Seminars in Hematology
Volume 40, Issue 1 , Pages 59-71, January 2003

Allogeneic stem cell transplantation for chronic myeloid leukemia☆☆☆

Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.

Article Outline

Abstract 

Allogeneic stem cell transplantation (SCT) plays a central role in chronic myeloid leukemia (CML) because it remains the only treatment with proven curative potential. For this reason, SCT has been more frequently performed in CML than in any other disease. The susceptibility of CML to the graft-versus-leukemia (GVL) effect and our ability to monitor minimal residual disease are particular features that place this disease at the forefront of GVL research. This review describes the mechanism of cure of CML by SCT, current results of transplantation, factors determining outcome, management of relapsed or persistent disease, and recent treatment advances. Semin Hematol 40:59-71. This is a US government work. There are no restrictions on its use.

 

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The graft versus leukemia effect 

Clinical observations 

Evidence that the alloresponse of donor immune cells could impact on leukemia persisting after stem cell transplantation (SCT) first came from observations by the Seattle group that patients developing either acute or chronic graft-versus-host disease (GVHD) had a lower risk of leukemic relapse.86 A subsequent publication by the International Bone Marrow Transplant Registry (IBMTR) analyzed relapse after SCT for chronic myeloid leukemia (CML),40 a powerful effect of donor lymphocytes on CML was evidenced by the much higher relapse rate in recipients of T-cell–depleted transplants. Of note was the detection of a graft-versus-leukemia (GVL) effect in the absence of GVHD, demonstrated by the fact that even recipients of T-cell–replete transplants who did not develop GVHD had a relapse rate nearly sevenfold lower than that of T-cell–depleted transplant recipients. Further definition of the GVL effect in CML as an alloimmune response came from the observation that identical twin transplants (from T-cell–replete marrow grafts) had a higher relapse rate than T-cell–replete transplants from human leukocyte antigen (HLA)-identical siblings.27 In the same year as the IBMTR report, dramatic proof of a therapeutic role of lymphocytes in GVL came from studies in Munich, now widely confirmed, showing that donor lymphocyte infusions (DLI) could induce durable remissions in patients relapsing with CML after allogeneic marrow transplantation.47

Factors affecting GVL 

In the last decade factors regulating GVL have been defined, providing ways to optimize the effect2 (Table 1).

Table 1. Factors affecting GVL for CML
GVL Effect
FactorStrongIntermediateWeak
Disease statusCPAPBP
Disease burdenMolecular diseaseKaryotypic diseaseHematologic disease
GVHDAcute + chronicAcute or chronicGrade 0-1
Donor recipient matchHLA mismatch/unrelatedMatched siblingsTwins
Engraftment100% donor T cells Mixed chimerism
GVHD preventionNoneCyclosporine/MTXT-cell depletion

Abbreviations: CP, chronic phase; AP, accelerated phase; BP, blastic phase; MTX, methotrexate.

Disease status and leukemia burden play a major role in determining the efficacy of the GVL reaction. Patients with CML in acclerated phase (AP) or blastic phase (BP) have a reduced likelihood of responding to GVL. While the relationship between disease progression and treatment failure may seem intuitive, the exact reason for the decreased susceptibility to GVL of advanced leukemia is not known; possibilities include a close relationship between chemoresistance and immune resistance and defeat of the immune response by an overwhelmingly rapid proliferation rate of advanced leukemia. In the treatment of relapse post-transplant there is a clear relationship between the efficacy of DLI, leukemia burden, and probability of response—90%, 75%, and less than 70%, respectively, in molecular, cytogenetic, and hematologic relapse.48 Earlier studies demonstrated that both acute and chronic GVHD favor GVL, whether following the transplant or DLI.2

The GVL effect is driven by genetic disparity between donor and recipient and is greatest when the donor is unrelated to the recipient. Between identical twins only leukemia-specific antigens such as the bcr-abl junctional peptides can serve as antigens. However, as yet there is no evidence of a T-cell–mediated GVL mechanism in identical twin transplants for CML. Between HLA-identical sibling pairs, antigenic disparity expands to include minor histocompatibility antigens (mHA). Unrelated donors probably express more mHA disparities as well as major histocompatibility complex (MHC) locus differences. In HLA-mismatched transplants, the GVL effect may be further augmented by alloreacting natural killer (NK) cells recognizing class I mismatches on leukemia cells.74

Several studies describe an association between persisting mixed donor-host lymphoid chimerism and relapse in CML.73 This increased relapse risk may be directly due to the tolerizing effect of persisting recipient immunity blocking donor alloresponses, or to factors that predispose to mixed chimerism such as low-intensity preparative regimens and T-cell depletion. Immune suppression used to prevent GVHD inevitably compromises the GVL effect. Clinical observations suggest that the balance between GVL and immunosuppression used to prevent GVHD determines the persistence of residual leukemia. Thus, rapid tapering of cyclosporine (CSA) can induce cytogenetic or molecular remissions in many of patients relapsing post-transplant.2, 8

Mechanism of GVL in CML 

The GVL effect in CML attributable to donor T cells is illustrated in Fig 1.

  • View full-size image.
  • Fig. 1. 

    Cellular mechanisms and key molecules regulating GVL in CML. Induction of donor T-cell responses requires presentation of antigens on leukemia cells to CD4+ and CD8+ T cells of the donor by CML-derived dendritic cells (DC) (or indirectly via donor DC). Critical molecules required for antigen presentation and T-cell activation are peptide antigens presented by MHC class I and II molecules, costimulation via B7.1 /B7.2 interaction with CD28 on the T cell, and (for professional APC such as DC) CD40 interaction with CD40 ligand on the T cell (not shown). Expansion of the immune response generates CD4+ and CD8+ antigen-specific T cells. Cytokines IL-2 and IL-12 promote T-cell proliferation, IL-10 and IL-4 control the balance between Th1 and Th2 cells modifying the effector behavior: Th1 cells in favor of cytotoxic responses and Th2 cells in favor of humoral responses (not shown). The GVL effect is mediated by both CD4+ and CD8+ T cells. CML cells including progenitors are killed directly by perforin and granzyme release inducing cytoplasmic damage and apoptosis and by Fas ligand interaction with Fas on the target surface inducing apoptosis. (Both CD4+ and CD8+ cells use these pathways). Cytokines such as TNF-α and IFN-γ also suppress CML by inhibiting cell proliferation and inducing apoptosis.

GVL is initiated when donor T cells recognize leukemia-related antigens presented in the context of MHC class I or II by antigen-presenting cells (APC) of host origin. Among myeloid malignancies CML is unique in generating a complete hierarchy of functioning leukemic APC, including monocytes, dendritic cells (DC), and B lymphocytes. Thus, leukemic DC can directly stimulate the donor immune response. Furthermore, CML cells are highly susceptible to immune attack by lymphocytes. Cytototoxic T cells kill CML cells, including CD34+ progenitors, by fas-mediated apoptosis, by perforin-mediated lysis, and possibly by tumor necrosis factor (TNF)-α and interferon (IFN)-γ cytokine production. The particular sensitivity of CML to GVL resides in some or all of these features.3

Effector cells in GVL 

In addition to clinical data, experimental evidence supports T lymphocytes as the main GVL effectors: coincident with molecular cure of CML there is an increase in the frequency of leukemia-reactive helper and cytotoxic precursor T cells. CD4+ T cells are central to the GVL effect: cytotoxic CD4 T-cell clones with powerful cytoxicity to CML progenitors are readily generated from HLA-identical and -nonidentical donors and exhibit leukemia-specific (tissue-restricted) cytotoxicity.25 A GVL effect of CD4+ lymphocytes has been confirmed in clinical trials where recipients of CD8-depleted DLI achieve remissions in CML after post-transplant relapse.1 Furthermore transfusion of in vitro–generated leukemia-specific CD4+ T-cell clones resulted in a molecular remission in a patient relapsing with CML who had already failed to respond to unselected DLI.26 NK cells may also contribute to GVL: we found a correlation between sustained remission and high NK and lymphokine-activated killer (LAK) cell function following SCT and increases in NK and LAK cell activity after DLI.43

Antigens inducing the GVL response 

A number of defined antigens have been implicated in the GVL response (Table 2).

Table 2. Antigens implicated in the GVL response in CML
Evidence*
Antigen CategoryProteinPeptideHLA RestrictionExpressedCTLIn VivoReference
mHA—HA-1A2+++60
—HA-2A2+++60
SMCYHY-1A2++ 95
Tissue-restrictedProteinase 3PR-1A2+++56, 57
PR-7A2+ 13
WT-1WT-1A2++ 28
Leukemia-specificBCR-ABLKQSSKALQRA3+++12
B8++ 12
* “Expressed” = peptide presented by MHC on leukemia cell; “CTL” = peptide-specific cytotoxic T-cell clones inhibit CML progenitor cell growth; “In vivo” = tetramer stained T cells increase after transplant in patients achieving remission.
mHA are alleleic peptides presented by MHC class I and II molecules to donor lymphocytes from an individual of the opposite allele. Although many hundreds of mHA are believed to exist, only a handful have so far been defined.

There is increasing evidence that mHA are involved in GVL effects. For example, direct quantitation of T cells specific for the HLA-A2–linked mHA HA1 and HA2, measured using HLA tetramers, reveals a rapid increase coinciding with disease regression after DLI.60 Nonalleleic differentiation antigens restricted to cells of the myeloid lineage may also induce GVL effects. When presented by CML cells, the nonapeptide, PR-1, derived from proteinase-3 (a primary granule protein), induces leukemia-specific cytotoxic T lymphocyte (CTL) responses in normal HLA-A2 donors.56 Tetramer staining of lymphocytes from HLA-A2 CML transplant recipients in remission reveals that up to 13% of circulating CD8+ T cells are PR-1–specific.57 The leukemia-restricted peptide sequence spanning the breakpoint of the BCR-ABL fusion protein could serve as a truly leukemia-specific antigen and would serve as an ideal antigenic target. HLA-A3 CML cells present such BCR-ABL b3a2 fusion peptides. Priming lymphocytes with peptide-loaded APC induced cytotoxic T-cell responses to autologous CML cells.12 Furthermore, using tetramers for a nonamer b3a2 peptide, circulating BCR-ABL–specific CD8+ T cells were identified in CML patients. CD4+ T-cell clones recognizing an MHC class II presented BCR-ABL sequence have also been found after transplant, but they did not recognize the leukemia cells. This result suggests that antigens other than BCR-ABL are involved in the CD4+ T-cell GVL response.97 In conclusion, while the tetramer data linking a GVL effect with antigen-specific T-cell responses to particular antigens are compelling, the association is circumstantial and does not preclude the possibility that GVL effects are mediated by as yet unknown antigens. GVL may be mediated by a limited number or a diversity of antigens.

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Results of stem cell allotransplants in CML 

Matched sibling transplants 

For more than 20 years, allogeneic SCT using matched sibling donors has been widely performed for CML. Recent results, representing current practice, are summarized in Table 3. An IBMTR analysis of 5,816 CML patients transplanted between 1994 and 1999 showed survival of 69% ± 2% for 2,876 patients transplanted in chronic phase (CP) within 1 year of diagnosis, and 57% ± 3% for CP patients transplanted more than 1 year from diagnosis.41 Many factors affecting the success of the transplant are defined and results from individual centers vary, usually due to differences in the patient population treated. Age has a major impact on outcome, results being especially favorable for the minority pediatric CML population, while patients older than 40 years have a lower disease-free survival (DFS). Delaying transplantation by a year or more after diagnosis of CP is generally confirmed to result in a worse outcome. Disease stage is the other major variable affecting transplantation success. Both transplant-related mortality (TRM) and relapse are higher in transplants for AP and BP disease. However, patients who achieve a second CP have a better chance of DFS.94 Cytogenetic and molecular analysis is also helpful in predicting relapse: a study in patients transplanted in CP and AP found DFS rates of 77%, 32%, and 22% for patients whose pretransplant analysis showed BCR-ABL positivity only, BCR-ABL positivity with Ph chromosome positivity, and Ph positivity with other chromosomal abnormalities, respectively.49 Most reported results analyze survival in the first 5 years. However, longer term follow-up indicates that late relapses and deaths from chronic GVHD continue to affect survival many years after transplant.70 In evaluating outcome after transplant for CML, measuring DFS underestimates the final cure rate because DLI can cure relapsed disease. To provide a more accurate descriptor of therapeutic effectiveness, Craddock et al introduced the concept of the current DFS.16 This actuarial calculation provides a better estimate of the number of patients ultimately disease-free after transplant. With these provisos, it appears that in the long-term, allogeneic SCT from a matched sibling provides a cure in about 65% of individuals with CP CML.90

Table 3. Recent results of HLA-matched sibling transplants for CML
CenterNCohort CharacteristicRelapseDFSSurvivalReference
IBMTR2,876CP < 1 yr, age < 50 69% (5 yr)41
2,040CP > 1 yr 57%
AP 50%50%
BP 20%20%
EBMT373Long-term follow-up9%47%54% (8 yr)90
NMDP450CP < 1 yr, age <30 yr68% (5 yr)68% (5 yr) 96
30-40 yr67%67%
>40 yr57%57%
Mexico45<50 yr55%55%60%92
Minneapolis96Matched, 35 yr med, all < 1 yr 76% (5 yr)
Toronto179.5 yr med, CP/AP 80
Some MUD 87% ± 5%
Ulm96AP25%36% 34

Abbreviations: EBMT, European Group for Blood and Marrow Transplantation; NMDP, National Marrow Donor Program; MUD, matched unrelated donor; med, median.

Unrelated donor transplants 

There is now vast experience in transplants for CML using unrelated volunteer donors (Table 4).

Table 4. Recent results of unrelated donor transplants for CML
CenterNCohort CharacteristicRelapseDFSSurvivalReference
IBMTR613CP1 < 1 yr 54 ± 5%41
936CP1 > 1 yr 46 ± 3%
EBMT238CP1 DRB1 match no TCD2%51.5% (4 yr) 18
Others 6%
NMDP2,464CP1 < 1 yr, age < 35 yr, CMV− (subset of 1,423 total reported) 63% (5 yr) 53
NMDP CP1 < 1 yr (subset of 2,464), age < 30 yr 61%* (5 yr) 96
30-40 yr 57%
>40 yr 46%
Seattle196All 57% (5 yr) 35
CP1 < 1 yr, DRB1 match, age < 50 yr10%74%*
Spain87All 20%24% (4 yr)9
CP1 < 2 yr, DRB1 match, age < 40 yr 60%*
Italy89Transplants after 1993 66%* (3 yr) 19
Minneapolis45Matched, 35 yr med, all < 1 yr 70% (5 yr)17
*Not statistically different from a matched-related recipient cohort (see Table 3, ref 96).

Abbreviations: TCD, T-cell depletion; CMV, cytomegalovirus; BM, bone marrow; med, median.

There has been a trend to improved survival over the last decade as illustrated by data from the Italian transplant groups. Age, timing of transplant (early or late CP, more advanced disease), and degree of matching (especially DRB1 compatibility) strongly affect success of the transplant. For good-risk patients (youngerthan 40 years, in first CP, <1 year from diagnosis, and with an HLA-matched unrelated donor), a DFS rate of around 60% can be reproducibly achieved. This figure is not markedly inferior to the results currently obtained with a matched sibling donor. However, this good-risk transplant cohort represents a minority of patients transplanted from unrelated donors and poorer results can be anticipated from patients with less favorable presentations.

Transplants from identical twins 

Identical twin transplants in CML are associated with increased relapse risk compared with HLA-identical sibling transplants. However, DFS rates after twin and HLA-identical sibling transplants overlap because the increased relapse in twins is offset by decreased TRM. In an IBMTR study 3-year probabilities of relapse after identical twin compared with HLA-identical sibling transplants were 40% and 7%, respectively. However, 3-year DFS probabilities after twin compared with HLA-identical sibling transplants were not significantly different (59% and 61%, respectively).27 A recent analysis of identical twin transplants for leukemia (including patients with CML) identified a superior DFS and a significant reduction in relapse rates in patients receiving higher doses of marrow cells (>3 × 108 nucleated cells/kg).77 This relationship between relapse and transplant cell dose suggests that some form of nonclassical GVL effect may operate under these conditions.5

Mismatched transplants 

Transplants from HLA-mismatched family members have been performed in patients with advanced CML—either because rapid disease progression precludes the time required to find and harvest a volunteer donor, or because no matched donor can be located. Mismatched family donor transplants have a high risk of treatment failure in CML. In a comparison of 1,224 HLA-matched sibling and 340 mismatched family donor transplants, TRM was 21% versus greater than 50%.87 Among mismatched transplants, increasing HLA disparity increases the risk of treatment failure. A study by the European Group for Blood and Marrow Transplantion (EBMT) of 103 patients with CML receiving transplants from haploidentical family members found 5-year survival of 32% and DFS of 25%. DFS was 46% compared with 24% for patients mismatched for one versus two or three antigens. Survival was best in patients transplanted in first CP (47% v 24% for more advanced disease).85 Patients transplanted in first CP from a donor mismatched for zero or one HLA antigen had a probability of survival of 52% at 2 years compared with 19% for patients transplanted in advanced-disease stage from donors mismatched for two or three HLA antigens. Even in HLA-mismatched transplants, more encouraging results are possible by selecting the best match and transplanting patients before disease progression.

Optimizing transplant conditions 

Clinical investigators have striven to improve the outcome of CML transplants by modifying pretransplant treatment, the preparative regimen, and GVHD prophylaxis. From these clinical trials, treatment approaches have emerged that can improve the outlook for transplantation in CML whatever the stage of the disease or the donor type.

Pretransplant IFN-α 

The Seattle transplant group found that, in patients receiving IFN within 6 months of transplant, there was a decreased survival and an increase in grade III to IV GVHD.59 Subsequently, studies from two other centers identified respectively poorer outcome if IFN was given within 90 days of transplant and a correlation between poorer outcome and prolonged IFN use.3, 7 However four other multivariate analyses failed to identify IFN as an independent variable deleteriously affecting GVHD or transplant outcome,51, 64, 88, 98 The role of IFN in affecting transplant outcome therefore remains controversial. Given the increasing use of imatinib rather than IFN pretransplant, the issue of pretransplant IFN is likely to be less important in the future.

Pretransplant splenic irradiation 

Debulking leukemia prior to transplant by splenic irradiation seems an attractive method of increasing the curative potential of SCT, particularly because reducing the risk of splenic pooling should also increase the speed of hematologic recovery post-transplant. Several studies address this question. A retrospective analysis from the EBMT database found that splenic irradiation before transplant reduced relapse from 36% to 11% in a subgroup of patients with higher basophil counts receiving T-cell–depleted transplants.33 Recently, a lower relapse rate following 2,500 cGy fractionated splenic irradiation was also reported in 37 CML patients, 32 in CP, four in AP. All patients achieved a cytogenetic remission and no relapses occurred. Thus, a case can be made for further trials of splenic irradiation before transplant especially in CML patients with an increased risk of relapse.42

Choice of preparative regimen 

The question of the best choice of preparative regimen has stimulated a series of well-controlled comparative studies comparing busulfan and cyclophosphamide with total body irradiation (TBI) and cyclophosphamide regimens. Six large studies have been reported (Table 5).

Table 5. Busulfan/cyclophosphamide compared with cyclophosphamide + total-body irradiation for CML
CenterNBuCy DFSCyTBI DFSPComments
Paris84316 (4 long-term randomized studies)65%63%NSMore alopecia with Bu; more cataracts with TBI
Scandinavia7188 Bu/79 TBI*72%83%NSMore alopecia, cGVHD, bronchiolitis, and VOD with Bu; more cataracts with TBI
Seattle14142 (69 TBI)72%72%NSBuCy better tolerated
Hamburg5050 (sequential)70%58%NSMore chronic GVHD, hemorrhagic cystitis, and liver toxicity with Bu
Korea4553 (randomized)75%59%NSMore cataracts with TBI
Meta-analysis36CML + other leukemiaNo significant differenceMore VOD with Bu
* Includes patients with acute myeloid leukemia, results shown for CML.

Abbreviations: Bu, busulfan; Cy, cyclophosphamide; VOD, veno-occlusive disease of the liver; TBI, total-body irradiation; NS, not significant.

The consensus following a meta-analysis is that there is no significant difference in major transplant outcomes (DFS, survival, or relapse) between the two preparative regimens.

Cell dose 

In recent years, attention has focused on the impact of the cellular content of the transplant on outcome of SCT for leukemia. It is now clear that both the CD34 cell dose and the total nucleated cell (TNC) dose affect transplant results, with optimum results being obtained with doses above 3 × 108 TNC/kg or 3 × 106 CD34 cells/kg.77 CML is no exception. In HLA-identical siblings transplants for CML, treatment failure was associated with CD34 doses less than 3 × 106/kg.58 TRM was significantly decreased after unrelated donor marrow transplants with TNC doses greater than 3.65 × 108/kg.66 These findings further enforce the importance of determining the quantity of cells in the transplant to provide sufficient cells to optimize the outcome.

Bone marrow versus peripheral blood SCT 

Independent of dose, the source of stem cells used in the transplant also affects outcome. The increasing use of peripheral blood SCT (PBSCT) has prompted a series of comparisons of transplants with bone marrow (BMT) or PBSCT.77 In CML, PBSCT may reduce the risk of persisting residual disease and relapse. A study of HLA-matched sibling transplants from Germany reported a 7% and 0% incidence of molecular or cytogenetic relapse, respectively, following PBSCT, compared with a significantly greater 44% and 47% relapse incidence after BMT.21 In unrelated-donor SCT, the same group found a 94% 1,000-day survival with PBSCT compared with 66% using BMT.24 Relapse rates were lower but not significantly so with PBSCT. These results suggest that PBSCT are particularly advantageous in unrelated transplants for CML.

T-cell depletion to prevent GVH 

T-cell depletion of bone marrow was introduced in the 1980s as a strategy to decrease GVHD and TRM. In CML, it soon became apparent that relapse rates were considerably higher in recipients of T-cell–depleted transplants.40 T-cell depletion was subsequently used mainly in mismatched transplants where antigenic disparity increased the GVL effect and compensates for the relapse risk.38 Some groups have continued to perform T-cell–depleted transplants in CML on the basis that the higher relapse rates in these transplants would be offset both by the high salvage rate for treating relapse with DLI and the low TRM and GVHD incidence associated with T-cell depletion. Sehn et al compared the overall outcome in CML patients, 46 receiving a transplant depleted of T cells with a CD6 antibody and 40 receiving a non–T-depleted transplant.78 Predictably, the relapse rate was higher in the T-cell–depleted group (62% v 24%). However, due to the lower TRM associated with less GVHD, overall survival rates were comparable (72% v 68% for recipients of nondepleted transplants). Similar results were reported from Neijmegen.76 The Milwaukee group performed T-cell–depleted transplants using quantitative polymerase chain reaction (PCR) to detect residual disease and guide the use of DLI to preempt hematologic relapse. Although relapse occurred in 49%, most patients obtained complete responses with DLI, and the incidence of grade II to IV acute GVHD was 8%, with an 80% 5-year survival rate.20 Other investigators have used T-cell depletion to produce a well-tolerated early post-transplant phase, followed by a prophylactic add-back of donor lymphocytes at a set time and dose post graft to establish a GVL effect. This approach results in a low mortality from GVHD and up to 85% survival in CP and AP CML patients,4, 61 These results show that T-cell depletion can be used without any overall disadvantage to long-term survival in CML, provided that disease recurrence is preempted or treated early. While there is no clear treatment advantage for this strategy, an argument has been made for the use of T-cell depletion with subsequent DLI for relapse in CML subgroups at high risk of GVHD.15, 76

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Leukemic relapse and persistent disease 

Monitoring residual disease 

Relapse in patients transplanted for CML in CP usually follows a slow progression from minimal residual disease to leukemia detectable by bone marrow karyotype and finally full hematologic relapse. Some patients, particularly those transplanted in more advanced stages, can relapse into rapidly progressing AP or BP. Techniques to detect early relapse or persisting disease have become increasingly sophisticated and reliable. Relapse can be predicted in two ways: persistence of mixed T-cell chimerism,23, 29, 73 and detection of bcr-abl transcripts using PCR.79 Combinations of these monitoring systems have been shown to reliably identify patients at high risk of relapse, but they are probably rendered unnecessary by current real-time quantitative PCR (RT-PCR) technology. Patterns of disease disappearance and relapse after transplant are now known in some detail. After BMT all evidence of minimal disease may disappear within weeks of transplant, never to reappear.93 In contrast, some patients show persistence of detectable molecular disease. For the latter, progress to hematologic relapse can be predicted by the number of BCR-ABL transcripts detected within 6 months of transplant.62 Three years after SCT the cumulative incidence of relapse was 17%, 43%, and 86%, respectively, for patients with no detectible transcripts, less than 100 transcripts/μg RNA (low-level detection), or greater (high-level detection). The relationship between BCR-ABL transcript level and probability of relapse was apparent whether patients had received sibling or unrelated donor SCT and whether or not the transplant was depleted of T cells. Many studies confirm the utility of quantitative RT-PCR monitoring for predicting relapse and for determining response to DLI.44 Detection of BCR-ABL transcripts by quantitative RT-PCR is therefore a reliable method to monitor residual disease. There remains a subgroup of patients who have persisting but stable low levels of BCR-ABL transcripts for many years post-transplant without disease relapse. They may have residual disease in end-cells or a stable balance between small numbers of leukemic cells and regulatory mechanisms that prevent progression.46, 68

Treatment of relapse 

Donor lymphocyte infusion 

Durable molecular remissions are achieved between 3 and 12 months after DLI in up to 80% of patients relapsing in CP and for more than 90% of molecular relapses. Predictably, the occurrence of GVHD results in a much higher probability of leukemic response and the antileukemic effect of DLI is greatest in the absence of immunosuppression and when it induces full donor lymphoid chimerism.89

DLI may be accompanied by two major complications: bone marrow failure and lethal GVHD. Bone marrow failure is a greater risk in patients who have no detectable residual donor marrow cells at relapse. Marrow aplasia in these patients can be prevented or treated by infusing donor stem cells.89 Despite concerns that unrelated donor DLI would result in excessive toxicity, results show response and durable remission rates similar to those seen after the use of matched sibling DLI. While GVHD remains a hazard it does not appear to be more frequent or more severe than that encountered after matched sibling DLI.91

Improving the efficacy of DLI 

In the decade since the first use of DLI to treat relapsed CML after BMT progress has been made in determining the kinetics of the response, the effect of immune activation by cytokines and immune suppression by cyclosporine, the optimum lymphocyte dose required to achieve an effect, and the timing of DLI in relation to the progression of relapse. Careful sequential dose studies by the Memorial Sloan-Kettering group identified a CD3+ cell dose of 1 × 107/kg as usually sufficient to achieve a response of relapsed CML within 3 months with mimimal complications from GVHD.52 The Hammersmith Hospital group compared the use of DLI at the first sign of molecular relapse with DLI given to treat hematologic relapse and concluded that early treatment yielded the highest probability of complete response.67 Several investigators have used DLI in conjunction with IFN-α, with interleukin-2,55 or with both.31 Although there are no controlled studies, addition of IFN-α may increase remissions. Two studies have evaluated the effect of selected CD4+ donor lymphocytes on disease control and GVHD, showing a favorable effect of selected DLI on GVHD with comparable antileukemic effects to those seen with unmanipulated lymphocytes.1, 30 Antigen-pulsed lymphocytes to induce remission have been used successfully to increase the GVL effect.81

Other treatments for relapse 

Patients who relapse into an AP or BP rarely respond to DLI. Further remissions can be achieved with intensive chemotherapy or TBI followed by a second transplant but with a high TRM. Somewhat better may be PBSCT, but overall the outlook for second transplants remains gloomy, with less than 30% of patients experiencing prolonged survival.81

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New developments 

Reduced-intensity transplant regimens for CML 

Until recently investigators were slow to experiment with variations from the standard TBI or busulfan-based intensive preparative regimens because of concern for the reduced antileukemic efficacy of less intensive treatments. However, in an attempt to reduce TRM, investigators in Budapest were the first to use a low-intensity preparative regimen for CML. A recent update of 36 patients with CML transplanted following a chemotherapy-only preparative regimen of cyclophosphamide, cytarabine, and dibromomannitol reported 83% survival and 77% DFS.6 In the 1990s, with increased confidence in the curative potential of the GVL effect in CML, several groups began to explore low-intensity preparative regimens in CML, with the intention of using the transplant primarily to achieve donor T-cell engraftment and to establish a GVL effect. The application of such “minitransplants” was taken up almost simultaneously by Champlin in Houston10 and Slavin in Jerusalem82 who used fludarabine and busulfan, and by Storb in Seattle who administered low-dose (200 cGy) TBI as the conditioning regimen.54 After developing a very low-intensity fludarabine and cyclophosphamide regimen to treat patients with a variety of malignancies, the National Institutes of Health group prospectively evaluated the regimen in individuals over 50 years as well as selected younger patients with CML.11 Two patients received this preparative regimen followed by short-term cyclosporine as GVHD prophylaxis. Both had rapid donor T-cell engraftment but with initial hematopoietic recovery of recipient (CML) marrow. Between 2 and 3 months post-transplant, myeloid chimerism switched to 100% donor in origin, followed shortly by complete and sustained molecular remission between 3 and 4 months post-transplant. The delayed response was a clear indication that a GVL effect was sufficient—without myeloablation—to eradicate leukemia. Subsequently a further 11 patients with CML received the same transplant regimen. Disappointingly, only one of six patients transplanted with more advanced disease survived disease-free and only three of six patients in CP (including the two described above) achieved a molecular remission. However, no patient died of transplant-related complications.

Recent results of reduced intensity transplants for CML are shown in Table 6.

Table 6. Reduced-intensity SCT for patients with CML
CenterRegimenNMedian Age (yr)Median F/U (yr)CP1DonorGraft FailureRemissionGVHD II-IVTRM (N)Survival (actual)
Budapest6D + A3630-457.526S224M2183%
MDACC32F + Mel2752*16S/U119K—770%
NIH11F + Cy133428S24M4077%
Seattle75TBITBI + F949-71>16S06M3082%
Genova69Cy + Thio1552*2+9S011K—080%
Jerusalem82F + Bu + ATG734-561.26S0NA2270%
EBMT72F + other46501.523S/U0NA—35%65%
* Median age of larger cohort including non-CML patients.

Abbreviations: ATG, antithymocyte globulin; A, cytarabine; CP1, initial chronic phase; Cy, cyclophosphamide; D, dibromomannitol; F, fludarabine; K, karyotypic remission; M, molecular remission; Mel, melphalan; NA, not available; S, HLA-identical sibling; U, unrelated donor; TBI, 2 Gy total-body irradiation.

Using low-dose TBI, the Seattle group reported a high incidence of graft failure, which was later solved by the addition of fludarabine to the regimen, indicating that this drug is a particularly powerful immunosuppressive agent. Overall these results confirm that reduced intensity regimens are well tolerated even in older patients. However, more myelosuppressive regimens using TBI, busulfan, or melphalan may be more effective at eradicating CML, suggesting that disease debulking improves the efficiency of the GVL effect. These preliminary results mark an important step in the evolution of safer but still effective transplants for CML. Prospective studies comparing low-intensity with standard-intensity regimens, perhaps in patients in the 50- to 60-year age group where the choice of conditioning is less clear, are required to validate their role in CML.

Adoptive transfer of leukemia-specific CTL 

Falkenburg et al in Leiden recently showed that donor CTL expanded in vitro against the recipient's leukemia induced remission in CML patients relapsing after transplantation.26 The patient treated was refractory to the standard DLI approach using unmanipulated lymphocytes, yet only small numbers of leukemia-specific CTL were needed to achieve remission. While these experiments demonstrate the proof of principle that in vitro–generated leukemia-specific CTL are effective in vivo, the variability in the ability to generate such CTL in every donor-recipient pair and the technical competence required for prolonged T-cell culture limit the more general application of the technique. In the future, with the identification of specific antigens, leukemia-specific CTL should be easier to produce, thus facilitating clinical application.

The place of SCT in the era of imatinib mesylate (STI571) 

The introduction of the specific BCR-ABL tyrosine kinase antagonist imatinib mesylate has marked a new era in the treatment of CML. The reader is referred to other sections in this issue for detailed descriptions of the effect of imatinib in CML. The introduction of this agent has enormous implications for the future of SCT, and the role of imatinib in conjunction with SCT is still being defined. First, the ease of obtaining complete cytogenetic responses with imatinib has already altered standard practice indications for allogeneic SCT. Most teams would now only consider offering allogeneic SCT as the first treatment choice to good-risk patients—those under the age of 45 with HLA-identical siblings. Imatinib is beginning to alter transplant outcomes both favorably and unfavorably. In patients with BP CML still sensitive to imatinib, the agent can be used to rapidly control disease, and to achieve second CP in some, prior to allogeneic SCT. We have found that imatinib in conjunction with DLI can achieve remissions in patients with advanced disease relapsing post-transplant. In fact imatinib alone may be sufficient to treat relapse post-transplant: a recent case report describes a karyotypic remission following imatinib in a patient who had failed DLI.63 In this situation, imatinib may reduce the leukemia to a level where the GVL effect can eliminate the remaining cells. Imatinib may also find a place in preparative regimens as a low-toxicity debulking agent, coupled with powerful immunosuppressants such as fludarabine and cyclophosphamide to achieve engraftment. In contrast to these potential benefits, imatinib resistance is also creating new problems for transplantation–patients who do not respond to primary treatment with imatinib may have a lower chance of achieving a cure of CML by transplantation.

Vaccines 

In contrast to the complexity of adoptive transfer of leukemia-specific T cells, vaccination has the attraction of simplicity, low cost, and ease of clinical application. Clinical trials using BCR-ABL fusion proteins are underway in the autologous setting, which could be readily adapted to allogeneic transplantation by vaccination of either patient or donor.65 Vaccination of CML patients with the PR1 peptide is also under investigation. Eventually, both ex vivo and in vivo approaches to boosting the GVL response could be combined to maximize benefit.

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Conclusions 

CML remains one of the best leukemia models for studying the GVL effect after SCT. Through in vivo analysis of minimal residual disease, T-cell chimerism, and specific reactivity, we have learned much about the kinetics of the immune response. From in vitro studies, facilitated by the ability to grow CML cells in culture, the basis of the GVL response has been characterized. Now we are on the threshold of delivering highly targeted and effective immunotherapy to patients with CML undergoing SCT. A continuing concern is whether immune escape will limit the success of these techniques. As immunotherapy begins to be more widely applied, we will inevitably have to learn more about the mechanisms resulting in failure of GVL to eradicate disease. Understanding tumor escape and developing ways to modify malignant cells to be better immune targets will be crucial to the success of this approach.

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☆ Address reprint requests to John Barrett, MD, Hematology Branch, NIH-NHLB1, Building 10 Room 7C103, 9000 Rockville Pike, Bethesda MD 20892-0003.

☆☆ This is a US government work. There are no restrictions on its use.

PII: S0037-1963(03)70043-2

Seminars in Hematology
Volume 40, Issue 1 , Pages 59-71, January 2003

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