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Scand J Haematol (1978) 21, 323-332 Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States? MICHEL RENOUX,' JEAN-FRAN~IS BERNARD,' MARTINE TORRES,* & PIERRE BOIVIN' NICOLE SCHLEGEL,3 M I C H ~ L E AIVL~R,~ MANUEL LOPEZ4 1 Service dH6matologie clinique et Unit6 de Recherche dEnzymologie des cellules sanguines (INSERM: U 160 - CNRS ERA 573), Hopital Beaujon, Clichy, 2 Laboratoire central d'H6matologie-lmmunologie, Hopital Bichat, Paris, 3 Service central d'H6matologie-lmmunologie, Hopital Beaujon, Clichy and 4 Service dlmmunologie du CNTS - Dipartement St Antoine (INSERN: U 76), Paris, France Increased incidence of acute leukaemia (AL) following exposure to ionizing radiation is well documented. AL has also been reported with increased frequency after chemo- therapy for nonmalignant diseases. The effect of chemotherapy and/or radiotherapy on the following erythrocyte parameters: pyruvate-kinase (PK) activity, phospho- fructo-kinase (PFK) activity, HbF level, red cell antigens production and bone mar- row sideroblasts, has been studied in 31 patients with myelomatosis and in 33 patients with nonhaematological malignancies. We have demonstrated the appearance after chemotherapy or radiotherapy of some abnormalities usually associated with leukaemia or preleukaemic states. In patients treated for myelomatosis, a PK deficiency has been detected in 58 % of the cases, an increased HbF level in 47 %, a modification of blood groups antigens in 68 % and abnormal sideroblasts in 30 %. No PFK deficiency was found. In patients treated for solid tumors, a PK deficiency in 50 % of the cases, a PFK deficiency in 20 %, an increased HbF level in 10 %, a modification of blood group antigens in 40 % has been detected. Chemotherapy administered over a period of 3 months has been shown to induce these abnormalities. Localized radiotherapy may have a similar effect. The combination of these two factors seems to cause an increase in the frequency and intensity of these abnormalities. Key words: chemotherapy - dyserythropoiesis - preleukaemia - radiotherapy Accepted for publication July 20, 1978 Correspondence to: Dr. Michel Renoux, Service d'HCmatologie Clinique, Hopital Beaujon, 100 boulevard du GCnCral Leclerc, 92118 Clichy Cedex, France

Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

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Page 1: Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

Scand J Haematol (1978) 21, 323-332

Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy:

Induction of Preleukaemic States?

MICHEL RENOUX,' JEAN-FRAN~IS BERNARD,' MARTINE TORRES,*

& PIERRE BOIVIN' NICOLE SCHLEGEL,3 MICH~LE A I V L ~ R , ~ MANUEL LOPEZ4

1 Service dH6matologie clinique et Unit6 de Recherche dEnzymologie des cellules sanguines (INSERM: U 160 - CNRS ERA 573), Hopital Beaujon, Clichy, 2 Laboratoire central d'H6matologie-lmmunologie, Hopital Bichat, Paris,

3 Service central d'H6matologie-lmmunologie, Hopital Beaujon, Clichy and

4 Service dlmmunologie du CNTS - Dipartement St Antoine (INSERN: U 76), Paris, France

Increased incidence of acute leukaemia (AL) following exposure to ionizing radiation is well documented. AL has also been reported with increased frequency after chemo- therapy for nonmalignant diseases. The effect of chemotherapy and/or radiotherapy on the following erythrocyte parameters: pyruvate-kinase (PK) activity, phospho- fructo-kinase (PFK) activity, HbF level, red cell antigens production and bone mar- row sideroblasts, has been studied in 31 patients with myelomatosis and in 33 patients with nonhaematological malignancies. We have demonstrated the appearance after chemotherapy or radiotherapy of some abnormalities usually associated with leukaemia or preleukaemic states. In patients treated for myelomatosis, a PK deficiency has been detected in 58 % of the cases, an increased HbF level in 47 %, a modification of blood groups antigens in 68 % and abnormal sideroblasts in 30 %. No PFK deficiency was found. In patients treated for solid tumors, a PK deficiency in 50 % of the cases, a PFK deficiency in 20 %, an increased HbF level in 10 %, a modification of blood group antigens in 40 % has been detected. Chemotherapy administered over a period of 3 months has been shown to induce these abnormalities. Localized radiotherapy may have a similar effect. The combination of these two factors seems to cause an increase in the frequency and intensity of these abnormalities.

Key words: chemotherapy - dyserythropoiesis - preleukaemia - radiotherapy

Accepted for publication July 20, 1978

Correspondence to: Dr. Michel Renoux, Service d'HCmatologie Clinique, Hopital Beaujon, 100 boulevard du GCnCral Leclerc, 92118 Clichy Cedex, France

Page 2: Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

324 RENOUX, BERNARD, TORRES, SCHLEGEL, AMAR et al

Certain conditions are known to promote acute leukaemia (AL). The exposure to ionizing radiation increases the incidence of acute myeloblastic leukaemia (AML) (Brill et a1 1962, Court-Brown & Doll 1965). Drug-induced marrow aplasia has been shown to be a predisposing factor (Vigliani & Saita 1964, Fraumeni 1967). In recent years, many reports implicate chemotherapy alone in the development of AML (Allen 1970, Sypkens-Smit & Meyler 1970, Kaslow et a1 1972, Perlman & Walker 1973, Burton et a1 1976). Furthermore some cases of non- neoplastic diseases treated by chemotherapy have been recorded to have terminated in AML (Cobau et a1 1973, Kyle et a1 1974, Silvergleid & Schrier 1974, Tulliez & Ricard 1974, Roberts & Bell 1976, Tchernia & Mielot 1976, Chang & Ceary 1977).

The object of our study was to examine some parameters frequently affected in leukaemia, preleukaemic states, or bone marrow insufficiency. Red cell enzyme ac- tivities, HbF, red cell antigens production and bone marrow sideroblasts were studied in myelomatosis and solid cancer; these parameters were examined before and dur- ing treatment with cytostatics. This study was conducted in an attempt to recognize preleukaemic states.

Myelomatosis was chosen because of the unexpectedly frequent development of AML in this disease (Andersen & Videbaek 1970, Rosner & Grunwald 1974, Gonzalez et a1 1977); in many cases, sideroblastic anaemia appeared as a preleukaemic change (Kha- leeli et a1 1973).

PATIENTS AND METHODS

Patients with myelomatosis. The study was per- formed before treatment in 10 patients with myelomatosis. 21 patients were studied in the course of chemotherapy (3-48 months), using

three different regimens: 7 patients received daily treatment with melphalan, 3 patients were put on an intonnittent schedule of melphalan, and 11 patients were treated with a combination of cyclic chemotherapy using cyclophosphamid, melphalan, vincristine and prednisone. 8 of these 21 patients had received prior radiotherapy.

Patients with solid cancer. A total of 33 patients with nonhaematologic malignancies were treated with monthly courses of intensive chemotherapy. The first study was performed befolre treatment in 6 patients, and after radiotherapy alone in 6. 30 patients were studied after three or more courses of chemotherapy; 14 of the 33 patients had received prior radiotherapy. In 23 cases, a second study was performed 3 months after the first one. A bone marrow involvement was re- cognized by biopsy in 5 patients.

The patients were in steady state, and had not required blood transfusions for at least 3 months. Blood samples were obtained either 1 month after a cycle of chemotherapy, or before any treatment. Routine haematologic determinations and special stains on bone marrow were performed according to standard technique. We defined abnormal sideroblasts as those shown to contain coarse deposits of ferritin (+ 5) by conventional Prussian Blue staining; some of these were ringsideroblasts. The sideroblasts were studied only in myeloma- tosis.

Erythrocyte enzyme assays. Enzymatic activities of pyruvate-kinase (PK) and phospho-fructo-kinase (PFK) were measured according to the method summarized by Beutler (1975). The activity is ex- pressed in IU/g Hb at 37O C. In this paper the results are given as a percentage of the normal mean as determined in samples obtained from 50 blood donors. Only activity below the lowest level observed in normal subjects was considered defi- cient.

H b examinations. H b was analyzed by cellulose acetate electrophoresis using a Tris-EDTA borate buffer system (pH 8.6) as described by Drabkin (1949). The level of HbF was determined by al- kaline denaturation. Absolute amounts of HbF (mg/dl) were derived from the % of alkaline- resistent H b and the Hb level (g/dl).

Page 3: Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

DYSERYTHROPOIESIS IN CYTOSTATIC THERAPY 325

o r - - - - - -

0 -

m\5

L B C O E

S O L I D TUMORS

\ . .

F 6 H I J N

Figure 1. Percentage of erythrocyte pyruvate kinas, (PK) activities of patients having received prior radiotherapy (0 or H) and those having had no radiotherapy (0 or 0).

Group A: myelomatosis before any treatment. Group B: myelomatosis treated by chemotherapy. Group C: myelomatosis treated by radiotherapy and chemotherapy. Group F: cancers before any treatment. Group G: cancers treated by radiotherapy. Group H: cancers treated by chemotherapy. Group I: cancers treated by chemotherapy and radiotherapy. Groups D-E-J-K: second examination after three new courses of

chemotherapy in patients of groups B-C-H-I. The lowest level observed in normal subjects is indicated (.--.--.--. 1. Cross bars show median values for each group.

Blood group antigen examinations. Blood group antigens were analyzed by quantitative agglutina- tion technique, as stated by Cartron et a1 (1969) with human anti-A, anti-A1 (Dolichos biflorus), human anti-B, anti-H (Ulex europeanus), human anti-I and anti-i. Only those values outside the two standard deviations were considered abnor- mal.

RESULTS

Before chemotherapy

Of the patients with myelomatosis, one had an elevated level of HbF on presentation; there were no other abnormalities. 12 can-

cer patients were studied before chemother- apy. Two patients showed a slight decrease in the erythrocyte PK activity (Figure 1); one of these showed a decreased PFK ac- tivity as well (Figure 2). Two other patients showed an increased level of i-antigen and a decrease in H-antigen. These abnormal- ities were encountered in patients which had received previous radiotherapy.

After chemotherapy

The following erythrocyte abnormalities were noted in 21 patients with myelo-

Page 4: Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

326 RENOUX, BERNARD, TORRES, SCHLEGEL, AMAR et a1

MYELOMIIOSIS

.

L B C O I 1 6 H I J K

Figure 2. Percentage of erythrocyte phospho-fructo-kinase (PFK) activities of patients having reecived prior radiotherapy (0 or H) and those having had no radiotherapy (0 or 0).

Group A: myelomatosis before any treatment. Group B: myelomatosis treated by chemotherapy. Group C myelomatosis treated by radiotherapy and chemotherapy. Group F: cancers before any treatment. Group G: cancers treated by radiotherapy. Group H: cancers treated by chemotherapy. Group I: cancers treated by chemotherapy and radiotherapy. Groups D-E-J-K: second examination after three new courses of

chemotherapy in patients of groups B-C-H-I. The lowest level observed in normal subjects is indicated (---.--.--. 1.

matosis: decreased PK activity: 10 cases (Figure 1); increased HbF level: 9 cases (range: 2.5 to 6 %, median 4.1 %; Fig- ure 3); increase in blood group antigen i: 6 cases (Figure 5 ) ; decrease in antigen I: 4 cases (Figure 4); decrease in antigen H: 2 cases, decrease in antigen B: 1 case, anti- gen A: 1 case, antigen Al: 1 case. No defi- ciency was observed in PFK activity (Fig- ure 2). In .bone marrow aspirate, abnormal sideroblasts were evident in five cases, with ring-sideroblasts in 3 cases (12 %, 5 %, 5 % of the erythroblasts).

30 cancer patients were studied during

chemotherapy. A decreased PK activity was observed in 16 cases (Figure 1). In 6 cases, the PK activity decreased after 3 courses of chemotherapy. Six patients showed de- creased PFK activity (Figure 2). Three pa- tients showed an increased level of HbF (Figure 3). There was an increase of blood group antigen i in 4 cases; and a decrease of antigen H in 3 cases, antigen I in 4 cases, and antigen Al in 1 case.

The distribution of the abnormalities ac- cording to whether or not the patients had received prior radiotherapy is described in Table 1. Multiple erythrocyte abnormalities

Page 5: Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

DYSERYTHROPOIESIS IN CYTOSTATIC THERAPY 327

0.7

0.6

0.5

= 0.4

.L 0.3

\ m

a = 0.2-

0.1

my c I o ma t osis

-

$ - - -

-

-

1 I

A B

so l i d tumors

0

- C 0

Figure 3. HbF (g/dl) in patients with: Group A: treated myelomatosis. Group C: treated cancers. Groups B-D: second examination after three new

courses of chemotherapy in patients of groups A and C.

may be encountered in individual patients: 28 patients had one erythrocyte abnormal- ity, 9 patients had two abnormalities, 6 pa- tients had three and two patients had four or more abnormalities.

The mean PK activity was respectively: 23.06 IU/g Hb in 15 patients studied be- fore treatment, 20.50 IU/g Hb in 6 pa- tients treated by radiotherapy alone, 21.79 IU/g Hb in 24 patients treated by chemo- therapy and 18.60 IU/g Hb in 22 patients treated by radiotherapy and chemotherapy.

No relationship was found between the frequency or the degree of biochemical ab- normalities of the erythrocyte and the fol- lowing parameters: mono- or polychemo- therapy, Hb level, reticulocyte, leucocyte or platelet counts, bone marrow involvement

or degree of plasmocytosis. The erythrocyte abnormalities appeared more frequently and with greater intensity after combination of radio- and chemotherapy (Table 1). In gen- eral, the abnormalities appeared only after three or more courses of chemotherapy. Few studies have yet been performed after the treatment was stopped. In one patient, two enzyme deficiencies were present six months after this discontinuation.

Close study of two cases

AML occurred in 2 patients with myelo- matosis after 25 and 56 months of low-dose melphalan therapy. A complete remission of the myelomatosis was achieved in both cases. In the first case, we detected an ex- cess of myeloblasts (18 %) in the bone mar- row aspirate, an increased HbF level, and a decrease in blood group antigens Al and I. This patient died 3 months later dur- ing the institution of chemotherapy. The second patient developed sideroblastic anae- mia with an excess of myeloblasts (15- 20 %) and ringsideroblasts in the bone mar- row aspirate. These conditions remained stable for 2 years with blood transfusions twice monthly and 150 mg of oxymetholone daily. Both cases were in complete remis- sion of their myelomatosis for 28 and 78 months, respectively. Myelomatosis reap- peared only with the onset of overt leukae- mia in these cases.

DISCUSSION

The association of myelomatosis and AML - or its variants - can appear in either of two possible manners. Some cases are si- multaneously detected (Tursz et a1 1974), but most cases of AML have occurred after a long period of chemotherapy (Andersen

Page 6: Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

328 RENOUX, BERNARD, TORRES, SCHLEGEL, AMAR et a1

m y e l o m a t o s i s so l id t u m o r s

. /- . . - - fl

. .. .

I .

t ' P A B C 0 E F

Figure 4. Percentage of quantitative agglutination in blood group I in patients with: Group A: myelomatosis before treatment. Group B: treated myelomatosis. Group D: cancers before chemotherapy. Group E: cancers after three courses of chemotherapy. Groups C-F: second examination after three new courses

of chemotherapy in patients of groups B-E. The normal range (mean k 2 SD) is indicated (: = : = : = :).

& Videbaek 1970, Rosner & Grunwald 1974). In this cases, acquired sideroblastic anaemia was a frequent preleukaemic state (Catovsky et a1 1971, Khaleeli et a1 1973). In myelomatosis such easily recognizable forms of dysmyelopoiesis, as well as un- usual or unclassified form of bone marrow insufEciencies may be encountered infre- quently before chemotherapy (MacGibbon & Mollin 1965, Tursz et a1 1974). These dysmyelopoietic states are more frequent after chemotherapy. Moreover in neoplastic tumors treated by chemo- or radiotherapy, acute leukaemia has been reported, but these dysmyelopoietic states have rarely been systematically studied.

The erythrocyte abnormalities studied in this paper are frequently associated with dysmyelopoiesis states such as refractory anaemia or less frequently with smoldering or acute leukaemia (Dreyfus et a1 1969, Valentine et a1 1973). Certain forms of dys- myelopoiesis may develop into AL but the risk is not known (Dreyfus et a1 1969). The aim of the discussion was to determine whether these abnormalities could provide a valid marker of the presence of leukaemic cell lines.

Acquired changes in erythrocyte enzyme activities have been described in refractory anaemia, smoldering leukaemia and AML (Valentine et a1 1973, Boivin et a1 1975).

Page 7: Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

DYSERYTHROPOIESIS IN CYTOSTATIC THERAPY 329

mvelomatosis solid tumors

A B C

f

- D E F

Figure 5. Percentage of quantitative agglutination in blood group 'i' in patients with: Group A: myelomatosis before1 treatment. Group B: treated myelomatosis. Group D: cancers before chemotherapy. Group E: cancers after three courses of chemotherapy. Groups C-F: second examination after three new courses

of chemotherapy in patients of groups B-E. The normal range (mean k 2 SD) is indicated (: = : = : = :).

Decreased activity is most frequently ob- served in PK, PFK, adenylate kinase, and 2-3 diphospho-glycerate mutase (Boivin et a1 1975). Other enzyme activities may in- crease. No PK-deficiency has been pre- viously found in untreated patients with myelomatosis (Boivin et a1 1975, Hansen & Hanel 1976). Various mechanisms are prob- ably responsible for these acquired enzyme defects. Some are molecular defects with a decreased concentration of the enzyme mea- sured by immunologic titration. Others are functional defects (Kahn et a1 1976). The prognostic significance of each mechanism may be different. The significance of the enzyme defects has been discussed by many

authors. The deficiencies cannot be simply assimilated to a regression toward a fetal form of erythropoiesis as suggested by Rochant et a1 (1972) since low PFK and high PK activities are found in fetal red cells. These enzymatic defects are not a consequence of the aging of the red blood cell population of patients under chemo- therapy since these patients were in steady state and the enzyme abnormalities did not correlate either with Hb level or with re- ticulocy te count.

Increased levels of HbF are found in a wide range of haematological diseases (Newman et a1 1973, Sheridan et a1 1976, Shokuh et a1 1976). In some forms of

Page 8: Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

330 RENOUX, BERNARD, TORRES, SCHLEGEL, AMAR et a1

TABLE 1 Distribution of biochemical and cytochemical abnormalities among the different patient

groups studied (Number of patients showing abnormalities J Number of patients studied)

m m Before After

Trebhent Traatment

PYRWAW 0 KIEASE DWICIEICY

PHOSPEO FRUCTOKIEABE DEIICIEIICT

EBPLEVEL 1

BMOD-CROUP 0 AETICEII ABEOlInALITT

L B E O r n L 0

SIDEROBLAST

CAECER

Bafore After After After Treatment Radiotherapy Chemotherapy Chemo + Rtl

E O N S T U D I E D

leukaemia, i.e. juvenile chronic myeloid leukaemia, HbF production is high and appears to be a genuine reversion to a fetal form of erythropoiesis (Sheridan et a1 1976). A slight increase of HbF level has frequent- ly been reported in refractory anaemia (Dreyfus et a1 1969), and after severe mar- row aplasia (Bloom & Diamond 1968). Neither the mechanism nor the prognostic significance of this rise has yet been dis- covered: is it an absolute increase in the number of HbF cell lines, present in nor- mal adult or the appearance of an abnor- mal erythroid line? The pattern of reactiva- tion of HbF production is extremely com- plex. It is not specific to leukaemic cell lines, since this overproduction also ap- pears in physiologic marrow regeneration, pernicious' anaemia (Shokuh et a1 1976), thyrotoxicosis (Eng et a1 1967), and during pregnancy (Pembrey et a1 1973).

Various modifications of blood group antigens may occur in malignant haemo-

poiesis or in dysmyelopoiesis (Majsky et a1 1967, Salmon 1976).The main changes have been documented in the A, B, H, I and i substances. These modifications consist of a lack of antigens or an increase in uncon- verted substrate. Patients with the more common defects can show multiple changes. In contrast, the exceptional defects in elder- ly or normal subjects always affect only one clone. The pattern of modifications found in carcinoma is quite different (Majsky et a1 1967).

Conclusion

In this paper we demonstrate the appear- ance, after localized radiotherapy and/or chemotherapy, of several erythrocyte ab- normalities usually associated with dys- myelopoiesis and preleukaemic states.

The cell damages could occur early after chemotherapy administration since the ab- normalities appear after three months, time

Page 9: Erythrocyte Abnormalities Induced by Chemotherapy and Radiotherapy: Induction of Preleukaemic States?

DYSERYTHROPOIESIS IN CYTOSTATIC THERAPY 331

necessary to renew the whole erythrocyte populations.

However, none of these biochemical para- meters is specific to malignant states. The diagnostic values of each of these abnor- malities have been discussed. Several mech- anisms may account for each abnormality. No study is available at present as to the prognostic significance of the summation of the ‘markers’.

Does a transition exist from biochemical abnormalities to dysmyelopoietic states, and finally to overt leukaemia?

It is essential that the persistence of these abnormalities after interruption of chemo- therapy be analyzed. The study of the dis- tribution of these markers among erythro- cyte populations in selected patients could provide some evidence as to the clonal origin of the abnormalities. Certain abnor- malities of the leucocyte found in myelo- matosis (Debr6 et a1 1974) could provide an other marker of a stem cell injury.

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