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The MLL gene located at 11q23 has been described as a 'promiscuous' gene due its involvement with a large number of genetic partners. The EU Concerted Action Workshop on 11q23 provided 550 cases for study of which 82 showed abnormalities which did not involve the established translocations or deletion of 11q23. In these 'other' cases, which included inversions and duplications, 11q23 was found to be involved with 25 chromosome partners of which 10 had not been previously reported. These were 1q31, 4p11, 6q13, 8q21, 10q22, 10q25, 11q11, 11q21, 13q34 and 18q23. This study demonstrated the value of the Workshop, in confirming the diversity of chromosomal partner sites involved with 11q23 and in the identification of new partners.

Forty of the 550 patients (7%) entered to the 11q23 Workshop had secondary (s) acute lymphoblastic leukemia (nine cases), s-acute myeloid leukemia (25 cases, predominantly of FAB type M5), s-acute leukemia unspecified (one case) or s-myelodysplastic syndrome (five cases) following treatment for a primary malignancy. Breast cancer (12 cases) and non-Hodgkin's lymphoma (eight cases) were the most frequent primaries. Twenty-three patients had been treated with either an epipodophyllotoxin (seven patients) or an anthracycline (10 cases) or both (four cases) frequently combined with alkylating agents (12 cases) and with radiotherapy (six cases). Two further patients had alkylating agents and two had radiotherapy alone. Time between diagnosis of the primary and secondary malignancy was between 10 months and 22 years (median 24 months). The incidence of secondary malignancies in 11q23 subgroups was: t(11;19)(q23;p13.1) (33%), t(9;11) (8%), t(4;11) (5.5%), t(10;11)(5%), t (6;11) (3%), del11q23(2%) and 10 patients had a rare 'other' abnormality. No associations were seen between type of prior malignancy and 11q23 subgroup, or between prior malignancy and leukemia subtype. Remission, when achieved (32 patients), was short (median 5 months). Two patients survived following a bone marrow transplant for s-leukemia and s-myelodysplastic syndrome.

The EU Concerted Action Workshop on 11q23 Abnormalities in Hematological Malignancies collected 550 patients with abnormalities involving 11q23. Of these, 53 patients had a translocation involving chromosome 11, breakpoint q23, and chromosome 19, breakpoint p13. Karyogram review enabled each patient to be further defined as t(11;19)(q23;p13.1) (21 patients) or t(11;19)(q23;p13.3) (32 patients). There was a marked difference between the type of banding and the translocation identified: t(11;19)(q23;p13.1) was detected predominantly by R-banding, whereas t(11;19)(q23;p13.3) was detected almost solely by G-banding. Additional change was extremely rare in patients with t(11;19)(q23;p13.1) but occurred in nearly half of the patients with t(11;19)(q23;p13.3). Patients with t(11;19)(q23;p13.1) all had leukemia of a myeloid lineage, mostly acute myeloid leukemia (AML), and were predominantly adult. In contrast patients with t(11;19)(q23;p13.3) had malignancies of both myeloid and lymphoid lineage and were mainly infants less than 1 year old. The survival of both groups of patients was generally poor, over 50% of t(11;19)(q23;p13.1) patients died within 2 years of diagnosis and the median survival of acute lymphoblastic leukemia (ALL) patients with t(11;19)(q23;p13.3) was 17.6 months.

Balanced translocations of 11q23 are associated with specific clinical features and a poor outcome, but the relevance of deletions involving 11q23 is not clear. Fifty-seven patients with this deletion were collected by the Workshop, 30 had terminal and 27 had interstitial deletions. Twenty-seven patients had acute lymphoblastic leukemia (ALL), 16 had acute myeloid leukemia (AML), one had acute biphenotypic leukemia, one had acute undifferentiated leukemia and 12 had myelodysplastic syndrome (MDS). ALL patients had a median age of 7 years, median white blood cell count (WBC) of 15 x 10(9)/l, and 10/24 had common ALL. AML patients had a median age of 23 years, a median WBC of 49 x 10(9)/l, and 9/16 had M4 or M5. MDS patients were all adult, median age of 69 years, median WBC of 3 x 10(9)/l, and 7/12 had refractory anemia. The clinical outcome depended on diagnosis: children with ALL had a better prognosis (4/16 relapsed, one died) than AML patients; all adults and children with AML and 5/12 MDS patients died. Fluorescence in situ hybridization (FISH) identified 3 del(11q23) as translocations or insertions. Molecular studies revealed a MLL rearrangement in 8/10 patients. Because the involvement of MLL might be of prognostic relevance, identification of a del(11q23) should be an indication for FISH and molecular studies.

Most hematological neoplasms associated with 11q23 chromosomal rearrangement have been cases of acute lymphoblastic or acute myeloid leukemia. Although cases of myelodysplastic syndrome (MDS) are a minority, these syndromes should also be recognized as part of the spectrum of hematological disorders associated with 11q23 rearrangement. In this series of 550 patients with such rearrangement there were 28 (5.1%) who presented with MDS. A further five patients had a history of MDS but had evolved to AML by the time cytogenetic analysis was first undertaken. There were thus a total of 33 patients (6.0%) with an 11q23 abnormality whose initial presentation was as MDS. Of these 33 patients, a quarter (seven patients) were cases of secondary (therapy-related) MDS. Complex karyotypes and other poor prognosis chromosomal abnormalities such as -7 and 7q- were common and were not confined to secondary cases. The likelihood of presentation as MDS differed between different cytogenetic categories. The 28 patients in whom cytogenetic analysis was performed at presentation as MDS showed a wide age distribution, from 1 to 82 years; there were four children, two of 1 year of age. All FAB types of MDS were represented. Median survival was only 19.1 months. Leukemic transformation occurred in five patients including one case of transformation to a biphenotypic M5a/T-lineage acute leukemia.

This paper reports clinical and cytogenetic data from 125 cases with t(9;11)(p21-22;q32) which were accepted for a European Union Concerted Action Workshop on 11q23. This chromosome abnormality is known to occur predominantly in acute myeloid leukemia (AML) FAB type M5a and less often in AML M4; in this series it was also found to occur, uncommonly, in other AML FAB types, in childhood acute lymphoblastic leukemia (ALL) (nine cases), in relatively young patients with myelodysplastic syndrome (MDS) (five cases), acute biphenotypic leukemia (two cases), and acute undifferentiated leukemia (one case). All age groups were represented but 50% of the patients were aged less than 15 years. The t(9;11) was the sole abnormality in 57 cases with AML; trisomy 8 was the most common additional abnormality (23 cases, including seven with further abnormalities), and 28 cases had other additional abnormalities. Among the t(9;11)+ve patients with AML, the white cell count (WBC) and age group were significant predictors of event-free survival; central nervous system (CNS) involvement or karyotype class (sole, with trisomy 8, or with other), also contributed to prognosis although our data could not show these to be independent factors. The best outcome was for patients aged 1-9 years, with low WBC, and with absence of CNS disease or presence of trisomy 8. For patients aged less than 15 years, the event-free survival for ALL patients was not significantly worse than that of AML patients.

Finding a clone in the bone marrow of a patient with a hematologic disorder is important to confirm the neoplastic nature of the disease and may be indicative of prognosis. Since cytogenetic analysis detects only actively dividing clones, the presence of a single abnormal cell among 20 cells analyzed raises doubts about its clonal nature. Fluorescence in situ hybridization (FISH) enables rapid detection of certain chromosomal abnormalities in metaphase and interphase cells, thus enabling detection of minor or inactive clones. Seven patients with hematologic malignancy each having random cell(s) were investigated thus: at diagnosis, with MDS and a cell with +8 (two cases) or +9 (one case) and with AML and a cell with +4 (one case), +7 (one case), or two cells with +9, +22/ +10, +17, +17 (one case). One patient with ALL in remission had one cell with trisomy 4. One patient, a male aged 66 years with refractory anemia with ringed sideroblasts, was found to have a minor trisomy 8 clone in his diagnostic marrow. A follow-up marrow 42 months later showed no trisomy 8 cell among 62 metaphases analyzed, and the percentage of trisomic cells using FISH on interphase cells was within the control range. This patient has survived for more than 42 months requiring no treatment. Single-cell abnormalities in the other six cases proved to be random events. Thus it appears that single-cell abnormalities may not be clonal or at most indicate the presence of a minor clone well below the level of cytogenetic detection. The prognostic significance of such minor clones is at present unclear.

Twenty-five patients with loss of part or all of 17p were selected from 701 patients with hematologic malignancies karyotyped either at diagnosis and/or at relapse and/or in refractory disease. Loss of 17p resulted from partial arm deletion (eight cases), unbalanced translocation (12 cases), i(17)(q10)(five cases) or monosomy 17 (four cases). In three cases, both 17ps were missing; in one case, two sublines independently acquired loss of 17p. In eight cases, loss of 17p was confirmed as a secondary change. The karyotypes generally were complex, with an average of 4.0 structurally abnormal chromosomes in the simplest lines showing 17p loss. The incidence at diagnosis was acute lymphoblastic leukemia (ALL) 2.2%, acute myeloid leukemia (AML) 2.4%, and myelodysplastic syndrome (MDS) 3.4%. The incidence in relapse and refractory disease was ALL 8.9%, AML 3.3%, and MDS 6.3%. The increased incidence of 17p loss in relapse and refractory disease was statistically significant (p < 0.05). Loss of 17p appears to be a feature of late-stage or resistant disease in hematologic malignancy.

DNA synthesis inhibitors and vincristine greatly enhance the response of leukaemic and dysplastic cells to differentiation inducing agents such as retinoic acid (RET). Differentiation induction therapy is an attractive therapeutic approach in myelodysplasia (MDS) and in acute myeloid leukaemia (AML) in the elderly, since it should be possible to increase the production of mature cells, at the expense of precursor cells, without incurring the complications of intensive cytotoxic therapy. Single agent differentiation therapy has, however, not been highly successful. We have therefore investigated the use of synergistic combinations of agents. We treated nine patients (6 with MDS, 3 with AML) with 13-cis-retinoic acid (up to 100 mg/m2/day) in combination with either 6-thioguanine (20-40 mg/day in 14-57 day courses) or with vincristine (1-2 mg as a single injection during a four-day course of RET). Seven patients responded with an increase in the mature cells of at least one haemopoietic lineage. A concomitant decrease in marrow blasts was observed in 3/4 responding patients. The retention of dysplastic and karyotypic abnormalities and lack of a hypoplastic phase all suggested that differentiation induction was occurring in vivo. Prior failure to respond to therapy with single agents (RET in two and cytosine arabinoside in five patients) suggests that the synergy observed in vitro operates in vivo. In-vitro studies on marrow cells from seven patients demonstrated synergistic differentiation induction in 6/7 samples. The seventh patient was one of the two who did not respond clinically. The second of these clinically unresponsive patients had cells which were relatively refractory to RET in vitro, suggesting that in-vivo and in-vitro responses may be related.