Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. However, for a minority of patients who fail TKI or progress to advanced phase disease, allo-SCT remains the only therapeutic option. This review addresses the current indications for allo-SCT in CML and the role of conditioning (myeloablative vs reduced intensity), donor source (sibling vs volunteer unrelated donor), graft source (BM vs peripheral blood vs cord) and the value of pre-, peri- and post transplant use of TKI in the management of CML.
Management of CML in the TKI era
Imatinib mesylate (IM) was approved in 2001 for the treatment of patients with CML who failed IFN-α therapy1 and was subsequently established as first-line therapy for CML. Consequently, the annual number of allo-SCTs performed for CML has fallen markedly, with most of the decrease occurring for patients with CML in the first chronic phase (CML-CP1).2 It is estimated that 15–25% of patients fail IM therapy due to resistance or drug intolerance. Furthermore, small proportions of newly diagnosed CP patients have primary resistance to the drug and never achieve a complete hematologic response or a durable cytogenetic response (CyR). A minority of patients who start IM treatment in CP appears initially to respond, achieving either cytogenetic or major molecular responses, and then lose their response. Resistance appears more prevalent with advanced disease.
Strategies for overcoming IM resistance include dose escalation, which may induce or reinduce CyR. Patients who satisfy the criteria for resistance should be switched to second-generation tyrosine kinase inhibitors (TKIs) such as dasatinib or nilotinib and tested for the presence of a kinase domain mutation. If the T315I mutation is identified, one can predict that response to either of these two drugs will be poor, and alternative treatments should be considered. Dasatinib is a dual inhibitor of Abl and Src kinases and approved in CML (all phases) after IM failure or resistance; it inhibits all IM-resistant tyrosine kinase mutations except T315I, as well as the Src kinase family.3 Nilotinib is also approved for CML-CP or advanced phase (AP) after treatment failure or resistance to IM, and inhibits most BCR-ABL mutants, PDGFR, c-Kit, but not T3151 or the Src-kinase family. Studies evaluating nilotinib or dasatinib as the first-line treatment in CML-CP patients are currently under way and have shown improved CCyR in comparison with earlier studies of high-dose IM.1
The use of IM and other TKIs has now significantly delayed allo-SCT for most patients. Although some studies show a nonsignificant trend toward higher relapse mortality,4 most studies show that TKI use, while delaying time from diagnosis to transplant, does not result in worse outcomes.4, 5, 6, 7, 8, 9 IM is also increasingly used as a stabilizing bridge to the second CP before allo-SCT in patients with accelerated (AP) and blastic phase (BP).10 Weisser et al.8 showed that achieving a response to IM was associated with a better outcome post-SCT; patients with AP CML who had achieved a CyR on IM had significantly less acute toxicity, improved OS and leukemia-free survival (LFS) and less TRM.
National comprehensive cancer network (NCCN)11 and European LeukemiaNet (ELN)12 guidelines recommend consideration of allo-SCT in patients with suboptimal or failure of response to IM or other TKIs. This includes patients who fail to achieve a hematologic response after 3 months, a CyR by 6 months, an MCyR by 12 months, a CCyR by 18 months, or those who have lost their response after achieving these response landmarks. Patients in CML-AP or -BP should receive a TKI to obtain a second CP before transplant to improve outcome.
Upfront allo-SCT in the TKI era
Despite allo-SCT offering the only curative treatment for CML, the TRM13 associated with this procedure as well as the excellent outcomes demonstrated with TKIs14 argues against the use of allo-SCT as first-line therapy. The 8-year follow-up from the IRIS trial confirmed an OS of 85% for the IM group, and only one case of disease progression (in year 8) after the third year post-achievement of CCyR.14, 15 The superiority of drug therapy over early SCT was shown in a recent prospective trial evaluating CMP-CP patients over 11 years, which demonstrated that low-risk patients receiving drug therapy had superior OS in comparison with low-risk patients receiving allo-SCT, despite significantly more CCyR and major molecular responses in the transplant group.16 At present, there is no role for allo-SCT as first-line therapy for CML-CP. In the case of a patient with high disease risk (Sokal-score), the option of allo-SCT should be considered; however, the patient would most likely benefit from a trial of TKI to assess response and determine if an allo-SCT is indicated.
Interestingly, mutation scoring may assist in TKI choice for patients with IM failure who are treated with second-generation TKIs17, 18 A recent paper by Jabbour et al.17 found that mutational scoring (on the basis of in vitro inhibitory concentrations (IC50) required to inhibit the kinase activity and the proliferation of cells bearing different mutations) was able to predict outcome measures (including response rate, LFS and OS) in CML-CP patients with IM failure (treated with second-generation TKIs); however, for patients with AP disease, mutations did not correlate with LFS and OS.
We recently showed that three factors—CyR to IM, Sokal-score and recurrent neutropenia on IM—can accurately predict response to second-generation TKI in patients in whom IM treatment fails (the Hammersmith score). On the basis of the presence of each of the three factors, patients were categorized into good risk (n=24), intermediate risk (n=27) and poor risk (n=29) with 2.5-year cumulative incidence of achieving CCyR after initiation of second-generation TKI of 100, 52.2 and 13.8%, respectively.19 On the basis of these data, we recommend that patients with a low Hammersmith score should be offered dasatinib or nilotinib therapy. Patients with a high Hammersmith score may be a candidate for allo-SCT, particularly if they have a low EBMT score. Patients with intermediate or good-risk Hammersmith score or patients classified as poor risk for transplant should be treated with second-generation TKI; their CyRs at 3 or 6 months could be used to assess the need to maintain or change their therapeutic strategy. Patients in AP at diagnosis should be referred for allo-SCT as soon as possible, with initial therapy with TKI+/− chemotherapy to achieve a second CP. It is important to note that in these patients IM-induced responses are generally short-lived.20
How does the source of stem cells influence outcomes?
In patients with AP CML undergoing a myeloablative conditioning transplant (MST), the use of PBSCs compared with BM as the source of stem cells is associated with lower relapse rates, and improved OS and LFS.21, 22, 23 In a recent meta-analysis comparing myeloablative matched related donor (MRD) PBSCT vs BMT across various hematologic malignancies (n=1111 patients), PBSCT was associated with an improvement in relapse rates in all CML patients, although improved LFS and OS was seen only in AP disease.21 Similarly, a CIBMTR analysis comparing the outcome of CML patients undergoing MRD PBSCT or BMT reported that among patients with CML-CP1, the 1-year TRM, LFS and relapse rates were similar for patients receiving BMT or PBSCT.22 However, among patients with CML-CP2 or CML-AP, PBSCT was associated with lower incidence of treatment failure and higher probability of LFS at 1 year.22 A prospective randomized trial showed no significant difference in outcome between CML patients receiving HLA-matched related allogeneic-BMT or filgrastim-mobilized PBSCT; specifically, there was no significant difference in the incidence of acute or chronic GVHD (aGVHD or cGVHD), OS, LFS and TRM.24 However, in CP patients, a trend toward a higher incidence of relapse at 3 years was noted in BMT vs PBSCT recipients (7 vs 0%, P=0.10), along with a trend toward a higher incidence of cGVHD in PBSCT recipients (59 vs 40%, P=0.11),24 possibly due to the higher T-cell content of PBSC grafts.
Data on the impact of stem cell source and outcome in recipients of matched unrelated donor (URD) transplants are conflicting, notwithstanding the conditioning regimen. A retrospective analysis of 91 patients in CMP-CP1 undergoing an URD transplant found significantly improved outcomes for PBSCT compared with BMT, with better 3-year OS (94 vs 66%), faster engraftment, superior immune reconstitution and lower TRM (5 vs 30%).23 However, other studies have failed to confirm these results.25, 26
The role of unrelated cord blood transplantation (CBT) in CML is unclear. CBT has many potential advantages over URD BMT or PBSCT, including no risk to the donor and ease of availability. Previous data, mostly from pediatric studies, have shown that despite higher HLA-mismatch, CBT carries a lower risk of aGVHD and cGVHD in comparison with URD BMT.27, 28 The first prospective study evaluating CBT in nine patients with CML in different phases of disease reported donor engraftment in 7/7 evaluable cases and four patients transplanted in CML-CP were alive and in molecular remission 18–42 months after transplantation.29 A more recent retrospective analysis assessed 86 patients with CML who had received CBT and reported a 2-year OS of 53%; for patients in CP, AP and BP, the OS rates were 71, 59 and 32%, respectively, and compared favorably with OS rates after URD BMT.30 The study also demonstrated the applicability of the EMBT score in predicting overall risk in CBT and interestingly found that the duration from diagnosis to CBT did not impact outcome, endorsing IM use before CBT.30
In summary, for patients in CML-CP1, BMT may be the preferred option to reduce the risk of disabling cGVHD-related long-term complications, whereas PBSCT should be considered for patients in CMP-CP2 or CML-AP/BP. Data on the impact of BM vs PB as the stem cell source in reduced intensity conditioning (RIC) transplants are limited and conflicting (discussed below). CBT appears to be a promising approach and warrants further studies.
How does HLA matching influence outcome?
A number of studies have shown that patients with CML undergoing a MRD allo-SCT have the best outcome, whereas recipients of an URD transplant are at increased risk of GVHD and higher TRM.31, 32 In a large study comparing patients with CML-CP undergoing URD (n=2464) vs an MRD (n=450) transplant, the 5-year LFS for younger patients (<30 years) with CML-CP1, transplanted within 1 year of diagnosis was 61% for recipients of an URD transplants vs 68% with MRD transplants. However, URD transplantation was associated with significantly higher risk of graft failure, aGVHD, slightly inferior OS and LFS (with substantially worse 5-year LFS with longer delay to transplant) without the anticipated decrease in relapse rates.32 Although this and other earlier studies used an older definition of HLA matching, a more refined HLA classification with high-resolution allele level matching for HLA class-1 and DR1 loci is widely being used. Applying the new HLA classification to the above study revealed that only 37% of patients initially classified as ‘HLA matched’ were HLA ‘well matched’ and confirmed previous findings of greater risk of graft failure and GVHD and worse OS and LFS with all levels of unrelated donor allo-SCT (recategorized), but without significantly less risk of relapse.33, 34 In other words, there was no evidence of a stronger GVL effect with HLA mismatch.
Two studies from CIBMTR assessed the influence of locus-specific mismatching on outcome and found that mismatching at HLA-A, -B, -C and -DRB1 was associated with a worse outcome, whereas mismatching at DP or DQ loci had no impact on outcome.35, 36 A more recent CIBMTR study compared outcome in transplant recipients with CML-CP1 and included 3514 recipients of MRD and 1052 patients undergoing an URD (531 were matched at 8/8 alleles for HLA-A, -B, -C and -DRB1; 252 were mismatched for 1 HLA locus; 269 were mismatched for 2 or more loci).34 The 5-year OS was significantly inferior in 8/8 matched URD transplant recipients compared with the MRD group (55 vs 63%, P<0.001), with the greatest concordance within the first year of transplant. Higher TRM, lower LFS and OS were observed proportionally with greater degrees of mismatch. Despite a higher risk of grade II to IV aGVHD and cGVHD in recipients of 8/8 HLA-matched URD compared with MRD transplants, lower rates of relapse were not observed and data showed similar risks of relapse in MRD, matched and mismatched URD recipients,34 confirming previous data that there is no evidence for a stronger GVL effect with URD or mismatch allo-SCT.33
How does the conditioning regimen impact allo-SCT outcome with increasing age and earlier TKI use?
Attempts to increase the intensity of conditioning regimens have not translated into improved survival because of higher toxicity and TRM.37 Donor lymphocyte infusion (DLI), on the other hand, has proven to be effective in producing durable molecular remissions in patients with recurrent or residual disease post-SCT.38 As a result, RIC SCT (which relies on GVL effect) is available for older patients or patients with multiple comorbidities who would not have otherwise been considered for MST. To date, single and multi-institution studies comparing RIC SCT39, 40, 41, 42, 43, 44, 45, 46, 47, 48 with MST49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 have not provided consistent data with regard to OS, relapse rates and frequency of GVHD. A recent German study reported an OS advantage for MST vs RIC allo-SCT (5-year OS, 62 vs 42%), but patients receiving RIC were more frequently older (>40), with more advanced disease and more likely to have received their SCT more than 1 year from diagnosis of CML.49 This was in contrast to a study of 81 patients with CML that reported a significantly higher 5-year OS rate for the RIC group vs the myeloablative group (70 vs 56%), as well as better DFS and higher incidence of cGVHD (80 vs 66%) but a similar incidence of aGVHD (14 vs 18.7%).52
An EBMT study evaluated 186 patients who had received a variety of RIC regimens. TRM appeared lower for fludarabine, BU, ATG (Flu/BU/ATG)-based RIC regimens, possibly secondary to T-cell depletion by ATG, resulting in less aGVHD, but there was no significant effect of conditioning regimen on outcome.39 Patients receiving RIC were noted to have improved OS in CP1 or CP2 (3-year OS, 69 vs 57% respectively) and inferior OS with advanced disease (2-year OS in AP 24% and BC 8%). The poor outcome after RIC SCT in AP disease suggests that the GVL effect may not be strong enough and that the larger tumor burden may outpace the immunological antileukemia response; TKI given pre- or peri-transplant may reduce the tumor burden and improve transplant outcome. Higher EBMT scores also appeared to correlate with poorer OS in both MST and RIC regimens. The 3-year OS per EBMT score for MST vs RIC were as follows: EBMT score 1 (80 vs 69%), 2 (70 vs 69%), 3 (55 vs 67%), 4 (45 vs 42%), 5 (27 vs 35%). It appears that patients with low EBMT scores (1 and 2) have similar OS to those obtained by MST regimens; the significance of this is unknown due to lack of long-term relapse data with RIC SCT. These data suggest that RIC may be used for patients with higher EBMT score after IM failure, which applies to the majority of patients, given the longer time from diagnosis to SCT, more advanced disease and increasing age.39
The benefit of RIC regimens for young patients is unclear. Or et al.46 studied 24 patients with CML-CP1 with a median age of 35 years who underwent a Flu/BU/ATG RIC regimen within a median of 9 months from diagnosis; they reported an OS of 85% at 37 months. In contrast, Das et al.62 evaluated the outcome after a similar regimen of Flu/BU with ATG or 2 Gy TBI in CMP-CP1 patients with a median age of 34 years, and reported an OS of only 35% after a median follow-up of 30 months. Interpretation of these data is limited by the small number of younger patients receiving RIC regimen and the short follow-up. However, RIC allo-SCT is an important option for older patients (>50 years) or those with medical comorbidities that place them at higher risk for transplant-related complications. Although the EBMT score has been validated in patients with CML undergoing MST allo-SCT, it has not been specifically validated in recipients of RIC transplants. The role of RIC is being explored in older patients or patients with comorbidities in advanced disease and for younger patients wishing to preserve fertility.
Treatment of relapses post-allo-SCT
Post transplant TKI (relapse treatment, pre-emptive therapy and tolerance)
Multiple studies have shown post-SCT IM's efficacy both in the setting of relapse treatment and relapse prevention.45, 65, 66 Data on the use of second generation TKIs in these settings is also favorable but very limited.67, 68 Post-SCT IM is most effective in the treatment of early-stage disease, whereas alternative strategies are needed for patients who relapse in AP; one study reported CyR rates for CML-CP/AP or -BP patients of 63 and 43%,64 whereas another reported CR rates of 58% for CP and 22% for BP.69 Improved outcomes with post-SCT TKI may occur when TKI is initiated in molecular vs cytogenetic relapse; patients in molecular relapse have a higher likelihood of achieving complete molecular response (77.8 vs 47.4%) and shorter time to response (28 vs 114 days) than patients in cytogenetic relapse.70
It is to be noted that in the different studies the timing of initiation of TKI therapy for relapse post-SCT is hugely variable, ranging from a median of 5–54 months.64, 69, 70 Although the optimal time for initiation of IM therapy post-SCT remains to be determined, earlier administration of IM does not appear to correspond with increased toxicity. Carpenter et al.65 evaluated prophylactic IM in seven CML patients, initiated within 28 days of transplant, and found it to be well tolerated; five out of the seven patients remained in major molecular CR after 1.4 years. In another study where IM was started 35 days to 1 year after allo-SCT to delay relapse and postpone the requirement for DLI, 15 out of the 21 patients relapsed within a median of 17 months after transplantation (none relapsed while on IM).45 A recent trial showed that 50% of non-transplanted patients on IM lost molecular CR within 5 months of IM discontinuation.71 Interruption of IM therapies appears to be associated with a higher risk of disease recurrence. Optimal duration of preventative and therapeutic IM after allo-SCT is unknown; it is possible that longer duration of therapy is preferable given the range of duration of remission in the above studies.64, 65, 69, 72
The reported toxicities of post-SCT IM include pancytopenia, liver dysfunction, fluid retention and nausea but the drug is generally well tolerated. The incidence of GVHD in patients treated with IM post transplant is not yet known. It is also unclear whether post-SCT IM alone is sufficient to induce durable remissions. Although IM is effective at reducing the disease burden, it does little to eradicate the leukemic ‘stem cell,’73 so disease typically recurs after stopping the drug, necessitating other strategies such as DLIs.
Post transplant DLI with TKI
DLI is the established treatment modality for eradicating disease recurrence post-SCT and relies on the GVL effect to eradicate residual disease.74, 75 DLI results in durable response rates in 63–100% for CMP-CP1 patients.63 For patients with advanced disease, remissions have been observed in only 12–28% of patients and appear to be less durable.76 Predictive factors for response to DLI include disease burden, GVHD post-DLI and panyctopenia.77 When administered with dose escalation rather than higher dosing, DLI has been shown to result in reduced rates of both aGVHD and cGVHD (although the cytogenetic remission rates are similar between the two approaches).78 The effective cell dose appears to be dependent on the disease stage and the donor source,77 with a cell dose of ⩽107 CD3+ cells/kg more likely to produce a response in recipients of an URD transplant in molecular relapse.63 It is not yet clear whether unrelated DLI results in enhanced GVL activity, but both related and unrelated DLI appear to result in similar outcomes.76 Complications of DLI include GVHD and the development of pancytopenia. Acute GVHD and cGVHD are seen in up to 60% of patients post-DLI,76 grade II–IV aGVHD is reported in up to 41% of DLI recipients. Grade II–IV aGVHD and extensive cGVHD are associated with infusion of male recipients with female donors, and <3-year interval between allo-SCT and DLI, but not the total cell dose.63 Generally, practice is to avoid DLI in patients receiving daily immunosuppressive therapy for GVHD or with clinical evidence of aGVHD.
One strategy to minimize these toxicities is to postpone the infusion of DLI by reducing the risk of early relapse with adjunctive TKI post-allo-SCT.45 We previously compared the use of DLI alone vs IM alone vs DLI+IM (sequential or concurrent) in patients with CML who relapsed after T-depleted allo-SCT (molecular, cytogenetic or hematologic). We found that the DLI+IM combination group had a superior outcome with regard to OS, LFS and shorter time to achieving molecular remission.79 Larger studies are necessary to compare the value of IM and DLI+IM for relapsed CML post-SCT.
We would advocate treating high-risk patients (or at least those who fail to achieve molecular negativity post-SCT) with prophylactic post transplant TKI. The optimal duration of treatment remains to be determined, but benefits are seen with >1 year of therapy. Relapsed CML post-SCT should be treated with DLI possibly combined with TKI. For those patients who did not receive TKI prophylactically post-SCT and who relapse, we would recommend treatment with escalating dose DLI with IM. Patients who relapse post-SCT while on IM may benefit from DLI plus an alternative second-generation TKI (such as dasatinib or nilotinib).
Complications associated with TKI use in conjunction with transplantation
While pre-SCT TKI administration does not appear to affect TRM significantly,80 and may even reduce the risk of GVHD, the impact of prolonged TKI use post-SCT is unclear, with limited numbers of studies and small numbers of patients. In the post-SCT setting (complicated by transplant-related medications, underlying myelosuppression, GVHD), IM administration (either as therapy for relapse or as prophylaxis) has been reported to be associated with myelosuppression, fluid retention, weight gain and liver dysfunction.20, 66 Congestive heart failure has also been described as a rare complication of IM (in the non-transplant setting),81 although this has been disputed by other retrospective analyses which failed to show an increased risk of cardiotoxicity with IM.82, 83 It is possible that in elderly patients with pre-existing cardiac conditions IM results in increased cardiotoxicity. In the myeloablative allo-SCT setting (which can itself be associated with cardiotoxicity), Sohn et al.84 reported two patients with AP-CML who developed severe cardiac dysfunction after IM (BU/ CY conditioning); this was attributed to an increased risk for cardiotoxicity with IM exposure in AP patients, given that 45 other patients who had received only the myeloablative conditioning regimen did not develop cardiotoxicity. A recent retrospective study evaluating cardiotoxicity in patients on IM (pre or post transplant) compared with patients not on IM failed to show increased risk of cardiotoxicity in the IM group.51 However, the number of participants receiving IM post-SCT was very small, with variable dosage, duration and timing of initiation of IM therapy.
Reports on the use of second-generation TKIs in the post-SCT setting are limited and include small numbers of patients. With regard to second-line agents, such as nilotinib and dasatinib, toxicities also include myelosuppression, severe transaminitis, QTC prolongation.85 Dasatinib specifically is associated with increased risk of hemorrhage, as well as a significant risk of fluid retention (including pleural and pericardial effusions). This is especially important in patients undergoing MST allo-SCT. A minimum of 2–3 weeks of deconditioning is indicated to avoid increased risk of early post transplant complications. Dasatinib crosses the blood–brain barrier and has a role in the treatment of extramedullary relapse, as well as being indicated in patients with IM failure. In comparison, nilotinib is associated with milder fluid retention (in comparison with IM or dasatinib) and a more frequent incidence of hyperbilirubinemia and QTC prolongation. A recent case series by Klyuchnikov et al.67 evaluated 11 patients with either CML or Ph+ALL who received post transplant dasatinib or nilotinib and reported only 1 dose reduction of dasatinib secondary to gastrointestinal bleeding.
In summary, the use of first- and second-generation TKI post-SCT (either as preventative or salvage) does not appear to confer increased transplant-related toxicity, but more studies are warranted to identify the ideal dose of TKI, the best time post-SCT to initiate therapy, long-term side effects, treatment duration, as well as strategies for cumulative benefit with DLI.
Allo-SCT continues to occupy a considerable role in CML in the IM era. It is recommended as first-line therapy for patients with advanced disease (after TKI bridging), with T315I mutation; as second-line therapy after IM failure (with a suitable donor) vs second-generation TKI; and as third-line therapy after second-generation TKI failure or suboptimal response. Although earlier IM treatment does not appear to compromise the outcome of allo-SCT, patients with AP disease continue to demonstrate worse outcome. More predictive tools are needed to help detect early IM failure and prevent transformation of disease to advanced stages. Early mutational analysis may predict poor response to second-generation TKIs, and will likely have a key function in guiding a more rational selection of second-generation TKI or early allo-SCT after IM failure. Further elucidation of risk factors for TRM and morbidity will ultimately improve transplantation outcomes, expanding its role as second-line therapy after IM failure. PBSCT is associated with more cGVHD compared with BMT, and BMT is the preferred option in early phase CML. However, with increasing numbers of patients receiving allo-SCT after TKI failure, more data are needed to show superiority of BMT in preventing late transplant-related morbidity and late mortality in this group of patients. More studies are needed to evaluate outcomes with expanded use of CBT. RIC allo-SCT continues to be an important strategy for older patients and those with comorbidities, with better outcomes noted when performed early in the disease. The utility of EBMT scores with RIC allo-SCT needs to be addressed in prospective clinical studies. The role of TKI in prevention or treatment (with DLI) of relapse after transplantation, especially in patients with history of TKI failure, warrants more studies.
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The authors declare no conflict of interest.
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Venepalli, N., Rezvani, K., Mielke, S. et al. Role of allo-SCT for CML in 2010. Bone Marrow Transplant 45, 1579–1586 (2010) doi:10.1038/bmt.2010.138
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