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G J Swansbury

Publications and source records attributed to G J Swansbury.

At least 19 recordsLinked to original sources
PubMed2003

Impact of cytogenetics on the outcome of autotransplantation for acute myeloid leukemia in first remission: is the benefit of intensive pretransplant therapy limited to patients with good karyotypes?

A total of 81 adults with acute myeloid leukemia (AML) (47% favorable karyotypes) were autografted in first remission after melphalan-total body irradiation, having received 0 (n=7), 1 (n=19), 2 (n=51), or 3 (n=4) consolidation chemotherapy cycles before harvest. The cumulative 5-year incidences of relapse and transplant-related mortality were 37 and 17%, respectively. The actuarial 5-year probability of disease-free survival (DFS) was 46%. In Cox analysis, favorable karyotypes, increasing numbers of consolidation cycles (0 vs > or =1 or 1 vs >1), and higher nucleated cell doses were associated with lower relapse rates and higher DFS. Patients with favorable karyotypes benefited from every additional cycle of consolidation therapy (0 vs > or =1 as well as 1 vs >1). Among patients with other karyotypes, while the benefit of one cycle of consolidation was clear (0 vs > or =1), there was no obvious beneficial impact of further consolidation therapy (1 vs >1). Administration of consolidation chemotherapy prior to harvest is essential in AML. While it is possible to enhance the benefit of consolidation with favorable karyotypes by delivering two cycles, its usefulness is limited in others. In them, it may be worthwhile exploring alternatives not normally used in AML (eg high-dose cyclophosphamide) that could have antileukemic effects while permitting mobilization of stem cells.

Acute Disease↗
PubMed2000

Secondary myelodysplastic syndrome/acute myeloid leukaemia following mitoxantrone-based therapy for breast carcinoma.

Of 1774 patients with breast cancer given mitoxantrone (MTZ) with methotrexate (n = 492) or with methotrexate and mitomycin C (n = 1282), nine developed MDS/AML after a median of 2.5 years. Median duration of survival from diagnosis of MDS/AML was 10 months and six patients died. The crude incidence of developing MDS/AML after MMM or MM chemotherapy was 15 per 100,000 patient years follow-up, while the actuarial risk was 1.1% and 1.6% at 5 and 10 years respectively. MTZ-based regimens carry a 10 x higher risk of subsequent MDS/AML compared to that seen in the general population.

Acute Disease↗
PubMed2000

Disease features in acute myeloid leukemia with t(8;21)(q22;q22). Influence of age, secondary karyotype abnormalities, CD19 status, and extramedullary leukemia on survival.

Over a period of 14 years, 50 patients (12 children and 38 adults) of whom 46 had acute myeloid leukemia (AML) and 4 had myelodysplastic syndrome characterized by the t(8;21)(q22;q22) translocation were referred to the Royal Marsden Hospital. The clinicopathological features of these cases were analyzed to determine the influence of age, secondary karyotype abnormalities, and expression of the lymphoid marker CD19 on event free survival, and presence of extramedullary leukemia on overall survival. They were treated with a variety of chemotherapy protocols and some had bone marrow transplantation. There appeared to be no difference in survival between children (age <17 years) and adults (age >16 years). Out of the 50 cases, 16 (32%) had the (8;21) translocation alone, 17 (34%) had additional loss of a sex chromosome and the remaining 17 (34%) had other karyotype abnormalities of which deletion or translocation of the long arms of a #9 was most common (observed in 8 of the 17 patients). The karyotype groups had a significant impact on survival, the group with loss of a sex chromosome having a poorer outcome and the group with abnormalities of chromosome 9 having a better outcome. CD19 positivity was seen in 21 of the 33 cases (63%) in whom it was measured compared to 11% observed in controls with AML without a t(8;21). CD19 status did not exert any influence on event free survival. Extramedullary leukemia (EML) occurred in 5 of the 50 cases (10%). In one patient it was observed at diagnosis but in the others it presented concurrent with bone marrow relapse. The overall survival of patients with EML was worse than that of the other patients but did not achieve statistical significance and was probably adversely affected by other factors.

Acute Disease↗
PubMed1999

Long-term follow-up of patients with hairy cell leukaemia after treatment with pentostatin or cladribine.

We report the long-term follow-up results on two groups of patients with hairy cell leukaemia (HCL) treated with either pentostatin (deoxycoformycin) or cladribine (2-chlorodeoxyadenosine). 165 HCL patients received treatment with pentostatin (between 1986 and 1994), and 45 were treated with cladribine (between 1992 and 1997). Age and sex characteristics were similar in the two groups. 38 patients in the pentostatin group and 12 in the cladribine group were previously untreated. 22 patients in the cladribine group had received prior treatment with pentostatin; four were resistant, 17 had relapsed following partial (four) or complete (13) responses, and one was not evaluable for response. The response rates were the same in the two groups: 82% complete response (CR), 15% partial response (PR) for pentostatin and 84% CR, 16% PR for cladribine. Relapse rates were 24% for pentostatin and 29% for cladribine after median follow-up of 71 and 45 months respectively. At 45 months, however, the relapse rate for pentostatin was only 9.7%. We found a statistically significant difference in the disease-free interval (DFI) between the two groups suggesting that patients may relapse more quickly after cladribine. The majority of relapsed patients achieved second remissions following further therapy with either pentostatin or cladribine, with no evidence of cross resistance between the two agents. The 5-year survival for all patients was 97% and treatment- related toxicity was low. We conclude that both pentostatin and cladribine induce durable remissions in the majority of HCL patients. Longer follow-up is required to establish whether some patients are cured as there is no plateau in DFI, and which of these two agents may be the treatment of choice.

Adult↗
PubMed1999

The impact of karyotype on remission rates in adult patients with de novo acute myeloid leukemia receiving high-dose cytarabine-based induction chemotherapy.

One hundred and twenty-eight patients aged 15 years or over (median 34) with de novo acute myeloid leukemia (AML) received 2- or 3-drug induction chemotherapy comprising 5 days of daily high-dose cytarabine (2 g/m2 q12h) and etoposide (100 mg/m2), without (n=62, 1985-90, protocol BF11) or with (n=66, 1990-97, protocol BF12) daily 5 mg/m2 anthracycline (61 idarubicin, 5 mitoxantrone). Twelve patients with t(15;17) were not included. Evaluable karyotypes were obtained in 110 (86%): 30 (27%) favorable, 60 (55%) intermediate, and 20 (18%) adverse. Three patients dying during chemotherapy were inevaluable. Eighty-four (67%) patients remitted with one cycle, and the overall complete remission (CR) rate was 72%. CR rates were comparable for patients with and without evaluable karyotypes. CR rates with BF11 (64% after one cycle; 72% overall) and BF12 (70% after one cycle; 72% overall) were comparable (P=.4 and 1.0 respectively). CR rates after one cycle (86%, 61% and 55%; P=.03) as well as overall CR rates (90%, 69% and 55%; P=.02) were significantly different for patients with favorable, intermediate and adverse karyotypes respectively. In Cox analysis, the karyotype was the only factor found to influence CR independently. We conclude that the karyotype of the leukemic clone is the most important determinant of response to high-dose cytarabine-based induction chemotherapy in AML. The addition of idarubicin to high-dose cytarabine and etoposide does not appear to improve CR rates. A different treatment strategy may be needed to improve CR rates for patients with non-favorable karyotypes.

Acute Disease↗
PubMed1999

Monosomy X as the sole cytogenetic abnormality in acute lymphoblastic leukemia: a report of two new patients.

Monosomy X as the sole acquired cytogenetic abnormality is usually found in myeloid hematological malignancies, especially those with myelodysplastic features. Only three cases of acute lymphoblastic leukemia (ALL) with this abnormality have been previously reported. We add two cases to this series and comment on the likelihood of a tumor suppressor gene being located on the X chromosome.

Adolescent↗
PubMed1998

The proportion of clonal divisions varies in different hematologic malignancies. The United Kingdom Cancer Cytogenetics Group (UKCCG) [corrected].

The detection of clones by conventional cytogenetic studies in diagnostic hematoncology is heavily subject to the effects of many biological and laboratory factors, one of which is the number of divisions analyzed. Data from 20 laboratories were combined to get an impression of the true frequency of clonal divisions for comparison with the theoretical models that have been previously used to set laboratory policies. This study showed that low-percentage clones were more common in the myelodysplastic syndromes and that high-percentage clones were more common in acute myeloid leukemia than in acute lymphoblastic leukemia (ALL), although the clone detection rate in ALLs is higher. The inference is that the putative diagnosis should be taken into account when deciding how many divisions to analyze before concluding that no detectable clone is present.

Cell Division↗
PubMed1998

Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants.

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.

Acute Disease↗
PubMed1997

Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia.

We have analysed the prognostic influence of cytogenetic findings at diagnosis in a group of 502 children with acute lymphoblastic leukaemia (ALL), treated on MRC UKALL X, in whom clonal cytogenetic abnormalities were detected at diagnosis. Despite the overall improvement in outcome in children treated on this protocol compared with previous trials, some cytogenetically-defined groups were still associated with a poor outcome and ploidy retained some prognostic significance. Patients with high hyperdiploid ALL (39% of those with clonal abnormalities) had a favourable outcome with event free survival of 71% at 5 years. Those with near haploidy (1%), hypodiploidy (9%) and low hyperdiploidy (16.5%) had a relatively poor prognosis with event-free survival at 5 years of 17%, 42% and 49% respectively. Only two of 12 children with Ph-positive leukaemia are alive in remission and abnormalities of chromosome 11q23 were also associated with a high risk of treatment failure. In contrast, the t(1;19) was associated with improved event-free survival of 87.5% at 5 years. A number of other non-random abnormalities were identified with no clear prognostic significance. We conclude that identification of certain genetic changes remains important in the management of acute lymphoblastic leukaemia, although whether molecular diagnosis of clinically relevant abnormalities can now supplant cytogenetics in the clinical trials context remains to be determined.

Child↗
PubMed1997

Additional chromosome abnormalities confer worse prognosis in acute promyelocytic leukaemia.

Acute promyelocytic leukaemia (APL) has been associated with a favourable prognosis in many studies of acute myeloid leukaemia. A series of 54 patients treated at the Royal Marsden Hospital between 1979 and 1996, with APL and the t(15;17) chromosome translocation at presentation, was examined for the effect of additional chromosome abnormalities in their presentation karyotype on survival. The patients were aged between 2 and 62 years with a median age of 31 years. There were approximately equal numbers of males and females. Presentation white cell count ranged from O.7 to 156 x 10(9)/l with a median of 1.0 x 10(9)/l. 39% of patients (21/54) had additional chromosome abnormalities at presentation. Statistical analyses were performed for factors thought to influence survival such as age, sex, white cell count, and number of courses of chemotherapy required to enter remission. These showed that the presence of additional chromosome abnormalities has an adverse effect on prognosis, independent of other prognostic indicators, reducing it to the level of patients with AML from less-favourable cytogenetic subgroups. These data indicate that additional therapeutic strategies may be required in patients with APL who demonstrate cytogenetic aberrations over and above the t(15;17) at presentation. The biological basis for the more aggressive nature of these cases remains to be determined.

Adolescent↗
PubMed1997

Bilineal acute leukemia of B and T lineage with a novel translocation t(9;17)(p11;q11).

We describe a case of bilineal leukemia in a 5-year old boy with a rare immunophenotype and the novel translocation t(9;17)(p11;q11) as the sole chromosomal abnormality. Two immunologically distinct blast cell subsets expressed T-markers (CD2, CD5, CD7) and common ALL markers (TdT, CD19, CD22, CD10), respectively. Both cell populations were CD34 negative. The patient, who presented with CNS leukemia, responded promptly to standard chemotherapy for lymphoblastic leukemia and remains in complete remission 20 months from diagnosis. Other translocations between chromosomes 9 and 17 have been infrequently reported in a variety of leukemias but as yet their biologic significance is unknown. The clinical course of this case suggests that t(9;17)(p11;q11) may not have an adverse influence on the disease outcome. However, the role of t(9;17) in the pathogenesis of this unusual lymphoid phenotype remains unresolved.

Acute Disease↗
PubMed1997

Sequential development of myelodysplasia and acute myeloid leukemia but with no karyotypic evolution after autografting in a patient with Philadelphia positive acute lymphoblastic leukemia.

A woman with Philadelphia chromosome-positive c-ALL with +8 and i17q in addition underwent an unpurged blood stem cell autograft after 200mg/m2 melphalan in first relapse. Maintenance therapy with 6-mercatopurine was started following the autograft. Moderate pancytopenia developed after 4 months, and myelodysplasia (refractory anemia) was diagnosed which rapidly evolved into AML. The cytogenetic findings remained unchanged. She also developed CNS disease, but the blasts in the cerebrospinal fluid were lymphoid in character on immunophenotyping. She then received palliative treatment until death. The remarkable features here are the evolution into myelodysplasia and AML with retention of the original complex karyotype, and subsequent coexistence of lymphoid disease in the CNS and myeloid disease systemically. It is possible that the lineage switch and development of myelodysplasia in this case may have been secondary to treatment, but persistence of the original cytogenetic clone makes this unlikely. This may have been the result of some unusual effect of the treatment on the original clone, or expansion of a small unidentified myeloid clone present originally which gained a proliferative advantage due to the ALL-type treatment. This case confirms the aggressive and polymorphic nature of Ph+ ALL which may be the result of origin from an early progenitor cell (stem cell disease).

Acute Disease↗
PubMed1996

Analysis of clonal rearrangements of the Ig heavy chain locus in acute leukemia.

Clonal rearrangements of the Ig heavy chain (IGH) locus occur in nearly all cases of B-cell precursor acute leukemia (BCP-ALL). Some of these rearrangements may be detected by polymerase chain reaction (PCR) using VH gene framework III (FRIII) and JH consensus primers. However, about 20% of BCP-ALLs fail to amplify with this technique. To determine the causes of these PCR failures and to investigate any possible association with specific subgroups of disease, we analyzed 72 acute leukemias of defined immunophenotype and cytogenetics, comparing FRIII with VH-family leader-specific PCR methods and Southern blotting. Of 37 BCP-ALL cases, 6 (16.2%) failed totally to amplify with FRIII and JH primers. None of these cases amplified with VH leader primers. Additionally, all cases retained germline VH6 genes and 5 of 11 rearranged alleles amplified with a consensus DH primer, indicating that these rearrangements represented biallelic DH-JH recombinations. Among the 6 FRIII and VH leader PCR-negative BCP-ALL cases, there was no common immunophenotype or consistent cytogenetic abnormality, although all showed structural chromosomal abnormalities and 3 of 5 successfully karyotyped had abnormalities of chromosome 12p. 13 cases with t(9;22)(q34;q11) Philadelphia chromosome-positive [Ph+]) and IGH rearrangements (9 BCP-ALL and 4 biphenotypic cases) were also analyzed. Of 23 rearranged IGH alleles, 19 (82%) were positive by FRIII PCR, and all 4 remaining alleles were amplified by VH leader primers. Use of the leader primers in these Ph+ cases also detected 3 additional clonal rearrangements that were not anticipated from Southern blotting; such unexpected bands were not observed in 21 other Ph- cases. The additional bands represented "new" and unrelated VH rearrangements rather than VH-VH replacement events. We conclude that biallelic DHJH rearrangements occur in a subgroup of BCP-ALL; in these cases, the activation of the full VHDHJH recombination mechanism had not occurred. Therefore, these cases of BCP-ALL were arrested at an early stage of B-cell differentiation. In contrast, all Ph+ BCP-ALLs and biphenotypic acute leukemias, which may represent the transformation of multipotent hemopoietic stem cells, had undergone VHDHJH recombination. Of 9 Ph+ BCP-ALL cases, 3 also showed ongoing VHDHJH rearrangement, reflecting the persistent expression of the VHDHJH recombinase. Finally, sequence analysis of 33 rearranged VHDHJH genes showed that only 3 including 2 Ph+ BCP-ALL maintained an intact open-reading frame. Loss of the open-reading frame occurred not only because of out-of-frame VHDH and DHJH joining, but also because of VH gene mutation and deletion. These data show that most BCP-ALLs may represent the neoplastic transformation of BCPs destined to die in the bone marrow.

Acute Disease↗
PubMed1996

der(16)t(1;16)(q21;q13) as a secondary change in alveolar rhabdomyosarcoma. A case report and review of the literature.

Alveolar rhabdomyosarcoma is an aggressive childhood tumor that exhibits muscle cell differentiation. Cytogenetically, it is characterized by t(2;13)(q35;q14); no consistent secondary abnormalities have been reported. Cytogenetic analysis of bone marrow in a case of alveolar rhabdomyosarcoma revealed t(2;13)(q35;q14) and der(16)t(1;16)(q21;q13). The present case and a review of the literature suggest that up to 11% of these tumors possess der(16)t(1;16)(q21;q13). This is similar to the incidence observed in the Ewing family of tumors, where unbalanced der(16)t(1;16) translocations, resulting in partial trisomy of 1q, are regarded as a consistent secondary cytogenetic change.

Child↗
PubMed1996

Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients.

We have analysed the clinical and laboratory features in 544 patients with chronic lymphocytic leukaemia (CLL) with available cytogenetics and fluorescence in-situ hybridization (FISH) analysis for trisomy 12 in half of them, to examine the correlation between chromosome abnormalities and clinical or laboratory parameters. Five chromosome groups were defined: (1) trisomy 12 (18%), detected as the sole abnormality or associated with other changes; (2) del(13)(q12-14) (7%); (3) other abnormal karyotypes (20%); (4) normal karyotype (41%); and (5) no divisions (14%). There were no differences in the age distribution between the five groups. Clinical stages (Binet) were: A (74%), B (12%) and C (14%). Stage A was common in cases with del(13q)(82%), normal (84%) and other abnormal karyotypes (74%), whereas it was less common in trisomy 12 cases (64%) and those with no divisions (48%). Typical CLL morphology was found in 83% of cases; 10% had more than 10% prolymphocytes (CLL/PL) and 7% had other atypical features. CLL with trisomy 12 was the only group with a high frequency of either CLL/PL (31%) or atypical morphology (24%). Atypical morphology and CLL/PL were even more frequent when trisomy 12 was associated with other chromosomal abnormalities (70% v 46%). The incidence of cases with CLL/PL and other atypical morphology was significantly lower in the other chromosome groups (P < 0.001). There were no differences in immunophenotype among the various groups except for a higher frequency of stronger Smlg and FMC7 expression in cases with trisomy 12, particularly those with CLL/PL and other atypical morphology. Our findings confirm that trisomy 12 defines a subgroup of CLL with more frequent atypical morphology, including CLL/PL, stronger SmIg and FMC7 expression, more advanced stages (B and C in 18%) and possibly worse prognosis.

Aged↗
PubMed1996

Platinum agents and secondary myeloid leukaemia: two cases treated only with platinum-based drugs.

With the increasing use of chemotherapy for many different primary malignancies, secondary or therapy-related acute myeloid leukaemias (AML) and myelodysplastic syndromes (MDS) are becoming more common. The risk of developing sAML has been estimated to be between 2% and 10%, depending upon the type, duration and dosage of previous therapy (Michels et al, 1985; Shulman, 1993; Robinson & Mertens, 1993; Ballen & Antin, 1993). It is therefore one of the most serious long-term complications of current cancer treatment and is likely to increase as longer survival rates for the primary tumour are achieved. An increasing range of drugs have been reported to cause sAML, including the alkylating agents, the epipodophyllotoxins and the anthracyclines, both as single agents and in combination (Pedersen-Bjergaard & Philip, 1991; Pedersen-Bjergaard & Rowley, 1994). We report two cases of secondary AML in which platinum compounds were the sole prior chemotherapy.

Acute Disease↗