Experimental Hematology 31 (2003)

Transcription

1 Experimental Hematology 31 (2003) Busulfan-cyclophosphamide versus total body irradiation cyclophosphamide as preparative regimen before allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia: What have we learned? Christèle Ferry and Gérard Socié Service d Hématologie Greffe de Moelle, Hôpital Saint-Louis, Paris, France Most of the preparative regimens before allogeneic bone marrow transplantation include cyclophosphamide (Cy) with either busulfan (Bu) or total body irradiation (TBI). The Bu-Cy regimen has shown an advantage in chronic myeloid leukemia and TBI-Cy remains the standard conditioning regimen in acute lymphoblastic leukemia, but results are more conflicting in acute myeloid leukemia (AML). We report here the results of the most important studies comparing these two preparative regimens in AML. Survival is superior in all studies for patients treated with TBI and reached statistical significance in one of four trials. Two of three trials show significantly reduced transplant mortality and leukemia relapse. Higher incidences of veno-occlusive disease and hemorrhagic cystitis are reported with Bu. However, our long-term follow-up is limited, and to date no definitive conclusion can be drawn regarding late side effects. New approaches aiming at minimizing the toxicity without impairing the efficacy, such as targeted Bu plasma levels and nonmyeloablative conditioning regimens, seem promising but need to be evaluated further in future prospective studies International Society for Experimental Hematology. Published by Elsevier Inc. Bone marrow transplantation (BMT) is a well-established treatment for leukemia. The antileukemic activity of allogeneic BMT is provided both by the high dose intensity of the preparative regimen and by the immune mediated graftvs-leukemia reaction. Historically, combination of cyclophosphamide (Cy; 120 mg/kg) and total body irradiation (TBI) was the most used conditioning regimen [1,2]. In the 1980s, a radiation-free conditioning the use of Cy (200 mg/ kg) associated with busulfan (Bu) was reported [3,4]. In 1987, Tutschka et al. [5] developed a new conditioning with a reduce dose of Cy (120 mg/kg) to minimize the toxicity without compromising efficacy. Bu offered the advantage of an easier administration than TBI, particularly in small children. Moreover, it possibly could prevent the potential toxic effects of TBI, such as secondary malignancies, interstitial pneumonitis, cataract, growth retardation, and other endocrinologic disturbances. On the other hand, TBI has some advantages. It can eradicate leukemic cells in sanctuary sites such as the central nervous system or the testicles. Problems of drug excretion or metabolism do not exist with Offprint requests to: Gérard Socié, M.D., Ph.D., Service d Hématologie Greffe de Moelle, Hôpital Saint-Louis, AP-HP, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France; gsocie@chu-stlouis.fr TBI, unlike with Bu, which has some toxic effects that are rare with TBI, such as veno-occlusive disease of the liver (VOD), hemorrhagic cystitis, and permanent alopecia. Several prospective and retrospective studies were aimed at comparing TBI and Bu associated with Cy as a preparative regimen before allogeneic BMT for acute and chronic leukemia. In chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), results are concordant. In CML, similar or better results after Bu-based regimen were found [6 9]. In ALL, TBI remains the standard regimen, with lower relapse rates, better event-free survival (EFS) [10], and lower transplant-related mortality (TRM) [11] compared to Bu-based regimen. In acute myeloid leukemia (AML), results are not so clear. We report here the results of the most important studies. Survival (Table 1) Conflicting results have been reported in terms of survival. In 1992, a randomized trial comparing Bu (16 mg/kg)-cy (120 mg/kg) vs TBI (10 12 grays)-cy (120 mg/kg) as the preparative regimen in 101 patients with AML in first complete remission (CR1) showed better overall survival with the TBI-Cy regimen (75% vs 51%, p 0.02) [12] X/03 $ see front matter. Copyright 2003 International Society for Experimental Hematology. Published by Elsevier Inc. doi: /j.exphem

2 C. Ferry and G. Socié/ Experimental Hematology 31 (2003) Table 1. Overall survival, leukemia-free survival, toxicity-related mortality, and relapse after Bu-Cy vs TBI-Cy Reference OS LFS TRM Relapse Blaise et al. [12] 51% vs 75% 49% vs 73% 27% vs 8% 34% vs 14% Ringden et al. [15] 54% vs 63% (7 years) 59% vs 56% (7 years) 34% vs 14% 29% vs 29% (7 years) Socie et al. [17] 51% vs 63% (10 years) 47% vs 57% (p = 0.051) Litzow et al. [18] 55% vs 60% (5 years) 54% vs 58% (5 years) 27% vs 30% (5 years) 19% vs 12% (5 years) LFS leukemia-free survival; OS overall survival; TRM treatment-related mortality. This difference was explained by a higher TRM (27% vs 8%, p 0.06) and a higher relapse rate (34% vs 14%, p 0.04) in the Bu-Cy group. The long-term follow-up (median 10.8 years) reported in 2001 [13] confirmed the worst outcome in Bu-based regimen. The 10-year overall survival and leukemia-free survival (LFS) were 59% and 55% in the TBI group vs 43% and 35% in the Bu group, respectively (p 0.04 and p 0.02). In 1994, the Nordic Bone Marrow Transplantation group reported a randomized trial comparing Bu vs TBI in allogeneic transplantation for leukemia [14]. This study initially also found better results in patients receiving TBI. The 3- year overall survival was 76% in the TBI-treated group vs 62% in the Bu-treated group (p 0.03). Relapse-free survival was similar in the two groups. but TRM was higher in the Bu-treated group (28% vs 9%, p 0.006). For patients with advanced disease, LFS was significantly better in the TBI group (p 0.005). However, no separate analysis for patients with AML was provided in this study. In 1999, the same group reported the long-term results of this study [15]. No difference was found with regard to survival. The 7-year overall survival was 54% in the Bu group vs 63% in the TBI group, with no separate analysis with AML. The 7-year LFS also was similar in the Bu vs TBI group (59% vs 56%) in patients with AML. The 7-year cumulative incidence was the same in the two groups (29%). However, results were better with the TBI-based regimen in patients in high-risk groups, with no separate analysis for AML patients. The 7- year LFS was 17% in the Bu group vs 49% in the TBI group (p 0.01), and the 7-year TRM 64% vs 22% (p 0.004). In contrast, a retrospective study comparing Bu and TBI as the preparative regimen for autograft or allograft in acute leukemia found no difference between the two conditioning regimens [16]. Disease-free survival, TRM, and relapse were not significantly different. Four randomized studies have compared these two regimens [6,7,12,14]. The long-term outcome of 316 patients with CML and 172 patients with AML was analyzed [17]. Mean follow-up was more than 7 years. No significant difference in the 10-year overall survival (51% in Bu-treated patients vs 63% in TBI-treated patients) and LFS (47% vs 57%) was observed in patients with AML. A large IBMTR retrospective study compared outcome following allogeneic BMT with Bu-Cy vs TBI-Cy for AML in CR1 [18]. Overall survival, disease-free survival, and TRM were not significantly different in the two groups. Nevertheless, relapse was higher in the Bu group (19% vs 12%, p 0.042), particularly extramedullary relapse (14% vs 10%) and relapse in the central nervous system (3% vs 0%, p 0.016). This study suggested that TBI could be more effective in eradicating leukemic cells at these sites. These results suggest that TBI-Cy regimen is superior to BU-Cy regimen. This also is the conclusion of a metaanalysis of five prospective, randomized, controlled trials comparing the use of Bu-Cy vs TBI-Cy regimen for allogeneic BMT in patients with acute or chronic leukemia [19]. Only one of the five studies compared patients with AML only. Moreover, all of these studies only analyzed the impact of the preparative regimen. Factors known to influence the outcome, such as cytogenetics, number of cells infused, and graft origin, were not included in the different analysis. Toxicity (Table 2) Toxicity of the preparative regimen is a major limiting factor in BMT. Regimens using only chemotherapy, instead of Table 2. Early toxicity of Bu-Cy vs. TBI-Cy Reference Veno-occlusive disease Interstital pneumonia Hemorragic cystitis GVHD II IV Blaise et al. [12] 12% vs 4% 4% vs 10% 31% vs 31% Ringden et al. [14,15] 12% vs 1% 14% vs 10% 24% vs 8% 26% vs 22% Ringden et al. [16] 7% vs 3% 6% vs 12.5% 7% vs 2% 25% vs 31% Socie et al. [17] 6% vs 6% GVHD graft-vs-host disease.

3 1184 C. Ferry and G. Socié/ Experimental Hematology 31 (2003) irradiation-based regimens, have been developed to minimize these toxicities. Nevertheless, early toxicities are an important problem with Bu-containing regimens. In 1991, Morgan et al. [20] compared the toxicity of these two preparative regimens in 233 patients transplanted for acute or chronic leukemia with an HLA-identical sibling donor. Sixty-seven patients received the Bu-Cy preparation and 166 TBI-Cy. VOD and hemorrhagic cystitis appeared to be higher in the Bu-Cy group (19% vs 13%, p ; and 30% vs 14%, p 0.008, respectively). A similar incidence of interstitial pneumonitis was found in the acute leukemia group. Studies comparing the two conditioning regimens in patients with AML showed more early complications with the Bu-based regimen in most of the patients. The French study found no difference in the incidence of interstitial pneumonitis, VOD or hemorrhagic cystitis between the two groups. However, there was a trend toward a higher mortality from a nonleukemic cause in the Bu group (28% vs 8%, p 0.06). The Nordic Bone Marrow Transplant Group [14] found in its randomized trial a significantly higher incidence of TRM in patients both with early and with advanced disease receiving Bu (p 0.002). In the latter group, the difference was 62% for Bu patients vs 12% for TBI patients. The incidence of grade III IV acute graft-vs-host disease (GVHD) also was higher in the Bu group (15% vs 4%, p 0.04), as was the incidence of death related to GVHD (17 vs 2%, p 0.003). The incidences of VOD and hemorrhagic cystitis also were higher in the Bu group (12% vs.1%, p 0.009; and 24% vs 8%, p 0.003; respectively). No difference was found with regard to the incidence of interstitial pneumonitis. In a retrospective study, Ringden et al. [16] found a higher incidence of TRM with Bu in patients with AML in CR1. The incidence of acute GVHD was similar in the two groups. VOD and hemorrhagic cystitis were higher in the Bu group (7% vs 3%, p 0.02; and 7% vs 2%, p , respectively). Interstitial pneumonitis were more frequent in the TBI group (12.5% vs 6%, p 0.008). A more recent study showed a similar incidence of TRM but a higher incidence of VOD in the Bu group (13% vs 6%, p 0.009) [18]. In conclusion, VOD and hemorrhagic cystitis occur more frequently in patients receiving Bu, and no advantage of TRM was found in the Bu-based conditioning regimen. However, none of these studies measured Bu plasma levels. It now is well known that Bu plasma levels are an important factor for toxicity. In 1997, Ljungman et al. [21] demonstrated that high Bu concentrations ( 721 ng/ml) were independently associated with lower overall survival, LFS, and higher TRM. Monitoring of Bu plasma levels leads to a lower incidence of VOD without impairment of the efficacy [22]. Furthermore, as suggested by a reported by Lee et al. [23], the combination of Bu and Cy has a synergistic effect in terms of toxicity. Pharmacokinetics studies have shown that Bu affects the clearance of Cy. Hassan et al. [24] demonstrated that the clearance of Cy is affected by the time between its administration and the last dose of Bu. They found a longer elimination half-life of Cy and an increase of its cytotoxic metabolite if Cy is administered less than 24 hours after the last dose of Bu. The consequences are an increased incidence of VOD and mucositis. Better comprehension of the pharmacokinetics and pharmacodynamics of Bu and Cy is an important step to improving the tolerance and efficacy of this regimen. Future prospective studies are necessary to address these uncertainties. Late side effects (Table 3) If efficacy is one of the most important factors in the choice of preparative regimen, long-term side effects also should be considered. Secondary malignancies are a major concern in long-term survivors after BMT. Curtis et al. [25] evaluated the risk of the development of new solid cancer in 19,229 patients who received allogeneic BMT. In this study, patients receiving a preparative regimen including irradiation had a higher risk of second cancer than those who did not receive radiotherapy. This risk increased with the dose of radiation. A long follow-up is necessary to detect these complications, as the risk of new cancer increases over time. The cumulative incidence rate was 0.7% at 5 years, 2.2% at 10 years, and 6.7% at 15 years. In children, a study of long-term survivors after BMT for childhood leukemia [26] showed that children who received high-dose TBI before transplantation for leukemia were at higher risk for developing solid tumor (relative risk 3.1). In studies comparing Bu-based or TBI-based regimen in patients with AML, the authors did not observe a higher Table 3. Late effects of Bu-Cy vs. TBI-Cy Reference Follow-up Cataracts Alopecia Chronic GVHD Blaise et al. [12] 23 months 38% vs 30% Ringden et al. [15] 87 months 10% vs 31% 28% vs 6% 45% vs 35% Ringden et al. [16] 21% vs 25% Socié et al. [17] 7 years 12.3% vs 12.4% 72% vs 55% 20% vs 19% Litzow et al. [18] 55 months 39% vs 37% GVHD graft-vs-host disease.

4 C. Ferry and G. Socié/ Experimental Hematology 31 (2003) incidence of cancer in the TBI group, but follow-up may not have been sufficiently long (5 10 years) [13,15,17]. However, these studies demonstrated that secondary malignancies also could occur after Bu-based preparative regimen. Nonmalignant late effects are well described [27] and usually multifactorial. The conditioning regimen frequently is involved in the development of these side effects. Endocrinologic disturbances are frequent after TBI, but results are less clear after a Bu-based conditioning regimen. Growth impairment is well established after a TBI-based regimen. Several studies also suggest that the combination of Bu and Cy before BMT can similarly affect growth rates [28,29]. In contrast, other investigators did not find any significant growth impairment after a Bu-based regimen [30 32]. Irradiation is known to induce thyroid dysfunction, but some studies suggest that chemotherapy alone before BMT also can induce thyroid function abnormalities. In 1997, Al Fiar et al. [33] compared thyroid function in 270 adults, based on conditioning regimens. They found almost the same incidence of elevated thyroid stimulating hormone with the Bu-based regimen (11.7%) than with fractionated TBI at 12 grays (16.7%). Similar results were found in children. In a study from the SFGM after allogeneic BMT for AML in first CR1, children treated with TBI experienced a higher incidence of hypothyroidism than those treated with Bu (43% 15% vs 9% 8% at 6 years) [30]. However all patients who developed hypothyroidism after TBI received unfractionated TBI. Gonadal failure is one of the most frequent complications after BMT, whatever the type of preparative regimen [34,35]. After TBI, pregnancies are rare but possible, and the risk of spontaneous abortion is increased [36]. A study reported by Anserini et al. [37] analyzed the semen in 64 men after BMT and showed a trend toward higher spermatogenesis recovery rate after the Bu-Cy compared with the TBI-Cy preparative regimen (p 0.069). Other non life-threatening complications can affect quality of life after BMT. Cataract is a frequent late complication after TBI [38], but it also occurs after irradiation-free regimens. The long-term results of the Nordic BMT group [15] showed a higher incidence of cataracts in the TBI group (31% vs 10%, p 0.002), but most of the patients in the TBI group who developed cataract received TBI in a single session. The long-term follow-up of the four randomized studies comparing Bu and TBI as preparative regimen before transplantation for leukemia found an overall higher incidence of cataracts in the TBI group, but among patients with AML, the 7-year cumulative incidence was not different between the two groups (12.3% in the Bu group vs 12.4% in the TBI group) [17]. Permanent alopecia is a frequent complication affecting quality of life after transplantation. The Nordic BMT group [15] found partial or total alopecia in 37.7% patients after Bu conditioning and partial alopecia in 10.8% patients after TBI. Total alopecia did not occur after TBI. The longterm results of the four randomized studies [17] also showed an increased incidence of alopecia in patients with AML who received Bu-Cy. Chronic GVHD leads to late transplant-related morbidity or mortality. Only the Nordic study [15] found a higher incidence of chronic GVHD in the Bu group (59% vs 47%, p 0.05). They also found that death related to GVHD was more common in the Bu group (22% vs 3%, p 0.001). Others studies did not find any difference in chronic GVHD incidence [13,17,18], but GVHD-related mortality in the French study [13] was higher in the Bu-Cy group (p 0.05). Both regimens are responsible for late complications, and even today it still is difficult to establish which regimen provides the lower toxicity rate. Some complications, such as secondary malignancies, appear late after transplantation; thus, longer follow-up is needed to precisely compare late complications related to the conditioning regimen. Conclusion Cy-TBI appears to be superior to Bu-Cy in terms of survival and LFS in patients with AML, especially in patients with advanced disease. Both TRM and relapse are reduced in patients undergoing TBI. Statistical significance for these differences were reached in some but not all trials. Early toxicity is an important problem with Bu, and higher incidences of VOD and hemorrhagic cystitis are reported. Longterm side effects (alopecia, cataracts, chronic GVHD, second tumors) after a median follow-up of more than 7 years seem to be comparable in the two regimens. Where do we go from here?: patients with AML should receive TBI when available, and Bu should be second-choice regimen. Targeted Bu is a new promising method for administration of Bu, but we do not know how these early encouraging results will compare with conventional TBI-based regimens. Careful monitoring of early and late complications, as well as prospective randomized trials, hopefully will establish optimal conditioning regimens in the rapidly evolving world of allogeneic hematopoietic stem cell transplant for acute leukemia. References 1. Thomas ED, Buckner CD, Banaji M, et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. 1977;49: Thomas ED, Buckner CD, Clift RA, et al. Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N Engl J Med. 1979;301: Santos GW. Busulfan (Bu) and cyclophosphamide (Cy) for marrow transplantation. 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