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Haemopoietic stem cell transplantation for acute lymphoblastic leukaemia
CANCER TREATMENT REVIEWS 2003; 29: 3–10 doi:10.1016/S0305-7372(02)00092-0
ANTI-TUMOUR TREATMENT
Haemopoietic stem cell transplantation for acute lymphoblastic leukaemia Uday Popat, George Carrum and Helen E. Heslop Departments of Medicine and Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA The majority of children and some adults with acute lymphocytic leukaemia (ALL) can be cured with current intensive chemotherapy regimens. For those patients who relapse or who do not achieve remission, allogeneic haemopoietic stem cell transplantation (HSCT) offers the best chance for long-term disease control. Different sources of haemopoietic stem cells including marrow, peripheral blood, and cord blood are now available and the introduction of subablative regimens has increased the number of patients who are transplant candidates. Relapse remains the major cause of transplant failure and immunotherapy strategies post-transplant to augment the graft versus leukaemia effect are being explored. c 2003 Elsevier Science Ltd. All rights reserved. s
INTRODUCTION
DISEASE STAGE
While current chemotherapy regimens cure most pediatric and some adult patients with acute lymphoblastic leukaemia (ALL), haemopoietic stem cell transplantation (HSCT) provides better long-term disease free survival for those patients who have high-risk features or who relapse. The decision on whether an individual patient with ALL is an appropriate candidate for HSCT is complicated by continual redefinition of risk factors by newer molecular studies (1). In addition, there are relatively few prospective studies comparing the outcome with chemotherapy or transplant. Factors such as the intensity of previous chemotherapy and time of censoring limit the value of retrospective analyses and data from registries such as the International Bone Marrow Transplant Registry (IBMTR) and National Marrow Donor Program (NMDP).
Acute lymphoblatic leukaemia (ALL) in first remission
Correspondence to: Helen E. Heslop, Departments of Medicine and Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates St., Suite 1140 Houston, TX 77030, USA. Tel: +832-824-4662; Fax: +832-825-4668; E-mail: hheslop@bcm. tmc.edu
Outcomes with conventional chemotherapy and allogeneic stem cell transplantation are both improving. With the use of current induction regimens more than 90% of patients with ALL achieve complete remission. Factors that need to be considered before recommending HSCT as post-induction therapy include: 1. Cure rate with conventional chemotherapy. 2. Transplant related morbidity and mortality. 3. Cure rate with HSCT in first relapse or second remission. As the risk of transplant related mortality needs to be balanced against potential cure with standard chemotherapy alone, allogeneic HSCT as post-induction therapy is favored in patients who are at a high risk of relapse after standard chemotherapy. In children with ALL, the likelihood of cure with modern intensive chemotherapy range is 70–80% (2). Using available HLA identical donor versus no donor analysis, a Medical Research Council Study did not show benefit of allogeneic HSCT in first remission in high-risk children with an HLA identical sibling compared to those who did not have an HLA
c 2003 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED. 0305-7372/03/$ - see front matter s
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U. POPAT ET AL.
TA B L E 1 Comparative studies of Allogeneic HSCT in adults (P15 yrs.) with ALL in first CR Study
N
DFS with allogeneic HSCT (%)
DFS with autograft or chemo (%)
P value
HOVON 18 (56) UKALL XII(Ph)) (57) UKALL XII(Ph+) (58) LALA 87 (9) IBMTR (59) Japanese study (60) BGMT (28)
124 434 148 257 718 290 120
53 54 41a 46a 34 53b 68
36 34 27a 31a 32 30b 26
0.05 0.04 0.5 0.04 NS 0.02 <0.01
a b
Overall survival. AgeO30.
identical sibling (3). However, a recent multicenter study has confirmed that outcome post-treatment in children with Philadelphia chromosome-positive (Ph+) ALL is superior with use of HSCT versus chemotherapy alone (4). Patients with the t(4;11) translocation also do poorly with chemotherapy so that HSCT is usually recommended although a recent retrospective multicenter study suggests it does not improve outcome (5). Allogeneic HSCT should therefore be reserved for children whose leukaemia has poor prognostic features, such as the t(9;22) or the t(4;11) translocations or a delayed response to remission induction therapy. In adults the cure rate with chemotherapy is only 25–40%, because more patients have high-risk features [age > 35 years, WBC > 30 109 /L in B lineage ALL, WBC > 100 109 /in T lineage ALL, null cell phenotype, remission induction > 4 weeks, extramedullary disease or presence of the t(9;22) or t(4;11)]. Any one of these features reduces the chance of long-term DFS with chemotherapy to between 15% and 25%, making the patient a candidate for allografting in first remission. IBMTR data for patients transplanted between 1991 and 1997 show a DFS of 52% in patients receiving allografts in first remission (6), while single center rates range from 48% to 61% (7,8). These results are difficult to interpret because of varying proportions of patients with different risk factors in each study. Prospective randomized studies have been carried out by various cooperative groups. These studies have compared patients with HLA identical siblings assigned to the allogeneic HSCT group to those without HLA identical sibs assigned to either a standard chemotherapy or autologous HSCT group. A major limitation of these studies is that the proportion of patients in the allogeneic HSCT group actually undergoing transplant varies from study to study. Despite this limitation, a donor versus no donor comparison is the best way to answer the question about role of allogeneic HSCT in first remission. In a prospective French study, patients with matched sibling donors received allogeneic trans-
plants, while others were randomized to autografting or chemotherapy (9). In an intent to treat analysis, at 10 years the overall survival rate for allograft recipients was 46% compared to 31% in control patients. The benefit of an allograft was most pronounced in high-risk patients (Ph+, null or undifferentiated immunophenotype, age >35 years, or WBC > 30 109 /L or time to CR > 4 weeks), where the DFS was 44% in the allograft group compared with 11% in the control group (7,9). The outcome for recipients of an autologous transplant was not significantly greater than that for chemotherapy alone (34% versus 29%). The largest randomized study was conducted by the Medical Research Council and the Eastern Cooperative Oncology Group. Preliminary results indicate a beneficial effect of transplant. Results of these and other studies are summarized in Table 1. Notable features of all these studies include a high treatment related mortality and a lower risk of relapse in allogeneic transplant arm. Other studies comparing patients in the IBMTR database with control groups from cooperative groups have shown no difference or differences only in patients younger than 30 (Table 1). In summary, based on the currently available data, allogeneic HSCT is a reasonable treatment option for adults with high-risk ALL. Definitive recommendation should await the final results of these and other studies.
ALL in second remission After relapse, the chances of cure with chemotherapy are low in adults, and allogeneic HSCT should be performed. IBMTR data from 1991 to 1997 show a DFS of 42% for patients transplanted in second remission (6). For children who relapse on maintenance therapy, particularly after modern intensive chemotherapy, the chance of long-term survival with chemotherapy is less than 20%. A combined Pedi-
HAEMOPOIETIC STEM CELL TRANSPLANTATION FOR ALL
atric Oncology Group and IBMTR study yielded a DFS rate of 40% in patients receiving allografts, compared with 17% in those receiving chemotherapy (10). A similar trend towards beneficial effect of Allogeneic HSCT was observed in another study in patients with a short first remission (<2 years) (11). A Medical Research Council study confirmed a poor outcome (DFS 3%) for children with a short initial remission and a better outcome for those with late isolated extramedullary relapse. Allogeneic transplant showed an absolute increase in 5-year eventfree survival of 14% (from 26.4% to 40.7%) (12). The requirement for allografting in children with an isolated extramedullary relapse or in those who relapse than 6 months after completing maintenance therapy is more contentious, as these patients may be cured with salvage chemotherapy. In addition in many ongoing studies exploring risk-adapted therapy, children staged as low risk are treated with less intensive regimens. If such patients relapse, they may potentially be salvaged by more intensive chemotherapy, although no data are available as yet.
ALL after second relapse or primary induction failure Once patients are beyond second remission, the results of all allografting procedures worsen considerably, with only 10–15% of patients becoming longterm disease-free survivors (13,14). A small number of patients will also fail primary induction therapy. While the outcome with transplant is poor with only 10–15% DFS, it offers the only prospect of cure (15).
DONOR SOURCE Matched sibling The donor of choice is a matched sibling but less than a third of the patients who might benefit from allogeneic transplantation have this option and the remaining patients must consider use of an alternative donor.
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33% in second complete remission (CR2) (6). The NMDP reports 5-year DFS of 35% in CR1 in adults and 46% in children falling to 25% and 40%, respectively, in CR2. In primary induction failure or relapse DFS at 5 years is only 6% in adults and 11% in children (16). Over the past few years, improved results have been reported from several single center studies particularly in pediatric patients, reflecting improvements in donor/recipient matching, GVHD prophylaxis, and supportive care (17–21). In a recent analysis, the use of a younger donor and a younger recipient age were both associated with significantly improved outcome (22).
Haploidentical family donors While an unrelated donor search may take several months, most individuals have a haploidentical relative. Use of a mismatched family member donor is associated with an increased risk of GVHD due to increased alloreactivity, and this risk increases with the degree of mismatch. Three main approaches have been explored to reduce the risk of GVHD. The first is T-cell depletion of the donor marrow in conjunction with immunosuppression both pre- and post-transplantation. Henslee–Downey et al. (27) reported 2-year overall survival rates of 55% in low-risk patients and 27% in high-risk patients who underwent haploidentical transplantation by this approach. A second strategy is to use a G-CSF-mobilized, large-volume apheresis and CD34 selection with or without additional T-cell depletion. The reported DFS rates achieved with this alternative source of donors range from 17% to 40% (23,24). A third approach relied on the induction of anergy to inactivate alloreactive T cells in the donor marrow (25). In a preliminary report of 12 patients, bone marrow from a donor mismatched with the recipient for one HLA haplotype was cocultured with irradiated cells from the recipient for 36 h in the presence of CTLA-4-Ig, an agent that inhibits B7/CD28-mediated co-stimulation. Only 3 of 11 evaluable patients developed acute GVHD, and five patients were alive in remission (25).
Unrelated donors Historically, the outcome after transplantation from unrelated donors has been inferior to that observed after matched sibling transplantation due to increased rates of graft rejection and graft versus host disease (GVHD) resulting from increased alloreactivity in this setting. The IBMTR reports a DFS of 44% for patients receiving unrelated donor transplants for ALL in first complete remission (CR1) and
Autologous transplants Autologous HSCT remains an investigational approach in the therapy for ALL. This procedure allows the use of higher doses of chemotherapy, but carries the risk of reinfusion of leukaemic cells in the harvested marrow. A comparison of autologous and unrelated donor transplants performed at the Uni-
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versity of Minnesota and the Dana–Farber Cancer Institute showed an increased risk of relapse after an autograft and increased regimen related toxicity after an unrelated donor transplant (26). Disease-free survival was better after transplantation from an unrelated donor. The IBMTR reports overall DFS of 43% in CR1, 37% in CR2 or later CR and 5% in relapse for patients receiving autografts (6). The prospective French study showed no benefit of autograft in CR1 compared with chemotherapy (9). This question was also addressed in a prospective study carried out by BGMT group comparing autologous versus allogeneic HSCT for ALL in CR1 and showed significantly higher DFS (68% with allogeneic transplant compared to 26% with autologous transplant) (28). One potential use of autologous HSCT may be in patients who are poorly compliant with maintenance chemotherapy.
SOURCE OF STEM CELLS FOR ALLOGENEIC TRANSPLANTATION Bone marrow versus mobilized peripheral blood Cytokine-mobilized allogeneic peripheral blood stem cell (PBSC) harvest has recently become an alternative to bone marrow as a source of stem cells for matched-sibling transplants. Early phase II studies showed that this source of stem cells resulted in faster engraftment, no increase in acute GVHD (perhaps due to a G-CSF-mediated shift to Th2 helper cells) but an increased incidence of chronic GVHD (29,30). A recent prospective randomized study of allogeneic PBSC compared to marrow showed a 2-year actuarial overall survival of 54% in patients receiving marrow compared with 66% in those receiving PBSCs (31). Differences in survival were significant for patients with unfavorable-risk diseases but not for those with favorable-risk diseases (31). Faster engraftment, similar GVHD and improvement in overall survival was also reported in a recent Canadian and New Zealand study (32). In a retrospective multivariate analysis from the IBMTR comparing the results of 288 HLA-identical sibling blood stem cell transplants with the results of 536 HLA-identical sibling bone marrow transplants, the relapse incidence between the two transplant groups did not differ significantly (33). However, treatment-related mortality rates were lower and leukaemia-free survival rates were higher with use of blood stem cell transplants in patients with advanced versus early leukaemia (acute leukaemia in first remission or CML in chronic phase) (33). While the results of more studies should become available over the next few years, the current experience
U. POPAT ET AL.
suggests that peripheral blood should be the preferred source of stem cells for patients with high-risk disease. For patients with low-risk disease, the increased risk of chronic GVHD needs to be balanced against the risk of relapse.
Cord blood Another alternative source of stem cells that has been attracting much interest is cord blood. Several recent studies have demonstrated the feasibility of transplants with cord blood from unrelated donors (34,35). Compared to unrelated bone marrow transplants, cord blood transplants have slower engraftment, decreased GVHD and increased 100-day transplant-related mortality (36). The immediate availability of cryopreserved cord blood units eliminates the usual delay in HSCT when unrelated donor marrow is used. Locatelli et al. reported the outcome of 102 children with acute leukaemia who received either related or unrelated umbilical cord blood HSCT (37). In multivariate analysis, the most important factor influencing neutrophil engraftment was a nucleated cell dose greater than 3:7 107 kg 1 . The most important factor influencing event-free survival (EFS) was disease status at the time of transplantation: good-risk patients had a 2-year EFS rate of 49%, compared with 8% in patients with more advanced disease. Rubenstein et al. (34) reported the outcomes of 562 recipients of placental-blood transplant from unrelated donors. The speed of myeloid engraftment was associated with the leukocyte content of the graft, whereas transplantation-related events were associated with the patientÕs underlying disease and age, the number of leukocytes in the graft, the degree of HLA-disparity, and the transplantation center.
PREPARATIVE REGIMENS Ablative regimens Conditioning regimens used for allogeneic HSCT must achieve adequate immunosuppression of the recipient to prevent rejection of the donor marrow cells and destroy residual malignant cells while causing minimal toxicity. Most preparative regimens for ALL use total body irradiation (TBI) and Cyclophosphamide while some centers use Etoposide and cytosine arabinoside (Ara-C) in addition to or instead of Cyclophosphamide. Busulphan-cyclophosphamide has also been used to avoid radiation but a recent IBMTR study showed an inferior outcome with this regimen with a 3-year probability of DFS of
HAEMOPOIETIC STEM CELL TRANSPLANTATION FOR ALL
35% versus 50% when TBI and Cyclophosphamide were used (38). Because most chemo-radiation regimens are at the limits of toxicity, any further dose escalation in an attempt to reduce the risk of relapse would probably increase the regimen-related toxicity to unacceptable levels, particularly in older or heavily pretreated patients. The addition of biological agents like monoclonal antibodies or radioconjugates to conventional conditioning regimens can potentially provide an augmented anti-leukaemic effect without increasing treatment related toxicity.
Subablative regimens High-dose chemotherapy and allogeneic stem cell transplantation carry substantial treatment related morbidity and mortality in older patients (>50 years), those with compromised organ function (e.g., congestive heart failure), coexisting infections, or those who were heavily pretreated prior to HSCT. In all of these patients, treatment-related mortality can exceed 50%, making them ineligible for HSCT. More recently, new strategies for allografting have explored an approach of less intensive conditioning therapy with the aim of allowing partial engraftment of donor immune and haematopoietic systems with eventual replacement of the hostÕs own haematopoiesis and immunity. A variety of regimens based on low-dose TBI or fludarabine are under investigation (39–42). Such reduced intensity conditioning regimens may be more suitable for patients with indolent malignancies where there is sufficient time for a graft versus malignancy effect to operate. Patient with acute leukaemia who have active disease transplanted with subablative regimens have a high relapse rate. Another major problem with submyeloablative regimens is an increased rate of graft failure ranging from 5% to 30% versus 1% to 5% in patients who underwent full myeloablation prior to HSCT. The use of lymphodepleting antibodies or a combination of monoclonal antibodies in addition to cytotoxic or immunosuppressive drugs could potentially decrease rejection rates (43,44).
IMPROVING THE OUTCOME OF TRANSPLANT GVHD Prophylaxis Graft-versus-host disease results from alloreactivity between donor and recipient. The two major prophylactic regimens employed to prevent this complication are pharmacological (administration of
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immunosuppressive drugs), and immunological (in vitro T-cell depletion of the donor marrow). The standard pharmacologic prophylaxis has been cyclosporine and short-course methotrexate, but recent studies suggest that the incidence of GVHD is even lower if FK506 is substituted for cyclosporine (45). MMF also shows promise in animal models, and its combination with cyclosporine is being evaluated in clinical trials. Ex vivo T-cell depletion reduces the risk of both acute and chronic GVHD and may allow higher tolerance of mismatching but may also increase the risk of rejection and delay immune reconstitution. A confounding feature for interpreting the value of T-cell depletion is that a variety of methodologies are employed to remove T cells, including physical methods and monoclonal antibodies. Some techniques produce a pan-T depletion, whereas others use antibodies with more restricted T-subset specificities. A recent IBMTR study shows a better outcome when antibodies with narrow specificities are used (46).
Reducing the risk of relapse The major cause of failure after transplant for ALL is relapse. The outcome of patients who relapse after allogeneic HSCT is very poor. Remissions are possible with standard chemotherapy but are not durable. Those who relapse more than 1-year posttransplant are more likely to achieve a further remission. Donor leucocyte infusions have been used but their success rate in patients with ALL is much lower than in patients with myeloid malignancies (47). Philadelphia chromosome positive ALL patients have been treated with imatinib (Glivec, Gleevec) with a complete remission rate of 55% and 4 of 20 patients alive in CR with a short median follow up (48). Strategies to reduce the risk of relapse include intensifying conditioning regimens, altering the timing of transplant and augmenting the graft versus leukaemia effect. The risk of relapse may also be reduced by more precisely defining the biological risk factors that justify transplant in first remission, thus circumventing the possibility of selecting for leukaemia resistance during prolonged chemotherapy. Patients who receive an allogeneic bone marrow transplantation for ALL and develop graft versus host disease (GVHD) have a lower probability of relapse than patients who do not suffer this complication. A recent study showed that in patients with high levels of minimal residual disease (MRD) pre-transplant, the presence of acute or chronic GVHD may be needed to prevent relapse (49). The likely explanation for this observations is that the
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alloreactive T cells in the donor graft are able to destroy residual host leukaemia cells. In support of this contention, administering lower doses of cyclosporin reduces the relapse risk and improves DFS in children undergoing HSCT for leukaemia (50). Adoptive immunotherapy with donor mononuclear cells is less successful in ALL than in the myeloid leukaemias, although there is some evidence that use of immunostimulatory cytokines such as IL2 may amplify graft versus leukaemia mechanisms and induce remissions in patients who have failed to respond to donor lymphocyte infusions. Immune modulation post-transplant may therefore be a therapeutic alternative to reduce the risk of relapse. One means of reducing the risk of GVHD is to administer antigen-specific cytotoxic T-cell lines (CTL) lines when a specific antigen is known. Potential targets include minor antigens differentially expressed on haemopoietic cells (51) or lineagespecific antigens, such as WTI or proteinase 3 (52). Such lines could potentially mediate cytotoxic activity directed at recipient haemopoiesis (and leukaemia) but not donor haemopoiesis. An alternative approach when a tumor antigen is not defined is to increase the immunogenicity of the tumor and allow selection of the tumor antigen by responding immune system effector cells. This approach has shown efficacy in a number of animal models using molecules that modify antigen presentation such as Class I MHC molecules or GMCSF, co-stimulatory molecules such as B7 or T-cell activation factors such as IL2. For example pre B ALL cells lack B7-1(CD80) and induce allo-specific T-cell anergy. If ALL cells are transduced with B7, their antigen presentation capacity is improved and they are able to generate autologous leukaemia-specific CTL lines from marrow from the majority of patients (53). Murine data also suggests that combination of molecules acting on different phases of the immune response may produce increased anti-tumor activity (54) and this approach is currently being tested in a clinical trial in patients with ALL (55).
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ACKNOWLEDGEMENTS This work was supported by Grant No. R01 CA 78792 from the National Institute of Health and a Doris Duke Distinguished Clinical Scientist award to H.E.H.
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36. Rocha V, Cornish J, Sievers E, et al. Comparison of outcomes of unrelated bone marrow and umbliical cord blood transplants in children with acute leukaemia. Blood 2002; 97: 2962–2971. 37. Locatelli F, Rocha V, Chastang C, et al. Factors associated with outcome after cord blood transplantation in children with acute leukaemia. Eurocord–Cord Blood Transplant Group. Blood 1999; 93: 3662–3671. 38. Davies SM, Ramsay NK, Klein JP, et al. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukaemia. J Clin Oncol 2000; 18: 340–347. 39. Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant haematologic diseases. Blood 1998; 91: 756–763. 40. Giralt S, Thall PF, Khouri I, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with haematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001; 97: 631–637. 41. Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabinebased nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817–2824. 42. Storb R, Yu C, Deeg HJ, et al. Current and future preparative regimens for bone marrow transplantation in thalassemia. Ann N Y Acad Sci 1998; 850: 276–287. 43. Kottaridis PD, Milligan DW, Chopra R, et al. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation [in process citation]. Blood 2000; 96: 2419–2425. 44. Wulf GG, Rill DR, Luo K-L, et al. Complement fixing monoclonal antibodies to facilitate stem cell transplantation in mice. Ann N Y Acad Sci [in press]. 45. Nash RA, Pineiro LA, Storb R, et al. FK506 in combination with methotrexate for the prevention of graft- versus-host disease after marrow transplantation from matched unrelated donors. Blood 1996; 88: 3634–3641. 46. Champlin RE, Passweg JR, Zhang MJ, et al. T-cell depletion of bone marrow transplants for leukaemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities. Blood 2000; 95: 3996–4003. 47. Porter DL, Antin JH. The graft-versus-leukaemia effects of allogeneic cell therapy. Annu Rev Med 1999; 50: 369–386. 48. Ottmann OG, Wassmann B, Pfeifer H, et al. Activity of the ABL-Tyrosine Kinase Inhibitor Glivec (STI571) in Philadelphia Chromosome Positive Acute Lymphoblstic Leukaemia (PH+ ALL) Relapsing after Allogeneic stem cell transplantation (allo-SCT). Blood 2002; 98(11): 589a. 49. Uzunel M, Mattsson J, Jaksch M, Remberger M, Ringden O. The significance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia. Blood 2001; 98: 1982–1984. 50. Locatelli F, Zecca M, Rondelli R, et al. Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukaemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial. Blood 2000; 95: 1572–1579. 51. Mutis T, Verdijk R, Schrama E, Esendam B, Brand A, Goulmy E. Feasibility of immunotherapy of relapsed leukaemia with ex vivo- generated cytotoxic T lymphocytes specific for haematopoietic system-restricted minor histocompatibility antigens. Blood 1999; 93: 2336–2341.
10 52. Ohminami H, Yasukawa M, Fujita S. HLA class I-restricted lysis of leukaemia cells by a CD8(+) cytotoxic T- lymphocyte clone specific for WT1 peptide. Blood 2000; 95: 286–293. 53. Cardoso AA, Seamon MJ, Alfonso HM, et al. Ex vivo generation of human anti-pre-B leukaemia-specific autologous cytolytic T cells. Blood 1997; 90: 549–561. 54. Dilloo D, Bacon K, Holden W, et al. Combined chemokine and cytokine gene transfer enhances antitumor immunity. Nat Med 1996; 2: 1090–1095. 55. Rousseau RF, Bollard CM, Heslop HE. Gene therapy for paediatric leukaemia. Expert Opin Biol Ther 2001; 1: 663–674. 56. Dekker AW, Vant Veer MG, Van der Holt B, et al. Postremission treatment with autologous stem cell transplantation (AutoSCT) or Allogeneic stem cell trans- plantation (Allo-SCT) in adults with Acute Lymphoblastic Leukaemia (ALL). A Phase II Clinical trial (HOVON 18 ALL). Blood 2002; 98. 57. Rowe JM, Richards SM, Burnett AK, et al. Favorable results of Allogeneic Bone Marrow Transplantation (BMT) for Adults with Philadelphia (Ph)-chromosome-negative Acute
U. POPAT ET AL. Lymphoblastic Leukaemia (ALL) in first complete remission (CR): results from the International ALL trial (MRC UKALL XII/ECOG E2993). Blood 2001; 98. 58. Goldstone AH, Prentice HG, Durrant JI, et al. Allogeneic transplant (related or unrelated donor) is the preferred treatment for adult Philadelphia chromosome positive (Ph+) Acute Lymphoblastic Leukaemia (ALL). Results from the international ALL trial (MRC UKALL XII/ECOG E2993). Blood 2002: 98. 59. Zhang MJ, Hoelzer D, Horowitz MM, et al. Long-term follow-up of adults with acute lymphoblastic leukaemia in first remission treated with chemotherapy or bone marrow transplantation: the Acute Lymphoblastic Leukaemia Working Committee. Ann Int Med 1995; 123: 428–431. 60. Oh H, Gale RP, Zhang MJ, et al. Chemotherapy vs HLAidentical sibling bone marrow transplants for adults with acute lymphoblastic leukaemia in first remission. Bone Marrow Transplant 1998; 22: 253–257.
ANTI-TUMOUR TREATMENT
Haemopoietic stem cell transplantation for acute lymphoblastic leukaemia Uday Popat, George Carrum and Helen E. Heslop Departments of Medicine and Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA The majority of children and some adults with acute lymphocytic leukaemia (ALL) can be cured with current intensive chemotherapy regimens. For those patients who relapse or who do not achieve remission, allogeneic haemopoietic stem cell transplantation (HSCT) offers the best chance for long-term disease control. Different sources of haemopoietic stem cells including marrow, peripheral blood, and cord blood are now available and the introduction of subablative regimens has increased the number of patients who are transplant candidates. Relapse remains the major cause of transplant failure and immunotherapy strategies post-transplant to augment the graft versus leukaemia effect are being explored. c 2003 Elsevier Science Ltd. All rights reserved. s
INTRODUCTION
DISEASE STAGE
While current chemotherapy regimens cure most pediatric and some adult patients with acute lymphoblastic leukaemia (ALL), haemopoietic stem cell transplantation (HSCT) provides better long-term disease free survival for those patients who have high-risk features or who relapse. The decision on whether an individual patient with ALL is an appropriate candidate for HSCT is complicated by continual redefinition of risk factors by newer molecular studies (1). In addition, there are relatively few prospective studies comparing the outcome with chemotherapy or transplant. Factors such as the intensity of previous chemotherapy and time of censoring limit the value of retrospective analyses and data from registries such as the International Bone Marrow Transplant Registry (IBMTR) and National Marrow Donor Program (NMDP).
Acute lymphoblatic leukaemia (ALL) in first remission
Correspondence to: Helen E. Heslop, Departments of Medicine and Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates St., Suite 1140 Houston, TX 77030, USA. Tel: +832-824-4662; Fax: +832-825-4668; E-mail: hheslop@bcm. tmc.edu
Outcomes with conventional chemotherapy and allogeneic stem cell transplantation are both improving. With the use of current induction regimens more than 90% of patients with ALL achieve complete remission. Factors that need to be considered before recommending HSCT as post-induction therapy include: 1. Cure rate with conventional chemotherapy. 2. Transplant related morbidity and mortality. 3. Cure rate with HSCT in first relapse or second remission. As the risk of transplant related mortality needs to be balanced against potential cure with standard chemotherapy alone, allogeneic HSCT as post-induction therapy is favored in patients who are at a high risk of relapse after standard chemotherapy. In children with ALL, the likelihood of cure with modern intensive chemotherapy range is 70–80% (2). Using available HLA identical donor versus no donor analysis, a Medical Research Council Study did not show benefit of allogeneic HSCT in first remission in high-risk children with an HLA identical sibling compared to those who did not have an HLA
c 2003 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED. 0305-7372/03/$ - see front matter s
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U. POPAT ET AL.
TA B L E 1 Comparative studies of Allogeneic HSCT in adults (P15 yrs.) with ALL in first CR Study
N
DFS with allogeneic HSCT (%)
DFS with autograft or chemo (%)
P value
HOVON 18 (56) UKALL XII(Ph)) (57) UKALL XII(Ph+) (58) LALA 87 (9) IBMTR (59) Japanese study (60) BGMT (28)
124 434 148 257 718 290 120
53 54 41a 46a 34 53b 68
36 34 27a 31a 32 30b 26
0.05 0.04 0.5 0.04 NS 0.02 <0.01
a b
Overall survival. AgeO30.
identical sibling (3). However, a recent multicenter study has confirmed that outcome post-treatment in children with Philadelphia chromosome-positive (Ph+) ALL is superior with use of HSCT versus chemotherapy alone (4). Patients with the t(4;11) translocation also do poorly with chemotherapy so that HSCT is usually recommended although a recent retrospective multicenter study suggests it does not improve outcome (5). Allogeneic HSCT should therefore be reserved for children whose leukaemia has poor prognostic features, such as the t(9;22) or the t(4;11) translocations or a delayed response to remission induction therapy. In adults the cure rate with chemotherapy is only 25–40%, because more patients have high-risk features [age > 35 years, WBC > 30 109 /L in B lineage ALL, WBC > 100 109 /in T lineage ALL, null cell phenotype, remission induction > 4 weeks, extramedullary disease or presence of the t(9;22) or t(4;11)]. Any one of these features reduces the chance of long-term DFS with chemotherapy to between 15% and 25%, making the patient a candidate for allografting in first remission. IBMTR data for patients transplanted between 1991 and 1997 show a DFS of 52% in patients receiving allografts in first remission (6), while single center rates range from 48% to 61% (7,8). These results are difficult to interpret because of varying proportions of patients with different risk factors in each study. Prospective randomized studies have been carried out by various cooperative groups. These studies have compared patients with HLA identical siblings assigned to the allogeneic HSCT group to those without HLA identical sibs assigned to either a standard chemotherapy or autologous HSCT group. A major limitation of these studies is that the proportion of patients in the allogeneic HSCT group actually undergoing transplant varies from study to study. Despite this limitation, a donor versus no donor comparison is the best way to answer the question about role of allogeneic HSCT in first remission. In a prospective French study, patients with matched sibling donors received allogeneic trans-
plants, while others were randomized to autografting or chemotherapy (9). In an intent to treat analysis, at 10 years the overall survival rate for allograft recipients was 46% compared to 31% in control patients. The benefit of an allograft was most pronounced in high-risk patients (Ph+, null or undifferentiated immunophenotype, age >35 years, or WBC > 30 109 /L or time to CR > 4 weeks), where the DFS was 44% in the allograft group compared with 11% in the control group (7,9). The outcome for recipients of an autologous transplant was not significantly greater than that for chemotherapy alone (34% versus 29%). The largest randomized study was conducted by the Medical Research Council and the Eastern Cooperative Oncology Group. Preliminary results indicate a beneficial effect of transplant. Results of these and other studies are summarized in Table 1. Notable features of all these studies include a high treatment related mortality and a lower risk of relapse in allogeneic transplant arm. Other studies comparing patients in the IBMTR database with control groups from cooperative groups have shown no difference or differences only in patients younger than 30 (Table 1). In summary, based on the currently available data, allogeneic HSCT is a reasonable treatment option for adults with high-risk ALL. Definitive recommendation should await the final results of these and other studies.
ALL in second remission After relapse, the chances of cure with chemotherapy are low in adults, and allogeneic HSCT should be performed. IBMTR data from 1991 to 1997 show a DFS of 42% for patients transplanted in second remission (6). For children who relapse on maintenance therapy, particularly after modern intensive chemotherapy, the chance of long-term survival with chemotherapy is less than 20%. A combined Pedi-
HAEMOPOIETIC STEM CELL TRANSPLANTATION FOR ALL
atric Oncology Group and IBMTR study yielded a DFS rate of 40% in patients receiving allografts, compared with 17% in those receiving chemotherapy (10). A similar trend towards beneficial effect of Allogeneic HSCT was observed in another study in patients with a short first remission (<2 years) (11). A Medical Research Council study confirmed a poor outcome (DFS 3%) for children with a short initial remission and a better outcome for those with late isolated extramedullary relapse. Allogeneic transplant showed an absolute increase in 5-year eventfree survival of 14% (from 26.4% to 40.7%) (12). The requirement for allografting in children with an isolated extramedullary relapse or in those who relapse than 6 months after completing maintenance therapy is more contentious, as these patients may be cured with salvage chemotherapy. In addition in many ongoing studies exploring risk-adapted therapy, children staged as low risk are treated with less intensive regimens. If such patients relapse, they may potentially be salvaged by more intensive chemotherapy, although no data are available as yet.
ALL after second relapse or primary induction failure Once patients are beyond second remission, the results of all allografting procedures worsen considerably, with only 10–15% of patients becoming longterm disease-free survivors (13,14). A small number of patients will also fail primary induction therapy. While the outcome with transplant is poor with only 10–15% DFS, it offers the only prospect of cure (15).
DONOR SOURCE Matched sibling The donor of choice is a matched sibling but less than a third of the patients who might benefit from allogeneic transplantation have this option and the remaining patients must consider use of an alternative donor.
5
33% in second complete remission (CR2) (6). The NMDP reports 5-year DFS of 35% in CR1 in adults and 46% in children falling to 25% and 40%, respectively, in CR2. In primary induction failure or relapse DFS at 5 years is only 6% in adults and 11% in children (16). Over the past few years, improved results have been reported from several single center studies particularly in pediatric patients, reflecting improvements in donor/recipient matching, GVHD prophylaxis, and supportive care (17–21). In a recent analysis, the use of a younger donor and a younger recipient age were both associated with significantly improved outcome (22).
Haploidentical family donors While an unrelated donor search may take several months, most individuals have a haploidentical relative. Use of a mismatched family member donor is associated with an increased risk of GVHD due to increased alloreactivity, and this risk increases with the degree of mismatch. Three main approaches have been explored to reduce the risk of GVHD. The first is T-cell depletion of the donor marrow in conjunction with immunosuppression both pre- and post-transplantation. Henslee–Downey et al. (27) reported 2-year overall survival rates of 55% in low-risk patients and 27% in high-risk patients who underwent haploidentical transplantation by this approach. A second strategy is to use a G-CSF-mobilized, large-volume apheresis and CD34 selection with or without additional T-cell depletion. The reported DFS rates achieved with this alternative source of donors range from 17% to 40% (23,24). A third approach relied on the induction of anergy to inactivate alloreactive T cells in the donor marrow (25). In a preliminary report of 12 patients, bone marrow from a donor mismatched with the recipient for one HLA haplotype was cocultured with irradiated cells from the recipient for 36 h in the presence of CTLA-4-Ig, an agent that inhibits B7/CD28-mediated co-stimulation. Only 3 of 11 evaluable patients developed acute GVHD, and five patients were alive in remission (25).
Unrelated donors Historically, the outcome after transplantation from unrelated donors has been inferior to that observed after matched sibling transplantation due to increased rates of graft rejection and graft versus host disease (GVHD) resulting from increased alloreactivity in this setting. The IBMTR reports a DFS of 44% for patients receiving unrelated donor transplants for ALL in first complete remission (CR1) and
Autologous transplants Autologous HSCT remains an investigational approach in the therapy for ALL. This procedure allows the use of higher doses of chemotherapy, but carries the risk of reinfusion of leukaemic cells in the harvested marrow. A comparison of autologous and unrelated donor transplants performed at the Uni-
6
versity of Minnesota and the Dana–Farber Cancer Institute showed an increased risk of relapse after an autograft and increased regimen related toxicity after an unrelated donor transplant (26). Disease-free survival was better after transplantation from an unrelated donor. The IBMTR reports overall DFS of 43% in CR1, 37% in CR2 or later CR and 5% in relapse for patients receiving autografts (6). The prospective French study showed no benefit of autograft in CR1 compared with chemotherapy (9). This question was also addressed in a prospective study carried out by BGMT group comparing autologous versus allogeneic HSCT for ALL in CR1 and showed significantly higher DFS (68% with allogeneic transplant compared to 26% with autologous transplant) (28). One potential use of autologous HSCT may be in patients who are poorly compliant with maintenance chemotherapy.
SOURCE OF STEM CELLS FOR ALLOGENEIC TRANSPLANTATION Bone marrow versus mobilized peripheral blood Cytokine-mobilized allogeneic peripheral blood stem cell (PBSC) harvest has recently become an alternative to bone marrow as a source of stem cells for matched-sibling transplants. Early phase II studies showed that this source of stem cells resulted in faster engraftment, no increase in acute GVHD (perhaps due to a G-CSF-mediated shift to Th2 helper cells) but an increased incidence of chronic GVHD (29,30). A recent prospective randomized study of allogeneic PBSC compared to marrow showed a 2-year actuarial overall survival of 54% in patients receiving marrow compared with 66% in those receiving PBSCs (31). Differences in survival were significant for patients with unfavorable-risk diseases but not for those with favorable-risk diseases (31). Faster engraftment, similar GVHD and improvement in overall survival was also reported in a recent Canadian and New Zealand study (32). In a retrospective multivariate analysis from the IBMTR comparing the results of 288 HLA-identical sibling blood stem cell transplants with the results of 536 HLA-identical sibling bone marrow transplants, the relapse incidence between the two transplant groups did not differ significantly (33). However, treatment-related mortality rates were lower and leukaemia-free survival rates were higher with use of blood stem cell transplants in patients with advanced versus early leukaemia (acute leukaemia in first remission or CML in chronic phase) (33). While the results of more studies should become available over the next few years, the current experience
U. POPAT ET AL.
suggests that peripheral blood should be the preferred source of stem cells for patients with high-risk disease. For patients with low-risk disease, the increased risk of chronic GVHD needs to be balanced against the risk of relapse.
Cord blood Another alternative source of stem cells that has been attracting much interest is cord blood. Several recent studies have demonstrated the feasibility of transplants with cord blood from unrelated donors (34,35). Compared to unrelated bone marrow transplants, cord blood transplants have slower engraftment, decreased GVHD and increased 100-day transplant-related mortality (36). The immediate availability of cryopreserved cord blood units eliminates the usual delay in HSCT when unrelated donor marrow is used. Locatelli et al. reported the outcome of 102 children with acute leukaemia who received either related or unrelated umbilical cord blood HSCT (37). In multivariate analysis, the most important factor influencing neutrophil engraftment was a nucleated cell dose greater than 3:7 107 kg 1 . The most important factor influencing event-free survival (EFS) was disease status at the time of transplantation: good-risk patients had a 2-year EFS rate of 49%, compared with 8% in patients with more advanced disease. Rubenstein et al. (34) reported the outcomes of 562 recipients of placental-blood transplant from unrelated donors. The speed of myeloid engraftment was associated with the leukocyte content of the graft, whereas transplantation-related events were associated with the patientÕs underlying disease and age, the number of leukocytes in the graft, the degree of HLA-disparity, and the transplantation center.
PREPARATIVE REGIMENS Ablative regimens Conditioning regimens used for allogeneic HSCT must achieve adequate immunosuppression of the recipient to prevent rejection of the donor marrow cells and destroy residual malignant cells while causing minimal toxicity. Most preparative regimens for ALL use total body irradiation (TBI) and Cyclophosphamide while some centers use Etoposide and cytosine arabinoside (Ara-C) in addition to or instead of Cyclophosphamide. Busulphan-cyclophosphamide has also been used to avoid radiation but a recent IBMTR study showed an inferior outcome with this regimen with a 3-year probability of DFS of
HAEMOPOIETIC STEM CELL TRANSPLANTATION FOR ALL
35% versus 50% when TBI and Cyclophosphamide were used (38). Because most chemo-radiation regimens are at the limits of toxicity, any further dose escalation in an attempt to reduce the risk of relapse would probably increase the regimen-related toxicity to unacceptable levels, particularly in older or heavily pretreated patients. The addition of biological agents like monoclonal antibodies or radioconjugates to conventional conditioning regimens can potentially provide an augmented anti-leukaemic effect without increasing treatment related toxicity.
Subablative regimens High-dose chemotherapy and allogeneic stem cell transplantation carry substantial treatment related morbidity and mortality in older patients (>50 years), those with compromised organ function (e.g., congestive heart failure), coexisting infections, or those who were heavily pretreated prior to HSCT. In all of these patients, treatment-related mortality can exceed 50%, making them ineligible for HSCT. More recently, new strategies for allografting have explored an approach of less intensive conditioning therapy with the aim of allowing partial engraftment of donor immune and haematopoietic systems with eventual replacement of the hostÕs own haematopoiesis and immunity. A variety of regimens based on low-dose TBI or fludarabine are under investigation (39–42). Such reduced intensity conditioning regimens may be more suitable for patients with indolent malignancies where there is sufficient time for a graft versus malignancy effect to operate. Patient with acute leukaemia who have active disease transplanted with subablative regimens have a high relapse rate. Another major problem with submyeloablative regimens is an increased rate of graft failure ranging from 5% to 30% versus 1% to 5% in patients who underwent full myeloablation prior to HSCT. The use of lymphodepleting antibodies or a combination of monoclonal antibodies in addition to cytotoxic or immunosuppressive drugs could potentially decrease rejection rates (43,44).
IMPROVING THE OUTCOME OF TRANSPLANT GVHD Prophylaxis Graft-versus-host disease results from alloreactivity between donor and recipient. The two major prophylactic regimens employed to prevent this complication are pharmacological (administration of
7
immunosuppressive drugs), and immunological (in vitro T-cell depletion of the donor marrow). The standard pharmacologic prophylaxis has been cyclosporine and short-course methotrexate, but recent studies suggest that the incidence of GVHD is even lower if FK506 is substituted for cyclosporine (45). MMF also shows promise in animal models, and its combination with cyclosporine is being evaluated in clinical trials. Ex vivo T-cell depletion reduces the risk of both acute and chronic GVHD and may allow higher tolerance of mismatching but may also increase the risk of rejection and delay immune reconstitution. A confounding feature for interpreting the value of T-cell depletion is that a variety of methodologies are employed to remove T cells, including physical methods and monoclonal antibodies. Some techniques produce a pan-T depletion, whereas others use antibodies with more restricted T-subset specificities. A recent IBMTR study shows a better outcome when antibodies with narrow specificities are used (46).
Reducing the risk of relapse The major cause of failure after transplant for ALL is relapse. The outcome of patients who relapse after allogeneic HSCT is very poor. Remissions are possible with standard chemotherapy but are not durable. Those who relapse more than 1-year posttransplant are more likely to achieve a further remission. Donor leucocyte infusions have been used but their success rate in patients with ALL is much lower than in patients with myeloid malignancies (47). Philadelphia chromosome positive ALL patients have been treated with imatinib (Glivec, Gleevec) with a complete remission rate of 55% and 4 of 20 patients alive in CR with a short median follow up (48). Strategies to reduce the risk of relapse include intensifying conditioning regimens, altering the timing of transplant and augmenting the graft versus leukaemia effect. The risk of relapse may also be reduced by more precisely defining the biological risk factors that justify transplant in first remission, thus circumventing the possibility of selecting for leukaemia resistance during prolonged chemotherapy. Patients who receive an allogeneic bone marrow transplantation for ALL and develop graft versus host disease (GVHD) have a lower probability of relapse than patients who do not suffer this complication. A recent study showed that in patients with high levels of minimal residual disease (MRD) pre-transplant, the presence of acute or chronic GVHD may be needed to prevent relapse (49). The likely explanation for this observations is that the
8
alloreactive T cells in the donor graft are able to destroy residual host leukaemia cells. In support of this contention, administering lower doses of cyclosporin reduces the relapse risk and improves DFS in children undergoing HSCT for leukaemia (50). Adoptive immunotherapy with donor mononuclear cells is less successful in ALL than in the myeloid leukaemias, although there is some evidence that use of immunostimulatory cytokines such as IL2 may amplify graft versus leukaemia mechanisms and induce remissions in patients who have failed to respond to donor lymphocyte infusions. Immune modulation post-transplant may therefore be a therapeutic alternative to reduce the risk of relapse. One means of reducing the risk of GVHD is to administer antigen-specific cytotoxic T-cell lines (CTL) lines when a specific antigen is known. Potential targets include minor antigens differentially expressed on haemopoietic cells (51) or lineagespecific antigens, such as WTI or proteinase 3 (52). Such lines could potentially mediate cytotoxic activity directed at recipient haemopoiesis (and leukaemia) but not donor haemopoiesis. An alternative approach when a tumor antigen is not defined is to increase the immunogenicity of the tumor and allow selection of the tumor antigen by responding immune system effector cells. This approach has shown efficacy in a number of animal models using molecules that modify antigen presentation such as Class I MHC molecules or GMCSF, co-stimulatory molecules such as B7 or T-cell activation factors such as IL2. For example pre B ALL cells lack B7-1(CD80) and induce allo-specific T-cell anergy. If ALL cells are transduced with B7, their antigen presentation capacity is improved and they are able to generate autologous leukaemia-specific CTL lines from marrow from the majority of patients (53). Murine data also suggests that combination of molecules acting on different phases of the immune response may produce increased anti-tumor activity (54) and this approach is currently being tested in a clinical trial in patients with ALL (55).
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ACKNOWLEDGEMENTS This work was supported by Grant No. R01 CA 78792 from the National Institute of Health and a Doris Duke Distinguished Clinical Scientist award to H.E.H.
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