Bone marrow transplantation for adults with acute leukaemia and 11q23 chromosomal abnormalities

Bone marrow transplantation for adults with acute leukaemiaand 11q23 chromosomal abnormalities

D. L. FORREST, T. J. NEVILL, D. E. HORSMAN,* D. A. BROCKINGTON, H. C. FUNG, C. L. TOZE, E. A. CONNE ALLY,D. E. HOGGE, H. J. SUTHE RL AND, S. H. NANTEL, J. D. SHEP HERD AND M. J. BARNETT The Leukemia and Bone MarrowTransplantation Program of British Columbia: Divisions of Hematology and *Laboratory Medicine, British ColumbiaCancer Agency, Vancouver Hospital and Health Sciences Centre and the University of British Columbia, Vancouver,British Columbia, Canada

Received 3 May 1998; accepted for publication 12 August 1998

Summary. Adults with acute leukaemia and abnormalities ofchromosome 11q23 have a poor prognosis when treatedwith conventional chemotherapy. To determine whethermore intensive therapy can improve outcome for patientswith this karyotypic finding, a retrospective analysis of allpatients with acute leukaemia and 11q23 abnormalitiestreated at our centre was performed. 12 patients weretreated with conventional chemotherapy alone (CC); 20patients received high-dose chemo/radiotherapy (HDCT)with autologous (seven patients) or allogeneic (13 patients)bone marrow transplantation (BMT). The treatment-relatedmortality was 25% [95% Confidence Interval (CI) 7–69%]for the CC group and 46% (CI 25–73%) for the BMT group

(P ¼ 0·69). Cumulative risk of leukaemia progression was89% (CI 61–100%) in the CC patients and 38% (CI 12–69%)in the BMT patients (P ¼ 0·001). The 2-year event-freesurvival for patients treated with CC was 8% (CI 0–31%) andfor patients receiving HDCT and BMT was 34% (CI 14–54%)(P ¼ 0·03). These results confirm that conventional chemo-therapy is rarely curative for adults with acute leukaemiaand 11q23 abnormalities but that HDCT with BMT canresult in long-term survival in a significant proportion ofpatients.

Keywords: acute leukaemia, chromosome 11q23, bonemarrow transplantation, conventional chemotherapy.

A number of studies have evaluated the prognosticsignificance of bone marrow karyotype in acute leukaemia(Bloomfield et al, 1986; Arthur et al, 1989; Fenaux et al,1989; Schiffer et al, 1989; Secker-Walker et al, 1989; Walterset al, 1990; Marosi et al, 1992; Stasi et al, 1993). It is nowclear that cytogenetic analysis can assist in stratifyingpatients into subgroups with respect to their probability ofobtaining a complete remission (CR) and their risk ofrelapse (Buchner & Heinecke, 1996). Patients withacute leukaemia and t(9;22), ¹5, ¹7 or chromosomalabnormalities involving 11q23 have been shown to have apoor prognosis when treated with conventionalchemotherapy alone (Bloomfield et al, 1986; Arthur et al,1989; Schiffer et al, 1989; Secker-Walker et al, 1989; Walterset al, 1990).

A diverse set of abnormalities involving the chromosomelocation 11q23 (the site of the MLL gene) have been

demonstrated in patients with acute leukaemia, the mostfrequent of which are t(4;11), t(9;11), del(11)(q23), t(11;19)and t(6;11) (Secker-Walker, 1998). Much of the informationon the outcome of patients with acute leukaemia andchromosome 11q23 abnormalities has been derived frompaediatric experience. It represents the most commonkaryotypic abnormality in acute leukaemia of infancy andis associated with a poor prognosis (Chen et al, 1993;Heerema et al, 1994; Sorensen et al, 1994; Cimino et al,1995; Taki et al, 1996).

In adults, abnormalities of 11q23 are seen in 2–5% ofacute lymphoblastic leukaemia (ALL) cases, 5–10% of denovo acute myelogenous leukaemia (AML) and 80–90% oftopoisomerase II inhibitor-induced AML (tAML) (Heim &Mitelman, 1992; Bredeson et al, 1993). Treatment of thesepatients with conventional chemotherapy has generallyresulted in an unfavourable outcome, with high relapse ratesand short overall survival times (Arthur et al, 1989; Schifferet al, 1989; Marosi et al, 1992; Stasi et al, 1993). These earlyreports have more recently been confirmed at the EuropeanUnion Concerted Action Workshop on 11q23 abnormalities

British Journal of Haematology, 1998, 103, 630–638

630 q 1998 Blackwell Science Ltd

Correspondence: Dr T. J. Nevill, Department of Medicine, VancouverHospital and Health Sciences Centre, 910 West 10th Avenue,Vancouver, British Columbia, Canada V5Z 4E3.

631BMT for Acute Leukaemia with 11q23 Chromosomal Abnormalities

q 1998 Blackwell Science Ltd, British Journal of Haematology 103: 630–638

(Harbott et al, 1998; Johansson et al, 1998; Moorman et al,1998; Secker-Walker et al, 1998; Swansbury et al, 1998).Less is known about the impact of high-dose chemo/radiotherapy (HDCT) and bone marrow transplantation(BMT) on event-free survival (EFS) of adults with 11q23abnormalities. Therefore a review of all acute leukaemiakaryotypes performed at our centre was undertaken todetermine whether outcome has been improved by thedelivery of more intensive therapy to adult patients with11q23 chromosomal abnormalities.

PATIENTS AND METHODS

Cytogenetics. Between January 1980 and September 1997the Vancouver Hospital and Health Sciences Centre (VHHSC)Cytogenetics Laboratory studied bone marrow samples atdiagnosis on 840 adult patients with acute leukaemia.Karyotypic analysis of leukaemic cells was performed oncultured bone marrow aspirates by standard methods. 25Giemsa-stained metaphases were analysed where possibleand the karyotype was defined according to guidelines forcancer cytogenetics (ISCN, 1991). 469 patients (55·8%) hadkaryotypic abnormalities identified in the malignant clone atdiagnosis; of these cases, 49 patients (10·4%) had abnormal-ities of chromosome 11q23. Detailed treatment and outcomedata was available on the 32 patients in this group that weretreated at the VHHSC and/or the British Columbia CancerAgency (BCCA). The karyotypic profiles for these 32 patientsare shown in Tables I–III. The most common abnormalities of11q23 observed were: t(9;11) (10 patients), del(11)(q23) (10patients), t(4;11) (six patients), and t(11;19) (two patients);four patients had miscellaneous abnormalities of 11q23.

Patient characteristics. 26 patients had de novo acuteleukaemia (17 AML, seven ALL, one acute biphenotypicleukaemia [ABL] and one acute undifferentiated leukaemia[AUL]). Six patients had tAML due to treatment of aprior malignancy with radiotherapy (endometrial cancer),multiagent chemotherapy (non-Hodgkin’s lymphoma[NHL]), or both (three breast cancer, one NHL); all sixpatients had a t(9;11) karyotypic abnormality. 19 of theAML patients had either FAB M4 or M5 subtypes. 12patients, treated with curative intent, received only conven-tional chemotherapy (CC), whereas 20 patients ultimatelyunderwent HDCT and BMT. Patients underwent allogeneicBMT if a suitable related or unrelated donor couldbe identified; if no donor was available or if the patient was51–60 years of age, autologous BMT was recommended.Patients were given CC only on the basis of refractoryleukaemia (four patients), advanced age (three patients),lack of a suitable bone marrow donor (one patient),physician preference (one patient) or patient refusal toundergo BMT (three patients).

Bone marrow transplantation. Characteristics of the 20patients who underwent HDCT and BMT are shown inTables I and II. Median age was 34·5 years (range 14–60)with a median WBC count at presentation of 10·0 × 109/l(range 0·9–721). 18 patients received CC prior to BMT; twopatients with tAML had no induction chemotherapy andproceeded directly to HDCT. 11 patients with AML received

one or two courses of cytosine arabinoside (Ara-C),mitoxantrone (Mitox) and etoposide (VP16) (Shepherd etal, 1994) prior to BMT. Five patients with ALL received oneto three courses of multiagent induction/consolidationchemotherapy (Forman et al, 1995) prior to BMT. Thetwo patients with ABL and AUL were induced with Ara-C 1·5 g/m2 every 12 h ×12, daunorubicin (DNR) 45 mg/m2/d ×3, vincristine (VCR) 2 mg weekly ×4 and prednisone60 mg/m2/d ×28; remission was consolidated with VP161·2–2·4 g/m2 and cyclophosphamide (CY) 4–7·2 g/m2

prior to BMT in CR1. 17/18 patients pre-treated withCC achieved a CR; of these, 12 patients underwent BMTin CR1, two patients in first relapse, two patients in CR2,and one patient in CR3. Two patients (UPN 250 andUPN 911), both of whom received an allogeneic BMT,were refractory to CC at the time of transplantation.Conditioning regimens included CY and total body irradia-tion (TBI) with (seven patients) or without (twopatients) other chemotherapeutic agents; busulphan (BU)and CY with (five patients) or without (five patients)other chemotherapeutic agents; or VP16/TBI (one patient).The source of the stem cells was a histocompatible siblingin eight patients, a matched unrelated donor in fivepatients and purged autologous bone marrow in sevenpatients. Autologous bone marrow was purged with 4-hydroperoxycyclophosphamide (4-HC) (Yeager et al, 1986)in four cases and with interleukin-2 (IL-2) in threecases (Klingemann et al, 1994); one patient (UPN 855)received G-CSF-primed, unpurged peripheral blood stem cellsin addition to a 4-HC-purged BMT. Median nucleated cellsinfused was 2·38 × 108/kg (range 0·37–6·9) in the donorBMT patients and 1·75 × 108/kg (range 0·5–5·24) in theautologous BMT patients. Graft-versus-host disease (GVHD)prophylaxis consisted of: cyclosporine (CsA) and methotrexate(MTX) with (two patients) (Storb et al, 1990; Phillips et al,1995) or without (six patients) (Storb et al, 1986) anotheragent; CsA and immunomagnetic T-cell depletion (twopatients) (Simpson et al, 1996); CsA and methylprednisolone(one patient) (Shepherd et al, 1988); or CsA alone (twopatients).

Conventional chemotherapy. Characteristics of the 12patients who received only CC are shown in Table III.Median age was 59·5 years (range 15–74) with a medianWBC at diagnosis of 48 × 109/l (range 2·2–566). Sevenpatients with de novo AML and one patient with tAML wereinduced with Ara-C and Mitox 6 VP16 as previouslydescribed (Shepherd et al, 1993, 1994). Two patients (onede novo AML and one tAML) received Ara-C 1·5 g/m2 every12 h × 12 and DNR 45 mg/m2/d ×3 (Shepherd et al, 1995).Four patients in the CC group had refractory disease (two denovo AML, one tAML and one ALL). The seven patients withAML that achieved a complete remission were consolidatedwith one or two courses of identical chemotherapy; oneelderly patient with pre-existing cardiac dysfunction wasconsolidated with two cycles of Ara-C 200 mg/m2/d ×7 andDNR 45 mg/m2/d ×2. The two patients with ALL receivedinduction DNR, VCR, prednisone and L-asparaginase whichwas to be followed by six cycles of intensive consolidation asdescribed elsewhere (Forman et al, 1995). Central

nervous system (CNS) prophylaxis was with intrathecal MTXand 1200 cGy cranial irradiation (Forman et al, 1995).

Supportive care. Patients were treated in a high-efficiencyparticulate air (HEPA)-filtered positive-pressure Leukaemiaand Bone Marrow Transplantation Unit at either theVHHSC or the BCCA. Low bacterial content food andHickman catheters were used routinely. Empiric intravenous(i.v.) antibiotics, amphotericin B, acyclovir, CMV-negativeblood products, high-titre CMV immunoglobulin products,ganciclovir and total parenteral nutrition were given asrequired. All patients received fluconazole (200–400 mg/di.v.) as antifungal prophylaxis from June 1992until December 1994, when this was changed to i.v.amphotericin B 10 mg/m2/d. Hepatic venocclusive diseaseprophylaxis with low-dose heparin (100 units/kg/d)was given routinely to BMT patients after September 1992(Attal et al, 1992). BMT patients receiving BU were also givenphenytoin as anti-seizure prophylaxis. Patients on high-doseCY received hyperhydration (3 l/m2/d) for uroepithelialprotection except between October 1987 and January 1990,when patients were randomly assigned to receive hyperhy-dration or mesna (Shepherd et al, 1991).

Statistical methods. The actuarial event-free survival (EFS)and leukaemia progression probabilities were calculatedusing the product limit estimates of Kaplan & Meier (1958).Time to leukaemia progression was calculated from the firstday of induction chemotherapy (CC group) or from the day ofBMT (BMT group). CC and BMT results were comparedutilizing a proportional hazards Cox regression model (Cox,1972).

RESULTS

SurvivalSeven patients (four AML, one ALL, one ABL and one

AUL) are alive without evidence of leukaemia followingBMT (four allogeneic and three autologous) with amedian follow-up of 75·0 months (range 12·5–147·0).Six of these seven patients had their BMT in CR1 (Tables Iand II). Only one of 12 CC patients is alive with AML inCR1 26·3 months after institution of therapy (Table III).The 2-year EFS (Fig 1) for the BMT and the CC groups is34% (CI 14–54%) and 8% (CI 0–31%), respectively(P ¼ 0·03).

Treatment-related mortality (TRM)In the BMT group there were eight treatment-related deaths.Six patients died post-allogeneic BMT, two patients due toacute GVHD and one patient each from pulmonaryhaemorrhage, fungal infection, graft failure, and CNStoxicity. One patient died following autologous BMT as aresult of pulmonary haemorrhage and a second patient fromCMV pneumonia. In the CC group, one patient died duringinduction of multi-organ failure and one patient died duringthe first course of consolidation due to fungal pneumonia.The cumulative risk of TRM was 25% (CI 7–69%) in the CCgroup and 46% (CI 25–73%) in the patients who underwentBMT (P ¼ 0·69).

Leukaemia-related mortalityAmongst those patients treated with BMT, five patients(four AML and one ALL) died of recurrent disease at amedian of 13·1 months (range 5·6–19·8) post-allogeneic(three patients) or autologous (two patients) BMT. Inthe CC patient cohort there were four deaths (threeAML and one ALL) due to primary refractory diseaseand five deaths (four AML and one ALL) due torelapse of leukaemia at a median of 9·7 months (range7·4–29·1) following CR1. The cumulative risk of leukaemiaprogression for the BMT and the CC patients (Fig 2) was 38%


632 D. L. Forrest et al

Table I. Allogeneic bone marrow transplantation: patient characteristics and outcome.

Age (yr)/ Disease status Stem cell OutcomeUPN sex Diagnosis at BMT source Karyotype (months*)

86 27/F AML-M5 CR1 SIB 46,XX,t(11;17)(q23;q22) [23] A (147·0)138 33/F ALL CR1 SIB 46,XX,t(4;11)(q21;q23) [25] D/A-GVHD (1·7)250 37/F AML-M5 IF SIB 45,XX,add(9)(q34),t(9;11)(p22;q23),¹11 [3] D/A-GVHD (1·3)300 21/F ALL CR1 SIB 46,XX,t(4;11)(q11;q23) [25] D/PULM (1·3)357 39/F tAML-M5 REL1 UD 47,XX,þX, t(9;11)(p21;q23) [25] D/REL (8·3)525 49/F tAML-M5 IND SIB 46,XX,t(9;11)(p22;q23) [21] D/REL (4·2)553 21/M ABL CR2 UD 46,XY,¹11, þder(11),t(1;11)(q21;q23) [4] A (84·0)588 36/F tAML-M5 IND SIB 46,XX,t(9;11)(p22;q23),t(10;18)(q24;q21) [11] D/CNS (3·1)697 28/M ALL CR1 SIB 46,XY,t(11;19)(q23;p13) [25] D/INF (7·3)911 38/M AML-M5 REL1 UD 46,XY,del(11)(q23) [15] D/GF (1·7)969 14/F ALL CR2 UD 47,XX,t(4;11)(q21;q23),þder(4) t(4;11)(q21;q23) [5] D/REL (3·9)981 28/F ALL CR1 SIB 46,XX,t(8;14)(q11;q32),del(11)(q23q25) [13] A (35·0)

1244 43/M AML-M1 CR1 UD 46,XY,del(11)(q23) [4] A (12·5)

Abbreviations: UPN, unique patient number; BMT, bone marrow transplantation; F, female; M, male; AML, acute myelogenous leukaemia;tAML, treatment-related AML; ALL, acute lymphoblastic leukaemia; ABL, acute biphenotypic leukaemia; CR, complete remission; IF, inductionfailure; REL, relapse; IND, induction; SIB, histocompatible sibling; UD, unrelated donor; A, alive; D, dead; A-GVHD, acute graft-versus-hostdisease; PULM, pulmonary haemorrhage; CNS, central nervous system toxicity; INF, infection; GF, graft failure.

* From time of BMT.



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(CI 17–69%) and 89% (CI 61–100%) respectively(P ¼ 0·001).

Outcome with t(9;11)All 10 patients with t(9;11) had AML-M5; six of thesepatients had tAML. The four patients with t(9;11)who received an allogeneic BMT, three of whom had tAML,have died; two patients died of TRM and two patients had arelapse of their leukaemia. Both t(9;11) patients whounderwent autologous BMT remain alive and well. Oneof the four t(9;11) patients who received CC only is alivewithout evidence of disease but the other three patients(including two patients with tAML) have died of theirleukaemia.

Outcome with t(4;11) and del(11)(q23)All six patients with acute leukaemia and t(4;11) have dieddespite CC (two patients), allogeneic BMT (three patients) orautologous BMT (one patient). In the group of patientswith del(11)(q23), two of the three allogeneic BMT patientsand one of the three autologous BMT patients are alive and

well; none of the four CC patients with del(11)(q23)survived.

Survival with tAMLFour patients underwent BMT for tAML (three allogeneicand one autologous). Only one of these patients (UPN 747)is alive and well 60 months following an IL-2-purgedautologous BMT. Two patients with tAML were treatedwith CC; one patient was refractory to treatment andone patient relapsed 9·7 months after achieving CR1.

Influence of disease status at BMTOf the 13 patients that underwent allogeneic BMT, sixpatients were in CR1 at the time of transplantation. Three ofthese six patients are alive and leukaemia-free and no relapseshave been observed. Of the seven patients who were not in CR1at the time of allogeneic BMT, only one patient (an ABL inCR2) is alive and well. Six of the seven patients receiving anautologous BMT were in CR1 and three of these patients arelong-term survivors; one patient underwent autologous BMTin CR3 and died of CMV pneumonia 3 months later.



Fig 2. Kaplan-Meier estimates of thecumulative risk of leukaemia progression forpatients receiving conventional chemotherapy(CC) or bone marrow transplantation (BMT)for acute leukaemia with 11q23abnormalities.

Fig 1. Kaplan-Meier estimates of event-freesurvival for patients receiving conventionalchemotherapy (CC; n ¼ 12) or bone marrowtransplantation (BMT; n ¼ 20) for acuteleukaemia with 11q23 chromosomalabnormalities.



DISCUSSION

Whether or not BMT offers a survival advantage overstandard chemotherapy for high-risk patients with acuteleukaemia in CR1 remains unclear. It has been suggestedthat the lower relapse risk associated with BMT in thispatient population is offset by a higher TRM resulting in nosurvival advantage (Zander et al, 1988; Gale et al, 1989;Zhang et al, 1995). However, these studies did not reliablyinclude cytogenetic data as a variable predictive of diseaseoutcome. Indeed, there are few reports examining the issueof whether BMT can overcome poor-risk cytogenetics, amajor adverse prognostic factor in adult leukaemia.

The influence of cytogenetics on outcome after treatmentwith conventional chemotherapy in acute leukaemia hasbeen well documented. Patients with acute leukaemia and akaryotype that includes an abnormality of chromosome11q23 have been regarded as having a poor prognosis with alow CR rate (50–60%), a high relapse rate and an inferiorEFS (<20%) (Arthur et al, 1989; Schiffer et al, 1989; Marosiet al, 1992; Stasi et al, 1993; Harbott et al, 1998; Johanssonet al, 1998; Moorman et al, 1998; Swansbury et al, 1998).Previous reports have failed to convincingly show that HDCTand BMT can improve results in this poor-risk group.

Utilizing registry data, the IBMTR attempted to address theimpact of cytogenetic abnormalities on outcome afterallogeneic BMT for adult patients with AML in CR1 (Galeet al, 1995). Patients with t(9;22), ¹5, ¹7, and del(11q)were defined as having poor-risk cytogenetics. Even afterBMT, this subgroup had a high relapse rate (58%) and a lowEFS (24%), suggesting that HDCT and BMT does not alter theprognosis conferred by poor-risk cytogenetics. This conclu-sion has been challenged by a reported 49% 2-year EFS inpatients undergoing unrelated donor BMT for Philadelphiachromosome-positive ALL, a disorder with a very poorprognosis when treated with conventional chemotherapy(Sierra et al, 1997). In a subsequent study performed by theEBMT, cytogenetics did appear to influence outcome afterboth allogeneic and autologous BMT for AML in CR1(Ferrant et al, 1997). Of interest, patients in this multicentrestudy with abnormalities of 11q23 were found to be poor-risk with allogeneic BMT but standard-risk with autologousBMT due to a higher risk of relapse in the former group.Although we observed a similar result in our t(9;11) cohort(no survivors after allogeneic BMT [n ¼ 4] and bothautologous BMT patients alive and disease-free), this findingprobably reflects patient selection. Indeed, the median timefrom diagnosis and CR1 to BMT for patients in the EBMTstudy was significantly longer in the autologous BMT group,suggesting some time censoring occurred.

Although others have found that BMT may be successfulin patients with acute leukaemia and abnormalities of11q23 (Copelan et al, 1987; Allouche et al, 1989; Emmingeret al, 1991), our report is the first single-centre studycomparing results of conventional chemotherapy with thoseof BMT in this cytogenetic subgroup. The outcome ofpatients receiving conventional chemotherapy alone wasdismal, with only one of 12 patients surviving. This onepatient was young (25 years) and had t(9;11) with an

additional abnormality, both factors that may have had afavourable influence on outcome (Swansbury et al, 1998).Refractory and recurrent disease was the primary reason fortreatment failure with CC, confirming previous reports thatchemotherapy alone is rarely curative for such patients.Compared with the CC group, patients who underwent BMThad an improved EFS at 34%, despite the expected increasein TRM, due to a lower risk of relapse.

It has become apparent that treatment outcome for bothCC and BMT patients may be dependent upon the specific11q23 abnormality observed. A recent report suggests thatadults with AML and t(9;11) had a superior outcome toother 11q23 abnormalities when patients were treated withintensive consolidation (Mrozek et al, 1997). In ourexperience, patients with t(9;11) may be long-term survivorsafter CC (one of four patients alive) and may do particularlywell with autologous BMT in CR1 (both patients alive). Thepoor results seen with allogeneic BMT in patients witht(9;11) are difficult to interpret, since all four patients werenot in CR1 at the time of BMT, three patients had tAML andthe other patient was refractory to CC.

The results that we observed with BMT in patients withdel(11)(q23) are encouraging. Three patients are long-termsurvivors (two patients after allogeneic BMT and one patientafter autologous BMT); all four patients with del(11)(q23)who were given CC have died, a result that is consistent withpreviously reported experience (Harbott et al, 1998).Unfortunately, none of the patients in our cohort witht(4;11) benefited from HDCT and BMT, with both relapseand TRM contributing to an unsuccessful outcome.Despite earlier paediatric reports which appeared promising(Copelan et al, 1987; Allouche et al, 1989; Emminger et al,1991), BMT may not improve outcome in adults with thiscytogenetic abnormality (Johansson et al, 1998).

When comparing the patient characteristics of the CC andBMT groups in our study, it is evident that the median ageand presenting WBC count were both higher in the CCpatients. The former is related, in part, to the age restrictionsfor BMT at our institution. However, it is also worth notingthat more patients in the BMT group had tAML and eightpatients were not in CR1 at BMT, both independent poorprognostic factors that may have reduced EFS in this group.Indeed, there were no relapses amongst the six patientsreceiving allogeneic BMT in CR1; three of the four survivorsof allogeneic BMT were in CR1 at the time of transplant.These significant differences between the CC and BMTgroups place some limitation on the comparison of treatmentoutcomes in our study. A randomized trial might provide amore definitive result but seems unlikely to be done given thepoor results seen with conventional chemotherapy.

The successful outcomes after purged autologous BMT inour study were somewhat unexpected; the effectiveness ofautologous BMT in poor-prognosis acute leukaemia has beenlimited by high relapse rates, approaching 70% in high-riskALL (Gilmore et al, 1991). Despite a variety of marrowpurging techniques and the use of post-BMT immunomo-dulatory strategies aimed at reducing the risk of diseaserecurrence, relapse remains the most common cause offailure following autologous BMT (Kersey et al, 1987;

Gilmore et al, 1991). Perhaps surprisingly, three of sevenpatients who received purged autologous BMT in our study,including one patient with tAML, are alive and remain inremission. It is evident that results of CC treatment oftAML with 11q23 abnormalities have been unsatisfactory(Secker-Walker et al, 1998). Although the patient numbersare small, follow-up is sufficiently long to concludethat HDCT and 4-HC or IL-2 purged autologous BMTcan be a curative treatment option for some patients withde novo or treatment-related acute leukaemia with poor-riskcytogenetics.

In summary, a significant proportion of patients withacute leukaemia associated with 11q23 cytogeneticabnormalities can experience long-term EFS with HDCTand BMT. Given that the probability of cure with conven-tional chemotherapy in this patient subgroup in ourexperience is <10%, the outcome with BMT is encouraging.Although this retrospective analysis should be interpretedwith caution, the results support that HDCT and BMT shouldbe considered the treatment of choice for all suitablepatients with acute leukaemia and 11q23 chromosomalabnormalities.

ACKNOWLEDGMENTS

The authors acknowledge the contribution of the medicaland nursing staff of East 6 Ward and Medical Day Care at theVancouver Hospital and Health Sciences Centre, the staff of 6West Ward at the British Columbia Cancer Agency, and MsShawna Lumer for preparation of the manuscript and tables.

REFERENCES

Allouche, M., Georgoulias, V., Bourinbaiar, A., Dupuy, I.,Clemenceau, C., Gaget, H., Mathe, G. & Jasmin, C. (1989) Bonemarrow transplantation following busulphan, cyclophosphamideand high-dose cytarabine–arabinoside as treatment for infantswith translocation (4;11) acute leukaemia. British Journal ofHaematology, 65, 411–418.

Arthur, D.C., Berger, R. & Golomb, H.M. (1989) The clinicalsignificance of karyotype in acute myelogenous leukemia. CancerGenetics and Cytogenetics, 40, 203–216.

Attal, M., Huguet, F., Rubie, H., Huynh, A., Charlet, J.P., Payen, J.L.,Voigt, J.J., Brousset, P., Selves, J., Muller, C., Pris, J. & Laurent, G.(1992) Prevention of hepatic veno-occlusive disease after bonemarrow transplantation by continuous infusion of low-doseheparin: a prospective, randomized trial. Blood, 79, 2834–2840.

Bloomfield, C.D., Goldman, A.I., Alimena, G., Berger, R.,Borgstrom, G.H., Brandt, L., Catovsky, D., de la Chapelle, A.,Dewald, G.W., Garson, O.M., Garwicz, S., Golomb, H.M.,Hossfeld, D.K., Lawler, D.S., Mitelman, F., Nilsson, P., Pierre, R.V.,Philip, P., Prigogina, E., Rowley, H.D., Sakurai, M., Sandberg, A.A.,Secker Walker, L.M., Tricot, G., Van Den Berghe, H., VanOrshoven, A., Vuopio, P. & Whang-Peng, J. (1986) Chromosomalabnormalities identify high-risk and low-risk patients with acutelymphoblastic leukemia. Blood, 67, 415–420.

Bredeson, C.N., Barnett, M.J., Horsman, D.E., Dalal, B.I., Ragaz, J.& Phillips, G.L. (1993) Therapy-related acute myelogenousleukemia associated with 11q23 chromosomal abnormalitiesand topoisomerase II inhibitors: report of four additional cases andbrief commentary. Leukemia and Lymphoma, 11, 141–145.

Buchner, T. & Heinecke, A. (1996) The role of prognostic factors inacute myeloid leukemia. Leukemia, 10, s28–s29.

Chen, C.-S., Sorensen, P.H.B., Domer, P.H., Reaman, G.H.,Korsmeyer, S.J., Heerema, N.A., Hammond, G.D. & Kersey, J.H.(1993) Molecular rearrangements on chromosome 11q23 pre-dominate in infant acute lymphoblastic leukemia and areassociated with specific biologic variables and poor outcome.Blood, 81, 2386–2393.

Cimino, G., Rapanotti, M.C., Rivolta, A., Lo Coco, F., D’Arcangelo, E.,Rondelli, R., Basso, G., Barisone, E., Rosanda, C., Santostasi, T.,Canaani, E., Masera, G., Mandelli, F. & Biondi, A. (1995)Prognostic relevance of ALL-1 gene rearrangement in infantacute leukemias. Leukemia, 9, 391–395.

Copelan, E.A., Kapoor, N., Murcek, M., Theil, K. & Tutschka, P.J.(1987) Marrow transplantation following busulphan and cyclo-phosphamide as treatment for translocation (4;11) acute leukae-mia. British Journal of Haematology, 70, 127–128.

Cox, D.R. (1972) Regression models and life tables. Journal of theRoyal Statistical Society (B), 34, 187–220.

Emminger, W., Emminger-Schmidmeier, W., Ambros, P., Haas, O.A.,Hocker, P., Koller, U. & Gadner, H. (1991) Unusually long survivalafter autografting in second partial remission of translocationt(4;11) acute infant leukemia. Bone Marrow Transplantation, 8,311–313.

Fenaux, P., Preudhomme, C., Lai, J.L., Morel, P., Beuscart, R. &Bauters, F. (1989) Cytogenetics and their prognostic value in denovo acute myeloid leukaemia: a report on 283 cases. BritishJournal of Haematology, 73, 61–67.

Ferrant, A., Labopin, M., Frassoni, F., Prentice, H.G., Cahn, J.Y.,Blaise, D., Reiffers, J., Visani, G., Sanz, M.A., Boogaerts, M.A.,Lowenberg, B. & Gorin, N.C. (1997) Karyotype in acutemyeloblastic leukemia: prognostic significance for bone marrowtransplantation in first remission. A European Group for Bloodand Marrow Transplantation study. Blood, 90, 2931–2938.

Forman, S.J., Chao, N., Niland, J.C., Levitt, L., Champlin, R., Gajewski,J., Lee, J., Schiller, G., Nantel, S., Barnett, M., Levine, A., Saez, R.,Phillips, G. & Blume, K.G. (1995) Intensive chemotherapy or bonemarrow transplantation for adult ALL in first complete remission: aphase III trial. Blood, 86, Abstract 2453.

Gale, R.P., Horowitz, M.M., Biggs, J.C., Herzig, R.H., Kersey, J.H.,Marmont, A.M., Masaoka, T., Rimm, A.A., Speck, B., Weiner, R.S.,Zwaan, F.E. & Bortin M.M. (1989) Transplant or chemotherapy inacute myelogenous leukaemia. Lancet, i, 1119–1122.

Gale, R.P., Horowitz, M.M., Weiner, R.S., Ash, R.C., Atkinson, K.,Babu, R., Dicke, K.A., Klein, J.P., Lowenberg, B., Reiffers, J.,Rimm, A.A., Rowlings, P.A., Sandberg, A.A., Sobocinski, K.A.,Veum-Stone, J. & Bortin, M.M. (1995) Impact of cytogeneticabnormalities on outcome of bone marrow transplants in acutemyelogenous leukemia in first remission. Bone Marrow Transplan-tation, 16, 203–208.

Gilmore, M.J.M.L., Hamon, M.D., Prentice, H.G., Katz, F., Slaper-Cortenbach, I.C.M., Hunter, A.E., Gandhi, L., Brenner, M.K.,Hoffbrand, A.V., Mehta, A.B., Secker-Walker, L.M., Skeggs, D. &Collis, C.H. (1991) Failure of purged autologous bone marrowtransplantation in high risk acute lymphoblastic leukemia in firstcomplete remission. Bone Marrow Transplantation, 8, 19–26.

Harbott, J., Mancini, M., Verellen-Dumoulin, C.H., Moorman, A.V. &Secker-Walker, L.M. (1998) Hematological malignancies with adeletion of 11q23: cytogenetic and clinical aspects. Leukemia, 12,823–827.

Heerema, N.A., Arthur, D.C., Sather, H., Albo, V., Feusner, J.,Lange, B.J., Steinherz, P.G., Zeltzer, P., Hammond, D. &Reaman, G.H. (1994) Cytogenetic features of infants less than12 months of age at diagnosis of acute lymphoblastic leukemia:





impact of the 11q23 breakpoint on outcome. A report of theChildrens Cancer Group. Blood, 83, 2274–2284.

Heim, S. & Mitelman, F. (1992) Cytogenetic analysis in the diagnosisof acute leukemia. Cancer, 70, 1701–1709.

ISCN (1991) Guidelines for Cancer Cytogenetics: Supplement to AnInternational System for Human Cytogenetic Nomenclature (ed. by F.Mitelman). S. Karger, Basel.

Johansson, B., Moorman, A.V., Haas, O.A., Watmore, A.E.,Cheung, K.L., Swanton, S. & Secker-Walker, L.M. (1998)Hematologic, malignancies with t(4;11)(q21;q23): a cytogenetic,morphologic, immunophenotypic and clinical study of 183 cases.Leukemia, 12, 779–787.

Kaplan, E.L. & Meier, P. (1958) Nonparametric estimation fromincomplete observations. Journal of the American StatisticalAssociation, 53, 457–481.

Kersey, J.H., Weisdorf, D., Nesbit, M.E., LeBien, T.W., Woods, W.G.,McGlave, P.B., Kim, T., Vallera, D.A., Goldman, A.I., Bostrom, B.,Hurd, D. & Ramsay, N.K.C. (1987) Comparison of autologous andallogeneic bone marrow transplantation for treatment of high-riskrefractory acute lymphoblastic leukemia. New England Journal ofMedicine, 317, 461–467.

Klingemann, H.-G., Eaves, C.J., Barnett, M.J., Eaves, A.C., Hogge, D.E.,Nantel, S.H., Reece, D.E., Shepherd, J.D., Sutherland, H.J. &Phillips, G.L. (1994) Transplantation of patients with highrisk acute myeloid leukemia in first remission with autologousmarrow cultured in interleukin-2 followed by interleukin-2administration. Bone Marrow Transplantation, 14, 389–396.

Marosi, C., Koller, U., Koller-Weber, E., Schwarzinger, I., Schneider, B.,Jager, U., Vahls, P., Nowotny, H., Pirc-Danoewinata, H., Steger, G.,Kreiner, G., Wagner, B., Lechner, K., Lutz, D., Bettelheim, P. &Haas, O.A. (1992) Prognostic impact of karyotype and immuno-logic phenotype in 125 adult patients with de novo AML. CancerGenetics and Cytogenetics, 61, 14–25.

Moorman, A.V., Hagemeijer, A., Charrin, C., Rieder, H. & Secker-Walker, L.M. (1998) The translocations, t(11;19)(q23;p13.1) andt(11;19)(q23;p13.3): a cytogenetic and clinical profile of 53patients. Leukemia, 12, 805–810.

Mrozek, K., Heinonen, K., Lawrence, D., Carroll, A.J., Koduru, P.R.K.,Rao, K.W., Strout, M., Hutchison, R.E., Moore, J.O., Mayer, R.J.,Schiffer, C.A. & Bloomfield, C.D. (1997) Adult patients with denovo acute myeloid leukemia and t(9;11)(p22;q23) have asuperior outcome to patients with other translocations involvingband 11q23: a Cancer and Leukemia Group B study. Blood, 90,4532–4538.

Phillips, G.L., Nevill, T.J., Spinelli, J.J., Nantel, S.H., Klingemann, H.-G., Barnett, M.J., Shepherd, J.D., Chan, K., Meharchand, J.M.,Sutherland, H.J., Reece, D.E. & Messner, H.A. (1995) Prophylaxisfor acute graft-versus-host disease following unrelated-donorbone marrow transplantation. Bone Marrow Transplantation, 15,213–219.

Schiffer, C.A., Lee, E.J. & Tomiyasu, T. (1989) Prognostic impact ofcytogenetic abnormalities in patients with de novo acutenonlymphocytic leukemia. Blood, 73, 263–270.

Secker-Walker, L.M. (1998) General report on the European UnionConcerted Action Workshop on 11q23, London, UK, May 1997.Leukemia, 12, 776–778.

Secker-Walker, L.M., Chessells, J.M., Stewart, E.L., Swansbury, G.J.,Richards, S. & Lawler, S.D. (1989) Chromosomes and otherprognostic factors in acute lymphoblastic leukaemia: a long-termfollow-up. British Journal of Haematology, 72, 336–342.

Secker-Walker, L.M., Moorman, A.V., Bain, B.J. & Mehta, A.B. (1998)Secondary acute leukemia and myelodysplastic syndrome with11q23 abnormalities. Leukemia, 12, 840–844.

Shepherd, J.D., Pringle, L.E., Barnett, M.J., Klingemann, H.-G.,

Reece, D.E. & Phillips, G.L. (1991) Mesna versus hyperhydrationfor the prevention of cyclophosphamide-induced hemorrhagiccystitis in bone marrow transplantation. Journal of ClinicalOncology, 9, 2016–2020.

Shepherd, J.D., Reece, D.E., Barnett, M.J., Klingemann, H.-G.,Nantel, S.H., Sutherland, H.J. & Phillips, G.L. (1993) Inductiontherapy for acute myelogenous leukemia in patients over 60 yearswith intermediate-dose cytosine arabinoside, mitoxantrone andetoposide. Leukemia and Lymphoma, 9, 211–215.

Shepherd, J.D., Reece, D.E., Barnett, M.J., Nantel, S.H., Klingemann, H.-G.,Sutherland, H.J., Spinelli, J.J. & Phillips, G.L. (1994) Inductionchemotherapy with continuous infusion ara-C, mitoxantrone,and VP-16 for patients < 65 with acute myeloid leukemia.Proceedings of the American Society of Clinical Oncology, 13, Abstract1007.

Shepherd, J.D., Reece, D.E., Shore, T.B., Barnett, M.J., Bow, E.J.,Nantel, S.H., Sutherland, H.J., Brockington, D.A., Fung, H.C.,Spinelli, J.J., Klingemann, H.-G. & Phillips, G.L. (1995) Highdose cytarabine, daunorubicin, and etoposide induction andconsolidation therapy of acute myeloid leukemia in adults < 60years of age. Clinical and Investigative Medicine, 18, (Suppl. B),Abstract 611.

Shepherd, J.D., Shore, T.B., Reece, D.E., Barnett, M.J., Klingemann,H.-G., Buskard, N.A. & Phillips, G.L. (1988) Cyclosporine andmethylprednisolone for prophylaxis of acute graft-versus-hostdisease. Bone Marrow Transplantation, 3, 553–558.

Sierra, J., Radich, J., Hansen, J.A., Martin, P.J., Petersdorf, E.W.,Bjerke, J., Bryant, E., Nash, R.A., Sanders, J.E., Storb, R.,Sullivan, K.M., Appelbaum, F.R. & Anasetti, C. (1997) Marrowtransplants from unrelated donors for treatment of Philadelphiachromosome-positive acute lymphoblastic leukemia. Blood, 90,1410–1414.

Simpson, D.R., Phillips, G.L., Thomas, T.E., Lansdorp, P.M.,Barnett, M.J., Nantel, S.H., Shepherd, J.D., Shultz, K.R.,Davis, J.H., Sutherland, H.J., Hogge, D.E., Toze, C.L. & Klingemann,H. (1996) Ex vivo depletion of T-lymphocytes by immuno-magnetic beads to decrease graft-versus-host disease afterunrelated donor marrow transplantation. Blood, 88, Abstract1667.

Sorensen, P.H.B., Chen, C.-S., Smith, F.O., Arthur, D.A., Domer, P.H.,Bernstein, I.D., Korsmeyer, S.J., Hammond, G.D. & Kersey, J.H.(1994) Molecular rearrangements of the MLL gene are present inmost cases of infant acute myeloid leukemia are stronglycorrelated with monocytic or myelomonocytic phenotypes.Journal of Clinical Investigation, 93, 429–437.

Stasi, R., Del-Poeta, G. & Masi, M. (1993) Incidence of chromosomeabnormalities and clinical significance of karyotype in denovo acute myeloid leukemia. Cancer Genetics and Cytogenetics,67, 28–34.

Storb, R., Deeg, H.J., Whitehead, J., Appelbaum, F., Beatty, P.,Bensinger, W., Buckner, C.D., Clift, R., Doney, K., Farewell, V.,Hansen, J., Hill, R., Lum, L., Martin, P., McGuffin, R., Sanders, J.,Stewart, P., Sullivan, K., Witherspoon, R., Yee, G. & Thomas, E.D.(1986) Methotrexate and cyclosporine compared with cyclo-sporine alone for prophylaxis of acute graft versus host diseaseafter marrow transplantation for leukemia. New England Journal ofMedicine, 314, 729–735.

Storb, R., Pepe, M., Anasetti, C., Appelbaum, F.R., Beatty, P.,Doney, K., Martin, P., Stewart, P., Sullivan, K.M., Witherspoon, R.,Bensinger, W., Buckner, C.D., Clift, R., Hansen, J., Longton, G.,Loughran, T., Petersen, F.B., Singer, J., Sanders, J. & Thomas, E.D.(1990) What role for prednisone in prevention of acute graft-versus-host disease in patients undergoing marrow transplants?Blood, 76, 1037–1045.

Swansbury, G.J., Slater, R., Bain, B.J., Moorman, A.V. & Secker-Walker, L.M. (1998) Hematological malignancies witht(9;11)(p21-22;q23): a laboratory and clinical study of 125cases. Leukemia, 12, 792–800.

Taki, T., Ida, K., Bessho, F., Hanada, R., Kikuchi, A., Yamamoto, K.,Sako, M., Tsuchida, M., Seto, M., Ueda, R. & Hayashi, Y. (1996)Frequency and clinical significance of the MLL gene rearrange-ments in infant acute leukemia. Leukemia, 10, 1303–1307.

Walters, R., Kantarjian, H.M., Keating, M.J., Estey, E.H., Trujillo, J.,Cork, A., McCredie, K.B. & Reireich, E.J. (1990) The importance ofcytogenetic studies in adult acute lymphocytic leukemia. AmericanJournal of Medicine, 89, 579–587.

Yeager, A.M., Kaizer, H., Santos, G.W., Saral, R., Colvin, O.M.,Stuart, R.K., Braine, H.G., Burke, P.J., Ambinder, R.F., Burns, W.H.,Fuller, D.J., Davis, J.M., Karp, J.E., May, W.S., Rowley, S.D.,Sensenbrenner, L.L., Vogelsang, G.B. & Wingard, J.R. (1986)Autologous bone marrow transplantation in patients with acute

nonlymphocytic leukemia, using ex vivo marrow treatment with4-hydroperoxycyclophosphamide. New England Journal of Medicine,315, 141–147.

Zander, A.R., Keating, M., Dicke, K., Dixon, D., Pierce, S.,Jagannath, S., Peters, L., Horwitz, L., Cockerill, K., Spitzer, G.,Vellekoop, L., Kantarjian, H., Walters, R., McCredie, K. & Freireich,E.J. (1988) A comparison of marrow transplantation withchemotherapy for adults with acute leukemia of poorprognosis in first complete remission. Journal of Clinical Oncology,6, 1548–1557.

Zhang, M.-J., Hoelzer, D., Horowitz, M.M., Gale, R.P., Messerer, D.,Klein, J.P., Loffler, H., Sobocinski, K.A., Thiel, E. & Weisdorf, D.J.(1995) Long-term follow-up of adults with acute lymphoblasticleukemia in first remission treated with chemotherapy orbone marrow transplantation. Annals of Internal Medicine, 123,428–431.



Bone marrow transplantation for adults with acute leukaemia and 11q23 chromosomal abnormalities

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