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Prior Invasive Fungal Infection Is Not a Contraindication for Subsequent Allogeneic Bone Marrow Transplantation in Adult Patients With Hematologic Malignancies

National Taiwan University Hospital, Taipei, Taiwan
College of Medicine, National Taiwan University, Taipei, Taiwan

To the Editor:Invasive fungal infection, with an incidence ranging from 4.5% to 11%, is a major infectious complication associated with a high morbidity and mortality rate in patients with acute leukemia undergoing cytotoxic chemotherapy with or without subsequent bone marrow transplantation (BMT).^1-3 Even after an apparently curative antifungal treatment, nearly 50% of the cases of invasive fungal infections relapse when patients undergo subsequent courses of cytotoxic chemotherapy and BMT,¹ and the mortality rate may be as high as 80%.² Therefore, prior invasive fungal infections, especially those caused by molds, has been considered a relative contraindication for subsequent BMT. With the improvement of antifungal therapy, successful transplantation without recurrence of prior invasive fungal infections has been increasingly reported in adult patients undergoing BMT since 1988.^4-9 As of December 31, 2000, a total of 12 such patients have been reported in the literature, and most of them underwent autologous BMT. Successful allogeneic BMT in the adult patients with prior invasive mold infections has been rarely described, however.

From October 1998 to May 2000, seven adult patients with a median age of 27 years (range, 20 to 50 years) who had had prior invasive mold infections underwent subsequent BMT or peripheral-blood stem-cell transplantation (PBSCT) in our hospital: five with acute myelogenous leukemia, one with severe aplastic anemia, and one with non-Hodgkin’s lymphoma (stage IVB). Four achieved first complete remission and two achieved second remission before undergoing BMT. The diagnosis of invasive fungal infections was definitely made by positive cultures of the sterile sites or histopathologic examination of biopsy specimens in four patients and was presumptively made in another three based on the presence of positive cultures for molds from nonsterile sites and suggestive radiographic findings, plus prolonged neutropenic fever without responses to broad-spectrum antibiotics. Four of the patients underwent surgical resection of the invasive mold infections of the lung. The median duration between diagnosis and BMT was 82 days (range, 24 to 251 days), during which time four patients continued to receive courses of chemotherapy. The median total dose of amphotericin B was 1,150 mg (range, 450 to 2,000 mg) before resolution of clinical and radiographic findings suggestive of invasive mold infections was observed before BMT. Amphotericin B was subsequently replaced with itraconazole at a daily dose of 400 mg for a median duration of 60 days (range, 12 to 240 days).

All of the seven patients continued to receive amphotericin B from the beginning of conditioning for BMT to the recovery of granulocyte count to greater than 500 x 10⁶/L. The median duration between transfusion of bone marrow or peripheral-blood stem cells to recovery of granulocyte count was 18 days (range, 13 to 41 days). As of December 31, 2000, four of the seven patients were still alive, and no relapses of prior invasive mold infections and underlying diseases were observed after a median duration of 327 days after transplantation (range, 105 to 796 days). Three other patients died: two as a result of disseminated tuberculosis on day 105 and 110 post-BMT and one as a result of septic shock owing to Stenotrophomonas maltophilia after relapse of underlying disease on day 183 post-BMT. No evidence of relapse of prior fungal infections was found in the three fatal cases.

During the same study period, another 21 adult patients who had no prior invasive fungal infections underwent BMT or PBSCT in our hospital. Seven patients with identical underlying hematologic diseases were selected as control on the basis of the identical risk stratifications for BMT or PBSCT. In the control group, the median duration between transfusion of bone marrow or peripheral-blood stem cells to recovery of granulocyte count was 16 days (range, 10 to 20 days), which was not statistically different from that of the case patients (P = .305, by Mann-Whitney rank sum test). The mortality rate of the 32 patients and the seven patients in the control group was 40.6% and 57%, respectively, which was similar to that of the case patients (P = .99, by Fisher’s exact test).

As of December 31, 2000, five patients had been described in the literature who had had prior invasive fungal infections caused by molds and subsequently underwent allogeneic BMT. Two of the patients died. Patients undergoing allogeneic BMT would be more intensively immunosuppressed during the post-BMT period than those undergoing autologous BMT. Therefore, the patients with prior invasive fungal infections who are going to undergo allogeneic BMT might have a higher risk of developing relapse of prior invasive fungal infections. In our limited experience of seven patients, none had relapse of prior invasive fungal infections after BMT or PBSCT after surgical resection of the involved lungs and prolonged treatment with antifungal agents.

Our findings suggest that with the concurrent use of antifungal agents during and after the neutropenic period following BMT, prior invasive mold infections in selected adult patients with hematologic diseases might not be a contraindication for their subsequent allogeneic BMT. Our study was limited by the retrospective study design and small number of cases, however. Prospective, randomized studies of a larger case number and longer follow-up duration are desperately needed to assess whether patients with prior invasive fungal infections may fare better post-BMT if they are treated aggressively with surgical resection and prolonged antifungal therapy.

REFERENCES

1. Meyers JD: Fungal infections in bone marrow transplant patients. Semin Oncol 17: 10-13, 1990 (suppl 6)[Medline]

2. Robertson MJ, Larson RA: Recurrent fungal pneumonia in patients with acute non-lymphoblastic leukemia undergoing multiple courses of intensive chemotherapy. Am J Med 84: 233-239, 1988[Medline]

3. Wingard JR, Beals S, Santos GW, et al: Aspergillus infections in bone marrow transplant recipients. Bone Marrow Transplant 2: 175-181, 1987[Medline]

4. Richard C, Romón I, Insunza A, et al: Invasive pulmonary aspergillosis prior to BMT in acute leukemia patients does not predict a poor outcome. Bone Marrow Transplant 12: 237-241, 1993[Medline]

5. Martino R, Nomdedéu J, Altés A, et al: Successful bone marrow transplantation in patients with previous invasive fungal infections: Report of four cases. Bone Marrow Transplant 13: 265-269, 1994[Medline]

6. Bjerke JW, Meyers JD, Bowden RA: Hepatosplenic candidiasis: A contraindication to marrow transplantation? Blood 84: 2811-2814, 1994[Abstract/Free Full Text]

7. Lupinetti FM, Giller RH, Trigg ME: Operative treatment of Fusarium fungal infection of the lung. Ann Thorac Surg 49: 991-992, 1990[Abstract]

8. Schattenberg A, De Vries F, De Witte T, et al: Allogeneic bone marrow transplantation after partial lobectomy for aspergillosis of the lung. Bone Marrow Transplant 3: 509-512, 1988[Medline]

9. Hoover M, Morgan ER, Kletzel M: Prior fungal infection is not a contraindication to bone marrow transplantation in patients with acute leukemia. Med Pediatr Oncol 28: 268-273, 1997[Medline]

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