Mini-Review Erythropoietin in Stem Cell Transplantation

CB Miller1 and HM Lazarus2

1Johns Hopkins Oncology Center, Baltimore, MD; and 2Department of Medicine, Ireland Cancer Centre, University Hospitals of Cleveland, Cleveland, OH, USA

Summary: in patients after autologous stem cell transplant, but markedly depressed at the time of marrow recovery in allogeneic Anemia is universal after allogeneic and autologous transplant recipients. They also found that erythropoietin stem cell transplantation, with both increased red cell response to anemia was lower in patients who had acute utilization and decreased production playing a role. GVHD, while chronic GVHD did not appear to affect This anemia sometimes is associated with a relative erythropoietin response.1,2 Cytomegalovirus infection also erythropoietin deficiency. In allogeneic stem cell trans- was an independent predictor of an impaired erythropoietin plantation, randomized trials have demonstrated response to anemia. Nephrotoxicity was more common in improved erythropoiesis and a decrease in red cell the allogeneic stem cell transplant patients compared to the transfusions in recombinant human erythropoietin autologous stem cell transplant patients. There was not a (rHuEPO)-treated patients. Studies of rHuEPO in significant correlation, however, between renal function and patients undergoing autologous stem cell transplants, impairment in the erythropoietin response to anemia. Abedi however, have not shown a benefit. The role of rHuEPO et al3 found that erythropoietin blood concentrations were in stem cell mobilization and treatment of delayed lower in patients who had received cyclosporine as prophy- erythropoiesis has yet to be defined and further studies laxis for GVHD compared to patients receiving T cell- are needed. Bone Marrow Transplantation (2001) 27, depleted transplants. However, they did not find a corre- 1011–1016. lation between acute GVHD and a decreased erythropoietin Keywords: anemia; stem cell transplantation; erythro- level. While patients with nephrotoxicity had lower erythropoietin poietin blood concentration than patients without nephrotoxicity, the decreased erythropoietin levels in the cyclosporin A-treated patients was seen in patients with and without renal impairment. On the other hand, investigators at Johns Hopkins found that for any given degree of anemia, erythropoietin concentrations were depressed in both Anemia in the course of hematopoietic stem cell allogeneic and autologous stem cell transplant patients transplantation compared to iron deficient controls (Figure 1).4 Anemia remains a universal problem after both autologous and allogeneic stem cell transplantation and red blood cell Table 1 Etiology of anemia during hematopoietic stem cell transplantation (RBC) transfusions usually are necessary in the post-transplant period. The anemia is multi-factorial and increased Increased RBC utilization/shortened RBC survival utilization, bleeding and inadequate production of RBCs fever play important roles for this condition (Table 1). hemolysis, eg ABO or Rh incompatibility,27,28 microangiopathy after cyclosporine,29 hemolytic-uremic syndrome30 Erythropoiesis and stem cell transplantation hepatic veno-occlusive disease31 The prolonged reticulocytopenia and resultant large trans- Hemorrhage thrombocytopenia, especially when protracted, eg chemically-purged fusion requirement after stem cell transplantation is, in part, autografts, immune mechanisms,32–34 or hepatic veno-occlusive related to a relative erythropoietin deficiency at the time of disease31 marrow recovery. A number of studies have demonstrated organ injury, eg hemorrhagic cystitis,35–39 gastritis an impaired erythropoietin response after stem cell trans- infection, eg adenovirus,40 BK virus38 41,42 plant. Shapira and co-workers1 and Beguin and colleagues2 GVHD of gastro-intestinal tract both found that the erythropoietin response was appropriate Inadequate production RBC impaired/inadequate erythropoietin response, drugs causing bone marrow suppression (ganciclovir, trimethoprim- Correspondence: Dr CB Miller, Oncology Center, Johns Hopkins Bunting- sulfamethoxazole) Blaustein Cancer Research Bldg, 1650 Orleans St 2M88, Baltimore, infection causing bone marrow suppression (cytomegalovirus, HHV6) MD21231–1000, USA Erythropoietin in stem cell transplantation CB Miller and HM Lazarus 1012 1000 Clinical studies of the use of rHuEPO after stem cell transplantation

Allogeneic stem cell transplantation rHuEPO has been demonstrated to be well-tolerated and effective in the allogeneic stem cell transplant setting 9–11 11 100 (Table 2). Steegman and co-workers randomly assigned patients to receive daily rHuEPO (100 units per kg days 0 to 7, then 150 units per kg days 7 to 30) or placebo. Thirteen subjects received rHuEPO and 11 patients received placebo for a period of more than 14 days and were considered evaluable. In the rHuEPO-treated group, times to reach reticulocyte counts of 1%, 5% and Log erythropoietin level (mU/ml) 20% were shorter and bone marrow erythroid cellularity 10 was increased. Importantly, RBC transfusion requirement was decreased from a mean of 12 units to 4 units (P Ͻ 5 0.05) during the first 30 days after transplant. Additionally, 8 9 10 11 time to platelet transfusion (Ͼ25 000/␮l) independence (19 Hemoglobin (g/dl) days vs 31 days, P Ͻ 0.05) and a decrease in platelet units transfused (36 vs 138, P Ͻ 0.05) were significantly better Figure 1 Erythropoietin:hemoglobin relationship week 4 after stem cell b in the rHuEPO-treated patients. transplant ( ) compared to iron deficiency controls (mean plus standard 9 deviation depicted by shaded area). Reproduced with permission. Klaesson and colleagues prospectively compared rHuEPO (200 units per kg per day for 4 weeks followed by twice weekly for 4 weeks) or placebo in 50 hematologic malignancy patients undergoing stem cell transplant. rHuEPO dose was decreased to 100 units per kilogram when hemoglobin exceeded 10 g/dl and was discontinued The etiology for the inadequate erythropoietin response when hemoglobin was greater than 12 g/dl. Five patients to anemia is unknown but may reflect toxic effects exerted (three rHuEPO and two controls) died before day 28 and upon erythropoietin-producing cells by drugs or infectious were not considered evaluable. RBCs were transfused to agents, or may be a result of direct suppression of erythro- maintain a hemoglobin of greater than 7.0 g/dl and platelets poietin production by cytokines. Tumor necrosis factor con- were transfused to maintain a count of greater than centrations, elevated after stem cell transplant,5 can sup- 30 000/mm3. At the 2 month evaluation, mean hemoglobin press erythropoietin production in Hep3B cell lines.6 Both in the rHuEPO-treated patients was higher compared to pla- cyclosporin A7 as well as amphotericin B8 can suppress cebo-treated patients (10.0 g/dl vs 9.0 g/dl, P = 0.02) and erythropoietin production in model systems. Regardless of RBC transfusion requirement was decreased 50% from 10 the etiology, the inadequate erythropoietin response to ane- units to 5 units. mia after stem cell transplantation suggests that exogenous Biggs and co-workers10 assigned 91 patients receiving recombinant human erythropoietin (rHuEPO) treatment matched-related allogeneic stem cell transplants for leuke- may be beneficial. mia or aplastic anemia to either placebo or rHuEPO (300

Table 2 Use of exogenous recombinant human erythropoietin in allogeneic transplant recipients

Author/Ref. Steegman et al11 Klaesson et al9 Biggs et al10 Link et al12

Type of trial randomized, placebo-control randomized, placebo-control randomized, placebo-control randomized, placebo-control Total No. patients entered 28 50 91 215 No. evaluable patients 13/11 22/23 43/48 106/109 rHuEPO/controls rHuEPO dose/duration 100 U/kg d1–7, 150 U/kg 200 U/kg d1–28, then 2 300 U/kg 3×/week d1–42 150 U/kg by continuous i.v. d7–30 ×/week d29–56 infusion up to d42 Mean or median No. RBC units 4/12 5.5/10.9 5/6 8.0/8.7 txn: rHuEPO/control P value Ͻ0.05 0.03 NS NS Faster reticulocyte recovery yes yes yes yes Shorter time to RBC txn yes yes yes yes independence

RBC = red blood cell; txn = transfusion; rHuEPO = recombinant human erythropoietin; NS = not signiﬁcant.

Bone Marrow Transplantation Erythropoietin in stem cell transplantation CB Miller and HM Lazarus 1013 units per kg) intravenously three times a week from day 0 reported by Link and associates,12 57 patients received to day 42. Study drug was withheld if the hemoglobin rose rHuEPO (150 units/kg/day) and 57 patients received pla- higher than 12 g/dl but was re-instituted at a 50% lower cebo, given by continuous infusion from the day of stem dose when hemoglobin fell below 12 g/dl. Four patients cell infusion (day 0) until RBC recovery or day 41. Treat- died prior to day 28 and were not evaluable for ment with rHuEPO did not affect the time to RBC trans- engraftment. Median hemoglobin levels and reticulocyte fusion independence, reticulocyte recovery or RBC counts did not differ between the two groups before day utilization during any time period. 14; however, at all other subsequent time points, hemoglo- Based on an increase in erythroid response in myelo- bin and reticulocyte counts were significantly higher in the dysplastic syndrome patients, Vannucchi et al7 studied the rHuEPO-treated group. On the other hand, RBC transfusion effect of combining rHuEPO with G-CSF on erythroid requirement was not improved. This finding may reflect, in recovery after autotransplant. Thirty patients were ran- part, the short follow-up and the time necessary for domized to receive G-CSF (5 ␮g/kg daily) alone (10 rHuEPO response. patients), G-CSF plus rHuEPO (n = 10; 150 units/kg daily) Link et al12 reported a prospective, randomized, placebo- or no additional cytokine (n = 10). The rHuEPO group had controlled, multi-center European study in both autotrans- an improved reticulocyte recovery compared to the G-CSF plant (see below) and allotransplant patients comparing pla- alone and the control groups but no significant effect on cebo vs rHuEPO therapy after transplant. In the allogeneic platelet recovery or RBC transfusion requirement. arm, subjects were given placebo (n = 109) vs rHuEPO (n Chao and colleagues14 also studied a combination of G- = 106), administered as 150 units/kg/day via continuous CSF and rHuEPO vs G-CSF alone in lymphoma autotrans- i.v. infusion from the day after marrow infusion until RBC plant patients. Subjects were randomized to receive independence for 7 days and a hemoglobin greater than 9 rHuEPO (600 units/kg, n = 18 patients) or placebo (n = 17 g/dl or until day 41. Erythroid recovery was significantly patients). Study drug was given thrice weekly i.v. beginning improved with a median time to RBC transfusion indepen- 4 weeks before transplant, on the day after bone marrow dence of 19 days (range 16 to 22) in the rHuEPO group harvest. Study drug was resumed 1 day after marrow compared to 27 days (range 22 to Ͼ42) in the placebo infusion. All patients were given G-CSF (10 ␮g/kg/day) group. Reticulocyte recovery was also significantly starting on day 1. Although rHuEPO therapy was well-tol- enhanced by treatment with rHuEPO. Although there was erated, no differences were observed in any engraftment no difference in the transfusion rate in the first 20 days, in parameter or blood product utilization. the subsequent 3 week period, transfusions were reduced a + mean of 1.4 2.5 units in the rHuEPO group compared to rHuEPO in pediatric stem cell transplants a mean of 2.7 + 4.0 in the placebo group (P = 0.0004). In a multivariate analysis, patients with severe acute GVHD, Locatelli and associates15 compared 20 children treated age greater than 35 years, severe bleeding or major ABO with rHuEPO during allogeneic (n = 10) and mafospham- incompatibility appeared to benefit most from rHuEPO ide-purged (n = 10) autologous stem cell transplants with therapy during this time period. untreated historic controls. rHuEPO was given i.v. at a dose of 75 units/kg/day for 30 days after marrow infusion and Autologous stem cell transplant was well-tolerated in the pediatric population. Erythropoie- tin response was suppressed after allograft, but normal after Table 3 summarizes the data for rHuEPO after autologous autograft. Compared to historic controls, erythroid reconsti- stem cell transplantation. None of the randomized trials tution was enhanced in the allogeneic transplant patients showed any benefit for this drug in this patient population. given rHuEPO. No effect, however, was seen in the treated We did a small study in patients with purged autografts autologous transplant patients. The number of RBC units which failed to show any benefit of rHuEPO in stimulating transfused was reduced in the rHuEPO-treated allogeneic erythropoiesis.13 In the autologous arm of the study transplant patients compared to the historic controls (1.7 Ϯ

Table 3 Use of exogenous recombinant human erythropoietin in autologous transplant recipients

Author/Ref. Miller et al13 Chao et al14 Link et al12

Type of trial randomized; 4-HC purged-marrow; randomized; unpurged grafts; randomized; hematologic hematologic malignancies lymphoma; G-CSF given malignancies Total No. patients entered 50 35 114 No. patients rHuEPO/controls 26/24 18/17 57/57 rHuEPO dose/duration 200 U/kg for d1–28, 3 ×/week 600 U/kg 3×/week from 3 weeks 150 U/kg by continuous i.v. d29–50 before marrow harvest until d30 infusion up to d42 Mean or median No. RBC units txn: 13/15 8/6 7.6/7.2 rHuEPO/control P value NS NS NS Faster reticulocyte recovery no no no Shorter time to RBC txn transfusion no no no independence

RBC = red blood cell; txn = transfusion; rHuEPO = recombinant human erythropoietin; NS = not signiﬁcant

Bone Marrow Transplantation Erythropoietin in stem cell transplantation CB Miller and HM Lazarus 1014 1.3 units vs 5.0 Ϯ 3.0 units, P Ͻ 0.05). Platelet transfusions with a median rHuEPO dose of 125 units per kg a week. also were decreased (4.0 Ϯ 2.3 units vs 8.4 + 6.8 units, Quality of life was not assessed. P Ͻ 0.05). No effects were observed on RBC or platelet transfusions in the patients who underwent autograft. Use HuEPO treatment in bone marrow donors of rHuEPO would not have reduced the overall cost of transfusion therapy vs transfusions plus drug in either auto- The effect of rHuEPO on the bone marrow donor homolo- logous or allogeneic transplant recipients. This group sub- gous RBC requirement was evaluated in two studies. Mitus sequently reported a pilot trial combining G-CSF and et al19 treated 11 donors with rHuEPO at a dose of 300 rHuEPO in 15 children undergoing allogeneic transplant16 units per kg subcutaneously 5 times a week starting 3 and compared the transfusion experience to untreated his- weeks before bone marrow harvest and continuing until 2 toric controls and patients who received rHuEPO alone. weeks after harvest (total 25 doses). One unit of RBCs was Those patients who received the combined therapy exhib- collected on the first day of study and then twice weekly ited a decrease in RBC transfusions (1.1 Ϯ 0.7 units) com- for the duration of the study, provided that the hematocrit pared to the rHuEPO alone group (2.7 Ϯ 1.2 units) and the was greater than 33%. Transplant recipients were given historic controls (4.2 Ϯ 2.3 units, P Ͻ 0.001). rHuEPO (200 units per kg) daily for 28 days starting 1 day after stem cell infusion. All 11 donors fulfilled phlebotomy rHuEPO therapy in delayed erythropoiesis requirements and donated a median of 6 (range 4–11) units. After marrow harvest five of the 11 donors used some of Symptomatic chronic anemia and the cost and incon- their stored autologous units but no homologous blood was venience of RBC transfusions may be a significant impedi- transfused to donors. Five of the 11 recipients received only ment in patients recovering from the effects of a stem cell donor-derived RBC transfusions; however, total RBC trans- transplant. Miller and co-workers13 reported a pilot trial fusion requirement during the 28 day study period did not using rHuEPO therapy in subjects who displayed evidence differ between the rHuEPO-treated patients and matched of delayed erythropoiesis, defined as hemoglobin less than historic controls (8.3 vs 8.1 units, respectively). 9 g/dl more than 21 days after stem cell transplantation. York and associates20 treated two children and eight Patients were treated with rHuEPO (150 units per kg) three adult donors with rHuEPO (100 units per kg) daily prior times a week subcutaneously for three weeks. If hemoglo- to bone marrow harvest. Eligibility included those who bin increased by 1 g/dl over the 3 weeks without trans- weighed less than 30 kg and did not have an autologous fusion, rHuEPO was withheld, while drug was re-started if blood unit stored prior to harvest, if they were anemic hemoglobin fell during the subsequent 3 weeks. Dose was (hematocrit Ͻ37%) and had only one unit stored, or if a doubled for an additional 3 to 6 weeks if the hemoglobin high blood loss was expected during the harvest procedure. failed to increase by 1 g/dl during the initial 3 weeks of After harvest subjects were treated with rHuEPO 150 units therapy. Twenty patients were entered (n = 13 allogeneic, per kg three times a week for 2 weeks, or until the hemato- n = 7 autologous transplants) at a median of day 44 after crit reached 40%. Each rHuEPO-treated donor was com- stem cell transplant. Two patients withdrew early (one early pared to two computer-generated, matched controls. Seven death due to CMV pneumonia, one patient request). Eleven of 10 subjects completed the prescribed course of rHuEPO. of the 18 remaining patients received only the 150 units No attempt was made to collect RBC units for transfusion per kg dose level, and 15 of 18 patients (83%) responded to the intended recipient. At the time of marrow donation, by a hemoglobin increase of at least 1 g/dl, or a decrease the hematocrit increased 18% above the on-study value in in transfusion requirement. Nine patients had a complete donors who were treated with rHuEPO compared to a 6% response, defined as a hemoglobin increase of greater than decrease in the historic controls (P = 0.0001). Furthermore, 2 g/dl, or a 100% decrease in transfusion requirement. Bone after harvest the hematocrit decreased 26% in the historic marrow cellularity also increased from 4% to 32% in the controls compared to only a 4% decrease in the rHuEPO- nine patients who were evaluated. Response to rHuEPO treated individuals. While the rHuEPO-treated donors did correlated with baseline serum erythropoietin concen- not become anemic and there was no use of homologous tration; a complete response was achieved in seven of eight blood in this high risk group, none of the adult donors patients who had a baseline erythropoietin level of less than required homologous blood. In the children, however, 50 mU/ml whereas only two of nine subjects responded neither of the rHuEPO-treated donors required blood who had a baseline level of greater than 50 mU/ml. whereas two of the four controls did. In another pilot trial involving nine transplant recipients 17 more than 50 days after allograft, six patients treated with rHuEPO in stem cell mobilization either 3000 rHuEPO units daily or 12 000 units three times a week responded with at least a 2 g/dl increase in hemo- In vitro and in vivo studies suggested that rHuEPO may globin. All three patients who failed to respond had have a role in expansion of the progenitor pool, with or severe GVHD. without other growth factors. In animal models Kessinger In a recent small trial conducted in patients with anemia et al21 demonstrated that use of EPO alone had a significant (median hemoglobin 8.4 g/dl) 35 days after allogeneic bone stimulatory role on collection of stem cells. Olivieri and marrow transplant, a dose of 500 units per kg a week was colleagues22 evaluated the effect of G-CSF (5 ␮g/kg/day; effective with nine of the 10 patients responding with a 3.6 n = 18) or G-CSF plus rHuEPO (50 units/kg/day, n = 16 to 6.1 g/dl increase in hemoglobin. A hemoglobin level of patients) after stem cell mobilization chemotherapy. The 13 g/dl was reached at a median of 9 weeks and maintained patients given rHuEPO had significantly higher erythroid

Bone Marrow Transplantation Erythropoietin in stem cell transplantation CB Miller and HM Lazarus 1015 (BFU-E) and myeloid (CFU-GM) progenitor cell content benefit for use of rHuEPO early after autograft, especially if in the apheresis product as well as significantly higher the transplant recipient was given bone marrow chemically CD34+ cell content. Kessinger et al21 reported the results purged in vitro. To date, there have been no published ran- of three sequential stem cell mobilization trials assessing domized trials which evaluate the effect of rHuEPO on the effect of rHuEPO. Eleven patients underwent mobiliz- either autologous or allogeneic peripheral blood stem cell ation using rHuEPO alone (300 units/kg/day), 11 received transplant. It is likely that studies addressing new formu- rHuEPO plus GM-CSF (250 ␮g/m2/day) and in 51 only lations of rHuEPO, such as the novel erythropoiesis-stimul- GM-CSF was administered. They found that the combi- ating protein, darbepoietin (NESP) will be initiated. This nation hematopoietic growth factor regimen required a product, a hyperglycosylated analogue of rHuEPO with larger apheresis volume to achieve adequate progenitor resulting greater metabolic stability in vivo, has a longer cells compared to both of the single growth factor groups. terminal half-life and is likely to need less frequent admin- All three types of apheresis product provided similar istration.25,26 We then can begin to address important ques- engraftment times, except that the rHuEPO-alone group had tions including the role of this drug in delayed erythro- a longer time to neutrophil engraftment. poiesis and its use after peripheral blood stem cell von Lintig et al23 published a randomized trial comparing transplantation. rHuEPO (150 units/kg/day) plus G-SCF (5 ␮g/kg/day) vs G-CSF alone after chemotherapy mobilization for breast References cancer autotransplant patients. Total mononuclear cells, + CD34 cells, or hematopoietic progenitors collected did not 1 Schapira L, Antin JH, Ransil BJ et al. Serum erythropoietin differ, nor were any differences in hematopoietic recovery levels in patients receiving intensive chemotherapy and radio- after infusion noted. A non-randomized study evaluated the therapy. Blood 1990; 76: 2354–2359. effect of adding rHuEPO to G-CSF (n = 10) compared to 2 Beguin Y, Clemons GK, Oris R, Fillet G. Circulating erythro- G-CSF alone (n = 10) in healthy allogeneic donors poietin levels after bone marrow transplantations: inappropri- undergoing stem cell mobilization.24 Ten ABO-matched ate response to anemia in allogeneic transplants. Blood 1991; donors were treated with rHuEPO at 600 units/kg day 77: 868–873. weekly for 4 weeks before stem cell collection, then bi- 3 Abedi MR, Backman L, Bostrom L et al. Markedly increased ␮ serum erythropoietin levels following conditioning for allo- weekly for 3 weeks thereafter. G-CSF (10 g/kg/day) was geneic bone marrow transplantation. Bone Marrow Transplant given to both donor groups. The recipients of the 1990; 6: 121–126. rHuEPO/G-CSF-mobilized cells also received rHuEPO 4 Miller CB, Jones RJ, Zahurak ML et al. Impaired erythropoie- after re-infusion as well as RBC transfusions collected from tin response to anemia after bone marrow transplantation. the donor. Use of rHuEPO resulted in an increase in num- Blood 1992; 10: 2677–2682. ber of BFU-E mobilized but had no effect on CD34-posi- 5 Holler E, Kolb HJ, Moeller A et al. Increased serum levels tive cells in the apheresis product. After re-infusion, time of tumor necrosis factor precede major complications of bone to reticulocyte recovery and RBC transfusion independence marrow transplantation. Blood 1990; 75: 1011–1019. was significantly shorter in the rHuEPO-treated donor 6 Welch R, James R, Wilkinson P et al. Recombinant human group. The two donor products did not differ with respect erythropoietin and platinum based chemotherapy in metastatic ovarian carcinoma. Am Soc Clin Oncol 1993; 12: 254 (Abstr.). to time to platelet or WBC recovery in the recipient. 7 Vannucchi AM, Grossi A, Bosi A et al. Impaired erythropoietin production in mice treated with cyclosporin A. Blood 1991; 78: 1615–1618. Conclusion 8 Lin AC, Goldwasser E, Bernard EM, Chapman SW. Ampho- tericin B blunts erythropoietin response to anemia. J Infect Dis Both allogeneic and autologous hematopoietic stem cell 1990; 161: 348–351. transplantation are complicated by a relative erythropoietin 9 Klaesson S, Ringden O, Ljungman P et al. Reduced blood deficiency for the degree of anemia. rHuEPO therapy after transfusions requirements after allogeneic bone marrow trans- stem cell transplantation is safe and well-tolerated. Four plantation: results of a randomised, double-blind study with randomized studies show a decrease in transfusion require- high-dose erythropoietin. Bone Marrow Transplant 1994; 13: 397–402. ment when rHuEPO is given early after allogeneic stem 10 Biggs JC, Downe K, Worthington B et al. A prospective dou- cell transplant although the magnitude of this benefit was ble blind trial to evaluate the effect of human recombinant small. In view of the multiple co-morbid factors which erythropoietin (rHUEPO in patients undergoing matched allo- develop in the course of a transplant, it has been difficult geneic bone marrow transplantation (ALLO BMT). Exp Hem- to show a significant improvement in cost and quality of atol 1993; 21: 1172 (Abstr.). life as a result of rHuEPO therapy when given early in the 11 Steegman J, Lopez J, Otero M et al. Erythropoietin treatment treatment course. The use of rHuEPO therapy in the chronic in allogeneic BMT accelerates erythroid reconstitution: results anemia after transplant deserves further investigation, of a prospective controlled randomized trial. Bone Marrow especially in those individuals in whom blood erythropoie- Transplant 1992; 10: 541–546. tin concentration is reduced. Use of this agent can not only 12 Link H, Boogaerts M, Fauser A et al. A controlled trial of recombinant human erythropoietin after bone marrow trans- result in avoidance of transfusions, but may also play a plantation. Blood 1994; 84: 3327 (Abstr.). more important role by enhancing quality of life. rHuEPO 13 Miller CB, Mills SR, Barnett AG et al. A randomized trial also may be useful in children who generally are unable of recombinant human erythropoietin (rHuEPO) after purged to deposit autologous blood units in blood banks before autologous bone marrow transplant (BMT). Blood 1993; 82: transplant. On the other hand, the data do not indicate a 285a (Abstr.).

Bone Marrow Transplantation Erythropoietin in stem cell transplantation CB Miller and HM Lazarus 1016 14 Chao N, Schriber JR, Long GD et al. A randomized study of patible bone marrow transplantation: removal of red blood erythropoietin and granulocyte colony-stimulating factor (G- cells from donor marrow avoiding recipient antibody CSF) versus placebo and G-CSF for patients with Hodgkin’s depletion. Lancet 1982; ii: 1061–1064. and non-Hodgkin’s lymphoma undergoing autologous bone 28 Braine HG, Sensenbrenner LL, Wright SK. Bone marrow marrow transplantation. Blood 1994; 83: 2823 (Abstr.). transplantation with major ABO blood group incompatibility 15 Locatelli F, Zecca M, Pedrazzoli P et al. Use of recombinant using erythrocyte depletion of marrow prior to infusion. Blood human erythropoietin after bone marrow transplantation in 1982; 60: 420–425. pediatric patients with acute leukemia: effect on erythroid 29 Holler E, Kolb HJ, Mraz HW et al. Microangiopathy in repopulation in autologous vs allogeneic transplants. Bone patients on cyclosporine prophylaxis who developed acute Marrow Transplant 1994; 13: 403–410. graft-versus host disease after HLA-identical bone marrow 16 Locatelli F, Zecca M, Bonetti F et al. Combined adminis- transplantation. Blood 1989; 73: 2018–2024. tration of erythropoietin and granulocyte colony-stimulating 30 Rabinowe SN, Soiffer RJ, Tarbell NJ et al. Hemolytic-uremic factor (G-CSF) to children after allogeneic bone marrow trans- syndrome following bone marrow transplantation in adults for plantation (BMT) accelerates trilineage marrow reconstitution. hematologic malignancies. Blood 1991; 77: 1837–1844. Blood 1993; 82: 284a (Abstr.). 31 Jones RJ, Lee KSK, Beschorner WE et al. Venoocclusive dis- 17 Fujimori Y, Kanamaru A, Saheki K et al. Recombinant human ease of the liver following bone marrow transplantation. erythropoietin for late-onset anemia after allogeneic bone mar- Transplantation 1987; 44: 778–783. row transplantation. Int J Radiat Oncol Biol Phys 1998; 67: 32 Banaji M, Bearman S, Buckner CD. The effects of splen- 131 (Abstr.). ectomy on engraftment and platelet transfusion requirements 18 Beguin Y, McDonald GB. Recombinant human erythropoietin in patients with CML undergoing marrow transplantation. Am (rHuEPO) therapy after allogeneic hematopoietic stem cell J Hematol 1986; 22: 275–283. transplantation. Blood 2000; 96: 395a (Abstr.). 33 First LR, Smith BR, Lipton J. Isolated thrombycytopenia after 19 Mitus J, Antin J, Rutherford J et al. Use of recombinant allogeneic bone marrow transplantation: existence of transient human erythropoietin in allogeneic bone marrow transplant and chronic thrombocytopenic syndrome. Blood 1985; 65: donor/recipient pairs. Blood 1994; 83: 1952–1957. 368–374. 20 York A, Clift R, Sanders J, Buckner C. Recombinant human 34 Anasetti C, Rybka W, Sullivan KM et al. Graft-versus-host erythropoietin (rh-Epo) administration to normal marrow disease is associated with autoimmune-like thrombocytopenia. donors. Bone Marrow Transplant 1992; 10: 415–417. Blood 1989; 73: 1054–1058. 21 Kessinger A, Sharp G. Mobilization of hematopoietic progeni- 35 Levine LA, Richie JP. Urological complications of cyclophos- tor cells with epoetin alfa. Semin Hematol 2001; 33 (Suppl. phamide. J Urol 1990; 141: 1063–1069. 10) (Abstr.). 36 Stillwell TJ, Benson RC. Cyclophosphamide-induced 22 Olivieri A, Ofﬁdani M, Cantori I et al. Addition of erythropo- hemorrhagic cystitis. Cancer 1988; 61: 451–457. ietin to granulocyte colony-stimulating factor after priming 37 Droller MJ, Saral R, Santos G. Prevention of cyclophospham- chemotherapy enhances hemopoietic progenitor mobilization. ide-induced hemorrhagic cystitis. Urology 1982; 20: 256–268. Bone Marrow Transplant 1995; 16: 765–770. 38 Arthur RR, Keerti VS, Baust SJ et al. Association of BK viru- 23 von Lintig F, Waller CF, Musahl V et al. Mobilization of ria with hemorrhagic cystitis in recipients of bone marrow peripheral blood progenitor cells in patients with breast can- transplants. New Engl J Med 1986; 315: 230–234. cer: a prospective randomized trial comparing rhG-CSF vs. 39 Brugieres L, Hartmann O, Travagli JP et al. Hemorrhagic cys- rhG-CSF plus rh erythropoietin (EPO) after VIC-E chemo- titis following high-dose chemotherapy and bone marrow therapy. Blood 1996; 88 (Suppl. 1): 408a (Abstr.). transplantation in children with malignancies: incidence, clini- 24 Miller CB, Dempsey H, Weiner RS et al. Recombinant human cal course and outcome. J Clin Oncol 1989; 7: 194–199. erythropoietin (r-HUEPO) does not promote ‘stem-cell steal’ 40 Ambinder RF, Burns W, Forman M et al. Hemorrhagic cystitis following autologous bone marrow transplant. Blood 1993; associated with adenovirus infection in bone marrow trans- 82: 638a (Abstr.). plantation. Arch Intern Med 1986; 146: 1400–1401. 25 Macdougall IC. Novel erythropoiesis stimulating protein. 41 Holland HK, Wingard JR, Saral R. Herpesvirus and enteric Semin Nephrol 2000; 20: 375–381. viral infections in bone marrow transplantation clinical presen- 26 Macdougall IC, Gray SJ, Elston O et al. Pharmacokinetics of tations, pathogenesis, and therapeutic strategies. Cancer Invest novel erythropoiesis stimulating protein compared with epoe- 1990; 8: 507–519. tin alfa in dialysis patients. J Am Soc Nephrol 1999; 10: 42 McDonald GB, Shulman HM, Sullivan KM, Spencer GD. 2392–2395. Intestinal and hepatic complications of human bone marrow 27 Blacklock HA, Prentice HG, Evans JPM et al. ABO-incom- transplantation. Part I. Gastroenterology 1986; 90: 460–477.

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