Dapsone for Pneumocystis Carinii Prophylaxis in Children Undergoing Bone Marrow Transplantation

Dapsone for Pneumocystis carinii prophylaxis in children undergoing bone marrow transplantation

HC Maltezou1,2, D Petropoulos3, M Choroszy3, M Gardner3, EC Mantzouranis2, KVI Rolston1 and KW Chan3

Departments of 1Medical Specialties, and 3Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; and 2Department of Pediatrics, University of Crete, Heraclion, Greece

Summary: when continual immunosuppressive treatment was required.1,6,7 Unfortunately, administration of TMP/SMX Children who undergo bone marrow transplantation can be associated with adverse effects, including myelo- (BMT) are at risk for Pneumocystis carinii pneumonia suppression, renal toxicity, skin rash, nausea and fever.6–8 (PCP). Prophylaxis using trimethoprim/sulfa- For patients undergoing BMT, myelosuppression is of methoxazole (TMP/SMX) is highly effective but the inci- major concern, especially if ganciclovir is required simul- dence of adverse drug reactions is significant. We retro- taneously. Renal dysfunction is problematic, particularly in spectively reviewed 33 pediatric BMT (25 allogeneic and patients already receiving potentially nephrotoxic drugs eight autologous) in whom dapsone was used for PCP such as cyclosporine. Nausea, vomiting, and skin rash in prophylaxis because patients were unable to receive the post-BMT period can be confused with acute graft-ver- TMP/SMX. Dapsone was administered at 50 mg/m2 p.o. sus-host disease (GVHD). once a week from engraftment to 180 days post-autolog- Oral dapsone has been used as an alternative to PCP ous BMT, and to 1 year or throughout the duration of prophylaxis in children with acquired immunodeficiency immunosuppressive treatment post-allogeneic BMT. syndrome (AIDS) or cancer who are intolerant to With a total of 7268 patient days of dapsone prophylaxis TMP/SMX.4,5,9 However, the use of dapsone prophylaxis and a median follow-up of 353 days post-BMT, no pro- in BMT recipients (children or adults) has not been reported ven PCP was diagnosed. Sixteen cases of chest radio- previously. We report here our experience of using dapsone graph abnormalities were noted in this patient popu- for PCP prophylaxis in pediatric BMT recipients who were lation but none was attributed to PCP. Dapsone was intolerant or allergic to TMP/SMX. well tolerated by all children with no serious adverse effects; however, one patient developed Toxoplasma gondii encephalitis during dapsone prophylaxis. Dap- sone warrants further evaluation as an alternative for Materials and methods PCP prophylaxis in pediatric BMT patients intolerant of TMP/SMX. Additional prophylaxis should be considered for patients at high risk for T. gondii encepha- The medical records of 96 consecutive children and ado- litis. lescents who received BMTs at The University of Texas Keywords: dapsone; Pneumocystis carinii; children; MD Anderson Cancer Center from July 1992 to October bone marrow transplantation 1996 were reviewed. Patients were followed from the day of admission for BMT to the most recent day of follow-up or death. The standard PCP prophylaxis regimen for BMT recipi- Without effective chemoprophylaxis, Pneumocystis carinii ents in our center is TMP/SMX (5 mg/kg/day twice a pneumonia (PCP) occurs in 5 to 15% of bone marrow trans- week). Dapsone was used instead of TMP/SMX when (1) plant (BMT) recipients, and is associated with a mortality the patients had a history of allergy or were already on 1–3 of approximately 60%. Trimethoprim/sulfamethoxazole dapsone prior to BMT; (2) were intolerant of the standard (TMP/SMX) is effective for prevention of PCP in the regimen after BMT; or (3) their clinical condition such as 1,4,5 immunocompromised host. Over the last decade, the slow hematologic recovery or skin rash rendered the use of institution of TMP/SMX prophylaxis has almost completely TMP/SMX less desirable. Prophylactic dapsone was eliminated PCP in BMT recipients; documented infections administered at a dose of 50 mg/m2 a week (rounded to were noted only after chemoprophylaxis had been interrup- the nearest 25 mg tablet) for 180 days to autologous BMT ted because of intolerance to the drug, noncompliance or recipients for 1 year to allogeneic BMT recipients or for as long as immunosuppressive treatment for GVHD was administered. P. carinii was routinely evaluated in lung Correspondence: Dr KW Chan, Department of Pediatrics, Box 87, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, tissue or broncho alveolar lavage (BAL) specimen by Groc- Houston, TX 77030, USA ott methenamine silver stain and correlated with clinical Received 4 April 1997; accepted 7 July 1997 and radiological signs compatible with pneumonia. Dapsone for PCP prophylaxis post-BMT HC Maltezou et al 880 Results to AP prophylaxis but none showed improvement of their liver function tests. No vomiting, diarrhea, skin rash, hemo- A total of 32 children underwent 33 (25 allogeneic and lysis or unexplained myelosuppression was temporally eight autologous) BMTs and received dapsone for PCP attributed to dapsone administration. Transfusion require- prophylaxis (Table 1). Patients were followed for a median ments were similar between patients receiving dapsone and of 349 days (range, 55 to 1245) post-BMT. The indications those on TMP/SMX (data not shown). One episode of for use of dapsone for PCP prevention were a history of Toxoplasma gondii encephalitis occurred 3 months post- allergic reaction to TMP/SMX (11 patients), concurrent BMT during dapsone prophylaxis in a patient from an skin rash (six patients), nausea and vomiting (seven endemic area. Dapsone prophylaxis was discontinued in 25 patients), slowly recovering blood counts (eight patients), cases: completion of prophylaxis schedule in 14 patients; and intolerance to the taste of TMP/SMX (one patient). death in five patients; hepatic GVHD in four patients and Dapsone was introduced at a median of 22 days (range, 11 change to TMP/SMX prophylaxis in two patients to 55) post-BMT and was administered for a median of 230 (including one patient with T. gondii encephalitis and one days (range, 14 to 667) in allogeneic BMT recipients and patient by the decision of his primary physician). Eight a median of 164 days (range, 47 to 275) in autologous BMT patients are still receiving dapsone at the time of this report. recipients. A total of 7268 patient-days of dapsone prophy- No PCP was diagnosed in the remaining 64 patients who laxis were evaluated. Fourteen (56%) of the allogeneic received TMP/SMX prophylaxis post-BMT during the BMTs were associated with grade II or greater acute same period of observation. GVHD and extensive chronic GHVD was diagnosed in nine (36%). Twenty-three (70%) of the patients received steroids for a median of 59 days (range, 5 to 518) for the Discussion treatment of GVHD, immune hemolytic anemia and recurrent leukemia. Regular administration of TMP/SMX has been proven to No episode of PCP or extrapulmonary P. carinii infec- be highly effective in the prevention of PCP in immuno- tion was diagnosed during the period of observation. There compromised patients. Unfortunately, 9–20% of children were 16 episodes of chest radiographic abnormalities; in 10 with leukemia have to discontinue TMP/SMX, mostly as episodes an infectious etiology other than PCP was diag- the result of myelosuppression or skin rash.8,10 The inci- nosed by culture and/or response to antimicrobial therapy. dence of intolerance is even higher in children with AIDS, Pulmonary hemorrhage was the cause in three other epi- probably as a result of the underlying disease and the num- sodes. In the two remaining episodes, both BAL and auto- ber of drugs these patients are taking concomitantly. psy showed no infectious etiology. In only one episode was Patients recovering after BMT are also often receiving mul- the diagnosis uncertain (in a patient with hepatic GVHD tiple medications and battling with GVHD and opportun- and leukemia in relapse, whose family requested that no istic infections. When adverse reactions results in interrup- invasive diagnostic or therapeutic interventions be tion of TMP/SMX prophylaxis post-transplant, PCP often performed). This patient had been switched to aerosolized develops.7 An alternative to TMP/SMX for PCP prophy- pentamidine (AP) prophylaxis 11 weeks earlier because of laxis is aerosolized pentamidine. The drawbacks of AP liver enzyme abnormalities. include a 5–9% incidence of bronchospasm,10,11 absence of Dapsone was well tolerated. Two children had prolonged activity against T. gondii and extrapulmonary P. carinii anorexia and nausea. While on dapsone four patients infection,5 and a significantly higher cost. developed GVHD involving the liver. They were switched From the current study, we found dapsone to be well tolerated in children intolerant or allergic to TMP/SMX. The once weekly schedule enhanced patient compliance. Table 1 Patient characteristics Despite the large number of medications these patients were receiving, we did not encounter any significant side- Characteristic Patients (n = 32) effects related to dapsone. Our experience is similar to that of AIDS patients given low-dose dapsone, in whom only Median age in years (range) 10 (1.5–21) mild and reversible effects were noted.5,11–13 The observed safety of dapsone in our population may be secondary to BMT total 33 allogeneic, related (%) 11 (33) the dosage and schedule used. allogeneic, unrelated (%) 14 (43) Much of the information about the use of dapsone as autologous (%) 8 (24) PCP prophylaxis is reported in AIDS patients. However, the optimal dosage and schedule has not been firmly estab- GVHD prophylaxis (%) 4,5,14 cyclosporine + MTX 16 (64) lished. Various studies have demonstrated the efficacy FK 506 + MTX 8 (32) of daily, twice weekly and weekly dapsone in the preven- MTX alone 1 (4) tion of PCP. The incidence of adverse reactions to dapsone appears to be related to the dose and frequency of adminis- Relapse of underlying disease post-BMT (%) 7 (21) tration.12,14,15 In the present study, we chose a lower dap- allogeneic 4 2 autologous 3 sone dose of 50 mg/m once a week, one successfully used by our leukemia service for over 10 years. Weekly adminis- BMT = bone marrow transplantation; GVHD = graft-versus-host disease; tration of dapsone is feasible because of its prolonged MTX = methotrexate plasma half-life and the long incubation period and repli- Dapsone for PCP prophylaxis post-BMT HC Maltezou et al 881 cation cycle of P. carinii.12,13 We believe that the progres- 5 Masur H. Prevention and treatment of pneumocystis pneu- sive recovery of the immune system and the relative short monia. New Engl J Med 1992; 327: 1853–1860. duration of immunosuppressive therapy post-BMT allow 6 Hoyle C, Goldman JM. Life threatening infections occurring the use of a less intensive regimen for PCP prophylaxis.6,7,14 more than 3 months after BMT. Bone Marrow Transplant It is noteworthy that BMT recipients are customarily given 1994; 14: 247–252. 7 Lyytikainen O, Ruutu T, Volin L et al. Late onset Pneumo- TMP/SMX twice weekly for PCP prophylaxis, whereas leu- cystis carinii pneumonia following allogeneic bone marrow kemia or AIDS patients frequently receive a three times per transplantation. Bone Marrow Transplant 1996; 17: 1057– 2,4,8 week regimen. 1059. One of our patients developed T. gondii encephalitis 8 Hughes WT, Rivera GK, Schell MJ et al. Successful intermit- while on dapsone prophylaxis. Dapsone possesses activity tent chemoprophylaxis for Pneumocystis carinii pneumonitis. against T. gondii and can achieve cerebrospinal fluid con- New Engl J Med 1987; 316: 1627–1632. centration inhibitory to this organism.16,17 In these reports, 9 Stavola JJ, Noel GJ. Efficacy and safety of dapsone prophy- dapsone was either administered with pyrimethamine or at laxis against Pneumocystis carinii pneumonia in human doses higher than those used in our patients. We suggest immunodeficiency virus infected children. Pediatr Infect Dis that in patients susceptible to reactivation of T. gondii, pyri- J 1993; 12: 644–647. 10 Mustafa MM, Pappo A, Cash J et al. Aerosolized pentamidine methamine should be incorporated in the current dapsone for the prevention of Pneumocystis carinii pneumonia in prophylaxis regimen. children with cancer intolerant or allergic to None of the patients on dapsone developed PCP after a trimethoprim/sulfamethoxazole. J Clin Oncol 1994; 12: 258– median observation time of 1 year. Similarly, no patients 261. given TMP/SMX during the same period had PCP infec- 11 Link H, Vohringer HF, Wingen F et al. Pentamidine aerosol tion. Because PCP occurs in less than 1% of BMT patients for prophylaxis of Pneumocystis carinii pneumonia after when effective prophylaxis is prescribed, it requires a very BMT. Bone Marrow Transplant 1993; 11: 403–406. large sample size to detect a difference in regimen efficacy. 12 Hughes WT. Comparison of dosages, intervals and drugs in The result of this retrospective study should therefore be the prevention of Pneumocystis carinii pneumonia. Antimicrob considered preliminary and further studies are warranted to Agents Chemother 1988; 32: 623–625. 13 Opravil M, Joos B, Luthy R. Levels of dapsone and pyrimeth- determine the efficacy of dapsone prophylaxis in BMT amine in serum during once weekly dosing for prophylaxis of recipients. Pneumocystis pneumonia and toxoplasmic encephalitis. Anti- microb Agents Chemother 1994; 38: 1197–1199. 14 Hughes WT, Kennedy W, Dugdale M et al. Prevention of References Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone. Lancet 1990; 36: 1066. 1 Tuan IZ, Dennison D, Weisdorf DJ. Pneumocystis carinii 15 Falloon JD, Lavelle J, Ogata-Arakaki D et al. Pharmacokinet- pneumonitis following bone marrow transplantation. Bone ics and safety of weekly dapsone and dapsone plus pyrimeth- Marrow Transplant 1992; 10: 267–272. amine for the prevention of Pneumocystis pneumonia. Anti- 2 Walters EA, Bowden RA. Infection in the bone marrow trans- microb Agents Chemother 1994; 38: 1580–1587. plant recipient. Infect Dis Clin N Am 1995; 9: 823–847. 16 Rich JD, Mirochnick M. Dapsone penetrates cerebrospinal 3 Meyers JD, Atkinson K. Infection in bone marrow transplan- fluid during Pneumocystis carinii pneumonia prophylaxis. tation. Clin Haematol 1983; 12: 791–811. Diagn Microbiol Infect Dis 1996; 24: 77–79. 4 Ioannidis JP, Cappelleri JC, Skolnik PR et al. A meta-analysis 17 Derouin F, Piketty C, Chastang C et al. Anti-Toxoplasma of the relative efficacy and toxicity of Pneumocystis carinii effects of dapsone alone and combined with pyrimethamine. prophylaxis regimens. Arch Intern Med 1996; 156: 177–187. Antimicrob Agents Chemother 1991; 35: 252–255.