Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders.

Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-alpha), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the collection of data on 317 patients who were first seen between 1983 and 1997 and achieved CCgRs with IFN-alpha alone or in combination with hydroxyurea. The median time to first CCgR was 19 months (95% CI, 17-21; range, 3-84 months). At last contact, 212 patients were still alive and in continuous CCgR; 105 patients had lost CCgR, but 53% of them were still alive and in chronic phase. IFN-alpha treatment was discontinued permanently in 23 cases for response loss, in 36 cases for chronic toxicity (15 are still in unmaintained continuous CCgR), and in 8 cases because it was believed that treatment was no longer necessary (7 of these 8 patients are still in unmaintained continuous CCgR). The 10-year survival rate from first CCgR is 72% (95% CI, 62%-82%) and is related to the risk profile. High-risk patients lost CCgR more frequently and more rapidly and none survived more than 10 years. Low-risk patients survived much longer (10-year survival probability 89% for Sokal low risk and 81% for Euro low risk). These data point out that a substantial long-term survival in CCgRs is restricted mainly to low-risk and possibly intermediate-risk patients and occurs significantly less often in high-risk patients.

Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Group.

A substantial minority of patients with chronic myelogenous leukemia (CML) achieve a complete response (CR) to treatment with interferon-alpha (IFN), defined as the disappearance of Philadelphia chromosome-positive metaphases. Currently it is unclear how long IFN treatment should be continued for such patients. We used a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to quantify levels of BCR-ABL transcripts in 297 peripheral blood specimens collected from 54 patients who had achieved CR with IFN. The median duration of observation was 1.9 years (range, 0.3-11.0 years). Total ABL transcripts were quantified as internal control and results were expressed as the ratio BCR-ABL/ABL. All 54 patients had molecular evidence of residual disease, although 3 patients were intermittently PCR negative. The median BCR-ABL/ABL ratio at the time of maximal response for each patient was 0.045% (range, 0%-3. 6%). During the period of observation 14 patients relapsed, 11 cytogenetically to chronic phase disease and 3 directly to blastic phase. The median ratio of BCR-ABL/ABL at maximal response was significantly higher in patients who relapsed than in those who remained in CR (0.49% versus 0.021%, P < 0.0001). Our findings show that the level of residual disease falls with time in complete responders to IFN, but molecular evidence of disease is rarely if ever eliminated. The actual level of minimal residual disease correlates with the probability of relapse. We suggest that for patients who reach CR, IFN should be continued at least until relatively low levels of residual leukemia are achieved. (Blood. 2000;95:62-66)

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.

Quantification of residual disease in chronic myelogenous leukemia patients on interferon-alpha therapy by competitive polymerase chain reaction.

Interferon-alpha (IFN-alpha) induces cytogenetic responses of variable degree in patients with chronic myelogenous leukemia (CML). We sought to establish the relationship between BCR-ABL transcript numbers measured by competitive 2-step reverse transcription polymerase chain reaction (RT-PCR) and cytogenetic status in CML patients treated with IFN-alpha. A total of 250 peripheral blood and 55 bone marrow samples with 127 Philadelphia chromosome positive (Ph+) and 6 Ph-/BCR-ABL+ CML patients were investigated. Twenty-one patients were studied at diagnosis with IFN-alpha, 24 had a complete cytogenetic response, 21 a partial response, 12 a minor response, 26 no response, and 23 were unknown. Using nested RT-PCR, all 305 samples were positive for BCR-ABL transcripts. To standardize results for variability in RNA and cDNA quantity and quality, we quantified total ABL transcripts in each sample as internal control. The validity of ABL as internal control was shown by comparison with glucose-6-phosphate dehydrogenase transcript levels in 145 samples. The median BCR-ABL transcript numbers (and BCR-ABL/ABL ratios expressed as percentages) were 400/micrograms RNA (O.04%) in complete responders, 20,500/micrograms RNA (7.1%) in partial responders, 170,000/micrograms RNA (21.0%) in minor responders, and 430,000/micrograms RNA (58.7%) in nonresponders (P < .001). The cytogenetic results correlated with the BCR-ABL transcript numbers (r = .82; P < .001) and BCR-ABL/ABL ratios (r = .84; P < .001). Grouping the ratios BCR-ABL/ABL as less than 2%, 2% to 14% and greater than 14% to compare with cytogenetic complete response, partial response, and minor/nonresponse, the concordance between the two methods was 82% (chi2 P< .0001). We conclude that quantitative PCR with internal controls is as sensitive and reliable method for monitoring patients on IFN-alpha and reduces the need for repeated marrow investigations.

Variable numbers of BCR-ABL transcripts persist in CML patients who achieve complete cytogenetic remission with interferon-alpha.

A substantial minority of patients with chronic myeloid leukaemia (CML) achieve a complete response to treatment with interferon-alpha (IFN-alpha), defined as the disappearance of Philadelphia chromosome positive metaphases or, for patients who are Philadelphia chromosome negative but BCR-ABL positive, the disappearance of the leukaemic clone as assayed by Southern blot. We have measured the levels of BCR-ABL transcripts in 20 such patients by quantitative PCR. Results were standardized for both quality and quantity of cDNA by quantification of ABL as an internal control. All 20 patients had evidence of residual disease; the median number of transcripts was 750/micrograms RNA (range 10-22,000) and the median BCR-ABL/ABL ratio was 0.17% (range 0.0008-3.6%). Our findings show that CML has not been eradicated in any patient and that the quantity of residual disease in complete responders may vary by as much as four orders of magnitude.

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.

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.

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.

Early delayed radiation injury to the brainstem after radiotherapy for lymphoma of the tongue and neck.

We describe a case of severe early delayed radiation injury to the brainstem after curative radiotherapy using a standard therapeutic irradiation regimen for lymphoma of the base of the tongue with cervical lymphadenopathy. Magnetic resonance imaging showed a lesion in the brainstem corresponding to an area of neural tissue coincidentally irradiated. A literature review of this rare complication is presented.

Haematological classification of the chronic myeloid leukaemias.

Chronic myeloid leukaemia (CML) includes five subtypes, and the term should be used in the same way as the term chronic lymphoid leukaemia to refer to a group of related conditions. The subtypes of CML are: 1. Chronic granulocytic leukaemia (CGL) (95% of all CML; 90% are Ph+, BCR+, 5% are Ph-, BCR+); 2. Juvenile CML (extremely rare; Ph-, BCR- in the few so far examined); 3. Chronic neutrophilic leukaemia (CNL) (extremely rare; Ph-, BCR- in the few so far examined); 4. Chronic myelomonocytic leukaemia (CMML). CMML with low or normal leukocyte counts is classified as a myelodysplastic syndrome; CMML with high leukocyte count is both myelodysplastic and myeloproliferative. Ph-, BCR-; 5. Atypical CML (aCML). Intermediate between CGL and CMML but has distinctive features. Ph-, mostly BCR-. Significance of few reported BCR+ uncertain. Markedly worse survival than CGL and probably worse than CMML. Definition needs refining. Types 2, 3, 4 and 5 account for 5% of all CML. CGL, CMML, aCML and CNL can be diagnosed in the great majority of cases from the morphological profile of presentation peripheral blood films, but high-quality Romanowsky staining is essential.