The use of recombinant human erythropoietin (rHuEPO) has been controversial after myeloablative allogeneic Stem cell transplantation (allo-SCT). Reduced intensity conditioning regimens (RIC) offer a novel approach that might translate into a different profile of erythropoietic recovery. We treated 20 consecutive patients with rHuEPO early after matched sibling RIC allo-SCT. Conditioning included fludarabine, busulfan and antithymocyte globulin. EPO treatment was analyzed in terms of toxicity, impact on the frequency of Red blood cell transfusions (RBCT) and kinetics of Hemoglobin recovery within the 60 days post-allo-SCT. Results were compared with 27 matched patients who did not receive rHuEPO. In the first 2 months after allo-SCT all patients receiving rHuEPO (100%) achieved an Hb level>11 g/dl at a median of 30 (15–35) days post-allo-SCT, as compared to only 63% of the patients not receiving rHuEPO (P=0.007) at a median of 35 (20–55) days (P=0.03). A total of 70% (95% CI, 50–90) of rHuEPO patients maintained an Hb over 11 g/dl in the second month as compared to only 19% (95% CI, 4–34) in the other group (P=0.0004). For patients receiving RBCT, the use of rHuEPO was associated with a trend towards reduced RBCT requirements. This pilot study suggests a potential benefit of early administration of rHuEPO after RIC allo-SCT on early erythropoietic recovery.
Anemia is a common problem after both autologous and allogeneic stem cell transplantation (allo-SCT). Virtually, every transplanted patient will require red blood cell transfusion (RBCT) support.1 Over the last decade recombinant human erythropoietin (rHuEPO) has become a well-established treatment for anemia in different hematological malignancies and solid tumors.2 However, the role of rHuEPO after allo-SCT is yet to be defined.3 Low EPO levels have been documented in patients with a low hemoglobin (Hb) level after allo-SCT making a rationale for its clinical use.4, 5 To date, rHuEPO use in standard myeloablative allo-SCT remains controversial. When given early after allo-SCT, rHuEPO only marginally decreases transfusion requirements and improves Hb levels. It has no significant impact on quality of life (QOL) and is not cost effective.6, 7, 8, 9 Recent EORTC guidelines for the use of erythropoietic proteins in anemic patients with cancer state that for patients undergoing allo-SCT, the clinical impact of erythropoietins is limited and they can only be recommended on an individual basis.10
Recently, better understanding of the mechanisms of allogeneic antitumoral control challenged the need for myeloablation during allo-SCT conditioning. The latter led to the development of reduced intensity conditioning (RIC) regimens, where efficacy of transplantation would derive mainly from the immunologic graft-versus-tumor effect. After the initial reports,11, 12, 13 our group and others confirmed the antitumor potential of this approach in different malignancies even in elderly or heavily pre-treated patients.14, 15 The Seattle experience with the use of a fludarabine and low-dose total body irradiation-based nonmyeloablative regimen for allo-SCT showed that both red blood cell (RBC) and platelet (PLT) transfusion requirements were significantly reduced in comparison with the standard myeloablative allo-SCT.16 Although the regimen used by our group (antithymocyte globulin (ATG), busulfan and fludarabine) is more myeloablative than the Seattle RIC regimen, we have recently shown that it is also associated with a lower requirement for RBC transfusions and quicker kinetics of Hb recovery as compared to standard myeloablative allo-SCT.17 Recently, the German group in a prospective randomized trial including 48% of patients receiving RIC reported that reconstitution of erythropoiesis is likely to be accelerated by early treatment with RHuEPO and that it reduces the number of RBC transfusions in the ABO minor incompatibility situation after allo PBSCT.18 With this background, we hypothesized that RIC allo-SCT may represent an attractive setting for the use of rHuEPO as opposed to standard highly myelotoxic and myeloablative conditioning regimens. Here, we report the results of a pilot study evaluating the efficacy and safety of early administration of rHuEPO after RIC allo-SCT.
Patients and methods
Between April 2002 and July 2003, 20 patients with hematological malignancies or metastatic solid tumors received an RIC allo-SCT from an HLA identical sibling in a pilot study assessing the impact of early administration of rHuEPO after RIC allo-SCT. These patients were matched and compared to a historical control group of 27 patients receiving the same preparative RIC regimen, but not receiving rHuEPO post-allo-SCT. Patients were treated with an RIC because of high-risk clinical features that made them ineligible for our standard myeloablative allo-SCT program. ‘High risk’ was defined by the presence of one or more of the following features that precluded the use of standard myeloablative allo-SCT: (1) patient age older than 50 years; (2) a condition with a high risk of relapse post-allo-SCT such as lymphoma and myeloma; (3) heavily pre-treated patients, with more than two lines of chemotherapy before allo-SCT, including patients with metastatic solid tumors; (4) patients with poor performance status due to significant medical co-morbidities. Protocols were approved by the Institut Paoli-Calmettes Institutional Review Board (Comité d'Orientation Stratégique), the local ethical committee of Marseille II (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale) and the French agency for health products security (Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS)) whenever applicable. Patients and donors gave their informed consent prior to participation.
Conditioning regimen and stem cell collection
The preparative regimen was identical for all patients and was adapted from the initial report by Slavin et al.11, 15 The RIC regimen included fludarabine (Fludara; Schering AG, Lys-Lez-Lannoy, France) at a daily dose of 30 mg/m2 for 6 or 5 consecutive days (administered intravenously, over 30 min), oral busulfan (4 mg/kg/day for 2 consecutive days) (Glaxo-Smith-Kline, Marly-le-Roi, France) and a single dose 2.5 mg/kg of ATG (Thymoglobulin®, SangStat-Genzyme, Lyon, France). All donors underwent a peripheral blood stem cell harvest after treatment with subcutaneous granulocyte colony-stimulating factor (G-CSF) at a daily dose of 5 μg/kg. The final stem cell product was analyzed in terms of hematopoietic progenitors (CD34+ cells) and lymphoid cells (CD3+ cells) using standard flow cytometry procedures. None of the patients included in this series received either donor lymphocyte infusion (DLI) or G-CSF stimulation during the first 60 days post-allo-SCT.
Immunosuppression and graft-versus-host disease evaluation
Cyclosporin A (CSA) was started intravenously on day-2 in all patients, at a dose of 3 mg/kg, and switched to an oral formulation as soon as oral intake was satisfactory. Dosage was adjusted for blood levels and renal function. Acute graft-versus-host disease (aGVHD) was graded according to standard criteria.19, 20
Supportive care and transfusion policies
Supportive care was performed according to standard procedures as previously reported,15, 17 and was similar for all patients. RBCT policy remained unchanged for all patients included in the study as previously reported.17 A transfusion was given when the Hb level was <8 g/dl or when the patient was symptomatic from anemia. RBCs were leukodepleted, irradiated and of the same ABO group when donor and patient were ABO compatible, of recipient or donor type in case of major (presence of isohemagglutinins in the recipient against donor RBC antigens) or minor (presence of isohemagglutinins in the donor against recipient RBC antigens) incompatibility and always of type O in cases of bidirectional incompatibility, respectively. All patients received RBC transfusions compatible with donor rhesus and Kell status.
A total of 20 patients eligible for RIC allo-SCT with a pre-transplant Hb level less than 14 g/dl and no history of thrombotic complications were included in this study over a period of 14 months. For all patients the day of the first intravenous (i.v.) injection of rHuEPO was the day after the last donor PBPC infusion. Nine patients received epoetine-beta (Neorecormon, Roche, Neuilly-sur-Seine, France) at a dose of 10.000 IU thrice weekly. The remaining 11 patients received darbopoetine alpha (Aranesp, Amgen, Neuilly-sur-Seine, France) 150 mg/week when approval for its use in hematological malignancies was granted in France. Erythropoietin was given by i.v. infusion during hospitalization and subcutaneously after patient discharge. Treatment was continued until the Hb level reached 14 g/dl, or day +60. All EPO+ patients received iron supplementation at a dose of 150–250 mg of elemental iron per day p.o. Patients from the matched control group were treated in the period immediately prior to, or immediately after the end of this pilot study. They were treated identically in every way except for rHuEPO and iron administration.
Primary endpoints of this study were to analyze the impact of early rHuEPO on both Hb recovery and RBC requirements during the first 60 days after transplantation, in patients treated with rHuEPO as compared with patients who had not received EPO treatment. For this purpose, only patients surviving beyond day 60 were considered. During the study period two patients died before day 60: one on day 5 (cerebral hemorrhage) and the other on day 59 (severe aGVHD). Both patients had not received EPO and were excluded from the analysis. All data were analyzed as of June 15, 2004.
Descriptive statistics are reported as frequencies and percentage, median and range. Distributions of categorical variables were compared using standard χ2 tests. Continuous variables were compared between groups using the t-test, Wilcoxon or Kruskal–Wallis when applicable, and the Mann–Whitney test otherwise. All analyzes were performed using SAS 8.2© (SAS Institute, Cary, NC, USA) or SEM (SILEX, Mirefleurs, France)
Patients, donors and transplant characteristics are summarized in Table 1 and did not differ between the two groups (Table 1). Two patients from the EPO+ group and three patients from the EPO− group were transfused at least once in the month preceding conditioning. The median Hb level prior to conditioning was 10.8 (range, 6.8–15.2) g/dl. Out of the 47 patients, 25 patients (53%) had an Hb level under 11 g/dl prior to the beginning of conditioning without any significant difference between the two groups. An Hb level cut off of 11 g/dl was chosen for further subgroup analysis following the WHO grading system for anemia and to differentiate grade 0 anemia (Hb⩾11 g/dl) vs. more advanced anemia grades.21 After transplantation, 26 patients experienced grade II–IV aGVHD at a median of 30 (range, 15–60) days post-allo-SCT, with no significant difference between the two groups. A total of nine patients (Group EPO+: three (15%); Group EPO−: six (22%); P=NS) had severe gut GVHD. No significant differences in GVHD characteristics could be documented between patients receiving epoetine-beta or darbopoetine-alpha. In this series no serious unexpected adverse events, notably thromboembolic episodes or signs of pure red-cell aplasia,22 were attributed to rHuEPO administration. RHuEPO was withdrawn at a median of 42 (range, 1–56) days after allo-SCT, with no difference between the two products.
Times to achieve an absolute neutrophil count (ANC) above 0.5 × 109/l and a PLT count >20 × 109/l, were, respectively, 17 (range, 0–24) and 13 (range, 0–23) days with no significant difference between patients either treated with rHuEPO or not (Table 1). Accordingly, PLT transfusion requirements appeared to be identical between both patient groups. In total, 13 patients in the (EPO+) group (65%) and 12 patients in the control (EPO−) group (44%) received no PLT transfusions during the study period (P=NS). For transfused patients, PLT requirements were minimal in both groups: 1 (range, 1–2) unit for EPO+ and 1 (range, 2–3) unit for EPO−.
Overall, RBCT requirements were relatively low: 12 patients (six in each group, P=NS) were never transfused, while 35 patients received a median of 2 (range, 2–12) RBC units with a trend towards less transfusions for patients treated with rHuEPO (Group EPO+: 2 (2–4); group EPO−: 4 (2–12); P=0.07). There were two patients in the EPO+ (10%) and seven patients in the EPO− group (26%, P=NS) with ABO blood group donor/recipient incompatibility. There were no cases of hemolysis in ABO mismatched recipients during the post transplant period. The highest number of RBC units transfused (12 from day 0 until day +60) was found in three ABO-compatible patients from the EPO− group.
The major difference between the two groups consisted of a hastened Hb recovery after day 15 (Table 2; Figures 1 and 2). In addition, after discontinuation of rHuEPO, this difference remained and continued to be evident during the second month after allo-SCT (Figure 1): at any time point during the second month, 14 patients in the EPO group (70%, 95%CI: 50–90) had an Hb above 11 g/dl as compared to five patients (19% (95% CI, 4–34)) in the EPO− group (P=0.0004) (Figure 2).
The Hb level prior to transplantation was predictive of RBCT requirements. Of the 22 patients with an Hb level ⩾11 g/dl, 10 were never transfused while 12 received one transfusion of 2 RBC units, as compared to the 25 patients presenting with an Hb level <11 g/dl: two patients were never transfused (P=0.003) while 23 received a median of 4 (range, 2–12) RBC units (P<0.001).
Patients presenting with a low Hb count before conditioning were likely to benefit more from rHuEPO treatment (Figures 3a and b). The difference in Hb recovery between the two groups (EPO+ vs EPO−) was achieved earlier in patients with a lower pre-transplant Hb level. It was also the only situation where RBCT requirements differed between the two groups: patients with a low pre-transplant Hb level treated with rHuEPO received significantly less RBC units than did those not receiving rHuEPO (Group EPO+: 2 (range, 0–4); Group EPO−: 4 (range, 2–12); P=0.01).
The median follow-up of surviving patients was 16 (range, 11–43) months. The 2 years survival did not differ between the two groups (Group EPO+: 57% (44–69); group EPO−: 51% (41–62).
We have recently reported that the use of fludarabine, busulfan and ATG-based RIC regimen was associated with lower RBCT requirements and quicker Hb recovery kinetics as compared to standard myeloablative conditioning in the allogeneic setting. In addition, our previous analysis suggested that Hb level prior to conditioning was an independent predictive factor for both RBCT requirement and Hb level recovery after such an RIC regimen.17
The use of rHuEPO after allo-SCT has been reported in the setting of myeloablative conditioning and has been rather disappointing. Although low levels of serum erythropoietin were documented after standard myeloablative allo-SCT, the use of rHuEPO did not translate into a substantial improvement in erythropoietic recovery or major reduction of RBCT requirements.6, 23, 24 Profound myeloablation resulting from standard conditioning is likely to induce elimination of progenitor cells targeted by EPO. This might explain, at least in part, these poor results. This hypothesis is in line with previous data showing that delayed administration of rHuEPO, that is, after bone marrow repopulation, is associated with a reduction in RBCTs.25
RIC regimens are by definition less myeloablative than standard regimens. This means that a substantial number of EPO-responsive erythroid progenitors of recipient origin might persist after allo-SCT, before being gradually replaced by the expansion of equivalent donor-derived cells. In this regard, the presence of relatively high and adequate endogenous erythropoietin levels reported after RIC-allo-SCT suggests that rHuEPO might exert its stimulatory effect early after allo-SCT.26 This is in accordance with the quicker Hb recovery we previously described after RIC allo-SCT as compared to myeloablative, standard allo-SCT. However, one could argue that the detection of adequate levels of endogenous erythropoietin cannot justify the use of rHuEPO in this setting.26 The latter may be partially true, but we can also hypothesize that the maintenance of erythropoietic progenitor cells early after allo-SCT can be an attractive situation arising from post-graft rHuEPO stimulation. One can also hypothesize that the peripheral blood stem cell source might also contribute to the greater efficiency of EPO in the PBSCT settings, since it has already been shown that PB-derived stem cells contain a larger amount of EPO-susceptible progenitor cells as compared to bone marrow-derived stem cells usually described in the older trials.27
In this study, we initially used rHuEPO thrice a week. However, when darbopoetin became available in France we switched to this product in order to administer a weekly, more practical treatment. Although the global experience with darbopoetin is relatively short, use of long-term acting rHuEPO derivatives every other or 3rd week is likely to be very attractive, being fully compatible with the ambulatory patient management that is increasingly used in the RIC allo-SCT setting.
From a statistical point of view, our analysis included a relatively small number of patients. Only a fully powered and randomized study would allow definitive conclusions to be drawn. However, results from this pilot study might pave the way for such a randomized large-scale study. Moreover, both patient groups were similar in terms of major factors influencing Hb recovery. They all received PBPC transplantation, a similar dose of CD34+ cells and the same dose of ATG. The proportions of RBCT dependent patients, and patients with a low initial Hb level were also similar, allowing a certain level of confidence in the interpretation of the results.
The use of rHuEPO was clearly associated with quicker Hb kinetics, with 80% of the patients achieving a level above 12 g/dl in the second month post-allo-SCT, in sharp contrast to patients not treated with rHuEPO. This effect started as soon as day 20, probably allowing patients to experience less fatigue.28 Evaluation of QOL was not part of this pilot study. Nonetheless, the effect on QOL can be expected to be even greater in patients presenting with a low Hb level prior to transplantation. Surprisingly, more rapid Hb recovery after early administration of rHuEPO was associated only with a trend towards decrease of RBCT requirements (P=0.07). This apparent discrepancy is probably related to two parameters: (i) the relatively low patient number in this study cannot provide sufficient statistical power to detect such a difference; (ii) the group of patients starting transplantation with the higher Hb level had already required few, if any, RBCT, contributing to the absence of difference. Finally, one should keep in mind that RBCT requirement is only a surrogate and incomplete marker of patient anemia and QOL.
In conclusion, despite its obvious limitations, this pilot study strongly suggests that the early use of rHuEPO can hasten Hb recovery and potentially lower transfusion requirements after ATG-based RIC allo-SCT. Better results can even be expected in situations combining both a high Hb level prior to allo-SCT transplant and post transplant rHuEPO treatment, giving a rationale for the use of rHuEPO in the weeks preceding allo-SCT. In such studies, prospective assessment of QOL and economic evaluation would obviously be major determinants for the ultimate outcome.
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We thank Dr G Ivanov (University of Cardiff, Cardiff, UK) for critical reading of the manuscript, the nursing staff for providing excellent care for our patients and thank the following physicians at the Institute Paoli-Calmettes for their important study contributions and dedicated patient care: AC Braud, A Charbonnier, JM Schiano de Collela, GL Damaj, JA Gastaut, AM Stoppa and F Viret.
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Ivanov, V., Faucher, C., Mohty, M. et al. Early administration of recombinant erythropoietin improves hemoglobin recovery after reduced intensity conditioned allogeneic stem cell transplantation. Bone Marrow Transplant 36, 901–906 (2005). https://doi.org/10.1038/sj.bmt.1705152
- allogeneic stem cell transplantation
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