Letters and Correspondence 305

0

I *= 100 = X

P

LD -. In c

50 8 y;1 z 0

case 0 control 1 3 4 5 6 1 9 10

* rr *P<O.Ol

Fig. 1. Effect of T cells on CFU-E colony formation by bone marrow mononuclear cells (BMMNC) from patients with MDS. 0: T cell-depleted BMMNC alone. IJ: addition of bone marrowT cells. .: addition of peripheral blood T cells.

These results suggest that an immune mechanism as the pathogenesis of ineffective hematopoiesis in MDS may exist in the minority of patients with MDS.

In conclusion, in vitro studies which detect the existence of inhibitory T cells in this syndrome may aid in the design of rational and individualized therapeutic approaches. Further studies will be necessary to clarify the underlying mechanisms in more detail and to develop clinical applications.

REFERENCES

I . Motoji T , Teramura M, Takahashi M, et al.: Successful treatment of refractory anemia with high-dose methylprednisolone. Am J Hematol 33:s. 1990.

2. Tichelli A. Gratwohl A, Wuersch A, Nissen C, Speck B: Antilymphocyte globulin for myelodysplastic syndrome? Br J Haematol 68: 139, I988

3 . Bennet JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189. 1982.

4. Miura A, Endo K, Sugawara T , et al.: T cell-mediated inhibition of erythropoiesis in aplastic anaemia: the possible role of IFN-7 and TNF-a. Br J Haematol78:442, 1991.

5. Tepperman AD, Curtis JE, McCulloch EA: Erythropoietic colonies in culture of human bone marrow. Blood 44:659, 1974.

6. Francis GE, Guimaraes JET, Granger S, et al.: Distinct T-lymphocyte sub- sets affect granulo-monocyte differentiation and proliferation. Stem Cells 2:76, 1982.

7. Smith MA, Smith JG: Thc occurrence subtype and significance of haemopoietic inhibitory T cells (HIT cells) in myelodysplasia: an in vitro study. Leuk Rcs 15597, 1991.

TOMOHIRO SUGAWARA KAZUYASU ENDO

TOMOAKI SHISHIDO AKIYOSHI SATO

JUNICHI KAMEOKA OSAMU FUKUHARA KAORU YOSHINAGA

Second Department of Internal Medicine, Tohoku University School of Medicine

Department of Internal Medicine, National Sendai Hospital, Sendai, Japan

AKIRA MIURA

Case Report: All-Trans Retinoic Acid, Hyperleukocytosis, and Marrow infarction

To the Editor: All-trans retinoic acid has been successfully employed as the differentiation therapy in acute promyelocytic leukemia (APL-M3) [ 1 4 1 . We describe a case of APL treated with all-trans retinoic acid, which led to hyperleukocytosis followed by bone marrow infarction and severe pancy- topenia.

CASE REPORT

A 55-year-old man was admitted in July, 1991, with anemia and severe thrombocytopenia and a leukocyte count of 17.1 X l0’lliter with 77% promyeloblasts. Bone marrow aspiration and morphology of circulating cells was congruent with the “microgranular” variant of acute promyelo- cytic leukemia. A coagulogram showed low-grade disseminated intravas- cular coagulation (DIC). Karyotypic analysis was not obtained on initial presentation. The patient was successfully treated with Idarubicin ( 1 2 mgl mz X 3 days) and ARA-C (150 rnglm’ X 7 days). Complete remission was attained by week 4. A similar course of consolidation therapy was adminis- tered 6 weeeks following initial presentation.

In January, 1992, the patient presented with thrombocytopenia (50 X 10’lIiter) and a leukocyte count of 7.4 X 10’lliter) with few circulat- ing promyeloblasts. Bone marrow aspirate confirmed acute leukemic re- lapse. Karyotype analysis revealed t( 15;17). As well, there was evidence of trisomy 8. A coagulogram showed elevated D-dimers.

Therapy was started with all-trans retinoic acid (30 mg bid PO) and prednisone 20 mg orally daily. By day 4 of treatment, the leukocyte count had escalated to 186.3 X IO‘lliter-with the differential count showing 57% promyeloblasts. Leukapheresis (three times) was instituted, and two doses of hydroxyurea (2 giday) in addition to methylprednisolone 120 mg IV daily were given. During this time the patient was symptomatic, with dyspnea and generalized bone pain requiring oxygen and narcotic therapy. Aggressive supportive transfusions with platelets and packed red cells were necessary as well. With these measures, hyperleukocytosis was effectively controlled, and, by day 19, the leukocyte count was 9.8 X 10”lliter and

306 Letters and Correspondence

thereafter rapidly dropped to a nadir of 0.4 X I0’iliter on day 29. All-trans retinoic acid was discontinued on day 16. The clinical course was compli- cated by febrile neutropenia and sepsis requiring broad-spectrum antibiotics in addition to the transfusion dependency for red cells and platelets. Severe pancytopenia lasted for a total of 21 days, and by day 39 the hemogram had fully recovered. A bone marrow biopsy on day 25 showed extensive mar- row infarction with few foci of promyeloblasts. Repeal biopsy on day 119 revealed focal fibrosis and islands of normal hematopoiesis but no leukemic infiltration.

DISCUSSION

The hyperleukocytosis syndrome has been well described in acute pro- myelocytic leukemia [2,3]. This case is unusual in that hyperleukocytosis secondary to all-trans retinoic acid therapy in APL was associated with bone marrow infarction and severe pancytopenia. With supportive mea- sures, eventual full hematopoietic recovery was achieved. As was sug- gested in a recent review, the mechanism of action of retinoic acid in APL may be through the induction of apoptosis [ 5 ] . Resulting hyperleukocytosis may have led, in our case, to occlusion of small blood vessels, with resulting anoxia, leading to marrow necrosis.

The ability of differentiation therapy to induce bone marrow remissions by circumventing an aplastic phase with its attendant risks has obvious advantages. This case demonstrates that this may not always be so. To our knowledge this complication of therapy with all-trans retinoic acid has hitherto not been reported.

P. LOPEZ 0. HAYNE

Department of Medicine, Dalhousie University and Cancer Foundation of Nova Scotia, Halifax, Nova Scotia, Canada

REFERENCES Huang ME, Ye YC, Chai JR, Lu J-X, Zhdo L, Gu L-J, Wang Z-Y: Use of all trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72567, 1988. Cdstaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, Degas L: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leuke- mia: 1. Clinical results. Blood 76:1704, 1990. Warrell RP Jr., Frankel SR, Miller WH Jr., Scheinberg DA, Itn LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A. Jakubowski A, Gabrilove J, Gordon M, Dmitrovsky E: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans retinoic acid). N Engl J Med 324:1385, 1991. ChenZ-X, Xue Y-Q, Zhang R, Tao R-F, Xia X-M, Li C, Wang W , Zu W-Y, Yao X-Z, Long B-J: A clinical experimental study on all-trans retinoic acid treated acute promyelocytic leukemia patients. Blood 78:1413, 1991. Smith MA, Parkinson DR, Cheson BD, Friedman MA: Retinoids in cancer ther- apy. J Clin Oncol 10:839, 1992.

Agranulocytosis Associated With Pyrithioxine Therapy

To the Editor: Pyrithioxine is used in the treatment of rheumatoid arthritis and as an antidepressive drug in many countries. It contains an active sulfhydryl group. Penicillamine. captopril, and 5-thiopyridoxine, which

also contain this group, can cause adverse side effects, including hemato- logical reactions [ 1,2], We treated a patient who developed agranulocytosis on three occasions after the administration of pyrithioxine.

An 81-year-old man had a cerebral infarction in 1982. After the episode, recurrent dizziness, depression and dyskinesia developed, and he was pre- scribed various drugs, including pyrithioxine (300 mgiday), beginning on September 21, 1985. On October 14, 1985, fever with suppurative tonsilli- tis developed; WBC count was 1 ,200/mm3, with 99% lymphocytes. Bone marrow aspirate was slightly hypocellular, with 7.2% granulocytes. All drugs were discontinued. He was transferred to another hospital on October 18, 1985, where piperacillin and isepamicin were administered. During the first 2 days after admission, fever abated, and WBC count increased to 1 ,500/mm3 with 24% granulocytes.

On March 6, 1987, he was again prescribed various drugs, including pyrithioxine (300 mgiday); WBC count and differential cell count obtained onMarch 12, 1987, werenormal. OnMarch 31, 1987, feverdeveloped; the patient had a WBC count of I ,000/mm3 with 3% granulocytes. All drugs were discontinued, and he was transferred to another hospital. On April 2, 1987, WBC count was 1,100/mm3 with 325 granulocytes, and the fever disappeared.

On April 21, 1989, he was again prescribed various drugs, including pyrithioxine (300 mgiday); WBC count (6,500imm’) and differential cell count obtained on April 21, 1989, were normal. On May 10, 1989, fever with sore throat developed; WBC count was 400imm’ with no granulo- cytes. Bone marrow aspirate was slightly hypocellular, with absence of granulocytes. All drugs were discontinued. He was transferred to our hos- pital, where treatment with clindamycin, isepamicin, and granulocyte col- ony-stimulating factor (G-CSF) (75 pglday) was initiated on May 13, 1989. On May 15, 1989, WBC count was 8OOimm’ with 13% granulo- cytes, and fever disappeared gradually thereafter.

The only drug used before all three episodes of agranulocytosis was pyrithioxine. Since pyrithioxine therapy was discontinued, he has experi- enced no further episodes. The occurrence of conspicuous granulocytope- nia on three separate occasions after the administration of pyrithioxine strongly suggests that this drug was the etiological agent of agranulocyto- sis. The slow decrease in circulating granulocyte count, which was detected about 24,21, and 19 days, respectively, after prescription, suggests that the neutropenia was toxic or dosage related. Although active sulfhydryl group drugs are known to produce many kinds of adverse reactions, including hematological effects, evidence of agranulocytosis induced by pyrithioxine is rare [2]; we could not find a previous case report. The findings in this case reflect the course of agranulocytosis induced by pyrithioxine and suggest its mechanism.

ATSUKO TSUKAMOTO FUMIO KAWANO

MASAHIKO SATOH ~ S A O SANADA

TADAHIRO SHIDO Department of lnternal Medicine, Kumamoto National Hospital, Ninomaru, Kumamoto, Japan

REFERENCES 1 . Jaffe IA: Adverse effects profile of sulfhydryl compounds in man. Am J Med

2 . Crouzet J, Berancck L: Pyrithioxine et polyarthrite rhumdtoide. Rev Rhumdt 80:471476, 1986.

5 3 ~ 4 8 , 1986.