Response to Pyridoxine Hydrochloride in Refractory Anemia Due to Myelofibrosis

ROBERT A. ROJER, M.D.’ NANNO H. MULDER, M.D. HENDRIK 0. NIEWEG. M.D., M.R.C.P. Edin.

Groningen,The Ne+berlands

Eleven of 14 patients with primary myelofibrosis were given a therapeutic trial with 250 mg of pyridoxine hydrochloride daily because of refractory anemia. The effect on the hemoglobin level and the hematocrit value was studied and compared to that in a group of untreated patients with the same degree of anemia. Six of 11 treated patients responded within three months with a rise in the hemoglobin level (at least 3 g/100 ml) and/or an increase in the hematocrit value (at least 10 per cent), and transfusions were no longer required. Deliberate discontinuation of pyridoxine treatment in one responding patient was followed by a relapse of the anemia; resumption of therapy once again induced an erythropoietic response. Spontaneous remissions of anemia were not observed in the untreated group. It is concluded that a trial with pyridoxine is warranted in patients with myelofibrosis and refractory anemia. Anemia in myelofibrosis is often due to a combination of factors, the most important of which are (1) decreased effective erythropoiesis in medullary and extramedullary sites [ 11, (2) reduced life span of circulating red blood cells [2], (3) expansion of the plasma volume leading to hemodilution [3], (4) pooling in the spleen. Iron and folate deficiency [4] or severe hemolysis [5,6] may occasionally contribute to the development of anemia; then appropriate replacement therapy and administration of corticosteroids or splenectomy may be beneficial. Androgens also can be effective [ 71. However, in many patients with myelofibrosis, anemia remains a therapeutic problem [8]. Pyridoxal phosphate is essential for heme synthesis and, in some cases of anemia refractory to other therapy, treatment with pyridoxine [9, lo] may be effective. The administration of pyridoxine in myelofibrosis has rarely been attempted [ 111. Presented here are the results of a study evaluating the effect of high doses of pyridoxine hydrochloride on refractory anemia due to myelofibrosis. MATERIALS AND METHODS

From the Division of Hematology, Department of Medicine, University of Groningen, Groningen, The Netherlands. Requests for reprints should be addressed to Dr. N. H. Mulder, Division of Hematology, Department of Medicine, University of Groningen, Obtersingel 59, Groningen, The Netherlands. Manuscript accepted May 3, 1978. Present address: Weg naar Welgelegen 24, Willemstad, Curagao, Netherlands Antilles. l

Patients. Of 29 patients with primary myelofibrosis seen in our wards between 1968 and 1977, anemia with hemoglobin levels of 9 g/ 100 ml blood or less was present in 14 patients. Eleven of these anemic patients received a therapeutic trial with 250 mg of pyridoxine hydrochloride daily. It was retrospectively discovered that three additional patients with the same degree of anemia had not received this drug

for reasons unknown. Hemoglobin and hematocrit values were regularly recorded in this latter group of untreated anemic patients as well as in the former group of pyridoxine-treated patients during comparable observation periods.

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ET AL.

r

Yo

% 350

350

300

100

I_

0

101 1

2

3

months I, 0

Llgure 1.

1

2

3

months

i

Horizontal axis: months of therapy with pyridoxine in six pat/ents with primary myelofibrosis. Vertical axis: rise oif F hemoglobin level (left) and increase in hematocrit value (right) in percentage of pretreatment values. Significance of symbols: Cl corresponds to Case 1; 0 to Case 2; A to Case 3; n to Case 4; 0 to Case 5 and A to Case 6 in Table 1.

In one patient, we studied the effect of temporary discontinuation and subsequent reinstitution of pyridoxine therapy on the level of hemoglobin and the reticulocyte count. Features of Anemia Before the Trial. Anemia in this group of 14 patients was typical of refractory anemia in primary myelofibrosis [12]. As judged by the mean corpuscular volume, the red cells were either normocytic or slightly macrocytic. In all cases, anisocytosis and a variable number of hypochromic cells were seen in the peripheral blood smear. Immune hemolysis was not observed in any of the cases presented. Iron or folic acid deficiencies were excluded before therapy with pyridoxine was started. Diagnosis. In all patients, bone marrow biopsy specimens were obtained from the posterior iliac crest using either the Westerman or the Jamshidi needle. The specimens were examined by Professor A. Arends and Dr. R. Eibergen of the Department of Pathology. Essential criteria for diagnosis included the presence in the biopsy specimen of an increase in fibrous tissue [ 131 (collagen and/or reticulin) and clusters of atypical megakaryocytes or megakaryoblasts [ 141. Splenomegaly was found in all patients at some stage of the

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disease. Leukoerythroblastosis, teardrop erythrocytes and poikilocytosis were always observed in May-GrunwaldGiemsa-stained smears of peripheral blood. Additional findings present in some patients included histologic proof of extramedullary hematopoiesis in spleen, liver or lymph node, bizarre or giant thrombocytes in the peripheral blood smear and, finally, evidence of osteosclerosis on x-ray examination. Hemoglobin; Hematocrit; Reticulocyte Counts. Hemoglobin was measured by standard laboratory technics. (Normal values in males 16 f 2; in females 14 f 2 g/100 ml blood; standard deviation of the technic 0.08 g/ 100 ml.) The hematocrit value was either determined by a microcentrifuge method (1968-1975) or calculated from the red cell count and mean corpuscular volume (Coulter-S counter, 19751977). (Normal values in males 47 f 5; in females 42 f 5 per cent; standard deviation of the technic 0.03 per cent.) Reticulocytes were counted per 1,000 red cells in brilliant cresyl blue stained smears. The number/p liter blood was calculated using the electronic count of red cells. (Normal reticulocyte count about 60.000/p liter blood [ 151.) Vitamin Bs Levels. Whole blood levels of vitamin 6s were

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TABLE I

IN MYELOFIBROSIS-ROJER

ET AL.

One year Follow-Up of Hemoglobin and Hemalocril in 14 Patients with Myelofibrosis and Refractory Anemia

___-

Treated initial

Case No.

Sex

1

F

2

M

3

F

4

F

5

F

6

F

7

F

8

M

9

M

10

M

11

M

12

F

13 14

F M

Value hb hct hb hct hb hct hb hct hb hct hb hct hb hct hb hct hb hct hb hct hb hct hb hct hb hct bh hct

4.4 13 7.4 25 5.2 22 6.1 20 8.0 23 6.3 20 7.4 22 9.0 27 9.0 27 7.7 23 8.0 23 7.9 22 9.0 31 7.1 22

Month

1 10 32 9.7 31 10.3 29 8.1 27 10.5 33 7.8 28

Y.9 24 9.2 27 7.3 21 9.2 27 7.4 20 8.3 32 7.5 22

6

2

3

11.5 36 9.5 30

14.1 40 10.4 33 10.1 29 12.7 41 12.2 44 9.0 30 8.5 25 7.7 23 f

‘1’1’.4 37 11.8 38 9.0 29

. a2 29 . .. .

12:; 39

9

12

12.0 39 12.7 37

12.0 36 12.5 38 l

‘1’3 40 12.2 44 9.0 30 9.6 32

t

‘9.3 32 10.3 33 5.5 17

12.8 46 8.9 29 9.2 27 8.0 26

with Pyridoxine + + +

+ + + + + + +

8.3 25

6.8 18

. . . ..

‘S.1 32 8.3 25

* 7.4 22 7 26 7.6 29

+ 5.6 19 7.2

-

26 6.5

-

19

NOTE: hb = hemoglobin, all values given in g/100 ml. hct = hematocrit, all values given in per cents. Patients died from cardiac failure. r Atypical lymphoblastic leukemia developed. l

measured by Dr. W. H. P. Schreurs of the Central Institute for Nutrition and Food Research, Zeist, The Netherlands, using a microbiological method based on the procedures described by Atkin et al. [16] (normal values 70 to 180 nmol/liter blood). Tryplophan Loading Test. The 24 hour urinary excretion of xanlhurenic acid following an oral loading dose of L-tryptophan (50 mg/kg body weight) [ 171 was determined by Mr. E.

W. Kwarts, Clinical Chemistry Laboratory. After extracting the acidified urine with ethyl acetate, the extract was dried, redissolved and subsequently electrophoresed on cellulose acetate in a pyridine-acetic acid buffer (pH 3.6) at 500 V. Normal excretion less than 0.27 per cent of the loading dose. The tryptophan loading test was performed during and after interruption of pyridoxine administration in one patient. RESULTS Hemalocril. A rise in the hemoglobin level varying from 2.7 to 9.7 g/100 ml and an increase in the hematocrit value varying from 7 to 27 per cent was found in six of 11 patients who were treated with pyridoxine (Table I, Cases 1 through 6; Figure 1). Hemoglobin;

These six patients responded rapidly, hemoglobin and hematocrit values increasing substantially within the first few weeks of therapy. This initially rapid reaction was not seen in the seventh pyridoxine-treated patient (Table I, Case 7) in whom the increase in hemoglobin and hematocrit values was slow, attaining its maximum after nine months of therapy (the total increase being 2.9 g/ 100 ml blood for hemoglobin and 11 per cent for the hematocrit). The requirement for blood transfusions in these seven patients (Table I, Cases 1 through 7) was eliminated following the administration of pyridoxine. All seven patients had needed regular blood transfusions before the trial. Four patients (Table I, Cases 8 through 11) did not show any increase in hemoglobin or hematocrit values during treatment with pyridoxine. Their requirement for blood transfusions persisted and was not affected by the administration of pyridoxine. Hemoglobin and hematocrit levels did not rise spontaneously in the group of untreated patients (Table

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rcticuloc (/mm

0

ET AL.

tes

r1

I,................... 2

4

6

8

10

12

14

16

19

20 weeks

hemoglobin (g/lOOml blood)

I....................

0

2

4

6

6

10

12

14

16

I, Cases 12 through 14). All these patients required blood transfusions at regular intervals. Discontinuation and Resumption of Pyridoxine Treatment. In one responding patient (Table I, Case 1) the administration of pyridoxine was temporarily withdrawn after six years of therapy. No other changes of therapy were made at the time of discontinuation and resumption of pyridoxine administration. Following withdrawal of pyridoxine, the hemoglobin level fell from 12.2 to 10.2 g/100 ml and eventually to 7.8 g/100 ml at the end of four and six weeks, respectively. Reticulocytes decreased from 127,500 to 27,120/p liter at the end of six weeks (Figure 2). Upon reinstitution of therapy with 250 mg of pyridoxine hydrochloride daily, the reticulocyte count increased to 238,560/p liter and the hemoglobin level

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16

20

weeks

Figure 2. The effect of withdrawal and resumption of pyridoxine therapy on hemoglobin (g/ 700 ml) and reticulocyte count (IF liter blood) in a patient with primary myelofibrosis ( Table I, Case 1).

rose to 12.4 g/100 ml at the end of two and three weeks, respectively (Figure 2). Vitamin BBLevels in Whole Blood. Vitamin l3s levels in whole blood prior to therapy were not lowered in all pyridoxine-responsive patients (Table II). Levels on the lower side of the normal range were found in the group of responders as well as in some patients who did not respond. Tryptophan Loading Test. In one patient (Table I, Case 1; Figure 2) the tryptophan loading test was performed during and following interruption of pyridoxine therapy. The 24-hour urinary excretion of xanthurenic acid following a loading dose of 50 mg/kg L-tryptophan would normally have to be less than 9.4 mg in this patient (0.27 per cent of the loading dose). The excretion of xanthurenic acid in response to the

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administration of tryptophan was increased (13 mg/24 hours) at the end of six weeks after withdrawal of pyridoxine. Following the resumption of therapy, the excretion normalized to 3.2 mg/24 hours within a period of three weeks.

TABLE II

Case No.

COMMENTS

Whether responsiveness to pyridoxine in this series of 14 patients with primary myelofibrosis is due to sideroblastic anemia, is difficult to evaluate as bone marrow aspirations invariably led to “dry taps.” However, some kind of pyridoxine deficiency is suggested in these patients by a (1) low or low to normal levels of circulating vitamin Bs in five of seven patients tested (Table II), whereas a deficiency is not excluded by the normal values in the other patients [ 181; (2) the excretion of increased amounts of xanthurenic acid after loading with tryptophan in one patient (Case 1); and finally (3) the response to pyridoxine treatment with an increase in hemoglobin and hematocrit in six of 11 patients (Table I, Cases 1 through 6). Exogeneous deficiency due to a faulty dietary intake of vitamin B6 does not seem a likely possibility considering the apparently normal nutritional state of these patients, their normal dietary history and the fact that only minimal amounts of vitamin B6 are normally required (about 2 mg daily) [ 191. Deficiency on account of an (selective) impairment of intestinal absorption remains a theoretic possibility which cannot be excluded on the data obtained in this study. However, the most attractive explanation for the pyridoxine deficiency in these anemic patients would be an increased demand for the coenzyme pyridoxal phosphate, an important factor in heme synthesis. The persistent high reticulocyte count in Case 1 during therapy suggests that erythropoiesis may remain ineffective in this situation. It is possible that the ineffective hemoglobin synthesis in myelofibrosis is due to blockade of one of several enzymes, which require pyridoxal phosphate as a coenzyme in the heme synthesis pathway. On the basis of in vitro studies, Freedman et al. [20] reported that a blockade of deltaamino-levulinic acid (&ALA) synthesis could to some extent be overcome by pyridoxal phosphate, a coen-

IN MYELOFIBROSIS---ROJER

Pretreatment Circulating Vitamin B6 Levels is Four Responders and Three Nonresponders to Pyridoxine Therapy Vitamin B6 Levels (nmol/liter whole blood)’

Pyridoxine Treatment

57 2 3 4 5 6 7

l

Responseto Therapy

-

+ + + + + +

+ + + + + +

+ +

f

75

+

180 88

+ +

‘35 110 75

a 9 10 11 12 13 14

ET AL.

Normal values: 70 to 160 nmol/liter

whole blood.

zyme needed for the synthesis of &ALA. An excess of pyridoxal phosphate may stimulate the activity of enzymes by “saturating the apoenzyme with coenzyme” [21]. In this way, a surplus in coenzyme can help to overcome a blockade of enzyme function. Not all patients seem to respond to pyridoxine therapy. Individual variations concerning the relative contributions of the liver and spleen to the process of extramedullary erythropoiesis and the importance of ineffective erythropoiesis in relation to other factors that lead to anemia in myelofibrosis may account for the limited number of responders to pyridoxine in our series. Additional investigations are needed in order to find suitable parameters for predicting a favorable response to pyridoxine administration. Possibly the tryptofan loading test could also be of some value. In summary, it may be concluded from the beneficial effect of pyridoxine in six of our 11 treated patients with refractory anemia due to primary myelofibrosis that a therapeutic trial with 250 mg of pyridoxine hydrochloride is warranted in this condition.

REFERENCES Szur L, Lewis SM: Iron kinetics. Clin Haematol 4: 407, 1975. Nathan DG, Berlin NI: Studies of the production and life span of erythrocytes in myeloid metaplasm. Blood 14: 666, 1959. Egelund Christensen B: Red cell kinetics. Clin Haematol 4: 393,1975. Forshaw J, Harwood L, Weatherall DJ: Folic-acid deficiency and megaloblastic erythropoiesis in myelofibrosis. Br Med J 1: 671, 1964.

5.

6.

7.

6.

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Bouroncle BA, Doan CA: Myelofibrosis. Clinical, hernatologic and pathologic study of 110 patients. Am J Med Sci 243: 697. 1962. Nakai GS, Craddock CG, Figueroa WG: Agnogenic myeloid metaplasia. A survey of 29 cases and a review of the literature. Ann Intern Med 57: 419, 1962. Gardner FH, Nathan DG: Androgen and erythropoiesis. Ill. Further evaluation of testosteron treatment of myelofibrosis. N Engl J Mad 274: 420, 1966. Ward HP, Block MH: The natural history of agnogenic myeloid

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9.

10. 11. 12.

13. 14.

15.

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metaplasia (AMM) and a critical evaluation of its relationship with the myeloproliferative syndrome. Medicine (Baltimore) 50: 357, 1971. Harris JW, Whittington RM, Weisman R Jr, et al.: Pyridoxineresponsive anemia in the human adult. Proc Sot Exp Biol Med 91: 427, 1956. Hines JD, Grass0 JA: The sideroblastic anemias. Semin Hemat01 7: 86, 1970. Horrigan DL, Harris JW: Pyridoxine-responsive anemia: analysis of 62 cases. Adv Intern Med 12: 103, 1964. Wintrobe MM, Richard Lee G, Boggs DR. et al.: Clinical hematology, chap. 57. Myelofibrosis, Philadelphia, Lea 8 Febiger, 1974. Lennert K, Nagai K, Schwarze EW: Patho-anatomical features of the bone marrow. Clin Haematol 4: 331, 1975. Waitz R, Mayer S, Mayer G: Splenomegalie myeldde et autres formes d’osteomyelosclerose. 0068: Enzyclopedic Medico-Chirurgicale (Paris) Sang Fast 13011 C 10: 3, 1963. Harris JW, Kellermeyer RW: The red cell, chap. 6. Normal Red

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19. 20.

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Cell Production, Cambridge, Harvard University Press, 1970. Atkin L, Schultz AS, Williams WL, et al.: Yeast microbiological methods for determination of vitamins. lndust Eng Chem 15: 141, 1943. Musajo L, Benassi CA: Tryptophan metabolism in man. Adv Clin Chem 7: 63, 1964. Coelingh Bennink HJT, Schreurs WHP: Improvement of oral glucose tolerance in gestational diabetes by pyridoxine. Br Med J 3: 13, 1975. Baker EM, Canham JE, Nunes WT: Vitamin Bs requirement for adult men. Am J Clin Nutr 15: 59, 1964. Freedman ML, Wildman JM, Rosman J, et al.: Benzene inhibition of in vitro rabbit reticulocyte haem synthesis at delta adminolaevulinic acid synthetase. Reversal of benzene toxicity by pyridoxine. Br J Haematol 35: 49, 1977. Miller LT. Johnson A, Benson EM, et al.: Effect of oral contraceptives and pyridoxine on the metabolism of vitamin B6 and on plasma tryptophan and alpha-amino nitrogen. Am J Clin Nutr 28: 846, 1975.

Response to pyridoxine hydrochloride in refractory anemia due to myelofibrosis.

Response to Pyridoxine Hydrochloride in Refractory Anemia Due to Myelofibrosis ROBERT A. ROJER, M.D.’ NANNO H. MULDER, M.D. HENDRIK 0. NIEWEG. M.D.,...
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