Preben Philip

In B-cell chronic lymphocytic leukaemia chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: A cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients

Of 560 consecutive, newly diagnosed untreated patients with B CLL submitted for chromosome study, G-banded karyotypes could be obtained in 480 cases (86%). Of these, 345 (72%) had normal karyotypes and 135 (28%) had clonal chromosome abnormalities: trisomy 12 (+12) was found in 40 cases, 20 as +12 alone (+12single), 20 as +12 with additional abnormalities (+12complex). Other frequent findings included abnormalities of 14q, chromosome 17, 13q and 6q. The immunophenotype was typical for CLL in 358 patients (CD5+, Slg(weak), mainly FMC7-) and atypical for CLL in 122 patients (25%) (CD5-, or Slg(strong) or FMC7+). Chromosome abnormalities were found significantly more often in patients with atypical (48%) than in patients with typical CLL phenotype (22%) (P < 0.00005). Also +12complex, 14q+, del6q, and abnormalities of chromosome 17 were significantly more frequent in patients with atypical CLL phenotype, whereas +12single was found equally often in patients with typical and atypical CLL phenotype. The cytomorphology of most of the +12 patients was that of classical CLL irrespective of phenotype. In univariate survival analysis the following cytogenetic findings were significantly correlated to a poor prognosis: chromosome 17 abnormalities, 14q+, an abnormal karyotype, +12complex, more than one cytogenetic event, and the relative number of abnormal mitoses. In multivariate survival analysis chromosome 17 abnormalities were the only cytogenetic findings with independent prognostic value irrespective of immunophenotype. We conclude that in patients with typical CLL immunophenotype, chromosome abnormalities are somewhat less frequent at the time of diagnosis than hitherto believed. +12single is compatible with classical CLL, and has no prognostic influence whereas chromosome 17 abnormalities signify a poor prognosis. In patients with an atypical CLL immunophenotype, chromosome abnormalities including +12complex, 14q+, del 6q and chromosome 17 are found in about 50% of the patients, and in particular chromosome 17 abnormalities suggest a poor prognosis.

Cytogenetic characteristics of therapy-related acute nonlymphocytic leukaemia, preleukaemia and acute myeloproliferative syndrome: correlation with clinical data for 61 consecutive cases.

Cytogenetic studies were performed on a new series of 23 patients with therapy‐related acute non‐lymphocytic leukaemia, preleukaemia or an acute myeloproliferative syndrome. In our total series of now 61 cases studied by chromosome banding techniques, at least one of the abnormalities – 7, 5q –, 7q– or – 5 or some related unbalanced translocations, primarily – 7, +t(1q7p), was observed in 40 patients. The critical region for the deletions of chromosome no. 5 comprises bands 5q22 to 5q33 and of chromosome no. 7 bands distal to 7q22. The third most frequently involved chromosome was no. 21, rearranged at band 21q22 in the three patients with 21q + and in one patient with 21q –. An i(21q) was observed in two patients, a –21 in four patients and a –22, + t(21q22q) and a –5.–21, + t(5p21q) in one patient each. Other characteristic abnormalities included total loss or rearrangements of the short arm of chromosome no. 17, observed in nine patients. One patient had a –12, three others had rearrangements resulting in a partial or total loss of the short arm of chromosome no. 12. A 19q + with translocation to band 19q13 was observed in three cases, a – 18 in three cases and a 3p– in four cases. Thirty‐one patients with multiple chromosome aberrations experienced a significantly shorter survival as compared to 13 patients with a normal karyotype (P= 0·02) and 17 patients with one single chromosome aberration (P<0·01).

Two different classes of therapy-related and de-novo acute myeloid leukemia?

Two different classes of therapy-related acute myeloid leukemia (t-AML) seem to emerge. One class follows therapy with alkylating agents, increases in frequency with age, often presents with myelodysplasia (MDS), responds poorly to chemotherapy, and shows monosomy 7(-7), monosomy 5(-5), or loss of various parts of the long arms of these chromosomes (5q- and 7q-). The other class is related to therapy with cytostatic drugs targeting at DNA-topoisomerase II, often presents with overt leukemia, responds more favorably to chemotherapy, and shows balanced chromosome aberrations, primarily translocations involving chromosome bands 11q23 and 21q22. These two classes of t-AML may have their counterparts in de-novo acute myeloid leukemia (de-novo AML).

B-cell chronic lymphocytic leukaemia: clonal chromosome abnormalities and prognosis in 89 cases

The results of cytogenetic studies are reported in 89 patients with B‐cell CLL. LPS (E.coli lipopolysaccharide), PWM (pokeweed mitogen), PHA (phytohaemagglutinin), EBV (Epstein‐Barr virus), TPA (phorbol 12‐myristate 13‐acetate), and LA (leucoagglutinin) were used as mitogens. Mitoses were obtained from 78 cases. Clonal aberrations could be demonstrated in 26 cases. Trisomy 12 was the most frequent finding (8 cases) and was sole abnormality in 4 cases. Chromosomes # 14, # 17, and # 11 were involved in structural aberrations in 5, 7, and 7 cases respectively, but a t(11;14)(q13;q32) was the only structural aberration seen more than once. The median observation time was 47 months (range 1–87). The presence of clonal abnormalities did not influence survival significantly, either when calculated from diagnosis or from cytogenetic analysis. Patients with more than one aberration, however, had a significantly shorter survival than patients with normal mitoses only (p < 0.05). The survival of 8 patients with trisomy 12 (in 4 as sole abnormality) was not different from that of patients with normal mitoses only.

Chronic neutrophil leukaemia in adolescence and young adulthood

Chronic neutrophil leukaemia (CNL) is a rare myeloproliferative disorder predominantly reported in elderly patients. We present a 15‐year‐old girl and a 25‐year‐old male with CNL. Clonal cytogenetic abnormalities were detected in both patients. One showed trisomy 21 evolving into tetrasomy 21. The second patient showed a unique chromosome aberration during blast crisis: t(2;2)(q32;p24). Both patients were successfully treated with allogeneic bone marrow transplantation (BMT). CNL should also be considered as a differential diagnosis in adolescence and young adulthood. BMT represents a potentially curative treatment option in such patients.

High risk of therapy‐related leukemia and preleukemia after therapy with prednimustine, methotrexate, 5‐fluorouracil, mitoxantrone, and tamoxifen for advanced breast cancer

Therapy‐related acute non‐lymphocytic leukemia or preleukemia was observed in five of 71 patients with advanced breast cancer treated with combination chemotherapy comprising prednimustine, methotrexate, 5‐fluorouracil, mitoxantrone, and tamoxifen. In this closely followed cohort of patients the cumulative risk of leukemic complications was 25.4% ± 10.3% (± SE) 37 months after start of chemotherapy. The relative risk of overt leukemia was 339 (95% CI: 41‐1223), as two cases were observed versus 0.0059 cases expected. The very high risk of leukemia and preleukemia observed may partly reflect the advanced age of the patients (mean, 61 years) and partly the diagnostic procedures used, which included cytogenetic screening of all patients developing refractory cytopenia. A particularly high leukemogenic effect of prednimustine or a synergism between prednimustine and other drugs used in this study cannot be excluded. In the light of the above results, the authors caution against the use of intensive combination chemotherapy with alkylating agents as in the current study in potentially curable patients with breast cancer.

Cytogenetic, clinical, and cytologic characteristics of radiotherapy-related leukemias☆

From 1978 to 1985, we observed eight cases of acute nonlymphocytic leukemia or preleukemia, three cases of acute lymphoblastic leukemia, and three cases of chronic myeloid leukemia in patients previously treated exclusively with radiotherapy for other tumor types. The latent period from administration of radiotherapy to development of leukemia varied between 12 and 243 months. Clonal chromosome aberrations reported previously as characteristic of acute nonlymphocytic leukemia following therapy with alkylating agents were observed in three of the eight patients with acute nonlymphocytic leukemia (5q- and -7) and in two of the three patients with acute lymphoblastic leukemia (-7 and 12p-). All three patients with radiotherapy-related chronic myeloid leukemia presented a t(9;22)(q34;q11). The results suggest that cytogenetic characteristics may reflect the etiology in radiation-induced acute leukemias, whereas radiation-related chronic myeloid leukemia does not seem to differ chromosomally from de novo cases of the disease.

Translocation (3;21)(q26;q22) in therapy-related myelodysplasia following drugs targeting DNA-topoisomerase II combined with alkylating agnets, and in myeloproliferative disorders undergoing spontaneous leukemic transformation

Translocation (3;21)(q26;q22) has been observed only rarely in de novo myelodysplasia (MDS) and de novo acute myeloid leukemia (AML), but, including the two new cases in the present study, the aberration has now been identified in at least 10 cases of t-MDS or t-AML. All these 10 patients had previously received alkylating agents, in nine patients combined with a drug targeting at DNA-topoisomerase II (doxorubicin in eight cases). Eight of the ten patients presented with t-MDS. A further 20 patients with various myeloproliferative disorders and an identical t(3;21) have been reported. In these cases, t(3;21) was not related to any specific type of previous therapy but was associated with transformation from chronic stage disease to overt AML.

Acute promyelocytic leukemia with t(15;17) and t(2;17;15)

Cytogenetic examination in a case of acute promyelocytic leukemia (FAB-M3) demonstrated a stem line with t(15;17) and a side line with t(2;17;15). This observation indicates either clonal evolution from the standard translocation or a de novo complicated translocation. Previous cases with three-way translocations in acute promyelocytic leukemia have been reviewed. Three-way translocations seem to occur with similar frequency in M2 and M3 types of acute myeloid leukemia and in chronic myelocytic leukemia.

Therapy‐related malignancies: A review

Although many cytostatic drugs have been shown to be both mutagenic and carcinogenic in experimental systems, only the alkylating agents have been demonstrated with certainty to induce malignancy in man. Thus, therapy with almost all alkylating agents in clinical use today results in a highly increased risk of acute nonlymphocytic leukaemia (ANLL). Other types of leukaemia are not observed in excess following cancer chemotherapy, and only one type of solid tumour has been convincingly related to treatment with cytostatic drugs: carcinoma of the urinary bladder following cyclophosphamide and the now abandoned alkylating agent chlornaphazine.