A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group.

BACKGROUND: Interferon alfa is a conservative and widely used alternative to bone marrow transplantation in treatment of patients with early chronic myeloid leukemia (CML). A meta-analysis was conducted to develop a reliable prognostic scoring system for estimation of survival of patients with CML treated with interferon alfa. METHODS: Patients treated in prospective studies, including major randomized trials, were separated into learning and validation samples. Cox regression analysis and the minimum P-value approach were used to identify prognostic factors for patient survival and to discover groups in the learning sample with the greatest differences in survival. These findings were then validated by applying the new scoring system to patients in the validation sample. RESULTS: We collected data on 1573 patients who were participants in 14 studies involving 12 institutions; 1303 patients (learning sample, n = 981; validation sample, n = 322) were eligible for inclusion in this analysis, and their median survival time was 69 months (range, 1-117 months). Because two previously described prognostic scoring systems failed to discriminate risk groups satisfactorily, we developed a new scoring system that utilizes the following covariates: age, spleen size, blast count, platelet count, eosinophil count, and basophil count. Among 908 patients with complete data in the learning sample, three distinct risk groups were identified (median survival times of 98 months [n = 369; 40.6%], 65 months [n = 406; 44.7%], or 42 months [n = 133;14.6%]; two-sided logrank test, P< or =.0001). The ability of the new scoring system to discriminate these risk groups was confirmed by analysis of 285 patients with complete data in the validation sample (two-sided logrank test, P = .0002). CONCLUSIONS: A new prognostic scoring system for estimating survival of patients with CML treated with interferon alfa has been developed and validated through use of a large dataset.

Therapeutic options in chronic myeloid leukaemia.

The treatment of CML is unsatisfactory. Only bone marrow transplantation offers the possibility of cure. At present all other therapies are palliative and none has been shown to extend survival consistently. Busulphan and hydroxyurea remain the most widely used drugs for chronic phase. Intensive and non-intensive combination chemotherapy regimens have not produced significant improvement in survival. Interferon therapy is promising in patients who respond but requires further evaluation. Splenectomy does not improve survival but may be useful in selected circumstances. Extramedullary disease carries a poor prognosis and responds best to local treatment. The treatment of blast transformation is very difficult. The lymphoid variety should be recognised as response is better to appropriate treatment. Some Philadelphia (Ph) chromosome negative cases have disease which is probably identical to Ph positive disease and respond well to treatment. The others carry a very bad prognosis and respond poorly to treatment.

beta-thromboglobulin and deep vein thrombosis.

The measurement of plasma beta-thromboglobulin as a potential diagnostic test for venous thrombosis has been investigated in 16 normal volunteers, 24 patients presenting with deep vein thrombosis (DVT) or pulmonary embolism and 46 patients screened by 125I fibrinogen test (IFT) for post-operative DVT. The normal mean was 33 ng/ml (range 15-117 ng/ml). Of the 24 patients with clinical thrombotic disease 22 presented with DVT confirmed by phlebogram or IFT and 2 presented with embolism confirmed by lung scan. At the time of first presentation 12 out of 24 had betaTG values greater than 70 ng/ml. All except 3 of this group of 24 patients had values of greater than 70 ng/ml at some stage during a subsequent week of daily sampling. DVT was detected in 13 out of 46 screened post-operative patients. There was a rise om betaTG observed within 24 hr of the IFT becoming positive but the mean rise did not reach significance at the 5% level. An association between DVT and high betaTG values has been confirmed. However, its clinical value cannot yet be fully elucidated until factors, probably related to blood sampling and clearance, are further investigated.

Progress with interferon in CML--results of the MRC UK CML III study.

527 patients with CML were entered into the multicentre randomised MRC CML III study comparing IFN-alpha n1 to standard chemotherapy, either busulphan or hydroxyurea. Haematologic response to IFN as assessed by the level of control of the WCC predicted cytogenetic response to IFN. Cytogenetic response (< 80% Ph + ve) was seen in 22% of all patients randomised, 11% showing major or complete responses. Major cytogenetic response rate was 18% in Sokal low risk patients, 15% in intermediate risk patients but only 4% in high risk patients. Mantel Byar analyses allowing for time to response showed a survival advantage for cytogenetic responders compared to non-responders. In addition, cytogenetic non-responders to IFN did significantly better than chemotherapy-treated patients. Median survival for all patients was 61 months in the IFN treated groups and 41 months in the no-IFN group. For Ph + ve patients only, the median survival was 63 months compared to 43 months. Sub-group analysis comparing busulphan or hydroxyurea treatment in the IFN and no-IFN treatment arms showed a significant advantage for IFN-compared to busulphan, but no significant difference between IFN and hydroxyurea treated patients, although there was a trend favouring IFN. A proposed overview of all randomised trials comparing IFN to hydroxyurea should, by virture of larger numbers, enable a more accurate assessment of the probable benefit of IFN compared to hydroxyurea therapy.

The Edinburgh spleen: source of a validated Kveim-Siltzbach test material.

Although it is true that some Kveim-Siltzbach test suspension may for reasons unknown behave in a totally nonspecific way and so be useless in the confirmation of active sarcoidosis, the experience with the Edinburgh spleen has shown that it is also true that a preparation can be made which acts specifically in the sarcoid context and fulfils all the Siltzbach criteria. The active principle probably resides in the membrane components of sarcoid tissue cells.

Serum protein analysis and bone marrow cytology in patients with an extreme elevation of the erythrocyte sedimentation rate.

One hundred patients in whom an Erythrocyte Sedimentation Rate (ESR) in excess of 100 mm. in the first hour was found on 2 consecutive occasions were investigated. Serum protein electrophoresis was performed on 96 of these patients and bone marrow examination on 55 patients. Acute infection was the commonest diagnosis though the majority of patients had 2 or more separate conditions each contributing to the elevation of the ESR. Quantitive serum protein electrophoresis was abnormal in all but one patient and was of limited diagnostic value. A definite band in the globulin region was detected in 11 patients, 7 of whom were found to have myelomatosis. Bone marrow examination was useful only in patients with a discrete band in the globulin fraction or with a specific haematological abnormality. It is suggested, therefore, that bone marrow examination be confined to patients with such abnormalities irrespective of an elevation of their ESR.

Methylprednisolone, etoposide, vindesine, and chlorambucil (PEEC) alone or alternating with CHOP as initial or salvage therapy for non-Hodgkin's lymphoma.

A novel cytotoxic drug combination, PEEC, has been tested in the initial or salvage treatment of lymphomas. The PEEC combination alone is active in high grade or intermediate grade NHL with two complete and two partial remissions out of four patients so treated. When combined with standard CHOP therapy using an alternating regime, seven out of 11 patients obtained a complete remission and four partial remission. Ten patients were well, off treatment, beyond one year from presentation. The combination was less impressive, however, as salvage therapy with two partial responses in a heavily pre-treated group of nine patients.

Severe haemolytic anaemia in pregnancy in Nigerians treated with prednisolone.

Haemolytic anaemia of obscure aetiology is a common complication of pregnancy in Nigeria. Treatment with antimalarials and folic acid is usually followed by a rapid remission, but response is slow in about 25% of patients and haemolysis continues uncontrolled in about 5%. The administration of prednisolone to six patients with uncontrolled haemolysis was followed by rapid recovery in five and possible benefit in one. Risks of prednisolone therapy to the mother appear to be slight and outweighed by the risks of continued severe anaemia and frequent blood transfusions. There seemed to be no appreciable increase of fetal loss compared with that in anaemic pregnancies not treated with prednisolone.

Primary ileocecal lymphoma. A study of 22 patients.

Twenty-two patients with primary ileocecal non-Hodgkin's lymphoma were reviewed. Abdominal pain (67%), altered bowel habits (50%), and weight loss (50%) were the most common presenting symptoms and an abdominal mass was palpable in 50%. Sixteen (73%) had histologic evidence of local lymph node involvement at diagnosis and another two (9%) had nonhistologic evidence of nodal involvement. An abdominal computed tomography (CT) scan was the most helpful staging investigation. Twenty-one (95.5%) patients underwent surgical resection of their disease. Subsequent chemotherapy, with or without radio-therapy, appeared to prolong survival (median, 34 months versus 14 months). There were three treatment-related deaths. Neither the age of the patient nor the stage of disease at presentation (Ann Arbor) appeared to influence survival. Adequate initial surgery combined with chemotherapy may provide optimum therapy in patients with primary ileocecal lymphoma.

Severe cytopenias associated with the sequential use of busulphan and interferon-alpha in chronic myeloid leukaemia.

We describe four patients who developed severe thrombocytopenia which progressed to aplasia after the use of alpha-interferon in maintenance therapy of chronic phase CML after busulphan induction. On reviewing over 400 patients in the MRC CML III trial we found that there is a risk of cytopenia developing after busulphan therapy and a lesser risk of cytopenias developing after alpha-interferon therapy. If the therapies are given in a sequential fashion the risk of cytopenia developing appears to be additive, may be pronounced, and may lead to clinically significant problems. Hydroxyurea alone does not lead to sustained cytopenia. Care should be taken to ensure that counts are stable after the use of busulphan before starting alpha-interferon as maintenance therapy.

UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. The UK Medical Research Council's Working Parties for Therapeutic Trials in Adult Leukaemia.

Interferon-alpha may be better than cytotoxic drugs in the long-term management of patients with chronic myeloid leukaemia (CML) in chronic phase. To test this possibility 587 patients with CML in chronic phase were randomly allocated to receive lymphoblastoid cell-line interferon-alpha n1 (IFN-alpha, n = 293) or chemotherapy with busulphan or hydroxyurea (no IFN-alpha, n = 294) as maintenance after initial induction treatment with cytotoxic drugs. There was a significant survival benefit for patients in the IFN-alpha arm when analysed on the basis of intention to treat (2p = 0.0009). The median survival for those allocated IFN-alpha was 61 months and no IFN-alpha was 41 months. Out of 269 patients with Philadelphia-positive CML in the IFN-alpha arm with at least 6 months follow-up, 211 were evaluable for haematological response: 145 (68%) achieved good responses (A+ or A type), 37 (18%) had partial responses (B type) and 29 (14%) had poor responses (C type). Patients with types A and B responses had a better survival than those in the no IFN-alpha arm; patients with type C responses had survival equivalent to the no IFN-alpha arm. Of these 269 patients, 26 of whom had not started IFN-alpha, 59 (22%) achieved a significant degree of cytogenetic response but 210 (78%) did not have a response. Cytogenetic responders survived significantly longer than non-responders and even non-responders survived longer than patients in the no IFN-alpha arm. Since cytogenetic non-responders had worse than average prognostic features, they may also benefit from IFN-alpha therapy. We conclude that treatment with IFN-alpha prolongs the survival of patients with CML; benefits of IFN-alpha are not confined to cytogenetic responders but may extend to most, if not all patients receiving IFN-alpha treatment; and cytogenetic response to IFN-alpha treatment identifies patients with a relatively good prognosis.

Eosinophilic leukaemia in association with a double Philadelphia chromosome.

A case of eosinophilic leukaemia in association with chromosomal abnormalities including a double Philadelphia chromosome is reported. Comment is also made on the cardiological problems which arise in this condition.

Idiopathic tropical splenomegaly syndrome in Ibadan.

Follow-up of 33 patients with idiopathic splenomegaly, 25 for a period ranging from 14 to 80 months after starting treatment with proguanil 100 mg. daily, showed that there was an excellent response of the splenomegaly, anaemia, and hepatomegaly, together with a definite gain in weight. Every patient improved, though a maximum result was not attained until after at least one year's treatment.Therapy with proguanil is considered superior to and safer than splenectomy. Malaria seems unlikely to have a causal role in the aetiology of the disease, which is probably a manifestation of a disorder of the normal immune mechanism. Idiopathic splenomegaly has a close relation with the type of chronic lymphatic leukaemia seen in Nigeria, and it is possible that the two diseases have a similar aetiological factor.

Thioguanine used in maintenance therapy of chronic myeloid leukaemia causes non-cirrhotic portal hypertension. Results from MRC CML. II. Trial comparing busulphan with busulphan and thioguanine.

Portal hypertension with varices developed in 18/675 patients with chronic myeloid leukaemia (CML) in a randomized trial comparing busulphan with busulphan and thioguanine. All 18 had received the drug combination and none busulphan alone (P less than 0.0001). Ascites was also seen significantly more often in the combination arm (P less than 0.05). These results strongly suggest that the addition of thioguanine was responsible for the development of portal hypertension. The histological features were predominantly those of non-cirrhotic portal hypertension--either idiopathic portal hypertension with minimal morphological abnormalities, nodular regenerative hyperplasia or in two cases leukaemic infiltration only was noted. Cirrhosis was present in 3/16 cases studied. Both treatment groups developed abnormal liver function tests during the chronic phase, but particularly with progression of the disease. During chronic phase abnormalities were significantly more frequent in those receiving busulphan and thioguanine-alkaline phosphatase (P less than 0.02), transaminases (P less than 0.04), bilirubin (P less than 0.05), multiple abnormalities (P less than 0.01). The development of portal hypertension was often associated with abnormalities of these tests; however, lack of specificity precludes their use as a predictor of subsequent clinical problems. Thioguanine confers no survival advantage in this disease. In view of its hepatotoxicity it should not be used routinely for maintenance of control in chronic phase CML.

Hodgkin's disease presenting as idiopathic thrombocytopenic purpura.

A case of Hodgkin's disease presenting as idiopathic thrombocytopenic purpura in a 23-year-old male is reported. This is a rare presentation of Hodgkin's disease having been previously described in only two cases.