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Hematopoietic cell transplantation in chronic myeloid leukemia

Hematopoietic cell transplantation in chronic myeloid leukemia
Author:
Robert S Negrin, MD
Section Editor:
Nelson J Chao, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Jan 2024.
This topic last updated: Jun 03, 2022.

INTRODUCTION — Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome t(9;22)(q34;q11) resulting in the BCR-ABL1 fusion gene. This genetic abnormality results in the formation of a unique gene product (BCR-ABL1), which is a constitutively active tyrosine kinase that causes CML. (See "Molecular genetics of chronic myeloid leukemia".)

Tyrosine kinase inhibitors that target BCR-ABL1 effectively treat CML. However, a small percentage of patients progresses from the relatively indolent chronic stable phase of CML to a more aggressive accelerated phase, which may culminate in blast crisis, an acute leukemia that is generally refractory to treatment. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

Treatment of CML with allogeneic hematopoietic cell transplantation (HCT) will be discussed here; autologous HCT is rarely utilized in this setting. Other treatments options for CML are presented separately. (See "Overview of the treatment of chronic myeloid leukemia" and "Initial treatment of chronic myeloid leukemia in chronic phase" and "Accelerated phase chronic myeloid leukemia: Diagnosis and treatment" and "Treatment of chronic myeloid leukemia in blast crisis".)

Throughout this review, the term "hematopoietic cell transplantation" (HCT) will be used to refer generically to transplantation of progenitor cells from any source (eg, bone marrow, peripheral blood, umbilical cord blood), unless a particular source of such cells is specified (eg, peripheral blood progenitor cell transplantation). (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

PRETRANSPLANT CONSIDERATIONS

Eligibility — Eligibility for allogeneic HCT varies across countries and institutions. Ultimately, decisions regarding transplant eligibility should be made on a case-by-case basis based on a risk-benefit assessment and the needs and wishes of the patient. General eligibility criteria are discussed in more detail separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Treatment decisions require extensive consultation between the patient and a physician highly knowledgeable about the different treatment options. Determining whether the patient has an HLA-matched sibling or initiating an unrelated donor search is warranted early in the course of therapy to determine which options are available. Since only 25 percent of siblings will be HLA matched, and it often takes several months to identify an unrelated donor, anticipating the next potential therapeutic intervention in CML patients is important.

Efficacy and toxicity

Efficacy — Initial trials in the 1980s demonstrated that CML could be effectively treated with myeloablative chemoradiotherapy followed by syngeneic (identical twin) HCT [1]. A significant percentage of these patients achieved long-term remission and cure of their disease. However, the advantage of avoiding graft-versus-host disease (GVHD) with syngeneic transplantation was counterbalanced by an increased incidence of relapse, which was one of the initial observations leading to the concept of a graft-versus-leukemia (GVL) effect. In one series that compared the outcome of 103 syngeneic and 1030 HLA-matched sibling transplants in patients with leukemia, the patients with CML who received a syngeneic transplant had a much higher three-year rate of relapse (40 versus 7 percent) [2]. (See "Biology of the graft-versus-tumor effect following hematopoietic cell transplantation".)

Using HLA-matched sibling donors, 50 to 85 percent of patients with CML transplanted in first or second chronic phase of their disease achieve long-term remissions and cure of their disease [3-7]. The percentage of patients achieving a long-term remission falls to 30 to 40 percent in patients transplanted in accelerated phase [4,8] and to 20 to 30 percent of patients in blast crisis.

The ability of allogeneic HCT to cure CML is related to the antileukemic effects of both the conditioning regimen and the GVL effect of the donor lymphocytes. As such, myeloablative conditioning regimens are expected to result in higher rates of long-term remission and better disease control than nonmyeloablative (NMA) or reduced intensity conditioning (RIC) regimens. However, this has never been formally tested, and our experience suggests that patients treated with NMA conditioning can also have excellent outcomes. However, allogeneic HCT is associated with an up-front mortality risk of 5 to 20 percent, making the use of tyrosine kinase inhibitors (TKIs) more attractive as up-front therapies given their low rates of short-term mortality. (See "Overview of the treatment of chronic myeloid leukemia" and 'Morbidity and mortality' below.)

Timing — Because of the invariable progression of the disease, allogeneic HCT has been widely used for patients with CML. Historically, the results obtained with this modality are directly related to the phase of disease at the time of the transplant; among patients in chronic phase, transplantation within the first year results in the best outcomes [3,4,9]. However, with the introduction of TKIs, the majority of patients are treated with one of these agents, and transplantation is only considered for patients who have failed this treatment modality. (See "Overview of the treatment of chronic myeloid leukemia" and "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy".)

Allogeneic HCT is generally reserved for patients with inadequate control of chronic phase CML despite initial treatment with a TKI, for patients who are intolerant of these drugs, or as an adjunctive treatment for patients who present with more advanced disease (accelerated phase or blast crisis). For patients with advanced disease, the aim of initial management is to revert to chronic phase with plans to proceed with allogeneic HCT in chronic phase, if possible. (See "Accelerated phase chronic myeloid leukemia: Diagnosis and treatment" and "Treatment of chronic myeloid leukemia in blast crisis".)

Morbidity and mortality — Allogeneic HCT can achieve excellent long-term control of CML, particularly in patients under the age of 50 years who are transplanted in chronic phase within one year of diagnosis. However, as with all allogeneic transplants, there is considerable up-front risk due to toxicity, infection, and GVHD. Mortality risk in the first 100 days following transplantation is in the range of 5 to 20 percent for ideal transplant candidates with fully HLA-matched sibling or unrelated donors; comorbid conditions increase this risk. (See "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'Estimating mortality risk' and "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'Risk assessment scoring systems'.)

Survivors of HCT have a higher prevalence of long-term health-related complications. However, significant morbidity is uncommon; chronic GVHD is the most important predictor of adverse medical late effects and poor overall health [10]. (See "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults", section on 'Quality of life'.)

The largest study to evaluate the long-term effects of HCT in patients with CML included 2444 patients who underwent myeloablative allogeneic HCT in first chronic phase prior to 1998 and survived in continuous complete remission for at least five years [11]. At a median follow-up of 11 years (range 5 to 25 years), the following were noted:

●Overall survival (OS) rates at 15 years after HCT from a matched sibling or unrelated donor were 88 and 87 percent, respectively.

●The cumulative incidence of relapse at 15 years for the same groups were 8 and 2 percent, respectively. The latest relapse was reported at 18 years after HCT.

●Chronic GVHD increased non-relapse and overall mortality rates, but reduced the risk of relapse.

●Once patients reached 15 years post-HCT, mortality rates were similar to those of age, race, and sex-matched normal populations.

Comparison to medical therapy — Medical therapy with TKIs has emerged as the preferred initial therapy for CML primarily because it lacks the up-front risk and morbidity of HCT and is able to provide good disease control in the majority of patients.

Treatment with a TKI is preferred by the majority of patients due to the low risk of side effects and excellent response rates. However, the majority of patients still have detectable disease using sensitive polymerase chain reaction (PCR)-based techniques. Therefore, careful monitoring is required in patients who would otherwise be candidates for allogeneic HCT. There are no trials comparing TKIs to allogeneic HCT in patients who would otherwise be candidates for transplantation.

Pretreatment with TKIs — TKIs are a key component of the initial treatment of all patients with CML. Although definitive data are lacking, it appears that prior treatment with TKIs does not negatively impact outcomes for patients who ultimately proceed to allogeneic HCT.

To date there is relatively little information regarding the outcome of patients who have been treated with TKIs (eg, imatinib, dasatinib, nilotinib) prior to allogeneic HCT. Initial reports have not found adverse outcomes and suggest that there may be a benefit to tumor load reduction with a TKI prior to HCT [12-18]. This is principally supported by two observations:

●The most important prognostic factor for survival following HCT for CML is the disease phase at the time of transplantation. Treatment with TKIs prior to HCT appears to be a key factor in the management of accelerated or blast phase disease. (See 'Disease phase' below and "Treatment of chronic myeloid leukemia in blast crisis", section on 'Eligible for HCT' and "Accelerated phase chronic myeloid leukemia: Diagnosis and treatment", section on 'Transplant-eligible'.)

●When compared with historical results, transplant-related mortality (TRM) rates have decreased in studies that have allowed the use of TKIs prior to HCT [18,19]. While there are many factors that impact TRM, this outcome is at least reassuring that the use of TKIs prior to HCT has not resulted in increased TRM. (See 'Morbidity and mortality' above.)

Prognostic factors — Disease phase at the time of HCT is the most important prognostic factor for survival following allogeneic HCT for CML. A variety of other prognostic factors and prognostic risk scores for predicting outcome after allogeneic HCT has been evaluated.

Prognostic risk scores — Prognostic risk scores have been developed with the aim of predicting outcome after allogeneic HCT. The most robust risk scores are presented below. Since the development of these risk scores, there have also been advances in transplant techniques, which have resulted in reduced toxicities and improved outcomes, including pharmacologic monitoring of drug levels, NMA preparative regimens with reduced toxicity, improved treatment of infections and other complications of transplantation, and the availability of different sources of hematopoietic stem cells. (See "Preparative regimens for hematopoietic cell transplantation" and "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells" and "Donor selection for hematopoietic cell transplantation".)

●The European Group for Blood and Marrow Transplantation (EBMT) devised a risk score based on five separate characteristics, which predicted treatment-related mortality and five-year OS following allogeneic HCT (table 1) [20]. The EBMT risk score was later validated using separate data from the International Bone Marrow Transplant Registry [21].

●The hematopoietic cell transplantation comorbidity index (HCT-CI) incorporates information on patient comorbidities and was designed to predict outcomes in patients undergoing allogeneic HCT for a variety of diseases (table 2). Using this score, one study found that patients with comorbidities (HCT-CI >0) and elevated levels of C-reactive protein had significantly higher rates of non-relapse mortality and lower OS at five years [22].

In contrast, the Sokal and Hasford scores do not predict survival in the setting of HCT [21]. Additional information about prognostic risk scores for patients considering HCT are presented separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'Risk assessment scoring systems'.)

Disease phase — Disease phase is the most important prognostic factor for survival following allogeneic HCT for CML [3-5,8,23,24]. Using HLA-matched sibling donors, 50 to 85 percent of patients with CML transplanted in first or second chronic phase of their disease achieve long-term remissions [3-7]. Disease-free survival (DFS) falls to 30 to 40 percent in patients in accelerated phase [4,8] and to 20 to 30 percent of patients in blastic phase (figure 1) [4]. These concepts, which were developed in the era prior to TKIs, still appear to be true following the use of TKIs such that it is important to monitor patients closely to avoid progression to accelerated or blastic phase of the disease.

Age — Younger age is associated with improved survival after allogeneic HCT in CML and is incorporated into the prognostic risk scores described above [5,23]. In the subgroup of patients under age 50, including children, who undergo this procedure during the first year of diagnosis, 70 to 80 percent will be alive and free of disease three to five years later [7,25,26]. Selected older adult patients (ie, >60 years of age) have successfully undergone allogeneic HCT for CML with myeloablative preparative regimens, although treatment-related mortality has been high [27]. The development of NMA regimens with reduced toxicity has permitted even older patients to be transplanted. (See 'Prognostic risk scores' above and 'Nonmyeloablative or reduced intensity HCT' below.)

Splenomegaly — Splenomegaly, which is present in the majority of patients with CML, does not appear to affect the outcome [5,23]. However, patients with massive splenomegaly may have refractory cytopenias following transplantation, and such patients may benefit from low-dose splenic irradiation or even splenectomy prior to transplantation. In many cases, low doses of radiation dramatically reduce splenic size, symptoms of hypersplenism, and splenic sequestration of red blood cells and platelets following transplantation. Neither splenectomy nor splenic irradiation appears to have an effect on outcome, and they should not be routinely performed [28,29].

Preparative regimen — The majority of studies that have evaluated allogeneic HCT in CML have used myeloablative preparative regimens. These regimens are preferred whenever possible. RIC or NMA HCT regimens are acceptable alternatives to myeloablative conditioning in older patients (>60 years) or those with medical comorbidities.

Myeloablative conditioning — Intravenous busulfan and cyclophosphamide (BU/CY) with pharmacokinetic monitoring of busulfan levels is the preferred preparative regimen for CML patients. This preference is based on the superior tolerability of BU/CY when compared with other myeloablative regimens and the ability to adjust dosing based on busulphan levels to avoid toxicities. (See "Preparative regimens for hematopoietic cell transplantation".)

Randomized trials have compared BU/CY to fractionated total body irradiation and cyclophosphamide (Cy/TBI) [25,30]. No difference was noted in DFS or OS; one study but not the other found a decreased risk of relapse in BU/CY treated patients [30]. In one study, among patients treated with BU/CY, those with steady-state plasma BU concentrations below 917 ng/mL had a lower estimated three-year OS than those with steady-state concentrations above this level (64 versus 82 percent, p = 0.33), although the study was not sufficiently powered to detect this difference [31]. However, in a later study of 131 consecutive patients with CML treated with a BU/CY regimen in which the busulfan dose was targeted to achieve a steady-state plasma concentration of ≥900 ng/mL, estimated three-year post-transplant OS was 86 percent, with most patients being in molecular remission [32].

Nonmyeloablative or reduced intensity HCT — Myeloablative allogeneic HCT offers potential cure to patients with CML, but is associated with a high treatment-related mortality rate in older patients (>60 years) [27]. Various RIC [33] or NMA [34] HCT regimens have been employed in older adults [35,36]. While the comparable efficacy of this approach remains to be proven, the use of NMA and RIC regimens are acceptable alternatives to myeloablative conditioning in older patients or those with medical comorbidities, assuming the disease is under good control. Additional information on NMA and RIC regimens is presented separately. (See "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)

NMA conditioning and RIC use a less intensive preparative regimen in order to permit transplantation in selected patients who would not ordinarily be candidates for HCT with an attendant decrease in regimen-related toxicity and treatment-related mortality. What constitutes a NMA or RIC regimen has been loosely defined, but full agreement regarding these definitions has not been reached. In general, an NMA regimen will cause minimal cytopenia by itself and does not require stem cell support (figure 2). In contrast, an RIC regimen will cause cytopenias, which may be prolonged and result in significant morbidity and mortality, and require hematopoietic stem cell support. (See "Preparative regimens for hematopoietic cell transplantation", section on 'Definitions'.)

The use of RIC and NMA regimens may be particularly useful in patients >60 years of age or those with other comorbid medical conditions. These approaches rely more on donor cellular immune effects (graft-versus-leukemia effect) and less on the cytotoxic effects of the preparative regimen to control the underlying disease (figure 3) [37]. If necessary, donor lymphocyte infusions (DLI) can be added to control the underlying disease [38,39]. (See 'Donor lymphocyte infusion' below.)

Many of the initial trials of RIC and NMA regimens in CML were performed before the widespread use of TKIs. As such, many of the patients included in these trials were in first chronic phase. The following is a survey of publications that have reported outcomes with these regimens in CML [39-47]:

●A case-series reported the outcomes of 24 patients with CML in first chronic phase who underwent NMA HCT using a preparative regimen of busulfan, fludarabine, and anti-thymocyte globulin (ATG) [42]. At a median follow-up of 42 months, 21 of the 24 were alive and disease-free. The incidence of acute GVHD was 54 percent initially, but increased when low-dose cyclosporine was withdrawn.

●A non-randomized prospective trial of the same regimen in 186 patients with CML (64 percent in first chronic phase) reported three-year OS rates of 58 percent, with a 23 percent transplant-related mortality at two years [45].

●Another analysis included 64 patients with advanced-phase CML (80 percent beyond first chronic phase) who were not eligible for myeloablative preparative regimens due to age or comorbid conditions and were enrolled in four prospective trials [48]. Low-dose melphalan-based or fludarabine-based regimens were used for conditioning, and DLIs were administered to patients without GVHD. At a median follow-up of seven years, the following were reported:

•Rates of five-year OS and progression-free survival (PFS) were 33 and 20 percent, respectively. Five-year OS rates were higher for patients with chronic phase disease (48 versus 19 percent) when compared with those with accelerated or blast phase disease.

•Incidence of treatment-related mortality was 33, 39, and 48 percent at 100 days, two years, and five years, respectively.

●A prospective non-randomized trial evaluated the use of 6 to 12 months of imatinib followed by RIC HCT (with fludarabine, melphalan, and alemtuzumab as the conditioning regimen) and subsequent DLI in 18 patients with CML in first chronic phase with matched sibling donors [39]. Of the 18 patients enrolled, 15 achieved a major cytogenetic response on imatinib and underwent transplant. Thirteen of these required DLI for disease control and four required a short course of imatinib after transplant. At a median follow-up of 31 months, all 15 patients were no longer taking imatinib. HCT was associated with significant morbidity including cytomegalovirus reactivation in 86 percent of patients at risk and Epstein-Barr virus-positive post-transplantation lymphoproliferative disorder in two patients.

●The CIBMTR performed a retrospective analysis of 306 adults over age 40 years who underwent RIC (78 percent) or NMA conditioning followed by allogeneic HCT from an HLA-identical sibling (56 percent) or unrelated donor [47]. The majority of patients had received imatinib before HCT (74 percent) and approximately half (52 percent) were in first chronic phase. Cumulative transplant-related mortality at one year ranged from 13 to 18 percent across age groups. At a median of 48 months from HCT, rates of OS at three years were 41 to 54 percent. In multivariate analysis, survival was primarily affected by disease stage at the time of HCT and the use of imatinib before HCT.

T cell depletion — Major obstacles to a successful outcome in allogeneic transplantation for CML, as in other diseases, are GVHD and infection. An alternative approach to the use of immunosuppressive drugs for the prevention of GVHD is T cell depletion. A variety of different T cell depletion techniques have been used; they generally result in less GVHD, but a higher risk of leukemic relapse [49-53]. One retrospective survey, for example, compared 46 patients who underwent allogeneic HCT with T cell-depleted bone marrow to 40 patients who received non-T cell-depleted marrow [51]. The T cell-depleted group had significantly lower rates of grade II to IV acute GVHD (15 versus 37 percent) and chronic GVHD (18 versus 42 percent), but a higher three-year probability of cytogenetic or hematologic relapse (62 versus 24 percent). Estimated three-year OS was similar in the two groups (72 versus 68 percent). (See "Prevention of graft-versus-host disease", section on 'In vivo TCD'.)

An alternative strategy has been to perform a T cell-depleted transplant to reduce GVHD followed by DLI to prevent leukemic relapse. In the above study, DLI led to complete remission in 17 of 20 such patients [51]. In three other reports of patients treated with a T cell-depleted transplant followed by DLI at the time of relapse, estimated three- to five-year survivals were 80 to 90 percent [53-55]. (See 'Monitoring MRD post-HCT' below.)

Donor selection — When available, an HLA-matched sibling donor is preferred over other donor sources due to improved clinical outcomes following transplant (eg, less GVHD) and the speed and cost-effectiveness of the search. For patients without a matched sibling donor, matched unrelated donor HCT is an acceptable alternative and may be preferred in some instances (eg, when the related donor is >65 years old). For patients without HLA-matched sibling or unrelated donors, other donor sources have been used. Among the options are haploidentical donors for patients with CML, who are usually in the advanced stages of their disease [56,57], and umbilical cord blood [58-60]. Both options have merits and problems and are generally utilized only for patients without a matched related or unrelated donor. However, outcomes with alternative donors continue to improve such that for the majority of patients a suitable donor can be identified. (See "Donor selection for hematopoietic cell transplantation".)

An important advance in identifying an unrelated donor has been the development of molecular typing techniques. With the current standard of molecular typing, outcomes for patients undergoing allogeneic HCT with fully matched related and unrelated donors are similar [61-63].

Because of the relatively indolent nature of CML, there is usually adequate time to perform a search for a matched unrelated donor, which may take up to one to three months, through the National Marrow Donor Program (NMDP) and other donor agencies. Such searches should be initiated as soon as possible. More rapid searches are possible if warranted by the patient's condition.

The NMDP reported a retrospective analysis of unrelated donor transplantation in 1423 patients with CML between 1988 and 1999 [64,65]. The incidence of grade III/IV GVHD was 33 percent (95% CI 30-36 percent), with 60 percent (95% CI 56-63 percent) developing chronic GVHD. The probability of DFS for the 914 patients transplanted in chronic phase was 43 percent at three years, with improved DFS for the following groups [63,65]:

●Transplantation in chronic phase

●Early transplantation (≤12 months from diagnosis)

●CMV seronegative recipients [66]

●Younger recipients (≤35 years of age)

●Grade 0 to II acute GVHD

Patients under the age of 35 undergoing matched unrelated donor transplantation in first chronic phase with a serologically HLA-matched donor had an overall five-year DFS of approximately 65 percent, while recipients >35 years of age with similar good prognosis features had a five-year DFS of 47 percent (figure 4). Patients transplanted in second chronic phase, accelerated phase, and especially blast crisis, fared worse.

Graft source — The preferred graft source (bone marrow versus peripheral blood progenitor cells) depends on numerous factors including donor (related versus unrelated), disease phase (chronic versus advanced), and donor preference. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) has compared outcomes using bone marrow versus granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPCs) from unrelated donors [67]. The use of bone marrow was associated with lower rates and severity of chronic GVHD, and many centers have utilized this donor source for patients with chronic phase CML who undergo allogeneic HCT with a related or unrelated donor. For patients with accelerated or blast crisis, mobilized PBPCs may be preferred due to the more robust graft-versus-tumor effects. However, these studies were not specifically performed in CML patients, and results must be inferred from other patient populations. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

CARE DURING TRANSPLANTATION — Allogeneic HCT is largely reserved for the inpatient setting, especially when utilizing a myeloablative preparative regimen. Virtually all patients require blood product support in the form of red blood cell and platelet transfusions until the transplanted marrow cells engraft sufficiently to support hematopoiesis. (See "Hematopoietic support after hematopoietic cell transplantation".)

Patients who undergo HCT are at risk for bacterial, viral, and fungal infections, the time course of which varies in the post-transplant period, according to the degree of immune deficiency and cytopenia induced by the transplantation procedure. Prophylactic therapies to prevent infection, including antiviral and antifungal drugs, are recommended during a period of increased risk. In addition, all markers of potential infection must be investigated thoroughly. These issues are discussed in detail separately. (See "Overview of infections following hematopoietic cell transplantation" and "Prevention of viral infections in hematopoietic cell transplant recipients" and "Prevention of infections in hematopoietic cell transplant recipients" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

IS THERE A ROLE FOR TKI POST-HCT? — Initial studies suggest that there may be a role for imatinib maintenance therapy after allogeneic HCT [68]. While awaiting further data, our decision regarding the use of post-HCT tyrosine kinase inhibitors (TKIs) depends at least partially on the disease phase and the intensity of the preparative regimen.

It is uncertain whether there is any benefit to using a TKI after HCT with a myeloablative regimen for patients transplanted for chronic phase CML if a molecular remission has been achieved. Frequent monitoring for BCR-ABL1 measurable residual disease (MRD; also referred to as minimal residual disease) is advisable for such patients. For patients transplanted for CML in myeloid or lymphoid blast crisis, we suggest the use of a TKI for two years after allogeneic HCT, if tolerable, rather than postponing its use until the emergence of MRD positivity, especially if nonmyeloablative conditioning is used. It should be noted, however, that there are few data about whether longer use of a TKI is advisable.

MONITORING MRD POST-HCT — Following transplant, it is critically important to carefully follow the patient's disease status on a regular basis. We perform quantitative polymerase chain reaction (Q-PCR) of BCR-ABL1 transcripts at least every three to six months. If Q-PCR assay is not available, then fluorescence in situ hybridization (FISH) is an acceptable alternative. (See "Overview of the treatment of chronic myeloid leukemia", section on 'Monitoring response'.)

Detection by PCR — The presence of the Philadelphia chromosome permits the sensitive detection of BCR-ABL1 transcripts by PCR, and thus the presence of measurable residual disease (MRD; also known as minimal residual disease). A number of studies have addressed the question of whether relapse can be predicted with PCR prior to a hematologic or cytogenetic relapse [69]. Initial findings in relatively small series were conflicting, due at least in part to variations in the techniques used and the time points at which patients were sampled [70-74]. Further evaluation of a larger number of patients found that the value of PCR positivity varied with time [75]:

●Positive results obtained at 6 to 12 months post-HCT, especially if they were persistent, were highly predictive of eventual relapse (42 versus 3 percent in PCR negative patients, relative risk 26)

●In comparison, positive results obtained within the first six months of transplantation were not predictive of relapse.

In a follow-up study by the same investigators, 379 consecutive CML patients alive at 18 months post-transplant were studied [76]. Ninety patients had at least one positive BCR-ABL1 test. Relapse was seen in 14 and 1 percent of the BCR-ABL1 positive and negative patients, respectively, with an unadjusted hazard ratio of relapse for BCR-ABL1 positivity of 19 (95% CI 5-68). Of the 73 BCR-ABL1 positive patients who failed to relapse, 69 percent had only one positive test at a median of 24 copies per microgram RNA. In contrast, the median positivity for those relapsing was >40,000 copies/mcg.

Quantitative PCR (Q-PCR) is also informative, as a positive result at three to five months post-transplant [77] and an increasing BCR-ABL1 with time [76,78] were both predictive of impending disease recurrence. Lineage-specific mixed chimerism, especially in the myeloid series, preceded cytogenetic relapse by 2 to 12 months and p190 (BCR-ABL) positivity preceded cytogenetic relapse by one to six months, suggesting that these two testable variables were highly predictive of impending disease recurrence [79]. Interestingly, a minority of patients in long-term remission after HCT may have detectable BCR-ABL1 transcripts by PCR that do not reflect reappearance of the original leukemic clone [80]. In contrast, a BCR-ABL1 transcript that increases over time is more suggestive of disease relapse.

Serial studies — Although the majority of patients who undergo allogeneic HCT become PCR negative, to date there has not been a clear consensus on what to do with a PCR positive result, although treatment with a TKI is the most reasonable approach [81]. To that end, a long-term study of serial Q-PCR results following allogeneic HCT in 243 patients with CML identified four groups of patients [82]:

●Negative – 15 percent were classified as persistently negative by Q-PCR or had only a single low-level positive result.

●Fluctuating – 21 percent had more than one positive Q-PCR result during follow-up but never more than two consecutive positive results.

●Persistent – 11 percent had three or more consecutive positive Q-PCR results, which never satisfied the authors' criteria for molecular relapse.

●Relapse – 53 percent satisfied Q-PCR, cytogenetic, or hematologic criteria for relapse.

At a median follow-up of seven years, the probability of disease relapse was 2.7, 20.8, and 30 percent for those in the negative, fluctuating, or persistent categories, respectively.

Given that CML may rarely relapse as late as 15 years following HCT, these results suggest a need for ongoing serial Q-PCR monitoring in all patients with CML following allogeneic HCT [83]. This will be especially important in order to assess patients for early intervention (eg, DLI, imatinib, or other kinase inhibitors) should results indicate an increasing risk for relapse [84].

RELAPSE AFTER HCT — Treatment options for relapsed CML after allogeneic HCT include reduction of immunosuppression, donor lymphocyte infusion (DLI), and treatment with tyrosine kinase inhibitors (TKIs).

All patients should be considered for treatment with a TKI at the time of relapse. Patients intolerant of TKIs in the past may not be able to use them at relapse. Reduction of immunosuppression and DLI should also be incorporated into the initial management of all patients with relapse unless concerns regarding graft-versus-host disease (GVHD) make this approach unfeasible.

Donor lymphocyte infusion — Patients who suffer a relapse of CML following allogeneic transplantation can be treated by obtaining donor leukocytes from the original donor [85-89]. These DLIs have been extremely effective and provide further direct evidence for a graft-versus-leukemia (GVL) effect. Patients who do not respond to DLI alone may respond to the addition of interferon alfa. Some groups routinely use both modalities in patients who relapse following HCT. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)'.)

Molecular remissions attained after DLI appear to be quite durable. In one report, the probability of durable remission at three years was 87 percent among patients with CML relapsing in chronic phase [87]. In a study of 66 consecutive patients with CML relapsing after allogeneic transplant, molecular remission was attained after DLI in 67 percent [90]. Survival at three years post-DLI was 95 and 53 percent for those achieving or not achieving molecular remission, respectively.

DLI has been complicated by GVHD in a substantial percentage of patients and in some instances graft failure [86,87]. Thus, the optimal dose and schedule of DLI continues to be explored. A retrospective study, involving 298 patients treated with DLI at 51 participating centers, indicated that a lower starting dose (≤0.2 x 108 mononuclear cells/kg) was associated with less GVHD, less myelosuppression, and less DLI-related mortality than higher doses, although subsequent dose escalation was often necessary in order to achieve a response [91].

An approach to DLI that we have taken based on these findings is to treat patients initially with 107 T cells/kg for those with cytogenetic or persistent molecular positive results. This dose has not been associated with significant GVHD risk. If no response is observed within two to three months, then dose escalation of DLI to 3 x 107 T cells/kg and eventually 108 T cells/kg can be pursued.

Tyrosine kinase inhibitors — All patients should be considered for treatment with a TKI at the time of relapse. The choice of TKI is largely dependent on mutation analysis of BCR-ABL1, side effect profiles of available TKIs, the patient's prior history with these agents, and the individual's comorbid conditions. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Choice of TKI'.)

A number of patients relapsing after allogeneic HCT have been brought into complete hematologic, cytogenetic, or molecular remission following use of imatinib [92-94]. Longer follow-up has indicated that these responses can be quite durable [93]. Of interest, the percentage of patients achieving molecular remissions following this treatment seems to be higher than that achieved with imatinib prior to allogeneic HCT. As an example, in a study of 44 patients with evidence of recurrence following allogeneic HCT, 70 percent achieved a complete molecular response using doses of imatinib ranging from 400 to 800 mg/day [94].

It remains unclear whether the drug can be stopped once a molecular response has been achieved. However, in one retrospective study, imatinib treatment alone resulted in a higher incidence of relapse and inferior leukemia-free survival than did the use of DLI [95]. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'TKI discontinuation for TFR'.)

Risk assessment after first relapse — Risk factors for survival following a first relapse after allogeneic HCT for CML were evaluated in 500 patients in the European Group for Blood and Marrow Transplantation registry. The following adverse factors were found on regression analysis [96]:

●Accelerated or blast phase at relapse (relative risk [RR]: 3.1)

●Time from transplant to relapse <1 year (RR: 2.3)

●Disease phase at transplant other than first chronic phase (RR: 2.0)

●Donor other than an HLA-identical sibling (RR: 1.6)

●Time from diagnosis to transplant ≥2 years (RR: 1.4)

The effects of individual adverse risk factors were cumulative: the probability of survival at 10 years after relapse was 42, 32, 14, 3, and zero percent for patients with no, 1, 2, 3, or 4 to 5 adverse risk factors, respectively.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Chronic myeloid leukemia (CML) in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY

●The treatment of chronic myeloid leukemia (CML) has been dramatically improved by the introduction of tyrosine kinase inhibitors (TKIs), which are the preferred option for the vast majority of patients with CML. Although definitive data are lacking, it appears that prior treatment with TKIs does not negatively impact outcomes for patients who ultimately proceed to allogeneic hematopoietic cell transplantation (HCT). (See "Overview of the treatment of chronic myeloid leukemia" and 'Pretreatment with TKIs' above.)

●HCT is a highly effective therapy that can achieve long-term remission in 50 to 85 percent of patients with first or second chronic phase CML, 30 to 40 percent of patients transplanted in accelerated phase, and 20 to 30 percent of patients in blast crisis. However, allogeneic HCT is associated with an up-front mortality risk of 5 to 20 percent. (See 'Efficacy and toxicity' above and 'Disease phase' above.)

●HCT is generally reserved for eligible patients with inadequate control of chronic phase CML despite initial treatment with a TKI, for individuals who are intolerant of TKIs, or as an adjunctive treatment for patients who present with more advanced disease (accelerated phase or blast crisis). For patients with advanced disease, the aim of initial management is to revert to chronic phase with plans to proceed with allogeneic HCT in chronic phase, if possible. (See 'Timing' above and 'Eligibility' above.)

●Treatment decisions require extensive consultation between the patient and a physician highly knowledgeable about the different treatment options. Determining whether the patient has an HLA matched sibling or initiating an unrelated donor search is warranted early in the course of therapy to determine which options are available. (See 'Donor selection' above.)

●The majority of studies that have evaluated allogeneic HCT in CML have used myeloablative preparative regimens. These regimens are preferred whenever possible. The preferred myeloablative regimen is intravenous busulfan and cyclophosphamide with pharmacologic monitoring of busulfan levels. Reduced intensity conditioning or nonmyeloablative HCT regimens are acceptable alternatives to myeloablative conditioning in older patients (>60 years) or those with medical comorbidities. (See 'Preparative regimen' above.)

●It is uncertain whether there is any benefit to using a TKI after HCT for patients transplanted for chronic phase CML if a molecular remission has been achieved. Frequent monitoring for BCR-ABL1 measurable residual disease (MRD; also referred to as minimal residual disease) is advisable for such patients. For patients transplanted for CML in myeloid or lymphoid blast crisis, we suggest the use of a TKI for two years after allogeneic HCT, if tolerable, rather than postponing its use until the emergence of MRD positivity, especially if nonmyeloablative conditioning is used. (See 'Is there a role for TKI post-HCT?' above.)

●Following transplant, it is critically important to carefully follow the patient's disease status on a regular basis commencing six months post-transplant. We perform quantitative polymerase chain reaction (Q-PCR) of BCR-ABL1 transcripts at least every three to six months. A persistent rise in transcript level is associated with an increased risk of relapse. (See 'Monitoring MRD post-HCT' above.)

●All patients are treated with a TKI at the time of relapse. Reduction of immunosuppression and donor lymphocyte infusion (DLI) should also be incorporated into the initial management of all patients with relapse unless concerns regarding graft-versus-host disease make this approach unfeasible. (See 'Relapse after HCT' above.)

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Topic 4494 Version 26.0

References

1 : Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins.

2 : Identical-twin bone marrow transplants for leukemia.

3 : Bone marrow transplantation for patients with chronic myeloid leukemia.

4 : Treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation after preparation with BuCy2.

5 : Therapy of chronic myelogenous leukemia with allogeneic bone marrow transplantation.

6 : Bone marrow transplantation for chronic myeloid leukemia: long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation.

7 : Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase.

8 : Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia.

9 : Bone marrow transplants in chronic myelogenous leukemia: an overview of determinants of survival.

10 : Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study.

11 : Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase.

12 : Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia.

13 : Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure.

14 : The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia.

15 : Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity.

16 : The effect of prior exposure to imatinib on transplant-related mortality.

17 : Successful allogeneic stem cell transplantation in second chronic-phase CML induced by the tyrosine kinase inhibitor nilotinib (AMN107) after blast crisis under imatinib.

18 : Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV.

19 : Treosulfan and fludarabine low-toxicity conditioning for allogeneic haematopoietic stem cell transplantation in chronic myeloid leukaemia.

20 : Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

21 : Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants.

22 : Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase.

23 : Marrow transplantation for the treatment of chronic myelogenous leukemia.

24 : Multivariate analysis of risk factors for survival and relapse in chronic granulocytic leukemia following allogeneic marrow transplantation: impact of disease related variables (Sokal score).

25 : Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide.

26 : Stem cell transplantation for chronic myeloid leukemia in children.

27 : Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older.

28 : A retrospective analysis of the long-term effect of splenectomy on late infections, graft-versus-host disease, relapse, and survival after allogeneic marrow transplantation for chronic myelogenous leukemia.

29 : No advantage for patients who receive splenic irradiation before bone marrow transplantation for chronic myeloid leukaemia: results of a prospective randomized study.

30 : Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM).

31 : Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation.

32 : HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen.

33 : Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research.

34 : Harnessing graft-versus-malignancy: non-myeloablative preparative regimens for allogeneic haematopoietic transplantation, an evolving strategy for adoptive immunotherapy.

35 : Hematopoietic cell transplantation from HLA-identical sibling donors after low-dose radiation-based conditioning for treatment of CML.

36 : Protective conditioning for acute graft-versus-host disease.

37 : Kinetics of minimal residual disease and chimerism in patients with chronic myeloid leukemia after nonmyeloablative conditioning and allogeneic stem cell transplantation.

38 : Mixed chimerism: preclinical studies and clinical applications.

39 : Complete molecular responses are achieved after reduced intensity stem cell transplantation and donor lymphocyte infusion in chronic myeloid leukemia.

40 : Reduced intensity thiotepa-cyclophosphamide conditioning for allogeneic haemopoietic stem cell transplants (HSCT) in patients up to 60 years of age.

41 : Dose-reduced conditioning for allografting in 44 patients with chronic myeloid leukaemia: a retrospective analysis.

42 : Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase.

43 : Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4Ig, and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant.

44 : Reduced-intensity conditioning using TBI (8 Gy), fludarabine, cyclophosphamide and ATG in elderly CML patients provides excellent results especially when performed in the early course of the disease.

45 : Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT.

46 : Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation.

47 : Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era.

48 : Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia.

49 : Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion.

50 : Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease-free survival in unrelated marrow transplantation for chronic myelogenous leukemia.

51 : Comparative outcomes of T-cell-depleted and non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: impact of donor lymphocyte infusion.

52 : HLA-identical sibling donor bone marrow transplantation for chronic myeloid leukaemia in first chronic phase: influence of GVHD prophylaxis on outcome.

53 : Outcome of transplantation of highly purified peripheral blood CD34+ cells with T-cell add-back compared with unmanipulated bone marrow or peripheral blood stem cells from HLA-identical sibling donors in patients with first chronic phase chronic myeloid leukemia.

54 : T-cell depletion plus salvage immunotherapy with donor leukocyte infusions as a strategy to treat chronic-phase chronic myelogenous leukemia patients undergoing HLA-identical sibling marrow transplantation.

55 : Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantation for chronic myelogenous leukemia.

56 : Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype.

57 : Use of partially mismatched related donors extends access to allogeneic marrow transplant.

58 : Umbilical cord blood transplantation in a patient with Philadelphia chromosome-positive chronic myeloid leukemia.

59 : Cord-blood transplantation from an unrelated donor in an adult with chronic myelogenous leukemia.

60 : Umbilical cord blood transplantation in adults: results of the prospective Cord Blood Transplantation (COBLT).

61 : HLA-identical sibling compared with 8/8 matched and mismatched unrelated donor bone marrow transplant for chronic phase chronic myeloid leukemia.

62 : Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.

63 : Equivalent outcomes in patients with chronic myelogenous leukemia after early transplantation of phenotypically matched bone marrow from related or unrelated donors.

64 : Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation.

65 : Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program.

66 : Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis.

67 : Peripheral-blood stem cells versus bone marrow from unrelated donors.

68 : Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia.

69 : Molecular studies in patients with chronic myeloid leukaemia in remission 5 years after allogeneic stem cell transplant define the risk of subsequent relapse.

70 : Detection of residual bcr/abl translocation by polymerase chain reaction in chronic myeloid leukaemia patients after bone-marrow transplantation.

71 : Molecular relapse in chronic myelogenous leukemia patients after bone marrow transplantation detected by polymerase chain reaction.

72 : Detection of residual leukemia after bone marrow transplant for chronic myeloid leukemia: role of polymerase chain reaction in predicting relapse.

73 : Clinical significance of bcr-abl gene rearrangement detected by polymerase chain reaction after allogeneic bone marrow transplantation in chronic myelogenous leukemia.

74 : Prognostic significance of Philadelphia chromosome-positive cells detected by the polymerase chain reaction after allogeneic bone marrow transplant for chronic myelogenous leukemia.

75 : Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients.

76 : The significance of bcr-abl molecular detection in chronic myeloid leukemia patients "late," 18 months or more after transplantation.

77 : Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia.

78 : Kinetics of increasing BCR-ABL transcript numbers in chronic myeloid leukemia patients who relapse after bone marrow transplantation.

79 : Molecular analysis of lineage-specific chimerism and minimal residual disease by RT-PCR of p210(BCR-ABL) and p190(BCR-ABL) after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190(BCR-ABL) detection precede cytogenetic relapse.

80 : In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib.

81 : Should polymerase chain reaction analysis to detect minimal residual disease in patients with chronic myelogenous leukemia be used in clinical decision making?

82 : Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy.

83 : Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results.

84 : Transplantation for CML: lifelong PCR monitoring?

85 : 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 hematologic diseases.

86 : Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia.

87 : Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients.

88 : Donor lymphocyte infusions for the treatment of chronic myeloid leukemia relapse following peripheral blood or bone marrow stem cell transplantation.

89 : Early administration of donor lymphocyte infusions upon molecular relapse after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia: a study by the Chronic Malignancies Working Party of the EBMT.

90 : Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia.

91 : Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose.

92 : Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia.

93 : Extended follow-up of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease.

94 : Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study.

95 : A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation.

96 : Risk assessment in patients with Ph+ chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: an EBMT retrospective analysis. The Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

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