Mini Review

Bone Marrow Transplantation (2003) 32, 459–469. doi:10.1038/sj.bmt.1704163

Transplantation for chronic myelogenous leukemia: yes, no, maybe so...an Oregon perspective

Richard T Maziarz1 and Michael J Mauro1

1Bone Marrow Transplantation Program/Leukemia Center, Center for Hematologic Malignancies, Oregon Cancer Institute, Oregon Health & Science University, Portland, OR, USA

Correspondence: Dr RT Maziarz, UNH73C, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239 USA

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Abstract

Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disorder in which allogeneic stem cell transplantation remains the only curative option, but its use is limited by donor availability and treatment-related morbidity and mortality. Imatinib mesylate is a targeted agent for CML with efficacy to date, which is superior to all other nontransplant therapy and has limited toxicity. The curative potential of imatinib remains to be proven and may be limited to a small number of patients. Optimal decision making regarding the use of these divergent therapies has not been defined. This paper reviews critical data relevant to these treatment options and provides an approach to current management of the CML patient.

Keywords:

Imatinib mesylate, allogeneic stem cell transplantation, chronic myelogenous leukemia

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Controversy in CML therapy

The use of allogeneic stem cell transplantation (SCT) for the upfront treatment of chronic myelogenous leukemia (CML) has declined dramatically in the past 3 years with its future use coming under increased scrutiny. This change was not a result of decreased efficacy since stem cell transplant remains the only proven curative therapy for CML. Rather, this was the result of the development of specific molecularly targeted medical therapy in the form of the BCR-ABL kinase inhibitor, imatinib mesylate. With dramatic efficacy and minimal toxicity, imatinib has changed the treatment landscape for CML and raised numerous questions regarding the upfront integration of this highly effective nontransplant therapy. This overview will address the current status of treatment options for CML, contrasting the current state of the art in stem transplantation with the uncertain curative potential of imatinib mesylate.

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Imatinib mesylate

Imatinib mesylate is an inhibitor of the protein tyrosine kinase domain associated with BCR-ABL, as well as the platelet-derived growth factor (PDGF) and c-kit receptors, but not other members of the type II receptor kinase family.1 Imatinib has been shown to inhibit cell growth under the control of the BCR-ABL tyrosine kinase oncoprotein and eradicate BCR-ABL-dependent tumors in animal models.2 Subsequent human studies of imatinib have been conducted in CML, with activity demonstrated in chronic, accelerated and blast phases and as well in Philadelphia-chromosome positive (Ph+) ALL (see Table 1).3,4,5 In chronic-phase patients who were refractory or intolerant to interferon-alpha,3 96% achieved a complete hematologic response (CHR) with imatinib, the majority occurring within 6–8 weeks. In this refractory population, 64% achieved major cytogenetic responses (MCRs; defined as 0–35% Ph+ metaphases identified by classical karyotype analysis) and 48% complete cytogenetic responses (CCRs; (0% Ph+ metaphases). A total of 87% of patients studied remain without progression to advanced stages of CML (median follow-up 29 months).


Analysis of the subset of these IFN failure patients treated at OHSU (n=144) indicates that patients with CHR and MCR have a significantly lower risk of relapse than patients who remain more than 95% Ph+.6 These latter patients typically relapse with chronic-phase disease before progressing to advanced phases, although a small percentage has relapsed directly into the blast phase. Time frame for delineation of meaningful response to imatinib was also revealed in this analysis. Those patients who achieved minimal cytogenetic responses (persistence of Philadelphia chromosome in 65–95% of metaphases) after 6 months had only a 10% chance of achieving an MCR with continued imatinib out to 18 months' therapy duration. Of patients with no cytogenetic response (remaining over 95% Ph+ at 6 months), none achieved MCR at later time points. Similar results have been reported by other groups. Review of patients treated at MD Anderson Cancer Center identified only 2/45 (4%) patients achieving CCRs with ongoing therapy when 100% Ph+ at 6 months.7 Analysis of imatinib-treated, IFN-failure chronic-phase CML patients from the Hammersmith Hospital revealed four distinct subgroups defined by myelosuppression and cytogenetic response.8 Dramatic differences in likelihood of progression were found; actuarial risk of progression at 1 year for those with at least a minor cytogenetic response and without cytopenias was 3%, compared with those without any cytogenetic improvement and with cytopenias, facing increased risk of progression to 67%. Similarly, if >grade 3 myelosuppression is sustained during imatinib induction, the likelihood of gaining major and/or CCRs by 6 months is significantly reduced.9,10

Imatinib, with remarkable activity as second-line therapy, was nonetheless prime for front-line comparison vs IFN-alpha in order to better define optimal nontransplant therapy. In the international phase III randomized trial in newly diagnosed CML (IRIS study), imatinib was compared to IFN-alpha/Ara-C in 1106 chronic-phase CML patients within 6 months of diagnosis.11 With a median follow-up of 19 months, CHR with imatinib were nearly universal (97%), similar to previous phase I/II studies. In comparison, CHR was achieved in 69% of subjects treated with IFN-alpha/Ara-C. MCR was achieved in 87% of imatinib-treated patients (including 76% CCRs) vs 35% of IFN-alpha/Ara-C-treated patients. Of additional importance was the degree of intolerance to therapy: 31% crossed over in the IFN-alpha arm compared with <1% in the imatinib arm due to intolerance to planned therapy. However, <5% of these newly diagnosed CML patients achieved a PCR undetectable state (ie >4.5 log-fold reduction in BCR-ABL), suggesting that imatinib is unlikely to eradicate minimal residual disease (MRD).12 Based on these data, a curative option with single agent imatinib cannot be anticipated for most patients.

Data from this randomized phase III study support front-line therapy with imatinib, and a new nontransplant upfront standard of care has emerged. However, many questions remain unanswered as we await maturation of these data. Previously, several risk stratifications were proposed to predict survival based upon the presenting characteristics of CML patients (Table 2) treated with chemotherapy or IFN-alpha.13,14 In the IRIS trial, with short follow-up (19 months), no difference in outcomes have been reported with regard to stratification of patients using the Euro (Hasford) score;11 no difference in progression-free survival has been observed to date between high-, intermediate- and low-risk patients on the imatinib arm. However, in a smaller upfront combination therapy trial, the Italian Cooperative Study Group identified that in 57 newly diagnosed, evaluable CML patients treated with the combination of imatinib and PEG-IFN-alpha, risk stratification using both Sokal and Hasford models predicted the achievement of MCRs.15 With a median observation period of 9 months, MCRs were achieved at 6 months in 70% of low-Sokal-risk patients, 41% of intermediate-risk and 8% of high-risk patients. Additionally, all studies as well have shown a small but significant progression to advanced disease within the first 2 years of imatinib therapy. All such data now must enter the complex decision making of an individual CML patient weighing imatinib-based nontransplant therapy against sibling or alternative transplant options since numerous questions have arisen regarding the stratification, timing and optimization of allogeneic SCT in CML (Table 3).



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Allogeneic hematopoietic SCT after marrow ablation

Allogeneic transplantation remains the only proven curative therapy for CML. The expected outcomes of patients undergoing allogeneic transplant after myeloablative therapy vary among institutions, but data from the International Bone Marrow Transplant Registry would suggest that 60% of patients transplanted in first chronic phase from sibling donors are alive and free of disease at 5 years from transplantation.16,17 Limitations of the application of allogeneic transplantation remain, based upon patient eligibility (age, comorbid conditions, available donors), the risk of early treatment-related mortality and the potential for long-term debility with chronic graft-versus-host disease (GVHD). Patients who do experience relapse can anticipate effective salvage therapy with the use of donor leukocyte infusions (DLI), due to results depending on the degree of relapse (ranging from molecular to hematological).18,19,20 Thus, it has been a long-standing recommendation, based upon retrospective data, that patients with sibling-matched donors should be transplanted within the first year of diagnosis.17,21 Similarly, in unrelated donor hematopoietic SCTs for the treatment of CML, it has been recommended that young patients be transplanted within the year from diagnosis as determined by quality-adjusted, life expectancy analysis22 and substantiated by retrospective analysis from the cohort of patients treated at the Fred Hutchinson Cancer Research Center.23 One study even suggested that CML patients eligible for unrelated donor transplant should be transplanted immediately rather than receive prolonged IFN-alpha therapy, since advanced GVHD was enhanced and survival decreased in patients who had been treated with interferon for greater than 6 months.24 These findings were not substantiated in large, EBMT- or IBMTR-sponsored retrospective studies.25,26 Finally, a risk assessment performed on 3142 patients after transplant identified five factors (age, disease stage, donor type, donor sex and time from diagnosis) that together may predict outcome with the lowest risk patients anticipating a 60% leukemia-free survival and 72% overall survival, while the highest risk patients anticipating a 16% leukemia-free survival and a 22% overall survival at 5 years.27

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Reduced intensity transplant

Recently, reduced intensity transplantation has been introduced as a means to provide patients, generally ineligible for standard myeloablative preparative regimens due to either increased age or significant comorbidity, an opportunity to benefit from allogeneic immune therapy. Most reports have focused on mixed populations of patients, but there are some studies that target specific cohorts of CML patients undergoing nonmyeloablative allogeneic transplantation with acceptable results observed. The group from the Hadassah-Hebrew University Hospital has recently reported that progression-free and overall survival of 85% was achieved with acceptable median follow-up of 37 months (range: 7–63) with the fludarabine (150 mg/m2), busulfan (8 mg/kg) and rabbit ATG (40 mg) preparative regimen.28 GVHD remained an issue since 75% of patients still experienced significant clinical grades II–IV acute GVHD (aGVHD) and 55% experienced chronic GVHD. Similar outcomes were noted within the FHCRC Consortium using the single-dose 200 cGy TBI +/- fludarabine 90 mg/m2 reduced intensity regimen.29 In their experience, 20 CML patients (13 CP1, four AP, three CP2) underwent the allogeneic transplant. With short follow-up with a median of 390 days, of 16 patients with sustained with engraftment, 13 had become cytogenetically negative within a median of 2.5 months and 10 had gained molecular remission with PCR negativity confirmed for the BCR/ABL transcripts by 5.5 months. Four patients treated with low-dose TBI alone rejected their grafts. Of 16 evaluable patients, 10 had developed grades II–IV aGVHD and five patients developed chronic GVHD. Finally, the EBMT registry, reported outcomes of 211 reduced intensity transplants performed for CML patients between 1994–2002.30 The patients represented a mixed population with multiple preparative regimens, varying donor and graft sources, varying disease states, different degrees of HLA matching and varying GVHD prophylaxis regimens. In spite of this heterogeneity in patient population, excellent outcomes were recorded. Overall survival at 2 years was 56% with a median survival of 1085 days. The 2-year survival based on disease stage was 68% for first chronic phase, 59% for second chronic phase, 32% for accelerated phase and 0% for blast crisis. Treatment-related mortality was 9% at 1 year. Grades II–IV GVHD was seen in 33% of patients but only 10% experienced grades III and IV. Rejection was 11% for this population of patients. Overall, these first reported single disease outcomes are quite encouraging and will hopefully be improved with modifications of either the preparative or immune suppressive regimens. Long-term questions remain regarding the comparative efficacy of reduced intensity vs standard myeloablative transplant regimens and many envision the need for randomized trials to answer these questions in the future.

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Comparison of transplantation to nontransplant therapy

To date, no randomized, prospective assessment of allogeneic transplantation vs standard nontransplant care for CML has been published. Hehlmann, representing the German CML Study group, presented a preliminary view of the first prospective CML transplantation trial based upon genetic assignment determined by the availability of HLA-matched sibling donors to determine who undergoes early transplantation.31 The trial, performed in the pre-imatinib era, compared patients without sibling donors undergoing standard therapy and subsequent late unrelated transplantation for IFN-alpha-resistant disease vs patients with sibling-matched donors transplanted within the first year of diagnosis. The preliminary data suggested that no difference in overall survival was demonstrated with all patients followed up to 4 years from diagnosis, and for patients with low-risk disease (determined by Hasford criteria (Table 2)), followed up to 6 years. Conclusions drawn from these data remain unclear until full maturation of the trial occurs. However, these data may suggest that stratification of patients within risk categories should be performed at diagnosis of CML and particularly transplantation from an allogeneic donor of either related or unrelated source need not be performed early. The authors own recommendations were to provide patients with a trial of IFN-alpha to determine responders and to delay allogeneic transplantation in those who achieved satisfactory responses. One could speculate that since imatinib is a more effective therapeutic agent than IFN-alpha that the differences might be sustained or be greater, if such a randomized trial was performed today between upfront imatinib and sibling-related transplantation. One could also postulate that the varied retrospective data analyses17,21,27 that have suggested the need for early allogeneic transplantation in CML may have been influenced by various biases: (1) IFN-alpha is ineffective CML therapy with most patients having little response with time; (2) data analysis was hampered by a lack of stratification of patients into proper prognostic risk groups at diagnosis; and (3) that patients deferred for later transplantation may reflect those with comorbid conditions for which upfront risk was felt significantly great so that the preferred approach was to delay transplant until clear resistance or progression was identified.

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Imatinib after allogeneic transplantation

Another cohort of patients for whom imatinib therapy is available and where some efficacy has been established is for those patients who require salvage therapy, after failing an allogeneic transplant. Based upon the excellent outcomes achieved with DLI, DLI should remain the treatment of choice for early relapse.18,19,20 However, several centers have reported their experience with imatinib salvage therapy for Ph+ leukemias, including for those patients who failed DLI. Olavarria et al32 described an individual who failed allogeneic transplant and subsequent DLI who responded to single agent imatinib at a dose of 400 mg/day. Complete donor hematopoiesis was restored by 6 months after therapy; however, persistence of the BCR/ABL transcript was noted by PCR. Several other groups have reported their experiences using imatinib salvage for all stages of disease.33,34,35,36,37 Not surprisingly, relative efficacy of imatinib therapy correlated with the degree of relapse. Patients that had stable-phase relapse were more successfully treated than those with more advanced disease, even if they had experienced prior failure with DLI. In our own center, approximately 30 patients who have failed allogeneic transplantation were treated with post transplant imatinib. A total of 18 of these patients were in blastic phase of disease. Imatinib was only effective in salvage as a single agent in patients who failed transplantation with either cytogenetic relapse or stable-phase hematologic relapse. With patients who had blast-phase recurrence post transplantation, all patients at our center who initially responded, died unless they proceeded to a second transplantation or DLI.

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Autologous transplant

Autologous transplantation for CML patients has been used in various clinical settings with the overall goal of decreasing host leukemic burden.16 This transplant option has been used for elderly patients and for patients with no allogeneic donors. Progenitor sources for these autografts have included both bone marrow and growth factor mobilized peripheral blood stem cells. Various strategies to harvest Philadelphia negative (Ph-) hematopoietic stem cells have been implemented, including ex vivo bone marrow manipulations such as costimulation with activated immune cells, differential adherence to stromal assays, antisense oligonucleotide treatments and short-term cell culture as well as in vivo strategies for mobilization and collection after chemotherapy or interferon.38,39 There are single center studies as well as retrospective analyses that have suggested low overall transplant mortality and prolongation of survival can be achieved, especially if performed in chronic phase. The work from Carella et al40 using chemotherapy mobilization of Ph- hematopoietic progenitor cells has demonstrated that infusion of such progenitors will lead to post transplant durable remissions with Ph- hematopoiesis.40 In 50 patients autografted in early chronic phase, overall survival was 80% at 5 years with 41 patients of the original 50 patients remaining in hematologic remission and 56% of those patients in major cytogenetic remission. Thus, although not a curative procedure, sustained clinical control of disease can be achieved in autologous transplant patients. McGlave et al41 reached similar conclusions in their retrospective analysis in which the median survival in chronic-phase patients had not yet been reached with over 7 years of follow-up post transplant.

Thus, with the advent of imatinib and its ability to achieve a high percentage of CCRs coupled with molecular remissions, a new potential for autologous transplantation is emerging. In our center, 15 CML patients who achieved CCR (0% Ph+) and had interphase FISH less than 10% positive for the BCR-ABL rearrangement (with 3/15 patients demonstrating no detectable BCR-ABL mRNA by quantitative RT-PCR) with imatinib therapy were considered for growth factor-stimulated autologous stem cell mobilization and cryopreservation.42 These patients lacked allogeneic sibling donors and are eligible for future autologous transplantation if their disease relapses in the future. In all patients, imatinib was maintained during the mobilization. Successful mobilization of stem cells was achieved in 11/13 evaluable patients. Nine patients required remobilization or augmented growth factor schedules. On preliminary evaluation, prolonged utilization of IFN-alpha negatively impacted on cell mobilization with a significant reduction in the median number of CD34+ progenitors per collection mobilized in patients treated with over 2 years of IFN-alpha. What remains to be determined if mobilization of these patients is necessary since those patients with marked sensitivity to imatinib therapy and optimal primary responses might have the greatest chance of maintaining long-term progression-free survival. Autologous transplantation, in the future, may be better served to target patients with MCRs – stabilized albeit with measurable residual tumor burden, for whom no allogeneic stem cell donors are available. The various measures to reduce minimal residual disease in the collection product used in the past with chemotherapy-assisted Ph- collections might again be validated, for example, the treatment with BCR-ABL antisense to a stem cell product with only molecularly determined minimal residual disease. In addition, the potential for ex vivo purging of the stem cell product with high concentrations of imatinib can be assessed, as well as in combination with other therapies, even potentially autologous anti-CML immune effectors.43 Long-term follow-up will determine such answers.

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Future of nontransplant therapy: optimizing response, resistance, and salvage

If the results from the German CML Study group's prospective genetic assignment trial31 are substantiated with longer follow-up, it may also be reasonable to consider, prior to transplant, alternative or second line-therapy in patients with evidence of suboptimal cytogenetic response or even early progression (molecular or cytogenetic) on imatinib, depending on the assessable risk of transplant associated morbidity/mortality the patient faces.27 These approaches may include dose escalation of imatinib44 or combination therapy with other active agents. In preclinical models, combinations of imatinib with conventional agents such as IFN-alpha and cytarabine as well as daunorubicin45 demonstrate additive or synergistic effects; novel agents such as arsenic trioxide46,47,48 and the class of compounds known as the farnesyl transferase inhibitors (FTI)49 have shown significant potential to overcome resistance in CML. Phase I data on imatinib combined with low-dose cytarabine,50,51 low-dose IFN-alpha,52 peg-IFN,53 arsenic trioxide,54 and FTIs55 are available with each regimen showing acceptable toxicity and promising antileukemic activity. Such agents are being tested in phase II studies for their potential to enhance the efficacy observed with imatinib monotherapy or salvage imatinib failures. One goal may be to achieve a higher proportion of patients with undetectable BCR/ABL transcripts, determined by quantitative PCR, than was seen in the IRIS study. A phase II study of combination imatinib/Ara-C has identified such an outcome.51 Large phase III trials are planned to further test these options as large numbers of patients may be needed to discern advantages or disadvantages associated with combination therapy, which may include rapidity of response and delineation of patients responding favorably or unfavorably to nontransplant therapy, comparative depth of log-fold reductions in BCR-ABL transcripts, or potentially increased toxicity.

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Risk stratification and transplantation

Stratification of patients with CML into various risk groups has suggested that early transplantation may benefit younger patients with higher risk disease.27 Data from the Collaborative CML Prognostic Factors Project would suggest that a modification of previous prognostic scales to include age, spleen size, platelet number and circulating eosinophil, basophil and blast counts (The New CML Score or Hasford Score) can be very effective at identifying patients for whom prolonged transplant-free survival would be anticipated vs those who could expect early progression to more aggressive phases of disease.14 This scoring system was validated by assessing CML survivors treated with IFN-alpha.

Only 18 months ago, using this prognostic scale and based upon the impressive observations of the efficacy of imatinib, Goldman and Druker56 initially proposed an algorithm for the management of new patients with CML. This algorithm used the Hasford score and age to guide in deciding optimal treatment in the first year of diagnosis and suggested that newly diagnosed CML patients should undergo early transplantation if they are under 35 with a sibling donor and under 25 with an unrelated donor. However, with the recent data obtained from the prospective German trial26 and the upfront imatinib (IRIS) study,11 we feel that it may be prudent for nearly all newly diagnosed, chronic-phase CML patients to first have a trial of imatinib and to assess carefully the cytogenetic response at 6 months to help guide the transplant decision. In patients who remain more than 65% Ph+, further planning for allogeneic transplant is warranted. If patients have a partial cytogenetic response (1–35% Ph+), they can maintain the option of pursuing allogeneic transplant or remaining on imatinib-based therapy. We would also make the recommendation that patients who are young with Sokal or Hasford score-determined high-risk disease15 consider pursuing immediate work-up in preparation for allogeneic transplant, even in the face of initiation of imatinib. This recommendation is also based upon the observation that approximately 10% of imatinib-treated patients in accelerated phase have relapsed directly into blast phase of disease.4 Identification of potential donors and early risk stratification for transplant will allow rapid and optimal movement to transplant in the face of resistant, or early relapsed disease, ideally still after partial disease reduction with imatinib. The reality remains that if blast transformation occurs, it is exceedingly likely that these patients will never have the curative option that they desire.

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Unanswered questions in an imatinib era

As we proceed in an era of markedly improved nontransplant therapy for CML, first and foremost reconsideration of response criteria will be necessary. Although we have well-established categories of meaningful responses from an IFN era, do these still apply today? For instance, do we need to rewrite the criteria for a MCR? Clearly, if 70% of imatinib-treated CML patients can achieve a complete cytogenetic remission, the presence of 1–35% residual Ph+ metaphases by karyotype may represent frank biologic resistance rather than defining a 'partial response' and may signal a need for either early transplantation or for alternative nontransplant therapy. Despite this concern, the survival advantage of MCRs as defined in an IFN era may now be emerging in similarly responding imatinib-treated patients based on improvements in progression-free survival in the IRIS trial.11 More relevant differences in long-term outcome may result from quantification and monitoring of minimal residual disease through PCR-based assays for BCR-ABL with increasing sensitivity. End points for planned clinical trials will focus on molecular responses and degree of log-fold reduction in BCR-ABL. Observation of dynamic changes in MRD by PCR, either with re-emergence of previously undetectable levels or consistent log-fold increase in patients responding favorably to imatinib, has been reported by several groups57,58 and may predict or portend relapse. With most patients achieving hematologic and favorable cytogenetic response but remaining BCR-ABL transcript positive, definitions of 'relapse' and 'progression' need to change and new relevant thresholds for response or lack thereof need to be determined likely based on analysis of trends in MRD.

In addition to early clues regarding prognosis, based on response and clinical disease features, emerging data from microarray studies16 may allow for stratification and prediction of response to imatinib therapy. In such experiments, pooled patient material from chronic phase and blast crisis of CML show clear differences in gene expression patterns. However, disparate cases exist with chronic- or accelerated-phase disease clinically, and 'blast-phase profile' with microarray. With further validation, such data at diagnosis would be invaluable, and would necessitate inclusion into current prognostic models. Experience with imatinib has also highlighted as a unique subset those patients with accelerated disease defined by clonal evolution only. These patients have rates of hematologic and MCR much like those of chronic-phase patients, superior to accelerated patients with clinical features of advanced disease. However, such patients may ultimately still have higher rates of relapse.59

A third concern stems from the possibility that other bone marrow changes may develop during non transplant therapy with imatinib, which may alter outcome. Our group has recently reported the identification of additional clonal cytogenetic abnormalities in cells lacking detectable Philadelphia chromosome/BCR-ABL rearrangement.60 Seven patients with chronic- or accelerated-phase CML, who were treated with imatinib, previously refractory or intolerant to interferon therapy, demonstrated favorable response to therapy (MCR or CCR). After a median of 13 months, additional cytogenetic abnormalities were detected in cells that lacked the Philadelphia chromosome, most commonly trisomy 8 (3/7); others included monosomy 7, t(3,10) and others. Varying degrees of dysplastic morphologic abnormalities were seen in all patients. One patient exhibited increased numbers of marrow blasts, yet consistently demonstrated 0% Philadelphia chromosome metaphases and the absence of morphologic features of CML. Similar observations have been reported by other groups.61,62 The presence of additional chromosome abnormalities in imatinib-treated CML patients with MCR and CHR highlights the importance of routine metaphase cytogenetic testing and long-term follow-up of all imatinib-treated patients. Whether such changes were intrinsic to the hematopoietic stem cell pool but overgrown in the face of the proliferative advantage associated with the BCR-ABL oncoprotein, secondary to prior therapy (IFN-alpha) or imatinib therapy, related remains to be clarified. With myelodysplasia as a potential complication now described during nontransplant therapy, curative transplantation may become more elusive yet seemingly more urgent given these circumstances.

A fourth concern that exists in the CML-treating community is the potential that prior imatinib may enhance potential toxicity and treatment-related morbidity and mortality in patients at the time of allogeneic transplantation. New initiatives within the IBMTR and the NMDP are being pursued that will hasten the resolution of this question, especially critical for early chronic-phase patients who could otherwise undergo transplant with relatively low risk. Although limited in scope, at least two studies would suggest that this issue may not prove to be of significant concern. Deininger et al63 presented data from 70 patients included within the EBMT registry and from OHSU with advanced-phase CML (87%>CP1) who went on to subsequent allogeneic transplantation.63 In this advanced-phase disease patient cohort, treatment-related mortality was 38%, within the expected range for this group of patients. No increase in GVHD was noted. Not surprisingly, the patients who had the best chance of remaining progression free were those in remission at the time of transplantation. Similar data lacking significant enhancement of transplant-related toxicities have been reported in a smaller patient cohort by Shimoni et al.64

Many questions remain in the rapidly evolving field of CML, particularly with regards to SCT and CML. Perhaps the most urgent are whether imatinib will really cure patients and offer an alternative to transplant, whether imatinib pretreatment will negatively impact transplant outcomes, and whether we can use nontransplant therapy for longer periods of time with imatinib or combinations as patients define themselves by response before utilizing stem cell transplant options. One rational conclusion from the success of imatinib might be that in an era of vastly superior nontransplant therapy, older axioms are no longer applicable. In the era of interferon as standard nontransplant therapy, limited success of obtaining significant response clearly defined the role of stem cell transplant. With variable but vastly superior degrees of success in an imatinib era, not only might we see a clear change in the natural history of CML but also a near blank slate with regards to the optimal utilization of SCT in the treatment for CML.

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Summary

Multiple attempts are being made to develop treatment algorithms for CML in the rapidly changing imatinib era. In our institution, we have developed our own approach, heavily weighted by sharing the uncertainty of options with individual patients. With close working relationships between nontransplant and transplant teams, we have developed our own dynamic strategy. Our approach for all new patients with CML is to recommend initial stratification based upon the Hasford and Sokal indices (at least until either model is validated or a new model is developed that best stratifies outcomes of imatinib-treated patients' presenting characteristics). All patients, who wish to consider SCT and for those whom SCT is feasible (including potential reduced intensity candidates), should have HLA typing and sibling typing, coupled with preliminary URD search where indicated. This information immediately segregates early-phase CML patients into two groups (Figure 1 and Figure 2). Based on current data, we recommend that patients should initiate imatinib-based therapy, even while awaiting typing for potential SCT. More aggressive first-line therapy may be offered, preferably on clinical trials, especially in higher risk patients. Early response based on standard cytogenetic testing as well as later stratification based on levels of MRD should be balanced with risk of TRM as patients continue nontransplant therapy (Figure 1). Factors that would lead to recommendation for early SCT include high-risk disease, overt imatinib resistance (ie lack of CHR) and as well, incomplete cytogenetic response in patients with low-risk disease with anticipated low TRM. Rapid achievement of low or undetectable levels of BCR-ABL by PCR may support delay of SCT, even in young patients. Careful and frequent monitoring for dynamic changes, progression at low levels, or the development of new abnormalities is especially important in these patients. Although there are no data currently which document adverse effects of imatinib prior to SCT,63,64 verifying that cure remains unaffected by delayed SCT or SCT in the face of disease highly resistant to imatinib is critical.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Suggested treatment algorithm, newly diagnosed chronic-phase CML with SCT option (CHR=complete hematologic response; MCR=major cytogenetic response; CCR=complete cytogenetic response; NR=no response; TRM=transplant-related mortality; URD=unrelated donor).

Full figure and legend (71K)

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Suggested treatment algorithm, newly diagnosed chronic-phase CML without SCT option (CHR=complete hematologic response; MCR=major cytogenetic response; CCR=complete cytogenetic response; NR= no response; MRD=minimal residual disease).

Full figure and legend (60K)

Patients without SCT options should proceed with imatinib-based therapy and be candidates for both upfront clinical trials of combination therapies, consideration of initial and/or subsequent increased intensity imatinib therapy as well as salvage trials in the face of incomplete response (Figure 2). For patients with advanced-phase CML at first presentation, rapid evaluation and proceeding to SCT after cytoreduction with imatinib is recommended where possible (Figure 3). With rapid establishment of CCR and low or absent levels of MRD, selected accelerated-phase patients, especially with those expected to have high risk of transplant-related complications,27 could delay SCT with careful monitoring.

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Treatment algorithm, newly diagnosed accelerated-phase or blast crisis CML (CHR=complete hematologic response; MCR=major cytogenetic response; CCR=complete cytogenetic response; NR=no response; TRM=transplant-related mortality; URD=unrelated donor; MRD=minimal residual disease).

Full figure and legend (74K)

The field of CML therapy continues to change rapidly. Currently, long-term follow-up is needed as well as careful clinical and basic science investigation before answers will be available to many of the posed questions. As we wait, and as treatment options advance (Table 4), the tasks will be to clarify detection and critical thresholds of residual disease, to understand molecular prognostic footprints and decipher mechanisms of resistance that will allow those in the clinic to better guide patients' treatment decisions. In parallel, clinical advances in reduced intensity transplantation and specific-targeted immune therapy may yet improve further the outcomes of patients with CML in need of cellular therapy by the reduction of the treatment-related morbidity and mortality. These combined advances will eventually mandate new treatment algorithms for this disease.


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Acknowledgements

We thank Dr Brian Druker for the multiple discussions on treatment strategies, Drs Philip McCarthy, Jose Leis and Aleksandra Sinic for their critical review of this manuscript, and Ms Paulette Wakeman and Ms Michelle Faford for assistance in its preparation.