Can chloroquine cause pancytopenia?/nA 47-year-old woman had taken three doses of chloroquine in th

Fråga: Can chloroquine cause pancytopenia? A 47-year-old woman had taken three doses of chloroquine in three weeks as a malaria prophylaxis (2x 250 mg/week). After the first dose, she experienced a short period of fever. The last dose, taken on January 30th 1993, was followed by the development of fever again, chills and diarrhoea and the patient was admitted to the hospital. A complete blood count showed pancytopenia, with lowered values for all cell types, but especially a low white cell count with almost no granulocytes. Her bone marrow aspirate showed signs of a toxic blockade. Now, one month later, the patient´s haematological status has not improved and the bone marrow aspirate contains 20 per cent immature lymphocytes.

Sammanfattning: Chloroquine has been described in association with several kinds of blood dyscrasias, including aplastic anaemia. The mechanism is not known. Concerning pancytopenia, a variety of possible causes need to be considered. Haematological diseases may develop very slowly and uncharacteristically, making them difficult to diagnose at the time of onset of the symptoms. Although drug-induced lowering of leukocyte counts seems to recover rather quickly, with a median time of about 14 days, this may sometimes take much longer. In conclusion, the possibility that chloroquine has caused the pancytopenia in this case cannot be excluded.

Svar: The possibility of haematological side-effects caused by chloroquine has been discussed in earlier Drugline documents (1,2). To summarise, chloroquine has been described in connection with several kinds of blood dyscrasias (3), but the information available is sparse and mostly based on case reports.

A retrospective controlled study (4) concerning 229 travellers using chloroquine as a malaria prophylaxis reported a significantly reduced leukocyte count in the chloroquine users compared with the controls. The reduction was observed only in the first 10 weeks of exposure and was due to a diminuation of lymphocytes, not neutrophils. Possible mechanisms were not discussed. One case report (5) mentions the appearance of neutropenia in a patient with dermatomyositis, who was treated with chloroquine for six months 500 mg/day. The white cell count returned to normal values within a few days after discontinuation of the drug. One report could be found of aplastic anaemia occurring in three patients following chloroquine therapy (6). In two patients, chloroquine had been administered in large doses over a long period and one of them subsequently developed acute myeloblastic leukemia. However, the third patient, who used the chloroquine as antimalarial therapy, developed symptoms within three weeks.

Three cases of agranulocytosis, three cases of leukopenia and one of aplastic anaemia have been reported to the Swedish Adverse Drug Reactions Committee, in possible connection with chloroquine treatment. However, these cases are difficult to evaluate because information about the dose and the concomitant use of other drugs is lacking.

In several handbooks, it is recommended that chloroquine be used with caution in patients with haematological diseases (7,8); however, these statements are not further referenced.

It should be stressed that pancytopenia may be found as a symptom of several serious disorders. In a follow-up study (9) concerning 100 patients with pancytopenia, aplastic anaemia was the cause in 16 patients, 50 patients had other conditions explaining their pancytopenia, but in 34 patients no obvious explanation was found at the time of discovery of this symptom. Sometimes, disorders such as aplastic anaemia or myelodysplastic syndrome seem to develop very slowly and with uncharacteristic morphological changes. In a population-based study (10) on the incidence of potentially drug-associated blood dyscrasias, 28 cases were diagnosed to have "transient pancytopenia", meaning that they recovered within 90 days after being diagnosed, with median leukocyte recovery times of about 14 days. Sixteen patients in this group had taken a variety of drugs within two weeks before the onset of symptoms. Therefore, it seems important not to underestimate the influence of drug-induced pancytopenia, even if the information available is not conclusive.

The mechanism of chloroquine-induced marrow injury is not known (6). In chloramphenicol, which is better documented, two main forms of chloramphenicol-induced aplasia have been identified: one is dose-related and reversible and seems to result from inhibition of mitochondrial protein synthesis, the other may not be dose-related, is of later onset and suggests a stem cell lesion.

Interestingly, a patient with moderate pancytopenia thought to be due to chloroquine (11) was shown to have bone marrow granulocyte progenitors (CFU-G) which were abnormally sensitive in vitro to chloroquine and also to proguanil. The authors considered this the first in vivo confirmation of in vitro CFU-G drug sensitivities.

The questioner is welcome to consult Dr Marianne Keisu if a further dicussion of this haematological problem is desired (12).

We recommend that the present case be reported to SADRAC.