Stem Cell Transplatation

The results, techniques, and practical aspects of SCT will be described in detail in Chapter 37. However, some important aspects of SCT in CML and its integration with other treatment options are discussed here. First, SCT may be curative for a significant fraction of eligible patients who receive a transplant from a human leukocyte antigen (HLA)-identical sibling. Unfortunately, because of the requirements for age, adequate organ function and performance status, and availability of donor, only a fraction of patients are eligible for this procedure. The expected proportion of all patients with CML that may be eligible for a stem cell transplant is unknown, but considering that the median age is 66 years,11 it is probably a small percentage.

The expected results with this procedure can be exemplified by a recent series from Seattle.12 This study used targeted busulfan plus cyclophosphamide as the conditioning regimen for 131 patients in early chronic phase with a median age of 43 years (range, 14-66 years). At 3 years, the projected nonrelapse mortality rate was 14%, and 78% were projected to be alive and free of disease. Among survivors, 60% had extensive chronic graft-versus-host disease (GVHD) 1 year after transplantation, but only 10% had a Karnofsky score less than 80%. Interestingly, 11% of patients had minimal residual disease documented by PCR, but had not relapsed at the time of the report, suggesting that a mechanism such as immune surveillance could prevent relapse of the disease.12 This phenomenon would be similar to the "functional cure" described with IFN-a. Occasionally, patients may relapse many years after SCT. Few series have analyzed the very long-term results of SCT, and thus the magnitude of this problem is difficult to measure. A recent series analyzed the very long-term follow-up of 89 patients transplanted at a single institution.13 Twenty-eight (32%) were alive 10 or more years after their transplant. The mean time to hematologic or cytogenetic relapse was 7.7 years, with five patients relapsing more than 10 years after transplantation.

Results with SCT for patients transplanted in more advanced stages of the disease (accelerated or blast phase) are worse, with 5-year survival probabilities of 40-60% for patients in accelerated phase and 10-20% for those in blast phase. Patients in blast phase who are transplanted in second chronic phase may have long-term outcomes similar to those of patients in accelerated phase. For patients who do not have a sibling donor, transplantation from a matched unrelated donor (MUD) is an option. The results with MUD transplants have been inferior, mostly because of the increased risk of GVHD. The long-term disease-free survival rate after MUD transplant for young patients transplanted within 1 year from diagnosis is 57% compared to 67% for those receiving transplants from matched siblings.14 The results with MUD are, however, improving in recent years with decreasing rates of GVHD and improving probability of long-term survival with the use of molecularly matched donors, although this may further limit the availability of donors. In an attempt to make the SCT option available to more patients, nonmyeloablative transplants have been used for those of older age or with other health considerations that would otherwise prevent them from receiving a SCT. Long-term results are not yet available with these techniques, but early results in small series report disease-free survival rates as high as 85% at 70 months.15 If these results hold in larger series with long-term follow-up, stem cell transplant would be applicable for the more typical patients (i.e., median age 66 years) who have matched sibling donors. The use of alternative donors, such as cord blood or haploidentical donors, is still in early investi-gational stages and has not demonstrated any advantage over nontransplant investigational options.

One important aspect to consider in the setting of other effective treatment options is the timing of SCT. Earlier results from the IBMTR suggested that SCT performed after 12 months from the time of diagnosis had a significantly inferior outcome. Recently, it has been suggested that transplant within the first 24 months,16 and in some series within 36 months,17 have similar outcomes to those performed within the first 12 months. Thus, decisions regarding SCT must be made early and reevaluated at early time points in patients who are treated with imatinib but are transplant candidates. These considerations will be further discussed later in the chapter.

Another important consideration is the possible effect that prior therapy with other agents may have on the results expected with stem cell transplant. Some studies had suggested that prior therapy with IFN-a adversely affected the outcome after transplan-tation.18 However, several subsequent trials demonstrated that no such adverse effect exists.19-22 Some early observations suggest that prior therapy with ima-tinib has no adverse impact on the outcome after SCT.23 24 Although these observations are still limited and have short follow-up, there is little reason to believe that a significant effect may be observed.

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