Patricia Shepherd

UK Medical Research Council randomised, multicentre trial of interferon-αn1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response

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.

Analysis of molecular breakpoint and m-RNA transcripts in a prospective randomized trial of interferon in chronic myeloid leukaemia: no correlation with clinical features, cytogenetic response, duration of chronic phase, or survival

Two hundred and nineteen cases of Ph+ve CML and 15 Ph‐ve, BCR+ve CML cases have been analysed to determine the breakpoint site and its relationship to clinical features, cytogenetic response, duration of chronic phase and survival. 119 cases have had RNA analysis performed to determine the type of BCR/ABL transcript and have also been analysed in a similar way. Presenting features at diagnosis including age, sex, white‐cell count and platelet count showed no significant difference for those with 5’and 3’breakpoints and those with either b2a2 or b3a2 BCR/ABL transcripts. However, in a subgroup of patients whose presenting white‐cell count was <100×p109/1, those with b3a2 transcript did have a significantly higher platelet count.

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

Summary .A substantial minority of patients with chronic myeloid leukaemia (CML) achieve a complete response to treatment with interferon‐α (IFN‐α), 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/μg 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.

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.

Telomere length shortening is associated with disease evolution in chronic myelogenous leukemia.

We studied telomere length in the peripheral blood leukocyte samples of a large group of patients with chronic myelogenous leukemia (CML) by Southern blot hybridization using the (TTAGGG)4 probe. The average telomere length expressed as the peak telomere repeat array (TRA) of the peripheral blood samples obtained from a group of 34 healthy age‐matched controls ranged between 7.6 and 10.0 kb and the mean peak TRA was 8.7 kb. Forty‐one patients in the chronic phase of CML were studied; 32/41 (78%) showed telomere reduction (<7.6 kb) relative to age‐matched controls and the mean peak TRA was 6.4 kb (range 4.0–10.6 kb). Serial samples were analysed from 12 patients at both chronic phase and during disease progression. The leukocyte DNA of all 12 patients in accelerated phase and/or blast crisis showed telomere reduction relative to age‐matched controls and the mean peak TRA was 4.1 kb (range 3.0–5.4 kb). The peak TRA in the accelerated or blast phase was reduced compared with the corresponding paired sample in the chronic phase in all cases studied. These data show that a marked reduction in telomere length is associated with disease progression in CML. Am. J. Hematol. 61:5–9, 1999.

Spontaneous clinical regression in chronic lymphocytic leukaemia

Summary. Chronic lymphocytic leukaemia (CLL) is a B‐cell disorder, which has a median survival of over 10 years from diagnosis for stage A disease. The natural history of stage A disease is generally indolent or only slowly progressive. It is less well known that CLL may undergo spontaneous regression. We report a series of 10 such cases (eight stage A and two stage B) followed at our institutions.

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

Summary 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<0.0001). Ascites was also seen significantly more often in the combination arm (P>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.

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 α‐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 α‐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 α‐interferon as maintenance therapy.