Subcutaneous erythropoietin for treatment of ...

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1992 80: 841-843

Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders [letter; comment] M Mittelman, S Floru and M Djaldetti

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CORRESPONDENCE

SUBCUTANEOUS ERYTHROPOIETIN FOR TREATMENT OF REFRACTORY ANEMIA IN HEMATOLOGIC DISORDERS Table 1.

To the Editor: ~~

In a recent issue of Blood, Cazzola et all report their experience with subcutaneous administration of recombinant human erythropoietin (rHuEPO) to patients with refractory anemia in hematologic disorders. Seven of eight patients with lymphoproliferative disorders achieved a complete response, while nine patients with hematopoietic stem cell disorders experienced minor and transient response, if any at all. The only response predictive factor was low serum erythropoietin (EPO) level, or as the investigatorsprefer, an observed/predicted (O/P) ratio of EPO that was below the reference range. These results and the correlation between the pretreatment serum EPO levels and the potential response to rHuEPO have been recently confirmed by others as well as by our experience. Rose et aI2have recestly treated 100 patients with myelodysplastic syndromes (MDS), whose serum EPO level was below 500 mU/ mL, with 150 to 300 U/kg subcutaneously, three times per week. Nineteen patients (19%) had at least a 50% reduction in red blood cell transfusions while being administered rHuEPO. The only predictor for good response was pretreatment serum EPO level, which was found to be in the range of 4 to 260 mU/mL (median 30) among the responders. Of note, during treatment, eight patients developed progressive splenomegaly, which was reversible in half of the cases on discontinuation of rHuEPO, consistent with Cazzola et al'sl report. Stone et a13 treated 16 MDS patients with rHuEP0 in doses ranging from 100 to 200 U/kg. Ten patients (63%) responded with 50% reduced transfusion requirements, and an increase in hemoglobin level or reticulocyte count. The mean serum EPO levels in the four patients whose hemoglobin level improved was lower than that of all other patients (31 v 190 mU/mL). In a recent pilot study we treated seven patients with hematologic stem cell disorders (Table 1). rHuEPO was administered subcutaneously in a dose of 200 to 300 Ulkg three times weekly for 2 months. Only one patient (patient 7) responded with increasing hemoglobin level requiring no transfusions. Analysis of serum

Pretreatment Patient

1. 2. 3. 4. 5. 6. 7.

ZS GA DG

JL BB DA

SB

Posttreatment

Age/Sex

Dg

Hb

BT

EPO

Hb

BT

Response

82/M 79/M 79/F 75/F 74/F 78/M 73/F

ISA ISA ISA ISA ISA ISA MF

8.0 7.8 7.9 8.1 8.3 8.1 8.0

2.5 2 2 2 3 2 2.5

300 ND 550 480 660 600 75

8.2 7.9 8.0 7.7 8.0 7.7 11

2.5 2 2.5 2 2.5 2 0

-

+

Abbreviations: Dg, diagnosis; ISA, idiopathic sideroblastic anemia; MF, idiopathic myelofibrosis; Hb, hemoglobin level (g/dL); BT, blood (RBC) transfusion requirements (unitdmonth); Epo-serumerythropoietin levels (mU/mL); ND, no data.

pretreatment EPO level, which was performed in six of the patients, showed values between 300 and 660 mU/mL in the five nonresponders. It is conceivable that the good response obtained in patient 7 could be related to the low (75 mU/mL) serum EPO level. Of note, this patient had also mild stable renal failure (serum creatinine level 2 mg/dL). These data together suggest that a prudent approach in patients with hematopoietic stem cell disorders would be to analyze their serum EPO levels. If this level is found to be low ( < 100 U/mL), a therapeutic trial with rHuEPO is warranted and likely to be successful.On the other hand, if the level is greater than 200 U/mL then such an attempt should be reconsidered. MOSHE MI'ITELMAN SHARON FLORU MEIR DJALDETTI Department of Medicine B and The Hematology Service Hasharon Medical Center Sackler School of Medicine Tel-Aviv University Petah-Tikva, Israel

REFERENCES 1. Cazzola M, Ponchio L, Beguin

Y,Rosti V, Bergamaschi G,

Liberato NL, Fregoni V, Nalli G, Barosi G, Ascari E Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase 1/11 clinical trial. Blood 79:29, 1992 2. Rose EH, Rudmick SA, Abels RI, Lessin LS,Hoagland HC, Prchal J, Schuster M, Johnson RW: Efficacy and safety of recombi-

nant human erythropoietin (r-HuEPO) in anemic patients with myelodysplasticsyndromes. Leuk Res 1913,1991 (suppl) 3. Stone R, Demetri G, Bernstein S, Facklam D, Arthur K, Aster J, Kufe D: A phase 1-11trial of erythropoietin [Epoetin-beta] (EPO) in patients with myelodysplastic syndromes (MDS). Leuk Res 15:13,1991 (suppl)

RESPONSE We appreciate the letter and comments of Mittelman et a1.l In this reply, we comment on the laboratory approach to the patient treated with recombinant human erythropoietin (rHuEPO), and the clinical results obtained in patients with myelodysplastic syndromes. Because clinical uses of rHuEPO are expanding and costs are high, it is necessary to define a rationale approach by

Blood, Vol80, No 3 (August 1). 1992: pp 841-846

identifying predictors and indicators of response. Strong candidates for these roles appear to be serum EPO, serum transferrin receptor (TW), reticulocyte count, and percentage of hypochromic red blood cells (RBCs). All of these parameters also have the advantage of being simple. The available evidence indicates that, as far as the EPO-

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generating apparatus in the kidney is efficient, serum levels increase exponentially as the hematocrit decreases.2 Consequently, serum EPO must be evaluated in relation to the degree of anemia. By defining the reference range, appropriateness of EPO response to anemia can be evaluated graphically or through the observed/ predicted log (EPO) ratio (O/P ratio).2 There is no doubt that blunted EPO production is the cause of anemia in various disorders, and that this constitutes a rationale basis for the treatment of these conditions with rHuEPO? In our phase 1/11 clinical trial and in subsequent studies, a low O / P ratio was found to be a good predictor of r e ~ p o n s eIt . ~is encouraging to hear that this also was the case in Mittelman et al's experience. The effects of rHuEPO on the erythroid marrow can be monitored by measuring the circulating T W and reticulocyte count. The soluble TfR assay is a very simple, noninvasive method of quantitating total erythroid marrow activity in a clinical setting.2 This measurement is ideal for the serial assessments needed for monitoring the erythropoietic response to rHuEPO. Furthermore, circulating T W appears to be a reliable predictor of response: in our study in nonrenal anemia,3 responders showed a consistent increase in serum transferrin receptor (> 40%) after 2 weeks of treatment, whereas most nonresponders did not show any significant change in serum TW. Exceptions to this rule did exist, eg, patients in whom rHuEPO stimulated ineffective erythropoiesis: the combined use of serum T W and reticulocyte count allows clinicians to recognize these exceptions.2 Reticulocyte count can be obtained conventionally but can also be determined by using flow cytometry, and by this way different populations of reticulocytes can be recognized. High fluorescence ratio (HFR) reticulocytes represent newly released RBCs (effective erythropoiesis), and in a study by Vannucchi et a14they appear to be particularly useful in evaluating the effect of rHuEPO. A management issue frequently associated with rHuEPO treatment is functional iron deficiency. This condition is characterized by reduced serum iron (