Acute Lymphoblastic Leukaemia High-Dose Melphalan And

Bone Marrow Transplantation (2004) 33, 1107–1114 & 2004 Nature Publishing Group All rights reserved 0268-3369/04 $25.00 www.nature.com/bmt

Acute lymphoblastic leukaemia High-dose melphalan and autotransplantation followed by post transplant maintenance chemotherapy for acute lymphoblastic leukemia in first remission

J Mehta1, R Powles, B Sirohi, J Treleaven, S Kulkarni and S Singhal1

Leukaemia Unit, The Royal Marsden Hospital, Surrey, UK

Summary: We have attempted to improve1 the relatively poor results of high-dose therapy and autotransplantation in adult A total of 65 adults with acute lymphoblastic leukemia acute lymphoblastic leukemia (ALL)2–15 by administering (ALL)received 200 mg/m 2 melphalan and an autograft in maintenance chemotherapy with 6-mercaptopurine (6MP), first remission, with a plan to receive 6-mercaptopurine methotrexate (MTX) and vincristine–prednisone (VP) for 2 (6MP), methotrexate (MTX), and vincristine–prednisone years after transplantation. The results, using melphalan (VP)for 2 years afterwards. There was no transplant- with total-body irradiation (TBI) and autologous bone related mortality. In all, 69% of patients received 6MP, marrow initially and high-dose melphalan alone with 54% received MTX, and 49% received VP. The blood-derived stem cells subsequently, have been very cumulative incidence of relapse at 5 years was 52%. encouraging and strongly suggest that post transplant The 5-year probabilities of disease-free (DFS)and overall maintenance chemotherapy is useful.1 (OS)survival were 48 and 55%. Age 430 years, 44 Our previous report on the outcome of this strategy weeks to attain remission, and t(9;22)or t(4;11) included patients conditioned with melphalan-TBI as well karyotypes were adverse prognostic features. Patients as melphalan, and some patients who had received purged with 0 (standard risk), 1 (intermediate risk), and 2–3 (high marrow.1 The current report includes a homogeneously risk)adverse features had 5-year cumulative incidences of treated group of 65 patients conditioned with high-dose relapse of 19, 59, and 100% (Po0.0001), and 5-year melphalan (200 mg/m2) and receiving unpurged blood- probabilities of DFS of 80, 41, and 0% (Po0.0001). The derived stem cells; 42 of whom were included in the 5-year probabilities of DFS for patients receiving 0, 1, 2, previous report. The report provides longer follow-up (just and 3 maintenance therapy agents were 19, 40, 51, and over 10 years) and assesses applicability of this TBI-free 70% (P ¼ 0.0097). Maintenance therapy intensity was an treatment modality in older patients. Also, a significantly independent determinant of outcome in Cox analysis. larger proportion of patients in this group were treated with These data show that a high-dose melphalan-based a more intensive remission-induction and intensification autograft is safe and could be widely applicable in ALL regimen; allowing assessment of the contribution of the in first remission, and that maintenance chemotherapy intensity of the pre-transplant conventional therapy to very likely contributes to improved outcome of auto- outcome. grafted ALL patients. Bone Marrow Transplantation (2004) 33, 1107–1114. Patients and methods doi:10.1038/sj.bmt.1704517 Published online 12 April 2004 All data were gathered prospectively.16 All consecutive Keywords: 6-mercaptopurine; acute lymphoblastic patients over the age of 15 years who were autografted for leukemia; autotransplantation; high-dose melphalan; ALL in first CR between January 1993 and February 2003 methotrexate; prednisone; vincristine at the Leukaemia Unit of the Royal Marsden Hospital were included. Table 1 shows the patient characteristics. Autotransplantation was performed as the procedure of choice irrespective of the availability of matched sibling donors as part of our ‘sequential high-dose therapy’ approach; the idea being to perform a low-morbidity Correspondence: Dr J Mehta, 676 N St Clair Street, Suite 850, Chicago, autograft as the first step – followed by a salvage allograft IL 60611, USA; E-mail: [email protected] in second remission in relapsing patients. Exceptions to the 1Current address: Hematopoietic Stem Cell Transplant Program, sequential high-dose therapy approach included patients Division of Hematology/Oncology, The Feinberg School of Medicine, taking 48 weeks to attain CR, those with CNS disease and The Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. t(9;22) – who were allografted in first CR if an HLA- Received 10 November 2003; accepted 22 February 2004 matched sibling donor was available. Patients with t(9;22) Published online 12 April 2004 were preferentially transplanted from unrelated donors in PBSCT for ALL in CR1 J Mehta et al 1108 Table 1 Patient characteristics (n ¼ 65) chemotherapy protocol or similar combination induction- intensification. In total, 47patients received phase I Female 29 (45%) (weeks 1–4; vincristine 1.4 mg/m2  4, prednisolone 60 mg/ 2 2 Age (years) 32 (16–67) m  28, daunorubicin 60 mg/m  4, L-asparaginase 10000 U  10) and phase II (weeks 5–9; cyclophosphamide Presentation leukocyte count 5.7(0.1–602) 650 mg/m2  3, cytarabine 75 mg/m2  16, 6MP 60 mg/ 2 Karyotype m  28) induction therapy according to the United King- T(9;22)a 3 (5%) dom Medical Research Council’s adult UKALL XII t(4;11) 6 (9%) chemotherapy protocol, which is more intense. Induction Other clonal 28 (43%) chemotherapy was administered either at the Royal Normal 22 (34%) Marsden Hospital (n ¼ 37) or at other regional hospitals Not available 6 (9%) (n ¼ 28) from where the patients were referred for CNS disease at presentation 2 (3%) autografting in first CR.

Immunophenotype B 51 (78%) Central nervous system prophylaxis T 8 (12%) Null 5 (8%) Patients received 2400 cGy cranial irradiation in 15 frac- Unknown 1 (2%) tions after hematologic recovery from intensification or phase II induction and before leukapheresis. No patient Induction therapy received testicular irradiation. Patients without CNS MRC UKALL X (or similar) 18 (28%) MRC UKALL XII (or similar) 47(72%) disease received six injections of intrathecal MTX (usually 15 mg) over the treatment period prior to the CR-transplant interval (weeks) 16 (1–90) transplant, and the two with CNS disease received triple intrathecal chemotherapy with MTX (15 mg), cytarabine Adverse prognostic factors Age 430 years 33 (51%) (30 mg), and hydrocortisone (100 mg) until six consecutive t(4;11) or t(9;22) 9 (14%) spinal fluid samples were free of disease. No intrathecal Time to CR 44 weeks 15 (23%) chemotherapy was administered post transplant based upon our observation that isolated CNS recurrence is Risk stratification exceedingly rare after transplantation in first remission Standard (0 adverse factors) 23 (35%) 17 Intermediate (1 adverse factor) 25 (38%) acute leukemia. High (2 adverse factors) 17(26%) Peripheral blood stem cell harvest aSix patients had Ph+ disease detected on conventional cytogenetic studies (G-banding). RT-PCR was not performed routinely. It is therefore possible The first seven patients received G-CSF (filgrastim) at the that the actual proportion of patients with Ph+ disease may be higher. dose of 125 mg/m2 subcutaneously q12 h starting 2 weeks after a back-up bone marrow harvest for a period of 7days. Stem cells were harvested on days 5–8 (4 consecutive days). the absence of a suitable sibling donor – which explains the The next 58 patients received 12–16 mg/kg filgrastim low number of patients with Ph þ disease in this series. subcutaneously q24 h on days 1–4, and stem cells were Patients with lymphoid blast crisis of chronic myeloid harvested on days 4 and 5. Leukapheresis was performed leukemia were not included. Patients with biphenotypic on a Cobe Spectra (Cobe Industries, Lakewood, CO, USA) disease (presence of myeloid markers) and those with continuous-flow cell separator with 150–200% of the Burkitt-type disease (FAB type L3) received different initial patient’s calculated blood volume being processed at each chemotherapy and were excluded. The transplants were session. performed as part of the standard therapy of adult ALL, and were not performed on a clinical protocol evaluating Cryopreservation and infusion the utility of transplantation. All research protocols were approved by the local institutional review board. All Cells were cryopreserved with 10% dimethylsulfoxide using patients gave informed consent for transplantation. a controlled-rate freezer and were stored in the vapor phase of liquid nitrogen. The cells were rapidly thawed in a water 1 Induction chemotherapy bath at 37 C by the bedside and infused within 2 weeks of collection. A total of 18 patients received induction (weeks 1–4; vincristine 1.5 mg/m2  4, prednisolone 40 mg/m2  28, 2 High-dose therapy and transplant daunorubicin 45 mg/m  2, L-asparaginase 6000 U/ m2  9) and early intensification therapy (weeks 5–6; The conditioning regimen comprised a single dose of vincristine 1.5 mg/m2  1, prednisolone 40 mg/m2  7, dau- 200 mg/m2 melphalan with hydration on day À1. All norubicin 45 mg/m2  2, etoposide 100 mg/m2  5, cytara- cryopreserved cells (excluding back-up marrow) were bine 100 mg/m2  10, 6-thioguanine 80 mg/m2  5) infused on day 0; 24 h after the administration of according to the United Kingdom Medical Research melphalan. No growth factors were administered post Council’s adult UKALL X Regimen B combination transplant to accelerate myeloid recovery.

Bone Marrow Transplantation PBSCT for ALL in CR1 J Mehta et al 1109 Supportive care Table 2 Outcome by type of adverse feature All patients were treated in protective isolation in rooms Relapse DFS OS with positive-pressure ventilation. Blood products trans- Age fused were not screened for cytomegalovirus (CMV) 430 years 66 (50–85) 34 (17–52) 38 (20–55) antibody in CMV-seropositive patients. Antibiotic prophy- p30 years 33 (19–59) 66 (46–86) 79 (62–96) laxis and therapy varied in accordance with prevalent P 0.022 0.0170.008 practices and research programs. Broad-spectrum antibio- Karyotype tic therapy was started for fever in the neutropenic phase. t(4;11) or t(9;22) 100 0 17(0–44) Irradiated random platelets were transfused to maintain the Other 45 (33–62) 54 (39–69) 61 (47–76) 9 platelet count at 20 Â 10 /l, and packed cells to maintain P o0.0001 o0.0001 0.0007 the hemoglobin at 100 g/l. Time to CR 44 weeks 100 0 16 (0–42) Maintenance chemotherapy p4 weeks 39 (27–57) 60 (45–75) 61 (46–75) P 0.001 0.0005 0.003 Maintenance chemotherapy with daily 6MP was usually begun when the leukocytes reached 3 Â 109/l and the The relapse figures represent cumulative incidences at 5 years, and the 9 disease-free (DFS) and overall survival (OS) figures, actuarial 5-year platelets 100 Â 10 /l, and was continued for 2 years. probabilities. Commencement of chemotherapy was not delayed by any factor except for poor hematologic recovery, relapse or ongoing medical problems (eg interstital pneumonitis), The disease risk stratification was based upon age, which could potentially be exacerbated by starting che- cytogenetics, and the time taken to attain CR (Table 2), motherapy. Therapy was started with 25 mg 6MP and this and was a modification of the German classification was increased weekly or fortnightly in 25–50 mg steps. proposed by Hoelzer et al.18 The following factors were Weekly oral MTX at the dose of 5 mg (increasing in 2.5– analyzed in Cox proportional-hazards regression models 5 mg steps) was added when the dose of 6MP reached for effect on relapse, DFS, and OS: disease risk (standard vs 75 mg. All maintenance chemotherapy was discontinued 2 intermediate vs high), gender, CR-transplant interval (o4 years after starting the first agent (6MP). vs X4 months), type of induction therapy (UKALL X or Drug doses were adjusted to maintain the absolute similar vs UKALL XII or similar), WBC count at 9 neutrophil count over 1 Â 10 /l. Initially, monthly vincris- presentation ( 30 vs X30 Â 109/l), intensity of mainte- 2 o tine (1.4 mg/m ; maximum 2 mg) with prednisone (40 mg/ nance therapy (0/1 agent vs 2/3 agents, and 0 vs 1 vs 2 vs 3 2 m for a week) were administered to patients who could not agents), and immunophenotype (null vs others). tolerate myelosuppressive chemotherapy. After 1995, this Patient follow-up data are current through 5 August was added routinely to all patients. 2003 when the median, minimum, and maximum follow-up 2 The target doses of 6MP and MTX were 80 mg/m daily duration for surviving patients was 5.0, 0.5, and 10.5 years, 2 and 20 mg/m weekly, respectively. Patients received folic respectively. acid and prophylaxis for Pneumocystis carinii pneumonia with oral trimethoprim-sulfamethoxazole (if on 50% of the target 6MP dose) or aerosolized pentamidine (if on less Results than 50% of target 6MP dose) while on maintenance chemotherapy. Acyclovir was administered to prevent Neutrophil recovery to 0.5 Â 109/l was complete and reactivation of Varicella zoster virus. sustained in all patients. No patient died of treatment- related causes. Statistical analysis Maintenance chemotherapy The probabilities of disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan–Meier method, Table 3 shows the time to starting each maintenance and compared using the log-rank test. The cumulative chemotherapy agent and the proportion of patients starting incidence of relapse was estimated using other events (only it. None of the 20 patients who did not receive 6MP one in this series; a homicide) as competing risks. The received MTX, whereas eight received VP. significance of differences in relapse was calculated using A total of 12 patients received no maintenance the likelihood-ratio statistic for proportional-hazards re- chemotherapy at all because of relapse within 4 months gression models. (n ¼ 2), sluggish hematologic recovery terminating in One patient died in CR from homicide 8 months post relapse beyond 4 months (n ¼ 3), unknown/patient pre- transplant, and was censored at the time of death for OS ference (n ¼ 6), and noncompliance/lifestyle (n ¼ 1; this and DFS, and was considered to have had a competing patient eventually became a homicide victim). A total of 11 event for calculating the cumulative incidence of relapse. patients received only 1 drug (eight VP and three 6MP), 25 One patient was lost to follow-up after having relapsed less received two drugs (18 6MP-MTX and 76MP-VP), and 17 than 3 months after the transplant. This patient was received all the three drugs. considered to have died at the date of the last follow-up for Maintenance chemotherapy was tolerated well, and other estimating OS. than transient myelosuppression requiring dose reduction

Bone Marrow Transplantation PBSCT for ALL in CR1 J Mehta et al 1110 Table 3 Time to starting maintenance chemotherapy

Drug n Time to starting drug (days post transplant) Cumulative proportion of patients on therapy post transplant

120 days 6 months 1 year

6-Mercaptopurine 45 (69%) 56 (15–678) 55% 62% 65% Methotrexate 35 (54%) 173 (34–891) 25% 31% 42% Vincristine–prednisolone 32 (49%) 77 (24–692) 35% 42% 46%

or temporary cessation of therapy, no other side effects 1.0 were seen.

0.8 Relapse and post-relapse therapy A total of 30 patients (39%) relapsed at 2–49 months 0.6 38 alive (median 9); 18 in the first year, seven in the second year, four in the fourth, and one in the fifth. Figure 1 shows the Survival 0.4 35 alive in continuous first remission cumulative incidence of relapse. Relapsed disease was confirmed to be identical to the original disease in all cases, and no case of second or secondary leukemia was 0.2 seen. Not a single relapse was an isolated extramedullary event. 0.0 In all, 16 patients died of relapsed disease or toxicity of 024681012 salvage chemotherapy; 12 underwent allografts from an Years HLA-matched sibling (n ¼ 6) or unrelated (n ¼ 6) donor in Figure 2 Disease-free and overall survival. second CR, and two are alive in second CR (one awaiting an allograft, and one who refused an allograft and is 15 months into the second CR). The conditioning regimen for transplant; 35 in continuous first CR. Figure 2 shows the the allografts was 60 mg/kg etoposide and 1050 cGy single- actuarial probabilities of DFS and OS. fraction TBI, the marrow or blood stem cells were unmanipulated and graft-versus-host disease prophylaxis comprised cyclosporine and methotrexate. A total of 11 Identification of risk groups died of transplant-related toxicity (n 7) or relapse (n 4), ¼ ¼ The three adverse risk factors; age 430 years, t(9;22), and one is alive and well in second CR 9 years after an t(4;11), and 44 weeks to attain CR; affected relapse, DFS allograft from an HLA-identical sibling. and OS, significantly (Table 2). These factors could be combined to produce three risk groups (no adverse factor, one adverse factor, or 2–3 adverse factors). The relapse Overall and disease-free survival rates and DFS of these three groups were significantly As of 5 August 2003, 38 patients were alive and in different (Figures 3 and 4). remission 6 months to 10.5 years (median 5 years) after the The effect of maintenance chemotherapy 1.0 Among the 62 patients alive and well at 120 days, increasing intensity of maintenance chemotherapy was 0.8 associated with a significantly lower relapse rate (Figure 5) and higher DFS (Figure 6). This time point was chosen to eliminate patients relapsing early; before becoming eligible 0.6 30 relapses to receive maintenance chemotherapy.

Relapse 0.4 Cox analysis Table 4 shows the results of the multivariable analysis 0.2 adjusted by survival on day 120 post transplant. Standard- risk disease, more intense maintenance chemotherapy, and lower leukocyte count at presentation were associated with 0.0 higher DFS and OS. Since there were no treatment-related 024681012deaths, the analysis for factors affecting relapse yielded Years results that were identical to DFS. Expectedly, a longer Figure 1 Relapse. CR-transplant interval was associated with better outcome,

Bone Marrow Transplantation PBSCT for ALL in CR1 J Mehta et al 1111 1.0 1.0 Two or three (high risk): 13 of 17 relapsed No maintenance chemotherapy; 6 of 10 relapsed 0.8 0.8

0.6 1 drug; 6 of 11 relapsed 0.6 One (intermediate risk):

13 of 25 relapsed Relapse 0.4 2 drugs; 11 of 25 relapsed Relapse 0.4 0.2 3 drugs; 4 of 16 relapsed 0.2 None (standard risk): 0.0 4 of 23 relapsed 024681012 0.0 Years 024681012 Years Figure 5 The effect of maintenance chemotherapy on relapse rates in 62 patients alive and well on day 120 following the autograft (P ¼ 0.019). Figure 3 Relapse: effect of the number of adverse factors (Po0.0001).

1.0 None (standard risk): 1.0 19 of 23 in CCR 0.8 0.8 3 drugs; 12 of 16 alive in CCR

0.6 One (intermediate risk): 0.6 2 drugs; 14 of 25 alive in CCR 12 of 25 in CCR 0.4 0.4 1 drugs; 5 of 11 alive in CCR

Disease-free survival 0.2 0.2 Two or three (high risk): Disease-free survival 4 of 17 in CCR No maintenance chemotherapy; 4 of 10 alive in CCR 0.0 0.0 024681012 024681012 Years Years Figure 4 Disease-free survival: effect of the number of adverse factors Figure 6 The effect of maintenance chemotherapy on disease-free (Po0.0001). survival in 62 patients alive and well on day 120 following the autograft (P ¼ 0.0097). although the difference was only of borderline significance In the previous series, difference in outcome was based (P ¼ 0.09). upon 0–1 vs 2–3 maintenance chemotherapy agents. Here, there is a much clearer trend illustrating the benefit of each The effect of maintenance chemotherapy by risk group additional maintenance chemotherapy agent (Figures 5 and 6). We believe that short of a prospective randomized Table 5 shows that receiving more intensive maintenance study, this is the strongest evidence that can be obtained to chemotherapy made a significant difference to outcome in support the use of maintenance chemotherapy after the standard-risk group and a less-marked difference to autotransplantation in ALL. Owing to the retrospective patients in the intermediate-risk group. On the other nature of the observations, it should be emphasized that the hand, it made no difference to patients in the high-risk ability to start and tolerate maintenance chemotherapy group at all. may have been a marker for a better overall situation; with the better outcome being attributable more to the clinical Discussion situation than to maintenance chemotherapy. There were some treatment-related deaths in the previous These data confirm our previous findings that maintenance secondary to the use of TBI. The use of a radiation-free chemotherapy can be administered safely after autotrans- regimen has eliminated TRM completely. It is unclear if the plantation to patients with ALL.1 Despite the overlap in antileukemic efficacy of the procedure has been compro- patients between the previous series1 and this one, there are mised by this, although our previous experience suggests important differences between the two reports that provide that it has not.1 The interesting implication of the new insights into the utility of autotransplantation followed elimination of TBI is that it could make the procedure by maintenance chemotherapy. more easily applicable to much younger patients (no

Bone Marrow Transplantation PBSCT for ALL in CR1 J Mehta et al 1112 Table 4 Cox analysis of factors affecting relapse and disease-free survival independently among patients alive and disease-free on day 120

Outcome Variable Favorable Adverse Risk ratio (95% CI) P

DFS Maintenance therapy 2–3 agents 0–1 agent 0.27(0.10–0.68) 0.005 Disease risk Standard High 0.13 (0.04–0.45) 0.002 Intermediate High 0.34 (0.13–0.88) 0.026

OS Maintenance therapy 2–3 agents 0–1 agent 0.18 (0.06–0.50) 0.001 Disease risk Standard High 0.18 (0.05–0.69) 0.012 Intermediate High 0.37(0.13–1.07) 0.066 Presentation leukocyte count o30 X30 0.34 (0.13–0.88) 0.026

DFS Maintenance therapy 3 agents 0 agent 8.7(1.7–44.5) 0.009 3 agents 1 agent 5.5 (1.4–24.6) 0.015 3 agents 2 agents 2.2 (0.6–7.6) 0.22 Disease risk Standard High 0.12 (0.03–0.44) 0.001 Intermediate High 0.36 (0.13–0.95) 0.038 Presentation leukocyte count o30 X30 0.38 (0.15–0.97) 0.043

OS Maintenance therapy 3 agents 0 agent 13.4 (2.2–81.2) 0.005 3 agents 1 agent 5.5 (1.3–23.5) 0.021 3 agents 2 agents 1.3 (0.4–4.9) 0.67 Disease risk Standard High 0.17(0.05–0.67) 0.011 Intermediate High 0.37(0.13–1.06) 0.065 Presentation leukocyte count o30 X30 0.30 (0.12–0.78) 0.013

Table 5 The effect of maintenance chemotherapy by risk group

Risk Number of maintenance chemotherapy agents n Relapse (%) DFS (%) OS (%)

Standard 0–1 6 50 (22–100) 50 (10–90) 31 (0–79) 2–3 17 8 (1–51) 92 (78–100) 92 (78–100) P 0.024 0.004 0.001

Intermediate 0–1 11 64 (39–100) 36 (4–86) 31 (0–65) 2–3 14 52 (31–88) 48 (21–75) 68 (43–94) P 0.14 0.13 0.027

High 0–1 4 75 (43–100)a 25 (0–67) 0 2–3 10 100 0 21 (0–56) P 0.38 0.370.97

aAt 2 years. The figures represent 5-year cumulative incidence of relapse and the 5-year probabilities of DFS and OS.

long-term consequences of TBI) as well as to significantly encouraging survival with intensified, cyclical therapy in older patients (no acute toxicity from TBI). ALL. It is possible that incorporation of an autograft in The UKALL XII regimen is considerably more complex their treatment scheme before commencing maintenance and intense than the UKALL X regimen in the induction as chemotherapy in low- and intermediate-risk group patients well as the early intensification and consolidation phases. It may improve outcome even further without compromising was therefore disappointing to see that it did not affect the safety. outcome beneficially. This is in contrast to our observations The prognostic model used here and previously,1 in acute myeloid leukemia where the overall intensity of modified from the German model,18 is powerful in prior therapy (specifically consolidation) does affect out- predicting outcome. Autotransplantation is totally inade- come after autograft significantly;19 with more intense prior quate for high-risk patients who must be allografted – using therapy being associated with lower post transplant relapse alternative donors if necessary. On the other hand, the and better DFS. One possibly critical and wide-ranging nontoxic approach is very successful in patients with low- implication of this observation is that a safe autograft risk disease. Such patients, in our opinion, should not be procedure following standard four-drug induction and allografted in first CR even if they have an HLA-identical modest intensification/consolidation followed by simple sibling donor because of the excellent results seen with maintenance chemotherapy could potentially replace very autotransplantation. complex ALL treatment regimens, which have failed in However, patients with a reasonably high chance of developing countries due to practical difficulties in im- relapse – such as those in the intermediate-risk group – plementing them.20,21 Linker et al22 have recently reported ought to be allografted if there is an HLA-matched sibling

Bone Marrow Transplantation PBSCT for ALL in CR1 J Mehta et al 1113 donor available. Over the last decade, we had been 3 Blaise D, Gaspard MH, Stoppa AM et al. Allogeneic or preferentially performing autografts even in patients with autologous bone marrow transplantation for acute lympho- HLA-identical siblings with a view to using the allograft as blastic leukemia in first complete remission. Bone Marrow salvage therapy in second CR. As the poor outcome of the Transplant 1990; 5: 7–12. allografted patients in this series shows, that approach was 4 Uckun FM, Kersey JH, Vallera DA et al. Autologous bone suboptimal. What should be done for intermediate-risk marrow transplantation in high-risk remission T-lineage acute lymphoblastic leukemia using immunotoxins plus 4-hydroper- patients who do not have an HLA-identical sibling? It is oxycyclophosphamide for marrow purging. Blood 1990; 76: difficult to recommend an unrelated donor transplant (even 1723–1733. one from a 10 of 10 allele-matched donor) over an 5 Gilmore MJML, Hamon MD, Prentice HG et al. Failure of autograft in face of data showing lack of superiority of purged autologous bone marrow transplantation in high risk the allograft procedure.23 Greater refinement of prognostic acute lymphoblastic leukaemia in first complete remission. factors would be helpful – with patients with higher risk Bone Marrow Transplant 1991; 8: 19–26. disease being subjected to allogeneic transplantation and 6 Doney K, Buckner CD, Fisher L et al. Autologous bone those with lower risk disease being autografted. The marrow transplantation for acute lymphoblastic leukemia. excellent tolerance of melphalan at the dose of 200 mg/m2 Bone Marrow Transplant 1993; 12: 315–321. et al. suggests that there could be a place for dose escalation in 7Soiffer RJ, Roy DC, Gonin R Monoclonal antibody- purged autologous bone marrow transplantation in adults with intermediate-risk group patients subjected to autotrans- acute lymphoblastic leukemia at high risk of relapse. Bone plantation in the form of a higher dose of melphalan Marrow Transplant 1993; 12: 243–251. (possibly with amifostine), or addition of etoposide, a 8 Sierra J, Granena A, Garcia J et al. Autologous bone marrow monoclonal antibody such as rituximab or alemtuzumab transplantation for acute leukemia. Results and prognostic (depending upon the characteristics of the specific patient factors in 90 consecutive patients. Bone Marrow Transplant being treated), a radiolabeled monoclonal antibody, or 1993; 12: 517–523. skeletal-targeted radiation with bone-seeking radioconju- 9 Weisdorf DJ, Anderson PM, Blazar BR et al. Interleukin 2 gated chelates. immediately after autologous bone marrow transplantation for Patients relapsing after an autograft are unlikely to acute lymphoblastic leukemia – a phase I study. Transplanta- tion benefit from a conventional etoposide-TBI allograft as 1993; 55: 61–66. 10 Fiere D, Lepage E, Sebban C et al. Adult acute lymphoblastic performed here, even with the superior graft-versus- leukemia: a multicentric randomized trial testing bone marrow leukemia effects exerted by the use of blood-derived stem transplantation as postremission therapy. The French Group 24 cells. A submyeloablative conditioning regimen with on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin GVHD prophylaxis adjusted towards high-risk disease Oncol 1993; 11: 1990–2001. may provide better results. 11 Attal M, Blaise D, Marit G et al. Consolidation treatment of We conclude that 200 mg/m2 autotransplantation fol- adult acute lymphoblastic leukemia: a prospective, randomized lowed by maintenance chemotherapy is an effective and trial comparing allogeneic versus autologous bone marrow safe way of intensifying therapy in adult patients with ALL. transplantation and testing the impact of recombinant inter- This strategy deserves consideration as consolidation leukin-2 after autologous bone marrow transplantation. Blood therapy for all low-risk and a proportion of intermediate- BGMT Group. 1995; 86: 1619–1628. 12 Bassan R, Lerede T, Di Bona E et al. Induction-consolidation risk adult patients (up to the age of 70 years) with ALL. with an idarubicin-containing regimen, unpurged marrow Trials in pediatric ALL patients, particularly geared autograft, and post-graft chemotherapy in adult acute towards developing countries, may also be worthwhile. lymphoblastic leukaemia. Br J Haematol 1999; 104: 755–762. This approach should be systematically evaluated in a large 13 Granena A, Castellsague X, Badell I et al. Autologous bone cooperative study such as the one that will replace the marrow transplantation for high risk acute lymphoblastic ongoing joint UK ALL XII and Eastern Cooperative leukemia: clinical relevance of ex vivo bone marrow purging Oncology Group (ECOG) 2993 study. with monoclonal antibodies and complement. Bone Marrow Transplant 1999; 24: 621–627. 14 Thomas X, Danaila C, Le QH et al. 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Blood 2001; 98 (Suppl. 1) Abstract #1788. transplant maintenance chemotherapy in improving the out- 17Singhal S, Powles R, Treleaven J et al. Central nervous system come of autotransplantation in adult acute lymphoblastic relapse after bone marrow transplantation for acute leukemia leukemia. Blood 2002; 100: 1641–1647. in first remission. Bone Marrow Transplant 1996; 17: 637–641. 2 Hoelzer D, Gokbuget N, Ottmann O et al. Acute lympho- 18 Hoelzer D, Thiel E, Loffler H et al. Prognostic factors in a blastic leukemia. Hematology (Am Soc Hematol Educ Pro- multicenter study for treatment of acute lymphoblastic gram) 2002, 162–192. leukemia in adults. Blood 1988; 71: 123–131.

Bone Marrow Transplantation PBSCT for ALL in CR1 J Mehta et al 1114 19 Mehta J, Powles R, Sirohi B et al. Impact of cytogenetics on 22 Linker C, Damon L, Ries C, Navarro W. Intensified and the outcome of autotransplantation for acute myeloid leuke- shortened cyclical chemotherapy for adult acute lymphoblastic mia in first remission: is the benefit of intensive pre-transplant leukemia. J Clin Oncol 2002; 20: 2464–2471. therapy limited to patients with good karyotypes? Bone 23 Weisdorf D, Bishop M, Dharan B et al. Autologous versus Marrow Transplant 2003; 32: 157–164. allogeneic unrelated donor transplantation for acute lympho- 20 Metzger ML, Howard SC, Fu LC et al. Outcome of childhood blastic leukemia: comparative toxicity and outcomes. Biol acute lymphoblastic leukaemia in resource-poor countries. Blood Marrow Transplant 2002; 8: 213–220. Lancet 2003; 362: 706–708. 24 Powles R, Mehta J, Kulkarni S et al. Allogeneic blood and bone- 21 Lilleyman J. Simple deliverable therapy needed for childhood marrow stem-cell transplantation in haematological malignant leukaemia. Lancet 2003; 362: 676–677. diseases: a randomised trial. Lancet 2000; 355: 1231–1237.

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