. Possible explanations for the high rate of reinduction include, firstly, the effects of active immunization with specific leukaemia antigen; secondly, non-specific adjuvant effect; thirdly, avoidance of drug resistance; and, fourthly, early diagnosis of relapse by frequent bone marrow examinations.