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Allogeneic transplantation for leukaemia using unrelated donors
Best Practice & Research Clinical Haematology Vol. 14, No. 4, pp. 793±805, 2001
doi:10.1053/beha.2001.0173, available online at http://www.idealibrary.com on
8 Allogeneic transplantation for leukaemia using unrelated donors David I. Marks
MB, BS, PhD, FRACP, MRCPath
Consultant in Haematology and Bone Marrow Transplantation Adult Bone Marrow Transplant Unit, United Bristol Healthcare Trust, Bristol Children's Hospital, Bristol BS2 8BJ England, UK
This chapter describes the current role of unrelated donor stem cell transplantation (UD-SCT) in the management of leukaemia. The available data are scant and incomplete and there are few randomized studies comparing UD-SCT with alternative therapies. Patients with many of the leukaemias require prolonged follow-up after allogeneic SCT to determine whether they are cured; the registry-based comparisons that have been initiated re¯ect the results achievable some years ago and may not help us in deciding what is best in 2001. In addition, new therapies such as STI571, even though the long-term outcome of patients treated with this agent is uncertain, may aect which patients with chronic myeloid leukaemia we decide to recommend for transplant. The focus here is on acute and chronic myeloid leukaemia, acute lymphoblastic leukaemia and chronic lymphocytic leukaemia, as well as the myelodysplastic syndromes. Patient selection, conditioning strategies, comparison with other therapies, timing of transplant and the major causes of treatment failure are discussed, and there is an exploration of where improvement will come from. Key words: unrelated donor; bone marrow transplantation; infection; indications; graft-versushost disease; T-cell depletion; relapse.
INTRODUCTION AND GENERAL PRINCIPLES: COMPARISONS AND DECISION MAKING Unrelated donor stem cell transplantation has an important role in the management of adults with haematological malignancies and severe aplastic anaemia.1 Time cohort analyses from the major transplant registries suggest that outcomes are improving to the point where, for some diseases, they are similar to those reported for matched sibling allografts.2 The literature regarding unrelated donor stem cell transplantation (UD-SCT) is really quite limited, and the short follow-up, the heterogeneity of protocols and the lack of quality-of-life data3 make judging its role dicult. Where other therapies, such as autologous stem cell transplantation (SCT), are possible there are no published randomized studies to compare them with UD-SCT. Large registry-based comparisons of UD-SCT and autograft are being performed but it is dicult to exclude selection 1521±6926/01/04079313 $35.00/00
c 2001 Harcourt Publishers Ltd. *
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biases in¯uencing the outcome of these studies. In addition, the comparative long-term toxicities (including second cancers) of the two procedures are not well understood. The role of UD-SCT in an individual patient may depend on the closeness of HLA matching, the age of the patient and the cytomegalovirus (CMV) serostatus of recipient and donor. However, even these putative prognostic factors have not been shown to be important in all studies2; a detailed analysis of their role in determining the appropriateness of transplant is beyond the scope of this chapter. Similarly, the type of myeloablative conditioning used will be discussed only brie¯y. Cord blood is rarely used as a source of unrelated donor stem cells in the adult setting and will not be discussed further here. Recent developments such as the use of peripheral blood stem cells from unrelated donors4, the use of the polymerase chain reaction (PCR) to diagnose CMV and fungal infections5 and the potentially decreased transplant-related mortality (TRM) of reduced intensity conditioning may make the procedure safer and more widely available. Protocols for patients undergoing UD-SCT should be individualized; the major causes of treatment failure should be assessed in each patient and a protocol designed to avoid the potential problems. The usual factors to consider include the chance of relapse, previous fungal infection and comorbid vital organ dysfunction. A matched sibling donor, when available, is almost always preferable to an unrelated donor, even allowing for the latter procedure's potentially enhanced graft-versustumour eect. If an autograft is the major treatment alternative, UD-SCT must be clearly superior to be indicated, given its greater toxicity and expense. Patients undergoing autografts have a shorter hospital stay, faster recovery and return to work, the procedure is about one-third the cost, and is much more widely available. Recommending upper age limits is dicult; advanced age is a relative contraindication to UD-SCT but if there is no other curative option it may be reasonable to proceed, but with a transplant protocol designed to reduce TRM. ACUTE MYELOID LEUKAEMIA In second complete remission, UD-SCT is indicated when there is antecedent myelodysplasia or when the cytogenetic abnormalities present at diagnosis persist. In other patients there are insucient data to decide between UD-SCT and autograft. A true randomized study would be dicult to conduct, and registry-based studies will have inherent selection biases as well as being out of date because the results of UDSCT are continuing to improve. Recently, the Bristol group reported 63% 4-year disease-free survival in 25 children and adults with acute myeloid leukaemia (AML) in second complete remission (CR2)6; there are no published autograft data as good as this, even in those with long ®rst complete remissions. Lazarus and colleagues from the International Bone Marrow Transplant Registry (IBMTR)7 have presented preliminary results of a comparison of unrelated donor bone marrow transplantation (UD-BMT) and autologous SCT for nearly 1200 patients with AML in CR1 and CR2. This study accrued patients from 1989 to 1996. Leukaemia-free survival at 3 years was 40 and 33% in the autograft and UD-SCT groups, respectively, but the latter group tended to be of poorer performance status (PS) and to have higher-risk disease. These autograft results for AML in CR2 were remarkably good. Busca and colleagues from Seattle8 compared the outcome of patients who had T-replete UD-SCT and autologous SCT (mixed purged and unpurged) for AML and acute lymphoblastic leukaemia (ALL) and found slightly higher survival in the UD-SCT group, although the
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dierence was not signi®cant. However, the TRM of the autograft group was unacceptably high for this to be a valid comparison, and the UD-SCT group had a very high incidence of acute and chronic graft-versus-host disease (GVHD). Moreover, results have improved since then.9 In the end there will be no simple conclusion about which type of transplant is better. Young patients with a 10-antigen matched donor, adverse cytogenetics and short ®rst remissions may be best treated by UD-SCT, and patients 440 years with long ®rst remissions will have acceptable disease control with autologous SCT and a much lower TRM. Adults with AML in ®rst complete remission fall into three categories. Good-risk patients with inversion 16, t(8;21) and t(15;17) do not require high-dose therapy as their outcome is excellent with chemotherapy alone10, and should they relapse there is a good chance of achieving CR2 and cure with high-dose therapy (HDT). Standard-risk patients who do not have unfavourable cytogenetics, and who remit after one course of chemotherapy, may have their outcome improved by a matched sibling allograft.11 Although this has a de®nite mortality associated with it, allograft is the most eective way of preventing relapse, and GVHD can be prevented by T-cell depletion (TCD) without substantially increasing the chance of disease recurrence.12 UD-SCT, in my view, has no current role in the management of patients with standard risk AML in CR1 because of its excessive mortality and morbidity; it should be reserved for CR2. Patients with poor-risk AML (adverse cytogenetics, failed remission induction and antecedent myelodysplasia) have a low chance of cure with conventional therapy and are undoubtedly candidates for UD-SCT if they lack a sibling donor. However, the evidence that allogeneic transplant can cure large numbers of them is lacking. Sibling allograft resulted in 25% of these high-risk patients surviving and was only marginally better (29 versus 21%) than autologous SCT.13 An alternative strategy to UD-SCT for poor-risk AML in CR1 is to identify a donor and then wait until early ®rst relapse, but this necessitates close monitoring (including frequent marrow aspirates) and an ability to move to transplant in 3±4 weeks ± which is not always possible. Most studies of T cell depletion in UD-SCT for leukaemia show no advantage over T-replete grafts: the reduced TRM from acute and chronic GVHD is balanced by an increased chance of relapse of most diseases and an increase in life-threatening infections probably associated with delayed immune reconstitution. AML appears to be the exception to this, with a large analysis of UD transplants ± facilitated by the National Marrow Donor Program (NMDP) ± showing a proven role for TCD in this disease (Wagner J, personal communication). A high marrow cell dose improves the outcome of UD-SCT for acute leukaemia.14 It results in more rapid engraftment of neutrophils and platelets, less acute GVHD and less non-relapse mortality ± possibly related to higher lymphocyte counts and better immune reconstitution.15 Attention should be paid to this important prognostic factor in donor selection and stem cell procurement. There may be a role for UD-SCT for younger patients with AML who do not achieve remission but who have only small numbers of blasts (5±10%), although haplo-identical transplants may exert a more potent antileukaemic eect and are quicker to organize.16 ACUTE LYMPHOBLASTIC LEUKAEMIA The most common indication for UD-SCT in patients with this disease is in second complete remission. In those lacking a sibling donor the other options are a purged or
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unpurged autologous stem cell transplant. Autografts are associated with a high chance of relapse but a low TRM. The results of purged autografts (with antibodies or cyclophosphamide derivatives) are disappointing, with major series reporting 520% disease-free survival.17,18 In a combined study of two large centres there was a trend for UD-SCT to be superior to autologous SCT in the 518 year age group19 with the two therapeutic modalities yielding similar results in older patients. Weisdorf and colleagues20, on behalf of the IBMTR, are currently comparing the two modalities. The preliminary data in 917 patients were presented at the American Society of Hematology meeting in December, 2000. Three-year survivals in the UD-SCT and autograft groups were 36 and 32% respectively (P NS), but the UD-SCT group had more patients with highrisk karyotypes and high white-cell counts at diagnosis. The study concluded that to take advantage of the better protection against leukaemic relapse, the TRM of UDSCT needed to be reduced (it was 440% in this study) before it could be recommended as the treatment of choice. This study has the limitations and selection biases of all registry-based retrospective studies. There is a need for speed in proceeding to transplant as the duration of CR2 in adults is brief. All patients with ALL for whom UD-SCT is a possibility in CR2 should have a computerized worldwide donor search at diagnosis so that, at relapse, transplant can occur within 4±8 weeks. There are no large published adult series but some important facts can be gleaned from the paediatric data.21 In a large series of T-depleted UD-SCT for ALL (including 88 in CR2), relapse was seen in up to 40%, the majority occurring in the ®rst year after transplant. Relapse appears to be particularly problematical in those who relapse on therapy and have a high level of minimal residual disease in marrow harvested immediately prior to transplant.22 The probability of relapse may be decreased by using T-replete transplants at the expense of more acute and chronic GVHD and a higher TRM.23 The Stanford/City of Hope regimen of VP16 and total body irradiation (TBI) may result in a lower relapse rate24 (this is currently being examined by the IBMTR) and it is a feasible conditioning regimen for UD-SCT (Marks D, unpublished observations). The problem with relapse of ALL post-allograft is that the chance of response to donor leukocyte infusion (DLI) is very low, 18 and 5% in the two largest published series25,26 and these may not be durable. The possibility of using pre-emptive DLI in those at high risk of relapse requires investigation. The Bristol unit has performed UD-SCT on 16 patients 5 17 years with ALL in CR2 with a median age of 23 years (range 17±49) and eight have survived. Actuarial DFS is 46 + 16% (+SE) at 18 months with a median follow-up of 19 months (Marks D, unpublished data). Two of these 16 patients have relapsed, both at less than 4 months post-BMT. To summarize, UD-SCT has a greater antileukaemic eect than an autograft and may be the treatment of choice for those with ALL in CR2 at high risk of relapse ± such as those with an unfavourable karyotype, marked leukocytosis or a short CR1 duration. The decision is made easier when the patient is young and the donor is well matched. UD-SCT is being increasingly used for adults with ALL in CR1 who present with high white-cell counts or other poor prognostic features identi®ed by Hoelzer and colleagues (1988), but there are no randomized studies or large series reporting outcome. The chance of cure with modern chemotherapy protocols is about 30% only, and the outcome of ALL allografted in CR1 using sibling donors is excellent, so that if the transplant-related mortality of UD-SCT can be made to approach that of sibling donor SCT then this will become a reasonable therapeutic option.
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PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKAEMIA Philadelphia-positive acute lymphoblastic leukaemia remains the clearest indication for unrelated donor SCT in ®rst remission. Chemotherapy alone achieves remission in over three-quarters of patients, but remissions are brief.27 There are some encouraging reports of cures in children with very intensive chemotherapy, particularly in those who present with a white cell count of 525 109/l28, but this has not been reproduced in adult patients. Autologous stem cell transplantation is another potential option for patients with Philadelphia-positive ALL, and it may be possible to collect cells with a degree of bcr-abl negativity29, but there are no long-term data to support the use of autografting for this disease. Sierra and colleagues30 in Seattle reported 18 patients with a median age of 25 years who had T-replete UD transplants for Philadelphia-positive ALL. Forty-nine percent survived leukaemia-free at 2 years with a 78% incidence of grade II±IV acute GVHD, a 450% incidence of extensive chronic GVHD and a 28% incidence of relapse. Marks and colleagues31 in Bristol reported 15 children and young adults treated with UDSCT for this disease (nine CR1 and six more advanced disease, median age 5 years) with 37 and 44% disease-free and overall survivals at 2 years. Five of nine transplanted in CR1 survived, although one survivor has developed a second tumour. The incidence of acute and chronic GVHD was much lower than that seen in Seattle but that is partly explained by the younger age of the patients. Six of 15 patients relapsed (40%), not signi®cantly more than would have been expected if the grafts were T-replete. Available data suggest that patients who are referred in CR2 are also curable30,31 and that there is clinical urgency to transplant them as second remissions in this disease are brief. Barrett and colleagues from the IBMTR32 found that sibling allografts cured a proportion of patients not in remission; there are no data in the unrelated donor setting that cast light on whether it is reasonable to oer UD-SCT to these patients. CHRONIC MYELOID LEUKAEMIA Management decisions in the newly diagnosed patient with chronic myeloid leukaemia (CML) without a sibling donor are complex, and the introduction of STI571 has made things even less clear.33 It is easiest to start with what we do know. The only proven curative therapy of CML is an allogeneic transplant.34 Alpha-interferon, which can produce median survivals of 46 years35, is not curative and substantially aects the quality of life in a proportion of responders. Complete cytogenetic responders, comprising 10±26% of all patients treated, may experience very prolonged survival, and it is entirely reasonable to observe them closely and transplant them when they relapse cytogenetically. However, it may take 18±24 months to ascertain the maximum response of any individual, and this therapy may aect the outcome of subsequent UDSCT by causing an excess of steroid-refractory chronic GVHD.36 This provocative ®nding arises from a single centre and requires veri®cation in a larger cohort of patients; this is the current subject of work by Lee and colleagues of the IBMTR. Interferon does not appear to aect the outcome of a subsequent sibling allograft37 but it is clear from many studies that patients with CML are optimally transplanted in the ®rst year after diagnosis.38 STI571, at doses 4300 mg/day, produces a nearly 100% haematological response rate in patients with CML in CP1.39 Major cytogenetic responses are seen in over half of patients (complete responses in 13%), and short-term toxicity is minimal. Molecular
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remission has not been documented to date, and given the small number of relapses seen in treated individuals, and the data concerning in vitro resistance mechanisms of tumour cell lines, it is not possible to be con®dent that responses will be truly durable.40,41 Although not curative, it is possible that complete cytogenetic responders will experience a survival of 410 years. There are, of course, no data about whether prior therapy with STI571 will compromise transplant outcome. It is also possible that combining STI571 with other agents, such as cytosine arabinoside or interferon, may avoid the problem of resistance.42 The Seattle experience in nearly 200 patients in CP1 most clearly de®nes what can be achieved with UD-SCT in this disease.2 There was an overall 5-year survival of 57%, but it was 74% in the subgroup of patients who were 550 years of age, HLA-matched and transplanted within a year of diagnosis. Survival was adversely aected by older age (450 years), HLA-DRB1 mismatches, a prolonged time from diagnosis to transplant (41 year) and a high body-weight index. There was no adjustment of donor T cell dose; grade II±IV acute GVHD occurred in 77% of those matched, with a higher incidence in those with class I or class II mismatches. The quality of life experienced by this transplant cohort is uncertain. Some 30% had a Karnofsky score of 590 at 1 year, extensive chronic GVHD occurred in 2/3 but immunosuppression was able to be discontinued in over half the patients who survived 5 years. The actuarial relapse rate was predictably low (10% at 5 years) and only half of these have died. TRM was 39%, most frequently associated with refractory GVHD. Similar results were achieved nationally in the USA, with a 63% 3-year DFS in the group of patients 535 years transplanted within a year of diagnosis.43 An Italian multicentre study of CML patients treated with UD-SCT reported that, in patients transplanted since 1993, there was 63% DFS and found that a high cell dose and early use of cyclosporin (at day ÿ8) were associated with better survival on multivariate analysis.44 The major alternative strategy to unmanipulated UD grafts is to T-cell-deplete the marrow, reduce the incidence of acute and chronic GVHD (possibly improving the quality of life) and accept a high incidence of relapse knowing that subsequent donor leukocyte infusions have a high probability of achieving molecular remission and longterm disease-free survival45 (Marks D, unpublished observations). T cell depletion is eective in reducing severe (grade III±IV) acute GVHD but is somewhat less eective at reducing chronic GVHD with rates of 29/39 (74%) with the T10B9 antibody46 and 77% with Campath antibodies.47 More modern technologies, such as the Clinimacs and Isolex devices, enable delivery of precise doses of CD3 cells and may be even more eective in eliminating GVHD, probably with the cost of more relapse. The other probable adverse eects of TCD include more viral and fungal infection due to slower immune reconstitution.48 The major problems associated with a T cell depletion strategy are that not all relapsed patients are able to receive DLIs and not all who do respond. In a national survey in the USA, in 25 patients who relapsed after UD-SCT for CML there was 65% 1-year DFS and one-quarter of the patients experienced grade II±IV acute GVHD.49 Very careful surveillance (3-monthly marrows and, if possible, quantitative PCR) is needed as early detection of relapse may improve the outcome of DLIs.45,50 The chance of relapse of CML with TCD varies. It exceeds 60% with the Campath antibodies51 but appears to be less with the T10B9 antibody.52 It is not known for Miltenyi CD34 selected stem cells, but given their ability to deplete grafts to 51 104 CD3 cells/kg of recipient weight it is likely to be high. Another problem identi®ed by the NMDP study of UD-SCT for CML is graft failure.43 Primary graft failure occurred in 10% and secondary graft failure in over 6%.
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This is more common in mismatched UD-SCT but may be partly overcome by increasing the cell dose. Larger patients, especially those with mismatches at the C locus and whose stem cells are being T-cell-depleted, might bene®t from the higher cell doses achievable with peripheral blood stem cells. The chances of cure are lower in accelerated phase or second chronic phase but UDSCT is certainly indicated where the performance status is good and the match acceptable. There are few data that report the outcome in these phases of the disease, but it is possible that the potentially enhanced graft versus leukaemia (GVL) eect of UD-SCT may be bene®cial. The Seattle group report approximately 35% 4-year survival in 56 patients in accelerated phase. The probability of survival in second chronic phase was somewhat less, about 27% in 15 patients.53 A relapse into accelerated phase is less likely to respond to DLIs and it may be worth considering performing these transplants with unmanipulated marrow. Against that is information indicating that a higher nonrelapse mortality is seen when patients are transplanted with advanced-phase disease.54 In my opinion, UD-SCT is not indicated for the true blast crisis CML. The Seattle group report about 9% survival at 3 years in 23 patients but there were only two patients more than 4 years post-BMT. In these patients leukaemia should be tested for chemosensitivity; if unresponsive, it is very unlikely that transplant will be curative. If they are successfully returned to chronic phase it is reasonable to proceed to transplant. CHRONIC LYMPHOCYTIC LEUKAEMIA The National Cancer Institute Chronic Lymphocytic Leukaemia (CLL) Working Group has recommended a three-risk group system, modi®ed from the 5 Rai stages, with median survivals of 14, 8 and 4 years respectively.55 Due to its indolent natural history, and partly because of the advent of ¯udarabine-based regimens56, there is something of a complacent attitude to CLL, even in young patients. Sibling allograft has an established role in this disease, with the European Bone Marrow Transplant Group (EBMT) reporting 40% 5-year leukaemia-free survival in 45 evaluable patients, mainly with Rai stage 3 and 4 disease.57 Similarly, the MD Anderson group reported 57% 3-year DFS in 38 patients with advanced CLL with a median of three prior therapies.58 In the opinion of the author all patients with CLL 545 years of age are candidates for allogeneic transplant, particularly if they have adverse prognostic features such as advanced stage, a high beta-2 microglobulin level at diagnosis, lymphocyte doubling time of 512 months and certain cytogenetic abnormalities.59 Refractoriness to ¯udarabine is another important factor in the decision to transplant.60 The IBMTR have data on 73 patients who had UD-SCT performed by 31 teams between 1993 and 2000, with a median age of 46 years and a median of 50 months from diagnosis to transplant. The majority received TBI-containing regimens and had cyclosporin and methotrexate GVHD prophylaxis. Fifty percent of evaluable patients are in complete remission, and the 2- and 4-year probabilities of survival are 52 + 14% and 41 + 16% respectively (95% CI) (Horowitz M, personal communication). UD-SCT will not become an important part of the management of patients with CLL until it can be performed with a lower TRM on a larger percentage of patients with the disease. Reduced intensity conditioning may be a way round these problems but long-term survival data are lacking.61,62 Relapse is a major problem after allograft for CLL but there appears to be a degree of responsiveness to DLIs63 and the delayed remissions achieved after allograft provide evidence for a GVL eect.
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MYELODYSPLASTIC SYNDROMES Allogeneic SCT is the only proven curative therapy for myelodysplastic syndromes (MDS).64 It is clearly indicated for patients with high- or intermediate-risk disease65 but is most eective for those with low-risk disease.66 Young patients with low-risk disease and a short disease duration are worth considering for UD-SCT; it is reasonable to follow closely the clinical progress of older patients (with low-risk disease) with a plan to transplant them at the ®rst sign of disease progression (increased blast count or the development of new cytogenetic abnormalities). This strategy requires frequent bone marrow aspirates but has risks associated because the transformation of MDS can be rapid. It is not certain whether patients should receive induction chemotherapy prior to BMT. Being in CR at transplant correlates with an improved outcome67 but chemotherapy may result in complications that prevent the patient proceeding to BMT. Castro-Malaspina and colleagues from the NMDP68 reported 320 NMDP-facilitated unrelated donor transplants. Sightly less than one-third were alive and disease-free at 2 years. Infection, GVHD and relapse appear to be the major problems associated with UD-SCT for MDS.69 A longer disease duration and a low neutrophil count at transplant are associated with a higher non-relapse mortality, possibly partly related to more exposure to transfusions. The EBMT recently reported its results in 118 patients with MDS or secondary AML.70 As with the NMDP data, there was 28% DFS at 2 years with a very high TRM of 58% and a relapse risk of 35%. Relapse risk was lower in oligoblastic disease and a GVL eect was apparent. This latter ®nding seemed to agree with the ®nding that DLI may be of some value for relapsed disease.71 An alternative strategy is to give AML-type chemotherapy to achieve a complete remission and then harvest autologous stem cells and use these to rescue the patient from high-dose chemotherapy.72 In 79 patients treated in this way, reported by the EBMT, 34% were disease-free at 2 years and relapse occurred in 64%. Results were better in those aged less than 40. Longer follow-up is required to determine whether any of these patients are cured. POTENTIAL DEVELOPMENTS IN UD-SCT FOR LEUKAEMIA The option of using peripheral blood stem cells (PBSC) from unrelated donors will become an important issue. In Germany, where PBSC have been available for some time, there is evidence suggesting that if they are given unmanipulated the incidence of chronic GVHD approaches 100%.73 The randomized study comparing blood and marrow stem cells for sibling allograft transplants performed by Seattle, Stanford and City of Hope suggests that there may be a survival bene®t in patients with high-risk leukaemia74 but not all studies agree with these ®ndings. A matched pair analysis of PBSC and marrow-derived unrelated transplants performed in Germany and Scandinavia showed no dierence in outcome between the two stem cell sources.4 Increasing the cell dose for UD-SCT is undoubtedly bene®cial, but if using PBSC leads to more GVHD then this may compromise outcome. Boosting the marrow cell dose by using T-depleted PBSC is one way of avoiding excessive numbers of T cells in the stem cell inoculum. The higher cell dose and rapid engraftment kinetics of UD-PBSC are clearly desirable in second transplants for primary graft failure. There are no large reports regarding reduced-intensity conditioning UD-SCT, but if the mortality could be reduced to that of matched sibling allografts then this will increase the subset of patients eligible for UD-SCT. However, a word of caution
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should be sounded. The durability of complete responses following non-myeloablative transplants is not known, nor is the ecacy of DLI for treating relapsed disease or persistent mixed chimerism. A signi®cant proportion of these transplants result in GVHD; this is poorly tolerated by older, in®rm patients. The ethics of using unrelated donors in this experimental setting require further debate. CONCLUSION In summary, UD-SCT has a clear role in the management of adult patients with CML in ®rst chronic phase and accelerated phase, AML and ALL in CR2 and severe MDS. As results approach those seen with matched sibling allografts it will be used increasingly for younger patients with high-risk ALL and AML in CR1, early MDS and treatmentrefractory CLL with multiple adverse prognostic factors. The role of reduced intensity conditioning for unrelated donor allografts requires further investigation but is appealing in older patients with slower paced diseases which may be responsive to cellular immunotherapy. Similarly, the role of UD-PBSC requires further study. Acknowledgements I wish to acknowledge my colleagues at the three institutions where I have performed unrelated donor transplants: John Goldman and John Barrett at the Hammersmith, Pam Crilley, Dave Topolsky and Mike Styler at Hahnemann University, Philadelphia, and the transplanters in Bristol, Tony Oakhill, Jackie Cornish, Derwood Pamphilon, Practice points . all patients with leukaemia who may require UD-SCT at some point in their disease should be tissue typed at diagnosis and a preliminary computerized search performed . recommendations for individual patients as to whether they should have UDSCT are dicult and involve taking into account the patient's individual prognostic factors and personal views; they require considerable extrapolation from the available literature . UD-SCT, in general, has a lower TRM if it is performed early in the course of a patient's disease
Research agenda . the role of reduced intensity conditioning in UD-SCT requires further investigation . the use of UD-PBSC as a means of increasing cell dose, speeding up both engraftment and immune reconstitution will be a major area of research . only randomized studies comparing UD-SCT with alternative therapies will determine its true role; these studies should incorporate quality-of-life measures . the identi®cation of `permissive mismatches' will improve outcome and increase the proportion of patients eligible for UD-SCT
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Colin Steward and Nick Goulden. Tony Oakhill and Jenny Bird read the manuscript and made many helpful comments. In addition, thanks should be given to the registrars, fellows, data managers and statisticians who have worked with me on my papers concerning UD-SCT; they are too numerous to mention individually. The data from the IBMTR have not been reviewed by the Advisory Committee. REFERENCES * 1. Marks DI, Otton S, Williamson E & Bird JM. Unrelated donor bone marrow transplantation in adults: some current controversies. Leukemia and Lymphoma 1999; 32: 459±466. * 2. Hansen JA, Gooley TA, Martin PJ et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. New England Journal of Medicine 1998; 338: 962±968. 3. Marks DI, Gale DJ, Vedhara K & Bird JM. A quality of life study in 20 adult long-term survivors of unrelated donor bone marrow transplantation. Bone Marrow Transplantation 1999; 24: 191±195. 4. Ringden O, Renberger M, Blass I et al. Peripheral stem cells versus bone marrow from unrelated donors. A match pair analysis of 214 patients. Biology of Blood and Marrow Transplantation 2001; 7: 96 (abstract). 5. Einsele H, Hebart H, Roller G et al. Detection and identi®cation of fungal pathogens in blood by using molecular probes. Journal of Clinical Microbiology 1997; 35: 1353±1360. * 6. Marks DI, Bird JM, Vettenranta K et al. T cell-depleted unrelated donor bone marrow transplantation for acute myeloid leukemia. Biology of Blood and Marrow Transplantation 2000; 6: 646±653. 7. Lazarus HM, Perez WS, Weisdorf D et al. Autologous versus unrelated donor transplantation for acute myeloid leukemia in ®rst or second remission. Blood 2000; 96: 414a (abstract no 1781). 8. Busca A, Anasetti C, Anderson G et al. Unrelated or autologous marrow transplantation for treatment of acute leukaemia. Blood 1994; 83: 3077±3084. 9. Sierra J, Storer B, Hansen JA et al. Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience. Bone Marrow Transplantation 2000; 26: 397±404. 10. Burnett AK, Goldstone AH, Stevens RM et al. Results of the MRC AML10 study. Lancet 1998; 351: 700±708. 11. Zittoun RR, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myeloid leukemia. New England Journal of Medicine 1995; 332: 217±223. 12. Papadopoulos EB, Carabasi MH, Castro-Malaspina H et al. T-cell-depleted allogeneic bone marrow transplantation as post-remission therapy for acute myelogenous leukaemia: freedom from relapse in the absence of graft versus host disease. Blood 1998; 91: 1083±1090. *13. Ferrant A, Labopin M, Frassoni F et al. Karyotype in acute myeloblastic leukemia: prognostic signi®cance for bone marrow transplantation in ®rst remission: a European Group for Blood and Marrow Transplantation study. Blood 1997; 90: 2931±2938. *14. Sierra J, Storer B, Hansen JH et al. Transplantation of marrow cells from unrelated donors for treatment of high risk acute leukemia: the eect of leukemic burden, donor HLA matching, and marrow cell dose. Blood 1997; 89: 4226±4235. 15. Davies SM, Kollman C, Anasetti C et al. Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the National Marrow Donor Program. Blood 2000; 96: 4096±4102. *16. Aversa F, Tabilio A, Velarde A et al. Treatment of high risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. New England Journal of Medicine 1998; 339: 1186±1193. 17. Ramsay N, LeBien T, Weisdorf D et al. Autologous BMT for patients with acute lymphoblastic leukemia. In Gale R & Champlin R (eds) Bone Marrow Transplantation: Current Controversies, pp 57±66. New York: Alan R. Liss, 1987. 18. Soier RJ, Roy DC, Gonin R et al. Monoclonal antibody-purged autologous bone marrow transplantation in adults with acute lymphoblastic leukemia at high risk of subsequent relapse. Bone Marrow Transplantation 1993; 12: 243±251. 19. Weisdorf DJ, Billett AL, Hannan P et al. Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia. Blood 1997; 90: 2962±2968. 20. Weisdorf DJ, Cairo M, Dharan B et al. Autologous versus allogeneic unrelated donor transplantation for acute lymphoblastic leukemia. Blood 2000; 96: 413a (abstract 1779). *21. Green A, Clarke E, Hunt L et al. Children with acute lymphoblastic leukemia who receive T-celldepleted HLA mismatched marrow allografts from unrelated donors have an increased incidence of primary graft failure but a similar overall transplant outcome. Blood 1999; 94: 2236±2246.
Allogeneic transplantation with unrelated donors 803 22. Knechtli CJ, Goulden NJ, Hancock JP et al. Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia. Blood 1998; 92: 4072±4079. 23. Vettenranta K, Saarinen-Pihkala UM, Cornish J et al. Pediatric marrow transplantation for acute leukemia using unrelated donors and T-replete or -depleted grafts: a case-matched analysis. Bone Marrow Transplantation 2000; 25: 395±399. 24. Snyder DS, Chao NJ, Amylon MD et al. Fractionated total body irradiation and high dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in ®rst remission. Blood 1993; 82: 2920±2928. 25. Collins RH, Shpilberg O, Drobyski WR et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. Journal of Clinical Oncology 1997; 15: 433±444. 26. Kolb HJ, Schattenberg A, Goldman JM et al. Graft versus leukemia eect of donor lymphocyte infusions in marrow grafted patients. Blood 1995; 86: 2041±2050. 27. Westbrook CA, Hooberman AL, Spino C et al. Clinical signi®cance of the BCR-ABL fusion gene in adult ALL: a Cancer and Leukemia Group B study (8762). Blood 1991; 80: 2983±2990. 28. Ribeiro RC, Broniscer A, Rivera GK et al. Philadelphia chromosome positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts. Leukemia 1997; 11: 1493±1496. 29. Martin H, Atta J, Zumpe P et al. Purging of peripheral blood stem cells yields BCR-ABL negative autografts in patients with BCR-ABL positive acute lymphoblastic leukemia. Experimental Hematology 1995; 23: 1612±1618. 30. Sierra J, Radich J, Hansen JA et al. Marrow transplants from unrelated donors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1997; 90: 1410±1414. 31. Marks DI, Bird JM, Cornish JM et al. Unrelated donor bone marrow transplantation for children and adolescents with Philadelphia positive acute lymphoblastic leukemia. Journal of Clinical Oncology 1998; 16: 931±936. 32. Barrett AJ, Horowitz MM, Ash RC et al. Bone marrow transplantation for Philadelphia chromosome prositive acute lymphoblastic leukemia. Blood 1992; 79: 3067±3070. 33. Goldman JM. Tyrosine kinase inhibition in chronic myeloid leukaemia. Lancet 2000; 355: 1031±1032. 34. Goldman JM, Apperley JF, Jones L et al. Bone marrow transplantation for patients with chronic myeloid leukaemia. New England Journal of Medicine 1986; 314: 202±207. 35. Kantarjian HM, Smith TL, O'Brien S et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. Annals of Internal Medicine 1995; 122: 254±261. 36. Morton AJ, Gooley T, Hansen JA et al. Impact of pre-transplant interferon-alpha on outcome of unrelated donor marrow transplants for chronic myeloid leukemia in ®rst chronic phase. Blood 1997; 90: 123 (abstract 536). 37. Giralt S, Szydlo R, Goldman JM et al. Eect of short term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukaemia: an analysis from the international bone marrow transplant registry. Blood 2000; 95: 410±415. 38. Biggs JC, Szer J, Crilley P et al. Treatment of chronic myeloid leukemia with bone marrow transplantation after preparation with BuCy2. Blood 1992; 80: 1352±1357. 39. Druker BJ, Talpaz M, Resta D et al. Clinical ecacy and safety of an ABL speci®c tyrosine kinase inhibitor as targeted therapy for chronic myelogenous leukemia. Blood 1999; 94: 368a (abstract 1639). 40. Weisberg E & Grin JD. Mechanism of resistance to ABL tyrosine kinase inhibitor STI571 in BCR/ABLtransformed hematopoietic cell lines. Blood 2000; 95: 3498±3505. 41. Mahon FX, Deininger MW, Shultheis B et al. Selection and characterization of BCR-ABL positive cell lines with dierential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 2000; 96: 1071±1079. 42. Theising JT, Ohno-Jones S, Kolibabo KS & Druker BJ. Ecacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl positive cells. Blood 2000; 96: 3195±3199. 43. McGlave PB, Shu XO, Wen W et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program. Blood 2000; 95: 2219±2225. 44. Dini G, Lamperelli T, Rondelli R et al. Unrelated donor marrow transplantation for chronic myelogenous leukaemia. British Journal of Haematology 1998; 102: 544±552. *45. Dazzi F, Szydlo RM, Cross NCP et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000; 96: 2712±2716. 46. Drobyski WR, Ash RC, Casper JT et al. Eect of T-cell depletion as graft versus host disease prophylaxis on engraftment, relapse, and disease-free survival in unrelated donor marrow transplantation for chronic myelogenous leukemia. Blood 1994; 83: 1980±1987.
804 David I. Marks *47. Marks DI, Cullis JO, Ward KN et al. Allogeneic bone marrow transplantation for chronic myeloid leukaemia using sibling and volunteer unrelated donors. A comparison of complications in the ®rst 2 years. Annals of Internal Medicine 1993; 119: 207±214. 48. Williamson E, Cornish JM, Pamphilon DH et al. Infections in adults undergoing unrelated donor bone marrow transplantation. British Journal of Haematology 1999; 104: 560±568. 49. Porter DL, Collins RH Jr, Hardy C et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95: 1214±1221. 50. van Rhee F, Lin F, Cullis JO et al. Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: the case for giving donor leukocyte transfusions before the onset of hematologic relapse. Blood 1994; 83: 3377±3383. 51. Craddock C, Szydlo RM, Dazzi F et al. Cytomegalovirus seropositivity adversely in¯uences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis. British Journal of Haematology 2001; 112: 228±236. 52. Hessner MJ, Endean DJ, Casper JT et al. Use of unrelated marrow grafts compensates for reduced graft versus leukemia reactivity after T cell depleted allogeneic marrow transplantation for chronic myelogenous leukemia. Blood 1995; 86: 3967±3996. 53. Hansen JA & Petersdorf EW. Unrelated donor hematopoietic cell transplantation. In Thomas ED, Blume KG & Forman SG (eds) Hematopoietic Cell Transplantation, pp 915±928. Malden, MA: Blackwell Science, 1999. 54. Martin PJ, Clift RA, Fisher LD et al. HLA-identical marrow transplantation during accelerated phase chronic myelogenous leukemia: analysis of survival and remission duration. Blood 1988; 72: 1978±1984. 55. Cheson BD, Bennett JM, Grever M et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990±4997. 56. Keating MJ, Smith TL, Lerner S et al. Prediction of prognosis following ¯udarabine used as secondary therapy for chronic lymphocytic leukemia. Leukemia and Lymphoma 2000; 37: 71±85. 57. Michallet M, Archimbaud E, Bandini G et al. HLA-identical sibling transplants for chronic lymphocytic leukaemia. A collaborative study of the EBMTG and the IBMTR. Blood 1993; 82: 345a. 58. Khouri IF, Keating MJ, Vriesendorp HM et al. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. Journal of Clinical Oncology 1994; 12: 748±758. 59. Foon KA & Gale RP. Chronic lymphoid leukemias. In Handin RI, Lux SE & Stossel TP (eds) Blood, Principles and Practice of Hematology, pp 783±811. Philadelphia: Lippincott, 1995. 60. Seymour JF, Robertson LE, O'Brien S et al. Survival of young patients with chronic lymphocytic leukemia failing ¯udarabine therapy: a basis for the use of myeloablative therapies. Leukemia and Lymphoma 1995; 18: 493±496. 61. Schetelig J, Held TK, Bornhauser M et al. Nonmyeloablative allogeneic stem cell transplants in chronic lymphocytic leukemia from related and unrelated donors. Blood 2000; 96: 200a (abstract 857). 62. Khouri I, Munsell M, Yajzi S et al. Comparable survival for nonablative and ablative allogeneic transplantation for chronic lymphocytic leukemia: the case for early intervention. Blood 2000; 96: 205a (abstract 877). 63. Rondon G, Giralt S, Huh Y et al. Graft versus leukemia eect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplantation 1996; 18: 669±672. *64. Anderson JE. Bone marrow transplantation for myelodysplasia. Blood Reviews 2000; 14: 63±77. 65. Greenberg P, Cox C, LeBeau MM et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079±2088. 66. Runde V, de Witte T, Arnold R et al. Bone marrow transplantation from HLA-identical siblings as ®rst line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Bone Marrow Transplantation 1998; 21: 255±261. 67. Yakoub-Agha I, de La Salmoniere P, Ribaud P et al. Allogeneic bone marrow transplantation for therapyrelated myelodysplastic syndrome and acute myeloid leukemia: a long term study of 70 patients-report of the French society of BMT. Journal of Clinical Oncology 2000; 18: 963±971. 68. Castro-Malaspina H, Collins JER, Gajewski J et al. Unrelated donor marrow transplantation for myelodysplastic syndromes. Blood 1997; 90: 106a (abstract 465). 69. Anderson JE, Anasetti C, Appelbaum FR et al. Unrelated donor marrow transplantation for myelodysplasia (MDS) and MDS-related acute myeloid leukaemia. British Journal of Haemotology 1996; 93: 59±67. 70. Arnold R, de Witte T, van Biezen A et al. Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: an EBMT survey. Bone Marrow Transplantation 1998; 21: 1213±1216.
Allogeneic transplantation with unrelated donors 805 71. Anderson JE. Allogeneic hematopoietic cell transplantation for myelodysplastic and myeloproliferative disorders. In Thomas ED, Blume KG & Forman SG (eds) Hematopoietic Cell Transplantation, pp 872±886. Malden, MA: Blackwell Science, 1999. 72. De Witte T, van Biezen A, Hermans J et al. Autologous bone marrow transplantation for patients with myleodysplastic syndrome or acute myeloid leukemia following MDS. Blood 1997; 90: 3853±3857. 73. Blau IW, Basara N, Schmetzer B et al. Comparison of unrelated peripheral blood stem cell transplantation with unrelated bone marrow transplantation. Blood 1999; 94: 562a (abstract 2512). 74. Bensinger W, Martin P, Clift R et al. A prospective, randomised trial of peripheral blood stem cells or marrow for patients undergoing allogeneic transplantation for hematologic malignancies. Blood 1999; 94: 368a (abstract 1637).
doi:10.1053/beha.2001.0173, available online at http://www.idealibrary.com on
8 Allogeneic transplantation for leukaemia using unrelated donors David I. Marks
MB, BS, PhD, FRACP, MRCPath
Consultant in Haematology and Bone Marrow Transplantation Adult Bone Marrow Transplant Unit, United Bristol Healthcare Trust, Bristol Children's Hospital, Bristol BS2 8BJ England, UK
This chapter describes the current role of unrelated donor stem cell transplantation (UD-SCT) in the management of leukaemia. The available data are scant and incomplete and there are few randomized studies comparing UD-SCT with alternative therapies. Patients with many of the leukaemias require prolonged follow-up after allogeneic SCT to determine whether they are cured; the registry-based comparisons that have been initiated re¯ect the results achievable some years ago and may not help us in deciding what is best in 2001. In addition, new therapies such as STI571, even though the long-term outcome of patients treated with this agent is uncertain, may aect which patients with chronic myeloid leukaemia we decide to recommend for transplant. The focus here is on acute and chronic myeloid leukaemia, acute lymphoblastic leukaemia and chronic lymphocytic leukaemia, as well as the myelodysplastic syndromes. Patient selection, conditioning strategies, comparison with other therapies, timing of transplant and the major causes of treatment failure are discussed, and there is an exploration of where improvement will come from. Key words: unrelated donor; bone marrow transplantation; infection; indications; graft-versushost disease; T-cell depletion; relapse.
INTRODUCTION AND GENERAL PRINCIPLES: COMPARISONS AND DECISION MAKING Unrelated donor stem cell transplantation has an important role in the management of adults with haematological malignancies and severe aplastic anaemia.1 Time cohort analyses from the major transplant registries suggest that outcomes are improving to the point where, for some diseases, they are similar to those reported for matched sibling allografts.2 The literature regarding unrelated donor stem cell transplantation (UD-SCT) is really quite limited, and the short follow-up, the heterogeneity of protocols and the lack of quality-of-life data3 make judging its role dicult. Where other therapies, such as autologous stem cell transplantation (SCT), are possible there are no published randomized studies to compare them with UD-SCT. Large registry-based comparisons of UD-SCT and autograft are being performed but it is dicult to exclude selection 1521±6926/01/04079313 $35.00/00
c 2001 Harcourt Publishers Ltd. *
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biases in¯uencing the outcome of these studies. In addition, the comparative long-term toxicities (including second cancers) of the two procedures are not well understood. The role of UD-SCT in an individual patient may depend on the closeness of HLA matching, the age of the patient and the cytomegalovirus (CMV) serostatus of recipient and donor. However, even these putative prognostic factors have not been shown to be important in all studies2; a detailed analysis of their role in determining the appropriateness of transplant is beyond the scope of this chapter. Similarly, the type of myeloablative conditioning used will be discussed only brie¯y. Cord blood is rarely used as a source of unrelated donor stem cells in the adult setting and will not be discussed further here. Recent developments such as the use of peripheral blood stem cells from unrelated donors4, the use of the polymerase chain reaction (PCR) to diagnose CMV and fungal infections5 and the potentially decreased transplant-related mortality (TRM) of reduced intensity conditioning may make the procedure safer and more widely available. Protocols for patients undergoing UD-SCT should be individualized; the major causes of treatment failure should be assessed in each patient and a protocol designed to avoid the potential problems. The usual factors to consider include the chance of relapse, previous fungal infection and comorbid vital organ dysfunction. A matched sibling donor, when available, is almost always preferable to an unrelated donor, even allowing for the latter procedure's potentially enhanced graft-versustumour eect. If an autograft is the major treatment alternative, UD-SCT must be clearly superior to be indicated, given its greater toxicity and expense. Patients undergoing autografts have a shorter hospital stay, faster recovery and return to work, the procedure is about one-third the cost, and is much more widely available. Recommending upper age limits is dicult; advanced age is a relative contraindication to UD-SCT but if there is no other curative option it may be reasonable to proceed, but with a transplant protocol designed to reduce TRM. ACUTE MYELOID LEUKAEMIA In second complete remission, UD-SCT is indicated when there is antecedent myelodysplasia or when the cytogenetic abnormalities present at diagnosis persist. In other patients there are insucient data to decide between UD-SCT and autograft. A true randomized study would be dicult to conduct, and registry-based studies will have inherent selection biases as well as being out of date because the results of UDSCT are continuing to improve. Recently, the Bristol group reported 63% 4-year disease-free survival in 25 children and adults with acute myeloid leukaemia (AML) in second complete remission (CR2)6; there are no published autograft data as good as this, even in those with long ®rst complete remissions. Lazarus and colleagues from the International Bone Marrow Transplant Registry (IBMTR)7 have presented preliminary results of a comparison of unrelated donor bone marrow transplantation (UD-BMT) and autologous SCT for nearly 1200 patients with AML in CR1 and CR2. This study accrued patients from 1989 to 1996. Leukaemia-free survival at 3 years was 40 and 33% in the autograft and UD-SCT groups, respectively, but the latter group tended to be of poorer performance status (PS) and to have higher-risk disease. These autograft results for AML in CR2 were remarkably good. Busca and colleagues from Seattle8 compared the outcome of patients who had T-replete UD-SCT and autologous SCT (mixed purged and unpurged) for AML and acute lymphoblastic leukaemia (ALL) and found slightly higher survival in the UD-SCT group, although the
Allogeneic transplantation with unrelated donors 795
dierence was not signi®cant. However, the TRM of the autograft group was unacceptably high for this to be a valid comparison, and the UD-SCT group had a very high incidence of acute and chronic graft-versus-host disease (GVHD). Moreover, results have improved since then.9 In the end there will be no simple conclusion about which type of transplant is better. Young patients with a 10-antigen matched donor, adverse cytogenetics and short ®rst remissions may be best treated by UD-SCT, and patients 440 years with long ®rst remissions will have acceptable disease control with autologous SCT and a much lower TRM. Adults with AML in ®rst complete remission fall into three categories. Good-risk patients with inversion 16, t(8;21) and t(15;17) do not require high-dose therapy as their outcome is excellent with chemotherapy alone10, and should they relapse there is a good chance of achieving CR2 and cure with high-dose therapy (HDT). Standard-risk patients who do not have unfavourable cytogenetics, and who remit after one course of chemotherapy, may have their outcome improved by a matched sibling allograft.11 Although this has a de®nite mortality associated with it, allograft is the most eective way of preventing relapse, and GVHD can be prevented by T-cell depletion (TCD) without substantially increasing the chance of disease recurrence.12 UD-SCT, in my view, has no current role in the management of patients with standard risk AML in CR1 because of its excessive mortality and morbidity; it should be reserved for CR2. Patients with poor-risk AML (adverse cytogenetics, failed remission induction and antecedent myelodysplasia) have a low chance of cure with conventional therapy and are undoubtedly candidates for UD-SCT if they lack a sibling donor. However, the evidence that allogeneic transplant can cure large numbers of them is lacking. Sibling allograft resulted in 25% of these high-risk patients surviving and was only marginally better (29 versus 21%) than autologous SCT.13 An alternative strategy to UD-SCT for poor-risk AML in CR1 is to identify a donor and then wait until early ®rst relapse, but this necessitates close monitoring (including frequent marrow aspirates) and an ability to move to transplant in 3±4 weeks ± which is not always possible. Most studies of T cell depletion in UD-SCT for leukaemia show no advantage over T-replete grafts: the reduced TRM from acute and chronic GVHD is balanced by an increased chance of relapse of most diseases and an increase in life-threatening infections probably associated with delayed immune reconstitution. AML appears to be the exception to this, with a large analysis of UD transplants ± facilitated by the National Marrow Donor Program (NMDP) ± showing a proven role for TCD in this disease (Wagner J, personal communication). A high marrow cell dose improves the outcome of UD-SCT for acute leukaemia.14 It results in more rapid engraftment of neutrophils and platelets, less acute GVHD and less non-relapse mortality ± possibly related to higher lymphocyte counts and better immune reconstitution.15 Attention should be paid to this important prognostic factor in donor selection and stem cell procurement. There may be a role for UD-SCT for younger patients with AML who do not achieve remission but who have only small numbers of blasts (5±10%), although haplo-identical transplants may exert a more potent antileukaemic eect and are quicker to organize.16 ACUTE LYMPHOBLASTIC LEUKAEMIA The most common indication for UD-SCT in patients with this disease is in second complete remission. In those lacking a sibling donor the other options are a purged or
796 David I. Marks
unpurged autologous stem cell transplant. Autografts are associated with a high chance of relapse but a low TRM. The results of purged autografts (with antibodies or cyclophosphamide derivatives) are disappointing, with major series reporting 520% disease-free survival.17,18 In a combined study of two large centres there was a trend for UD-SCT to be superior to autologous SCT in the 518 year age group19 with the two therapeutic modalities yielding similar results in older patients. Weisdorf and colleagues20, on behalf of the IBMTR, are currently comparing the two modalities. The preliminary data in 917 patients were presented at the American Society of Hematology meeting in December, 2000. Three-year survivals in the UD-SCT and autograft groups were 36 and 32% respectively (P NS), but the UD-SCT group had more patients with highrisk karyotypes and high white-cell counts at diagnosis. The study concluded that to take advantage of the better protection against leukaemic relapse, the TRM of UDSCT needed to be reduced (it was 440% in this study) before it could be recommended as the treatment of choice. This study has the limitations and selection biases of all registry-based retrospective studies. There is a need for speed in proceeding to transplant as the duration of CR2 in adults is brief. All patients with ALL for whom UD-SCT is a possibility in CR2 should have a computerized worldwide donor search at diagnosis so that, at relapse, transplant can occur within 4±8 weeks. There are no large published adult series but some important facts can be gleaned from the paediatric data.21 In a large series of T-depleted UD-SCT for ALL (including 88 in CR2), relapse was seen in up to 40%, the majority occurring in the ®rst year after transplant. Relapse appears to be particularly problematical in those who relapse on therapy and have a high level of minimal residual disease in marrow harvested immediately prior to transplant.22 The probability of relapse may be decreased by using T-replete transplants at the expense of more acute and chronic GVHD and a higher TRM.23 The Stanford/City of Hope regimen of VP16 and total body irradiation (TBI) may result in a lower relapse rate24 (this is currently being examined by the IBMTR) and it is a feasible conditioning regimen for UD-SCT (Marks D, unpublished observations). The problem with relapse of ALL post-allograft is that the chance of response to donor leukocyte infusion (DLI) is very low, 18 and 5% in the two largest published series25,26 and these may not be durable. The possibility of using pre-emptive DLI in those at high risk of relapse requires investigation. The Bristol unit has performed UD-SCT on 16 patients 5 17 years with ALL in CR2 with a median age of 23 years (range 17±49) and eight have survived. Actuarial DFS is 46 + 16% (+SE) at 18 months with a median follow-up of 19 months (Marks D, unpublished data). Two of these 16 patients have relapsed, both at less than 4 months post-BMT. To summarize, UD-SCT has a greater antileukaemic eect than an autograft and may be the treatment of choice for those with ALL in CR2 at high risk of relapse ± such as those with an unfavourable karyotype, marked leukocytosis or a short CR1 duration. The decision is made easier when the patient is young and the donor is well matched. UD-SCT is being increasingly used for adults with ALL in CR1 who present with high white-cell counts or other poor prognostic features identi®ed by Hoelzer and colleagues (1988), but there are no randomized studies or large series reporting outcome. The chance of cure with modern chemotherapy protocols is about 30% only, and the outcome of ALL allografted in CR1 using sibling donors is excellent, so that if the transplant-related mortality of UD-SCT can be made to approach that of sibling donor SCT then this will become a reasonable therapeutic option.
Allogeneic transplantation with unrelated donors 797
PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKAEMIA Philadelphia-positive acute lymphoblastic leukaemia remains the clearest indication for unrelated donor SCT in ®rst remission. Chemotherapy alone achieves remission in over three-quarters of patients, but remissions are brief.27 There are some encouraging reports of cures in children with very intensive chemotherapy, particularly in those who present with a white cell count of 525 109/l28, but this has not been reproduced in adult patients. Autologous stem cell transplantation is another potential option for patients with Philadelphia-positive ALL, and it may be possible to collect cells with a degree of bcr-abl negativity29, but there are no long-term data to support the use of autografting for this disease. Sierra and colleagues30 in Seattle reported 18 patients with a median age of 25 years who had T-replete UD transplants for Philadelphia-positive ALL. Forty-nine percent survived leukaemia-free at 2 years with a 78% incidence of grade II±IV acute GVHD, a 450% incidence of extensive chronic GVHD and a 28% incidence of relapse. Marks and colleagues31 in Bristol reported 15 children and young adults treated with UDSCT for this disease (nine CR1 and six more advanced disease, median age 5 years) with 37 and 44% disease-free and overall survivals at 2 years. Five of nine transplanted in CR1 survived, although one survivor has developed a second tumour. The incidence of acute and chronic GVHD was much lower than that seen in Seattle but that is partly explained by the younger age of the patients. Six of 15 patients relapsed (40%), not signi®cantly more than would have been expected if the grafts were T-replete. Available data suggest that patients who are referred in CR2 are also curable30,31 and that there is clinical urgency to transplant them as second remissions in this disease are brief. Barrett and colleagues from the IBMTR32 found that sibling allografts cured a proportion of patients not in remission; there are no data in the unrelated donor setting that cast light on whether it is reasonable to oer UD-SCT to these patients. CHRONIC MYELOID LEUKAEMIA Management decisions in the newly diagnosed patient with chronic myeloid leukaemia (CML) without a sibling donor are complex, and the introduction of STI571 has made things even less clear.33 It is easiest to start with what we do know. The only proven curative therapy of CML is an allogeneic transplant.34 Alpha-interferon, which can produce median survivals of 46 years35, is not curative and substantially aects the quality of life in a proportion of responders. Complete cytogenetic responders, comprising 10±26% of all patients treated, may experience very prolonged survival, and it is entirely reasonable to observe them closely and transplant them when they relapse cytogenetically. However, it may take 18±24 months to ascertain the maximum response of any individual, and this therapy may aect the outcome of subsequent UDSCT by causing an excess of steroid-refractory chronic GVHD.36 This provocative ®nding arises from a single centre and requires veri®cation in a larger cohort of patients; this is the current subject of work by Lee and colleagues of the IBMTR. Interferon does not appear to aect the outcome of a subsequent sibling allograft37 but it is clear from many studies that patients with CML are optimally transplanted in the ®rst year after diagnosis.38 STI571, at doses 4300 mg/day, produces a nearly 100% haematological response rate in patients with CML in CP1.39 Major cytogenetic responses are seen in over half of patients (complete responses in 13%), and short-term toxicity is minimal. Molecular
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remission has not been documented to date, and given the small number of relapses seen in treated individuals, and the data concerning in vitro resistance mechanisms of tumour cell lines, it is not possible to be con®dent that responses will be truly durable.40,41 Although not curative, it is possible that complete cytogenetic responders will experience a survival of 410 years. There are, of course, no data about whether prior therapy with STI571 will compromise transplant outcome. It is also possible that combining STI571 with other agents, such as cytosine arabinoside or interferon, may avoid the problem of resistance.42 The Seattle experience in nearly 200 patients in CP1 most clearly de®nes what can be achieved with UD-SCT in this disease.2 There was an overall 5-year survival of 57%, but it was 74% in the subgroup of patients who were 550 years of age, HLA-matched and transplanted within a year of diagnosis. Survival was adversely aected by older age (450 years), HLA-DRB1 mismatches, a prolonged time from diagnosis to transplant (41 year) and a high body-weight index. There was no adjustment of donor T cell dose; grade II±IV acute GVHD occurred in 77% of those matched, with a higher incidence in those with class I or class II mismatches. The quality of life experienced by this transplant cohort is uncertain. Some 30% had a Karnofsky score of 590 at 1 year, extensive chronic GVHD occurred in 2/3 but immunosuppression was able to be discontinued in over half the patients who survived 5 years. The actuarial relapse rate was predictably low (10% at 5 years) and only half of these have died. TRM was 39%, most frequently associated with refractory GVHD. Similar results were achieved nationally in the USA, with a 63% 3-year DFS in the group of patients 535 years transplanted within a year of diagnosis.43 An Italian multicentre study of CML patients treated with UD-SCT reported that, in patients transplanted since 1993, there was 63% DFS and found that a high cell dose and early use of cyclosporin (at day ÿ8) were associated with better survival on multivariate analysis.44 The major alternative strategy to unmanipulated UD grafts is to T-cell-deplete the marrow, reduce the incidence of acute and chronic GVHD (possibly improving the quality of life) and accept a high incidence of relapse knowing that subsequent donor leukocyte infusions have a high probability of achieving molecular remission and longterm disease-free survival45 (Marks D, unpublished observations). T cell depletion is eective in reducing severe (grade III±IV) acute GVHD but is somewhat less eective at reducing chronic GVHD with rates of 29/39 (74%) with the T10B9 antibody46 and 77% with Campath antibodies.47 More modern technologies, such as the Clinimacs and Isolex devices, enable delivery of precise doses of CD3 cells and may be even more eective in eliminating GVHD, probably with the cost of more relapse. The other probable adverse eects of TCD include more viral and fungal infection due to slower immune reconstitution.48 The major problems associated with a T cell depletion strategy are that not all relapsed patients are able to receive DLIs and not all who do respond. In a national survey in the USA, in 25 patients who relapsed after UD-SCT for CML there was 65% 1-year DFS and one-quarter of the patients experienced grade II±IV acute GVHD.49 Very careful surveillance (3-monthly marrows and, if possible, quantitative PCR) is needed as early detection of relapse may improve the outcome of DLIs.45,50 The chance of relapse of CML with TCD varies. It exceeds 60% with the Campath antibodies51 but appears to be less with the T10B9 antibody.52 It is not known for Miltenyi CD34 selected stem cells, but given their ability to deplete grafts to 51 104 CD3 cells/kg of recipient weight it is likely to be high. Another problem identi®ed by the NMDP study of UD-SCT for CML is graft failure.43 Primary graft failure occurred in 10% and secondary graft failure in over 6%.
Allogeneic transplantation with unrelated donors 799
This is more common in mismatched UD-SCT but may be partly overcome by increasing the cell dose. Larger patients, especially those with mismatches at the C locus and whose stem cells are being T-cell-depleted, might bene®t from the higher cell doses achievable with peripheral blood stem cells. The chances of cure are lower in accelerated phase or second chronic phase but UDSCT is certainly indicated where the performance status is good and the match acceptable. There are few data that report the outcome in these phases of the disease, but it is possible that the potentially enhanced graft versus leukaemia (GVL) eect of UD-SCT may be bene®cial. The Seattle group report approximately 35% 4-year survival in 56 patients in accelerated phase. The probability of survival in second chronic phase was somewhat less, about 27% in 15 patients.53 A relapse into accelerated phase is less likely to respond to DLIs and it may be worth considering performing these transplants with unmanipulated marrow. Against that is information indicating that a higher nonrelapse mortality is seen when patients are transplanted with advanced-phase disease.54 In my opinion, UD-SCT is not indicated for the true blast crisis CML. The Seattle group report about 9% survival at 3 years in 23 patients but there were only two patients more than 4 years post-BMT. In these patients leukaemia should be tested for chemosensitivity; if unresponsive, it is very unlikely that transplant will be curative. If they are successfully returned to chronic phase it is reasonable to proceed to transplant. CHRONIC LYMPHOCYTIC LEUKAEMIA The National Cancer Institute Chronic Lymphocytic Leukaemia (CLL) Working Group has recommended a three-risk group system, modi®ed from the 5 Rai stages, with median survivals of 14, 8 and 4 years respectively.55 Due to its indolent natural history, and partly because of the advent of ¯udarabine-based regimens56, there is something of a complacent attitude to CLL, even in young patients. Sibling allograft has an established role in this disease, with the European Bone Marrow Transplant Group (EBMT) reporting 40% 5-year leukaemia-free survival in 45 evaluable patients, mainly with Rai stage 3 and 4 disease.57 Similarly, the MD Anderson group reported 57% 3-year DFS in 38 patients with advanced CLL with a median of three prior therapies.58 In the opinion of the author all patients with CLL 545 years of age are candidates for allogeneic transplant, particularly if they have adverse prognostic features such as advanced stage, a high beta-2 microglobulin level at diagnosis, lymphocyte doubling time of 512 months and certain cytogenetic abnormalities.59 Refractoriness to ¯udarabine is another important factor in the decision to transplant.60 The IBMTR have data on 73 patients who had UD-SCT performed by 31 teams between 1993 and 2000, with a median age of 46 years and a median of 50 months from diagnosis to transplant. The majority received TBI-containing regimens and had cyclosporin and methotrexate GVHD prophylaxis. Fifty percent of evaluable patients are in complete remission, and the 2- and 4-year probabilities of survival are 52 + 14% and 41 + 16% respectively (95% CI) (Horowitz M, personal communication). UD-SCT will not become an important part of the management of patients with CLL until it can be performed with a lower TRM on a larger percentage of patients with the disease. Reduced intensity conditioning may be a way round these problems but long-term survival data are lacking.61,62 Relapse is a major problem after allograft for CLL but there appears to be a degree of responsiveness to DLIs63 and the delayed remissions achieved after allograft provide evidence for a GVL eect.
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MYELODYSPLASTIC SYNDROMES Allogeneic SCT is the only proven curative therapy for myelodysplastic syndromes (MDS).64 It is clearly indicated for patients with high- or intermediate-risk disease65 but is most eective for those with low-risk disease.66 Young patients with low-risk disease and a short disease duration are worth considering for UD-SCT; it is reasonable to follow closely the clinical progress of older patients (with low-risk disease) with a plan to transplant them at the ®rst sign of disease progression (increased blast count or the development of new cytogenetic abnormalities). This strategy requires frequent bone marrow aspirates but has risks associated because the transformation of MDS can be rapid. It is not certain whether patients should receive induction chemotherapy prior to BMT. Being in CR at transplant correlates with an improved outcome67 but chemotherapy may result in complications that prevent the patient proceeding to BMT. Castro-Malaspina and colleagues from the NMDP68 reported 320 NMDP-facilitated unrelated donor transplants. Sightly less than one-third were alive and disease-free at 2 years. Infection, GVHD and relapse appear to be the major problems associated with UD-SCT for MDS.69 A longer disease duration and a low neutrophil count at transplant are associated with a higher non-relapse mortality, possibly partly related to more exposure to transfusions. The EBMT recently reported its results in 118 patients with MDS or secondary AML.70 As with the NMDP data, there was 28% DFS at 2 years with a very high TRM of 58% and a relapse risk of 35%. Relapse risk was lower in oligoblastic disease and a GVL eect was apparent. This latter ®nding seemed to agree with the ®nding that DLI may be of some value for relapsed disease.71 An alternative strategy is to give AML-type chemotherapy to achieve a complete remission and then harvest autologous stem cells and use these to rescue the patient from high-dose chemotherapy.72 In 79 patients treated in this way, reported by the EBMT, 34% were disease-free at 2 years and relapse occurred in 64%. Results were better in those aged less than 40. Longer follow-up is required to determine whether any of these patients are cured. POTENTIAL DEVELOPMENTS IN UD-SCT FOR LEUKAEMIA The option of using peripheral blood stem cells (PBSC) from unrelated donors will become an important issue. In Germany, where PBSC have been available for some time, there is evidence suggesting that if they are given unmanipulated the incidence of chronic GVHD approaches 100%.73 The randomized study comparing blood and marrow stem cells for sibling allograft transplants performed by Seattle, Stanford and City of Hope suggests that there may be a survival bene®t in patients with high-risk leukaemia74 but not all studies agree with these ®ndings. A matched pair analysis of PBSC and marrow-derived unrelated transplants performed in Germany and Scandinavia showed no dierence in outcome between the two stem cell sources.4 Increasing the cell dose for UD-SCT is undoubtedly bene®cial, but if using PBSC leads to more GVHD then this may compromise outcome. Boosting the marrow cell dose by using T-depleted PBSC is one way of avoiding excessive numbers of T cells in the stem cell inoculum. The higher cell dose and rapid engraftment kinetics of UD-PBSC are clearly desirable in second transplants for primary graft failure. There are no large reports regarding reduced-intensity conditioning UD-SCT, but if the mortality could be reduced to that of matched sibling allografts then this will increase the subset of patients eligible for UD-SCT. However, a word of caution
Allogeneic transplantation with unrelated donors 801
should be sounded. The durability of complete responses following non-myeloablative transplants is not known, nor is the ecacy of DLI for treating relapsed disease or persistent mixed chimerism. A signi®cant proportion of these transplants result in GVHD; this is poorly tolerated by older, in®rm patients. The ethics of using unrelated donors in this experimental setting require further debate. CONCLUSION In summary, UD-SCT has a clear role in the management of adult patients with CML in ®rst chronic phase and accelerated phase, AML and ALL in CR2 and severe MDS. As results approach those seen with matched sibling allografts it will be used increasingly for younger patients with high-risk ALL and AML in CR1, early MDS and treatmentrefractory CLL with multiple adverse prognostic factors. The role of reduced intensity conditioning for unrelated donor allografts requires further investigation but is appealing in older patients with slower paced diseases which may be responsive to cellular immunotherapy. Similarly, the role of UD-PBSC requires further study. Acknowledgements I wish to acknowledge my colleagues at the three institutions where I have performed unrelated donor transplants: John Goldman and John Barrett at the Hammersmith, Pam Crilley, Dave Topolsky and Mike Styler at Hahnemann University, Philadelphia, and the transplanters in Bristol, Tony Oakhill, Jackie Cornish, Derwood Pamphilon, Practice points . all patients with leukaemia who may require UD-SCT at some point in their disease should be tissue typed at diagnosis and a preliminary computerized search performed . recommendations for individual patients as to whether they should have UDSCT are dicult and involve taking into account the patient's individual prognostic factors and personal views; they require considerable extrapolation from the available literature . UD-SCT, in general, has a lower TRM if it is performed early in the course of a patient's disease
Research agenda . the role of reduced intensity conditioning in UD-SCT requires further investigation . the use of UD-PBSC as a means of increasing cell dose, speeding up both engraftment and immune reconstitution will be a major area of research . only randomized studies comparing UD-SCT with alternative therapies will determine its true role; these studies should incorporate quality-of-life measures . the identi®cation of `permissive mismatches' will improve outcome and increase the proportion of patients eligible for UD-SCT
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Colin Steward and Nick Goulden. Tony Oakhill and Jenny Bird read the manuscript and made many helpful comments. In addition, thanks should be given to the registrars, fellows, data managers and statisticians who have worked with me on my papers concerning UD-SCT; they are too numerous to mention individually. The data from the IBMTR have not been reviewed by the Advisory Committee. REFERENCES * 1. Marks DI, Otton S, Williamson E & Bird JM. Unrelated donor bone marrow transplantation in adults: some current controversies. Leukemia and Lymphoma 1999; 32: 459±466. * 2. Hansen JA, Gooley TA, Martin PJ et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. New England Journal of Medicine 1998; 338: 962±968. 3. Marks DI, Gale DJ, Vedhara K & Bird JM. A quality of life study in 20 adult long-term survivors of unrelated donor bone marrow transplantation. Bone Marrow Transplantation 1999; 24: 191±195. 4. Ringden O, Renberger M, Blass I et al. Peripheral stem cells versus bone marrow from unrelated donors. A match pair analysis of 214 patients. Biology of Blood and Marrow Transplantation 2001; 7: 96 (abstract). 5. Einsele H, Hebart H, Roller G et al. Detection and identi®cation of fungal pathogens in blood by using molecular probes. Journal of Clinical Microbiology 1997; 35: 1353±1360. * 6. Marks DI, Bird JM, Vettenranta K et al. T cell-depleted unrelated donor bone marrow transplantation for acute myeloid leukemia. Biology of Blood and Marrow Transplantation 2000; 6: 646±653. 7. Lazarus HM, Perez WS, Weisdorf D et al. Autologous versus unrelated donor transplantation for acute myeloid leukemia in ®rst or second remission. Blood 2000; 96: 414a (abstract no 1781). 8. Busca A, Anasetti C, Anderson G et al. Unrelated or autologous marrow transplantation for treatment of acute leukaemia. Blood 1994; 83: 3077±3084. 9. Sierra J, Storer B, Hansen JA et al. Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience. Bone Marrow Transplantation 2000; 26: 397±404. 10. Burnett AK, Goldstone AH, Stevens RM et al. Results of the MRC AML10 study. Lancet 1998; 351: 700±708. 11. Zittoun RR, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myeloid leukemia. New England Journal of Medicine 1995; 332: 217±223. 12. Papadopoulos EB, Carabasi MH, Castro-Malaspina H et al. T-cell-depleted allogeneic bone marrow transplantation as post-remission therapy for acute myelogenous leukaemia: freedom from relapse in the absence of graft versus host disease. Blood 1998; 91: 1083±1090. *13. Ferrant A, Labopin M, Frassoni F et al. Karyotype in acute myeloblastic leukemia: prognostic signi®cance for bone marrow transplantation in ®rst remission: a European Group for Blood and Marrow Transplantation study. Blood 1997; 90: 2931±2938. *14. Sierra J, Storer B, Hansen JH et al. Transplantation of marrow cells from unrelated donors for treatment of high risk acute leukemia: the eect of leukemic burden, donor HLA matching, and marrow cell dose. Blood 1997; 89: 4226±4235. 15. Davies SM, Kollman C, Anasetti C et al. Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the National Marrow Donor Program. Blood 2000; 96: 4096±4102. *16. Aversa F, Tabilio A, Velarde A et al. Treatment of high risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. New England Journal of Medicine 1998; 339: 1186±1193. 17. Ramsay N, LeBien T, Weisdorf D et al. Autologous BMT for patients with acute lymphoblastic leukemia. In Gale R & Champlin R (eds) Bone Marrow Transplantation: Current Controversies, pp 57±66. New York: Alan R. Liss, 1987. 18. Soier RJ, Roy DC, Gonin R et al. Monoclonal antibody-purged autologous bone marrow transplantation in adults with acute lymphoblastic leukemia at high risk of subsequent relapse. Bone Marrow Transplantation 1993; 12: 243±251. 19. Weisdorf DJ, Billett AL, Hannan P et al. Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia. Blood 1997; 90: 2962±2968. 20. Weisdorf DJ, Cairo M, Dharan B et al. Autologous versus allogeneic unrelated donor transplantation for acute lymphoblastic leukemia. Blood 2000; 96: 413a (abstract 1779). *21. Green A, Clarke E, Hunt L et al. Children with acute lymphoblastic leukemia who receive T-celldepleted HLA mismatched marrow allografts from unrelated donors have an increased incidence of primary graft failure but a similar overall transplant outcome. Blood 1999; 94: 2236±2246.
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Mechanism of resistance to ABL tyrosine kinase inhibitor STI571 in BCR/ABLtransformed hematopoietic cell lines. Blood 2000; 95: 3498±3505. 41. Mahon FX, Deininger MW, Shultheis B et al. Selection and characterization of BCR-ABL positive cell lines with dierential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 2000; 96: 1071±1079. 42. Theising JT, Ohno-Jones S, Kolibabo KS & Druker BJ. Ecacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl positive cells. Blood 2000; 96: 3195±3199. 43. McGlave PB, Shu XO, Wen W et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program. Blood 2000; 95: 2219±2225. 44. Dini G, Lamperelli T, Rondelli R et al. Unrelated donor marrow transplantation for chronic myelogenous leukaemia. British Journal of Haematology 1998; 102: 544±552. *45. Dazzi F, Szydlo RM, Cross NCP et al. 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804 David I. Marks *47. Marks DI, Cullis JO, Ward KN et al. Allogeneic bone marrow transplantation for chronic myeloid leukaemia using sibling and volunteer unrelated donors. A comparison of complications in the ®rst 2 years. Annals of Internal Medicine 1993; 119: 207±214. 48. Williamson E, Cornish JM, Pamphilon DH et al. Infections in adults undergoing unrelated donor bone marrow transplantation. British Journal of Haematology 1999; 104: 560±568. 49. Porter DL, Collins RH Jr, Hardy C et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95: 1214±1221. 50. van Rhee F, Lin F, Cullis JO et al. Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: the case for giving donor leukocyte transfusions before the onset of hematologic relapse. Blood 1994; 83: 3377±3383. 51. Craddock C, Szydlo RM, Dazzi F et al. Cytomegalovirus seropositivity adversely in¯uences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis. British Journal of Haematology 2001; 112: 228±236. 52. Hessner MJ, Endean DJ, Casper JT et al. Use of unrelated marrow grafts compensates for reduced graft versus leukemia reactivity after T cell depleted allogeneic marrow transplantation for chronic myelogenous leukemia. Blood 1995; 86: 3967±3996. 53. Hansen JA & Petersdorf EW. Unrelated donor hematopoietic cell transplantation. In Thomas ED, Blume KG & Forman SG (eds) Hematopoietic Cell Transplantation, pp 915±928. Malden, MA: Blackwell Science, 1999. 54. Martin PJ, Clift RA, Fisher LD et al. HLA-identical marrow transplantation during accelerated phase chronic myelogenous leukemia: analysis of survival and remission duration. Blood 1988; 72: 1978±1984. 55. Cheson BD, Bennett JM, Grever M et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990±4997. 56. Keating MJ, Smith TL, Lerner S et al. Prediction of prognosis following ¯udarabine used as secondary therapy for chronic lymphocytic leukemia. Leukemia and Lymphoma 2000; 37: 71±85. 57. Michallet M, Archimbaud E, Bandini G et al. HLA-identical sibling transplants for chronic lymphocytic leukaemia. A collaborative study of the EBMTG and the IBMTR. Blood 1993; 82: 345a. 58. Khouri IF, Keating MJ, Vriesendorp HM et al. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. Journal of Clinical Oncology 1994; 12: 748±758. 59. Foon KA & Gale RP. Chronic lymphoid leukemias. In Handin RI, Lux SE & Stossel TP (eds) Blood, Principles and Practice of Hematology, pp 783±811. Philadelphia: Lippincott, 1995. 60. Seymour JF, Robertson LE, O'Brien S et al. Survival of young patients with chronic lymphocytic leukemia failing ¯udarabine therapy: a basis for the use of myeloablative therapies. Leukemia and Lymphoma 1995; 18: 493±496. 61. Schetelig J, Held TK, Bornhauser M et al. Nonmyeloablative allogeneic stem cell transplants in chronic lymphocytic leukemia from related and unrelated donors. Blood 2000; 96: 200a (abstract 857). 62. Khouri I, Munsell M, Yajzi S et al. Comparable survival for nonablative and ablative allogeneic transplantation for chronic lymphocytic leukemia: the case for early intervention. Blood 2000; 96: 205a (abstract 877). 63. Rondon G, Giralt S, Huh Y et al. Graft versus leukemia eect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplantation 1996; 18: 669±672. *64. Anderson JE. Bone marrow transplantation for myelodysplasia. Blood Reviews 2000; 14: 63±77. 65. Greenberg P, Cox C, LeBeau MM et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079±2088. 66. Runde V, de Witte T, Arnold R et al. Bone marrow transplantation from HLA-identical siblings as ®rst line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Bone Marrow Transplantation 1998; 21: 255±261. 67. Yakoub-Agha I, de La Salmoniere P, Ribaud P et al. Allogeneic bone marrow transplantation for therapyrelated myelodysplastic syndrome and acute myeloid leukemia: a long term study of 70 patients-report of the French society of BMT. Journal of Clinical Oncology 2000; 18: 963±971. 68. Castro-Malaspina H, Collins JER, Gajewski J et al. Unrelated donor marrow transplantation for myelodysplastic syndromes. Blood 1997; 90: 106a (abstract 465). 69. Anderson JE, Anasetti C, Appelbaum FR et al. Unrelated donor marrow transplantation for myelodysplasia (MDS) and MDS-related acute myeloid leukaemia. 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Allogeneic transplantation with unrelated donors 805 71. Anderson JE. Allogeneic hematopoietic cell transplantation for myelodysplastic and myeloproliferative disorders. In Thomas ED, Blume KG & Forman SG (eds) Hematopoietic Cell Transplantation, pp 872±886. Malden, MA: Blackwell Science, 1999. 72. De Witte T, van Biezen A, Hermans J et al. Autologous bone marrow transplantation for patients with myleodysplastic syndrome or acute myeloid leukemia following MDS. Blood 1997; 90: 3853±3857. 73. Blau IW, Basara N, Schmetzer B et al. Comparison of unrelated peripheral blood stem cell transplantation with unrelated bone marrow transplantation. Blood 1999; 94: 562a (abstract 2512). 74. Bensinger W, Martin P, Clift R et al. A prospective, randomised trial of peripheral blood stem cells or marrow for patients undergoing allogeneic transplantation for hematologic malignancies. Blood 1999; 94: 368a (abstract 1637).