Prognostic factors in chronic myeloid leukemia: Allografting☆

Article Outline

• Abstract
• Principles for risk assessment
  • Fixed and variable risk factors
  • Assessment of outcome after HSCT
• Factors influencing outcome
  • Pretransplant factors
    • Disease stage
    • Pretreatment
    • Patient factors
    • Donor pretransplant factors
    • Risk score analysis
  • Peritransplant risk factors
    • Conditioning
    • GvHD prevention
    • Transplant product
  • Post-transplant factors
    • Acute and chronic GvHD
    • Relapse
• Conclusions
• Acknowledgements
• References
• Copyright

Abstract 

Risk assessment for allografting differs from that for conventional therapy mainly because the transplant intervenes far from initial diagnosis and generates a new source of morbidity and mortality, graft-versus-host disease (GvHD). Major well-defined pre-, peri- and post-transplant risk factors influence two endpoints: transplant-related mortality (TRM) and relapse incidence (RI), which in turn determine the principal outcomes—leukemia-free survival (LFS) and survival. Some factors have concordant effects on both endpoints, like disease stage. Other risk factors have divergent effects: histocompatibility, intensity of conditioning, or GvHD prevention. The impact of risk factors with divergent effects differs in various time periods post-transplant. The main pretransplant factors are disease stage, patient age and sex, donor-recipient sex combination, histocompatibility, and time from diagnosis to transplant. The primary peritransplant factors are the intensity of conditioning and of GvHD prevention. The main post-transplant factor is severity of acute and chronic GvHD. Determination of the risk profile for an individual patient is reliable and should form an integral part of pretransplant counseling. The management strategies for patients with high-risk disease and low TRM risk profiles and for patients with low-risk disease and high TRM risk profiles should be different. Semin Hematol 40:13-21. Copyright 2003, Elsevier Science (USA). All rights reserved.

Allogeneic hematopoietic stem cell transplantation (HSCT) is, to date, the only therapeutic modality that results in consistent, long-lasting Bcr/Abl negativity.¹⁴, ³² Therefore, during the last two decades chronic myeloid leukemia (CML) has been the most frequent single indication for allogeneic HSCT and an estimated 40,000 allogeneic transplants have been performed worldwide for this diagnosis.¹⁹ However, the introduction of imatinib mesylate has changed this historic view, and the number of HSCTs for CML has declined since 1999.²⁰ It remains to be seen whether this promise of an easier path to disease eradication is justifed,⁹, ²⁶ but in the interim, assessment of the risk profile for individual patients becomes even more important. Allogeneic HSCT is associated with initial mortality but offers the prospect of improved survival in the long term. The decision whether and when to proceed with an HSCT for a patient with a donor is difficult and deserves careful consideration. Accumulated experience from many centers has led to the ability to assess precisely the risk at the individual patient level and to predict realistically the expected result.

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Principles for risk assessment 

Fixed and variable risk factors 

Risk assessment for patients with CML follows the same principles as for any other HSCT.³⁹ Cumulative experience with human leukocyte antigen (HLA)-identical sibling transplantation over three decades encompasses almost 300,000 autologous and allogeneic HSCTs worldwide.¹⁹ The outcome of any HSCT depends on stable factors fixed at the time of transplant, on variable factors that can be influenced by the transplant team, and on the development (or not) of graft-versus-host disease (GvHD) post-transplant. Pretransplant factors are related to the disease, the patient, and the transplant product; peritransplant factors are related to the therapeutic strategy chosen by the transplant team. Intensity of conditioning, GvHD prevention, and supportive care measures can be adapted to individual patients. In the allogeneic setting an additional element follows the successful transplant, namely, acute and/or chronic GvHD. The sum of these pre-, peri-, and post-transplant factors determines the principal outcome: survival. The impact of these individual risk factors is illustrated below.

Assessment of outcome after HSCT 

Outcome following HSCT depends on two main primary endpoints, transplant-related mortality (TRM) and relapse incidence (RI). The net sum determines leukemia-free survival (LFS) and thus the main final endpoint, survival. This simple approach designed very early in the history of HSCT has grown more complicated in recent years.⁶, ⁸ Relapse after HSCT is no longer uniformly associated with disease progression and death; patients who relapse can be re-treated and may become long-term survivors. Donor lymphocyte infusions (DLIs), second transplants, or re-treatment with imatinib mesylate can induce second complete molecular remissions with full donor chimerism.²², ²³ Conversely, TRM might not be the best endpoint, since single-organ failure can be compatible with long-term survival and yet appreciably impair the quality of life. For example, sterility or growth retardation as late sequelae of conditioning might be avoided with the appropriate choice of therapy but at the expense of a higher risk of relapse. Personal considerations may influence treatment choice.

Assessment of outcome is complicated by two additional elements: the need for prolonged follow-up and the discordant effects of many interventions and risk factors. Both are additionally interlinked. A few risk factors have concordant effects on both outcomes—RI and TRM—but the majority of risk factors and most therapeutic interventions have opposite impacts on TRM and RI. For example, increasing the intensity of the conditioning regimen reduces RI but increases the risk of TRM. Conversely, decreasing the intensity of the conditioning regimen increases RI but reduces the risk of TRM. Increased GvHD prevention and treatment reduces TRM but increases RI and vice versa. Furthermore, the effects can balance over time as exemplified by the influence of the donor recipient sex combination.¹⁸ Early post-transplant, increased TRM reduces survival chances for a male recipient with a female donor. Later, reduced risk of relapse leads to better long-term survival.

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Factors influencing outcome 

The major factors influencing outcome are summarized in Table 1.

Table 1. Factors influencing the outcome of HSCT

Abbreviations: AP, accelerated phase; BC, blast crisis; CP, chronic phase; CMV, cytomegalovirus; GvHD, graft-versus-host disease; BM, bone marrow; PB, peripheral blood.

They are grouped into pre-, peri-, and post-transplant factors and refer to disease, patient, donor, transplant procedure, and post-transplant events. Their impact on the main endpoints is represented in Table 2.

Table 2. Outcome of transplants depending on risk factors

NOTE. Data provided by the EBMT Chronic Leukemia Working Party (R. Brand, A. van Biezen) presented at the Annual EBMT Meeting, Montreux 2002, D. Niederwieser and based on a selection of 4,423 patients selected from 13,836 reports to the CLWP between 1983 and 1999.

Abbreviations: CP, chronic phase; AP, accelerated phase; BC, blast crisis; TCD, T-cell depletion.

While discussed here for patients with CML, most are valid for any type of HSCT and disease.

Pretransplant factors 

Disease stage 

The strongest predictor for outcome is the stage of disease at the time of transplant. Advanced CML clearly predicts a poorer outcome than does first chronic phase. More than 50% of all patients transplanted in first chronic phase can be expected to live more than 10 years post-transplant. This figure decreases to about 25% for patients transplanted in accelerated phase and to less than 10% to 15% for those transplanted in blast crisis (Fig 1).

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• Fig. 1. 

  Survival of patients with HSCT depending on disease stage at time of transplant. CP, chronic phase; AP, accelerated phase; BC, blast crisis.

This impact of disease stage has been reported in single-center series and by all national and international registries.⁷, ¹¹, ³⁷, ⁴¹ Similarly, the influence of stage holds true for all donor types and stem cell sources. This decrease in survival for advanced disease is related to a higher risk for both RI and TRM. The increase in RI with advanced stage is easily explained, but the increase in TRM with increasing disease stage is still poorly understood. It remains a matter of speculation whether prior therapy causes organ damage and thereby increases a patient's susceptibility to toxicity and complications or whether intrinsic cellular changes within the leukemic cells trigger the cytokine cascade during HSCT.

Within the subgroup of patients with CML in chronic phase, the interval from diagnosis to transplant is important. The Seattle group was the first to show that patients transplanted soon after diagnosis had a better survival than those transplanted later.⁷ The interpretation of data was initially controversial. Patients with poor risk features at the time of diagnosis, for example, a high leukocyte count, were referred to transplantation earlier than patients with initially low leukocyte counts. This trend was reversed in more recent years and patients were transplanted more frequently within 1 year of diagnosis. Multiple analyses from the European Group for Blood and Marrow Transplantation (EBMT) have confirmed the increased risk of TRM when the transplant is performed later than 12 months after diagnosis, with a 10% risk increase in TRM with a delay.¹⁶, ⁴¹ Since the introduction of imatinib, it is likely that this trend for early transplants will change again and more patients will be referred beyond 1 year from diagnosis.

The role of the Sokal or Hasford score²⁴, ³⁶ at the time of diagnosis on HSCT outcome is controversial. Only a few conclusive studies have been completed. There is consensus from retrospective analyses that high leukocyte or high basophil count at the time of diagnosis is predictive for a higher risk of relapse. However, recent International Bone Marrow Transplant Registry (IBMTR) analysis failed to show an impact of Hasford or Sokal score.²⁹

Pretreatment 

All patients with CML will have received some form of treatment prior to transplant and its role needs to be considered in all situations. Initially, debulking of the disease in the form of splenectomy or splenic irradiation was considered essential for eradication of the disease, but retrospective studies failed to show any advantage.¹⁵ A prospective randomized controlled study of the EBMT showed no benefit of additional splenic irradiation immediately prior to transplant. However, in the selected subgroup of intermediate-risk patients, those in chronic phase receiving non–T-cell–depleted HSCT but with a basophil count of over 3% at diagnosis had a significantly lower relapse rate. Splenectomy or splenic irradiation is clearly of no benefit for patients at high risk for relapse (those receiving T-cell–depleted transplants), nor is there any advantage for patients at a very low risk for relapse. On the other hand, splenectomy and splenic irradiation are not risk factors for HSCT and splenectomy can help patients with poor engraftment after HSCT.¹⁷

Busulfan and hydroxyurea were the treatments of choice for patients with CML in the early 1980s. An IBMTR analysis showed a clear disadvantage for patients pretreated with busulfan compared to hydroxyurea: they suffered from a higher incidence of transplant-related complications, interstitial pneumonitis in particular. Busulfan should not be given to any patient who is a potential candidate for an allogeneic HSCT.¹³ The impact of interferon alfa (IFN-α) pretreatment on transplant outcome is more difficult to assess. Theoretical considerations suggest a negative impact. IFN-α can trigger the cytokine cascade and increase TRM. The Essen and Seattle groups showed a higher increase of graft failure in unrelated or mismatched transplants, an increased risk of severe acute GvHD, and more fatal infectious complications in patients treated with IFN-α for more than 6 months. These data were disputed by others. Clarification came from Holler et al, who observed a higher TRM in patients treated with IFN-α within the 3 months prior to HSCT. This was confirmed by the German CML Study Group within the randomized CML studies I and II, which compared IFN-α with chemotherapy and included 197 transplant patients. IFN-α pretreatment had a negative impact, with a greater rate of TRM in patients who had received IFN-α in the 3 months immediately preceding the transplant. The 5-year survival rate was worse for patients who received IFN-α within the last 90 days before HSCT than for those who did not. When IFN-α was stopped 90 days prior to HSCT, there was no difference in outcome between patients with or without a pretransplant history of IFN-α therapy. Thus patients with a donor and a clear indication for an allogeneic transplant should be transplanted without IFN-α pretreatment and those receiving IFN-α should have the agent discontinued 3 months prior to the planned HSCT.², ²⁵

Beginning in 2002, most patients undergoing an HSCT for CML will probably have received imatinib mesylate as initial treatment. So far, no formal study has examined the impact of imatinib on subsequent HSCT outcome. Thus far, small retrospective studies do not suggest any negative impact on engraftment or GvHD.

Patient factors 

Age is an important risk factor, for all disease categories, donor types, and stem cell sources, as has been evident with large registry analyses.¹⁶ Children at comparable stages of the disease always have better outcomes than do adult patients. There is no cutoff above which age is no longer important, nor is there an age above which transplants can no longer be performed. TRM simply increases by about 5% with each decade. A few years ago many teams had age limits, based on personal experience. Now, especially with the introduction of reduced intensity conditioning approaches, age limits have disappeared and have been replaced by individualized risk assessment. Older patients with few other risk factors can undergo transplantation with a reasonable expectation of success.

The influence of gender alone on outcome is controversial. In the EBMT long-term analysis, female patients had a better outcome than did male patients due to lower TRM independent of other risk factors. The reasons for this discrepancy are unknown and need to be defined. Women with multiple myeloma also have a lower TRM. Gender becomes important in the context of the donor-recipient sex combination. Minor histocompatibility antigens are considered in the setting of a female donor for a male recipient.¹⁶, ¹⁸, ⁴¹

Few other patient factors have been carefully analyzed in CML. General well-being, assessed by Karnofsky score, World Health Organization score, Eastern Cooperative Oncology Group score, and others, is probably of importance.²⁹ Poor general health signals a generally higher risk for TRM in all HSCT studies.

The viral status of the patient is significant. Patients with cytomegalovirus (CMV) seropositivity or CMV-seronegative patients receiving CMV-seropositive transplants are at high risk for CMV reactivation and transplant-related complications. This risk has been particularly high for patients with CML undergoing unrelated HSCT. CMV status also may reflect viral infectivity and viral load in general. Seropositivity for more than three herpes group viruses in the recipient or donor correlates with greater TRM.⁴

Little attention has been paid so far to psychosocial aspects. Limited economic resources may prevent access to the transplant as such. One hint of the relationship of psychosocial status to outcome comes from the recent observation that helplessness before transplant was associated with higher TRM and a greater likelihood for relapse.²⁷

Donor pretransplant factors 

Several donor factors have prognostic relevance: histocompatibility, age, sex, ABO blood group, viral status, and stem cell source.³⁹

Histocompatibility between donor and recipient impacts differently on TRM and RI, best illustrated by the difference in outcome when identical-twin results are compared with mismatched transplants. Absence of histoincompatibility in identical-twin transplants abrogates the risks of rejection and GvHD and reduces TRM—but also reduces the graft-versus-leukemia effect and increases RI. Survival is influenced by the net sum. Because relapse is not necessarily equivalent to death, long-term survival for recipients of twin transplants is better than for recipients of human leukocyte antigen (HLA)-identical sibling transplants.¹

The role of major and minor histocompatibility antigens in related or unrelated HSCT for CML is determined by a basic principle: any mismatch increases the likelihood of TRM and decreases the risk of RI. So far, in most instances the increase in TRM has not been balanced by a gain in RI. Whether “perfectly matched,” unrelated transplants will decrease RI without increasing TRM, the possible identification of “permissible” mismatches in the unrelated setting, and selection criteria for mismatching prior to transplant remain open questions.¹⁴, ³⁹

The role of ABO incompatibility between donor and recipient is unresolved, as no large series has received careful analysis. There are preliminary indications that a bidirectional barrier may increase the risk of TRM³⁸ and could be a selection criterion when several otherwise indistinguishable unrelated donors are available. There are suggestions that older donors, independent of recipient age, increase the risk of TRM. The viral status of the donor is as relevant as that of the patient; CMV-positive donors represent a risk for CMV-negative recipients.

Two main stem cell sources are available today: bone marrow (BM) and peripheral blood (PB). Cord blood is still at an experimental stage, since the majority of patients with CML are adults. PB provides a higher number of CD34⁺ cells and granulocyte-macrophage colony-forming units (CFU-GM), but also more T cells. Recovery from aplasia with PB is rapid but there is a risk of higher incidence of GvHD with no evidence yet of better antileukemic efficacy in retrospective and prospective randomized trials. There is also a trend towards more chronic GvHD with PB. In advanced disease PB results in better overall survival. Whether graft-versus-leukemia effects will translate to better survival in early disease or, in contrast, to worse survival because of late chronic GvHD needs to be determined.⁵, ¹⁰, ³¹

Risk score analysis 

The EBMT Chronic Leukemia Working Party developed a simple standardized risk score for patients with CML (Table 3)¹⁶ based on the five main pretransplant risk factors: donor type, stage of disease at time of transplant, recipient age, donor-recipient sex combination, and interval from diagnosis to transplant.

Table 3. EBMT risk score

NOTE. Each of the five risk factors contributes 0, 1, or 2 points. The sum indicates the individual risk score.

Each risk factor contributes 0 to 2 points to the final risk score. The lowest possible score on this scale is 0, which applies to a patient who receives a graft from an HLA-identical sibling donor within 12 months of diagnosis, in first chronic phase who is below the age of 20 years, and who is not male with a female donor. The highest possible score on the scale is 7, as for a male patient over the age of 40 years in blast crisis who receives a graft from an unrelated female donor beyond 12 months from diagnosis. On the basis of 3,142 patients transplanted for CML between 1989 and 1999, the final scoring system was highly predictive for survival and TRM (Fig 2).

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• Fig. 2. 

  Survival and transplant related mortality depending on EBMT risk score. Reprinted with permission from Elsevier Science. (The Lancet¹⁷).

This study clearly shows that the identified risk factors are cumulative. The analysis provides an estimate of the price paid in increased TRM if the transplant is delayed beyond 12 months from diagnosis, or if the disease progresses. The result, recently confirmed by an IBMTR analysis, provides a rational basis for counseling, and suggests that risk-adapted treatment for patients with CML should be possible.

Peritransplant risk factors 

In contrast to pretransplant factors, the team can decide and select the therapeutic approach and can thus adapt the procedure to patient with high-risk disease and low transplant risk profile, or the opposite, and influence peritransplant risk factors.

Conditioning 

Conditioning has three goals: to reduce the disease, to suppress the recipient's host-versus-graft reaction, and to create space for the incoming stem cells. The initial concept and success of HSCT in the 1980s and 1990s was due to the introduction of a maximum-tolerated conditioning based on cyclophosphamide and total-body irradiation or busulfan and cyclophosphamide.³⁵, ³⁹ Attempts to further increase conditioning were associated with successful reduction of RI but at the price of increased TRM and no overall improvement.³³ Over the last few years focus has been on reduced-intensity conditioning in order to decrease TRM and to give access to HSCT for patients with high-risk profiles.³, ²⁸, ³⁴ Reduced-intensity conditioning transplants involve less early mortality than conventional transplants, but no formal comparisons are yet available. Reduced-intensity conditioning likely will be associated with less TRM but also with a higher relapse rate. In general, most teams have kept standard conditioning for patients with a low risk of TRM and high risk for relapse and reduced conditioning for patients with a high risk for TRM but standard disease.

GvHD prevention 

A converse concept relates to GvHD prevention. Highly effective T-cell depletion can prevent GvHD completely but also abrogates graft-versus-leukemia effects. Intensification of cyclosporine or the combination of cyclosporine/methotrexate has the same effect. More intensive GvHD prevention is associated with less GvHD and less TRM but higher RI. Both retrospective and prospective studies with T-cell depletion or minimal GvHD prevention method have failed to give superior results to standard methods.³⁸ Novel approaches such as the addition of selected T cells or natural killer cells may alter this balance.³⁰

Transplant product 

A high stem cell number reflected by the CD34⁺ cell count or CFU-GM count is associated with more rapid recovery, reduced TRM, and decreased RI. Whenever possible and as tolerated by the donor, high numbers of stem cell are preferable.¹

For PB products, T-cell content is probably the decisive endpoint. More T cells are associated with better engraftment but also more GvHD.⁴⁰

Post-transplant factors 

Acute and chronic GvHD 

Allogeneic HSCT is always associated with GvHD and the risk increases with greater degrees of histoincompatibility. Yet, even with HLA-identical sibling transplants, about 60% of patients will develop any grade of acute GvHD.²¹ Younger patients have less severe acute GvHD, and male patients with female donors more severe acute GvHD. Acute GvHD influences TRM directly with increasing acute GvHD grade; decreased relapse incidence also correlates with increasing acute GvHD grade. TRM has more weight than RI and in the first 3 years survival is best for patients with grade 0 acute GvHD (Fig 3A).

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• Fig. 3. 

  Influence of GvHD on outcome. (A) Influence of aGvHD grade (0, I, II, III, IV) between day 100 and 3 years. (B) Influence of cGvHD grade (none, limited, extensive) on survival beyond 3 years post-transplant. (Reprinted with permission from: Gratwohl A, Brand R, Apperley J, et al. Graft-versus-host disease and outcome in HLA-identical sibling transplants for chronic myeloid leukemia. Blood 2002;100:3877-3886. Copyright American Society of Hematology, used by permission.)

Beyond 3 years, chronic GvHD becomes the most important factor; patients with no chronic GvHD have a higher risk of relapse. Limited chronic GvHD confers the same risk for TRM as does the absence of GvHD, but reduced RI and better survival (Fig 3B). Since patients with grade I acute GvHD have the highest likelihood of developing limited chronic GvHD, survival ultimately is best for patients with grade I acute GvHD and limited chronic GvHD.

Relapse 

Patients with CML who relapse after first allogeneic HSCT still have a chance for long-term survival.²², ²³ There are several treatment options: DLI, retransplant, treatment with imatinib or with IFN-α, or intensive chemotherapy. Each approach has its specific advantages and disadvantages. Currently, DLI is the treatment of choice for patients with early disease; results at later stages are less convincing. Survival after relapse is significantly related to four factors: disease phase at time of first transplant, disease stage at time of relapse, time from transplant to relapse, and donor type. Patients transplanted initially in first chronic phase who relapse have better outcomes; patients with cytogenetic relapse or relapse in chronic phase have a better outcome than those who relapse with advanced phase; patients with a time interval of more than 1 year between first transplant and relapse have better survival; and patients transplanted from an HLA-identical sibling fare better. These risk factors are cumulative. The probability of survival at 10 years post-relapse varies between above 40% for patients with no factors and zero for patients with three or four factors. An escalating dosage schedule of DLI is probably prefable to a single “bulk” approach.

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Conclusions 

HSCT continues to carry an intrinsic risk of failure due to relapse of the disease or transplant-related complications. The risk of early death from TRM complicates the decision when a patient feels healthy and well. For the individual patient, the risks may seem unpredictable and thus HSCT may appear to be a lottery. This is not the case. Risks and benefits can be assessed on an individual basis. The risk associated with HSCT is a continuum, and ranges from about 10% TRM to close to 80%. The main risk factors are known, highly predictive, and cumulative. Today, we can discuss the personal risk profile with a patient and evaluate the benefits as well as risk of failure of HSCT compared with alternative therapeutic approaches. Depending on the personal situation, immediate transplant or deferment for a predetermined time will be appropriate. Adaptation of the techniques to each patient should ultimately improve the outcome of the whole cohort.

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Acknowledgements 

The Chronic Leukemia Working Party of the EBMT, its members and contributing teams, its data team (A. van Biezen, N. van't Veer), and its statistical team (R. Brand, S. Iacobelli) are acknowledged for supporting data, and A. Maerki for excellent secretarial help.

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