American Journal of Hematology 75:6–11 (2004)

Stem Cell Transplantation Post Invasive Fungal Infection Is a Feasible Task Irit Avivi,1,3 Ilana Oren,2,3 Nuhad Haddad,1 Jacob M. Rowe,1,3 and Eldad J. Dann1,3* 1

Department of Hematology and Bone Marrow Transplantation, Technion, Haifa, Israel 2 Infectious Disease Unit, Rambam Medical Center, Technion, Haifa, Israel 3 Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

Between March 1997 and January 2002, 18 consecutive patients (18–47 years) with hematological malignancies and previous proven invasive fungal infection underwent stem cell transplantation (SCT) (10 matched sibling allograft, 6 autograft, and 2 haploidentical). All patients had full myeloablative conditioning. The fungal pathogens diagnosed were Aspergillus (14), Fusarium (2), Mucor (1), Exserohilum (1), and Candida (1), involving the lungs (15), sinuses (5), and liver (1). All patients were treated pre- and during transplant with systemic antifungal therapy. Eleven out of 18 (61%) patients survived the transplant. Only 1 of 5 patients who transplanted with an active fungal infection accompanied with active leukemia survived the transplant, compared with 10/13 (84%) survivals in patients who had no clinical and radiological signs of infection or active leukemia (P < 0.025). None of the autografted patients has died, compared with 7/12 allografted patients, of whom 5 underwent transplant with active hematological/ active fungal disease. In only 3 patients was the cause of death reactivation of previous fungal infection. Both active fungal infection and active leukemia place patients at a very high risk for procedure-related mortality. Pre-transplant therapy of fungal infection, aiming to achieve a clinically undetectable state of infection, followed by an antifungal treatment during transplant may allow the SCT with no fungal reactivation in selected patients. Am. J. Hematol. 75:6–11, 2004. ª 2003 Wiley-Liss, Inc. Key words: fungal infections; Aspergillus; stem cell transplantation

INTRODUCTION

Prior invasive fungal infection places patients at a high risk for transplant-related mortality (TRM) due to reactivation of invasive fungal infection. A high TRM of up to 60–90% [1–9] often leads to the exclusion of these patients from stem cell transplantation (SCT). However, excluding all patients with prior fungal infection from having SCT is unnecessary [1,10–12] and may delay or even preclude essential treatment from patients who can tolerate it. There is no consensus on which patients should have SCT after previous invasive fungal infection and what is the optimal timing for having the transplant. Risk factors for reactivation of fungal infection should be accurately assessed in order to evaluate patients’ risk. Aggressive antifungal therapy pre and during the transplant period is essential. Patients with previous ª 2003 Wiley-Liss, Inc.

invasive fungal infection are usually treated with fulldose antifungal therapy during the transplant period, even if there are no signs of active infection [1,10,13]. This report describes 18 consecutive adult patients with hematological malignancies and prior invasive fungal infection who underwent SCT between March 1997 and January 2002. The feasibility of transplantation post fungal infection was assessed, evaluating risk factors for reactivation of fungal infection peri- and post-transplant *Correspondence to: Eldad J. Dann, M.D., Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, P.O. Box 9602, Haifa 31096, Israel. E-mail: e_dann@ rambam.health.gov.il Received for publication 23 December 2002; Accepted 15 August 2003 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.10447

Stem Cell Transplantation Post Invasive Fungal Infection Is Feasible

periods as well as the efficacy of antifungal prophylaxis administered.

PATIENTS AND METHODS Patients

Eighteen consecutive patients were retrospectively analyzed, 11 men and 7 women, aged 18–47 years (median age 32 years). Underlying hematological malignancies included AML (13), ALL (4), MM (1) (Table I). All patients had undergone SCT after prior invasive fungal infection. All patients had myeloablative conditioning, and haploidentical transplantations were performed with additional immunosuppression. Definitions Diagnosis of invasive fungal infection.

(a) Diagnosis of proven fungal infection was based on a positive culture, obtained from the infected tissue or peripheral blood, or pathological or cytological evidence for fungal infection in the

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presence of typical clinical and radiological findings [14]. (b) Diagnosis of probable fungal infection was made in the presence of typical clinical and radiological findings for fungal disease but without confirmatory pathological or microbiological evidence [14]. Hematological disease status. (a) Complete remission (CR) was defined as less than 5% blasts in the bone marrow biopsy and aspirate. (b) Partial remission (PR) was defined as 5–10% blasts in the bone marrow following therapy. (c) Early relapse was defined as less then 10% blast cells in the bone marrow, in a patient who had previously achieved a CR. (d) Active hematological disease was defined on the presence of more than 20% blasts or more in a normocellular/hypercellular bone marrow. Parameters evaluated. . .

Age and gender Underline hematologic disease and status of disease prior to procedure

TABLE I. Pre-transplant Evaluation: Patient Characteristics, Hematological Disease, and Fungal Infection*

Patient no.

Age/sex

Hematological malignancy

Clinical presentation

1

47/F

AML

Pneumonia

Aspergillus

2 3 4

44/F 45/M 20/M

AML MM ALL

Aspergillus Aspergillus Candida

5 6 7 8 9 10 11

32/M 27/F 23/M 28/M 46/M 18/M 23/M

AML ALL AML AML AML AML AML

Pneumonia Pneumonia Hepatosplenic candidiasis Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia

Aspergillus Aspergillus Aspergillus Aspergillus Aspergillus Aspergillus Aspergillus

12

22/F

ALL

Sinusitis

Fusarium

13

37/M

AML

Pneumonia

Aspergillus

14

41/F

AML

Exserohilum

15 16

41/F 39/F

AML AML

17 18

19/M 32/M

ALL AML

Pneumonia + sinusitis Sinusitis Pneumonia + sinusitis Pneumonia Pneumonia + sinusitis

Organism

Aspergillus Aspergillus Aspergillus Mucor mycosis, Fusarium

Diagnosis Micro + path + CT Micro + CT Cytol + CT Path + CT Cytol + CT Microbial + CT CT CT Path + CT Cytol + CT Micro + path + CT Micro + path + CT Micro + Cytol + CT Path + micro + CT Micro + CT Path + Micro + CT CT Path + Micro + CT

Proven (P) or probable (Pr) diagnosis

Time from fungal infection to BMT (days)

Treatment of IFI prior to BMT

P

50

I+S

P P P

135 90 50

P P Pr Pr P P P

NA 50 30 120 NA ND 195

A+I A+I A+F+ splenectomy A+I A+I A+I A+I A+I LA A+S

P

180

A+I

P

50

A + LA

P

55

A + LA + I

P P

120 40

A+I A + LA + I

Pr P

210 60

A+I A + LA + S

*Abbreviations: A, amphotericin; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; Cytol, cytological evidence for fungal; F, fluconazole; I, itraconazole; LA, liposomal amphotericin; Micro, microbiological evidence for fungal infection; MM, multiple myeloma; Path, histopathology evidence for fungal infection; Pr, probable fungal infection; P, proven fungal infection; S, surgical resection of fungal ball.

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Avivi et al.

Diagnosis of invasive fungal infection (proven or probable) Status of invasive fungal infection pre-transplantation Antifungal treatment before and during SCT Reactivation of fungal infection during SCT Transplant-related morbidity and mortality, unrelated to fungal reactivation

Statistics

Fisher’s exact test was used to compare risk of mortality between patients with different stages of their fungal infection and hematological disease.

RESULTS

Eighteen consecutive patients were evaluated, 11 men and 7 women, aged 18–47 years (median age 32 years). Fungal Infection and Hematological Disease Status, Prior to BMT

Invasive fungal infection prior to SCT was proven in 15 patients (patients nos. 1–6, 9–16, and 18) (Table I). In 3 other patients, diagnosis was probable (Table I, patients nos. 7, 8, and 17). Invasive aspergillosis was the most frequent infection (14/18 patients), followed by Fusarium (n ¼ 2), and Exserohilum, Mucor, and Candida, each isolated in 1 patient. Sites of involvement included lung (n ¼ 15), sinuses (n ¼ 5), liver and spleen (n ¼ 1). (Three patients had more than one site of involvement). All patients with prior fungal infection were initially treated for at least 2 weeks with amphotericin B (1 mg/kg) or liposomal amphotericin (5 mg/kg) until marked clinical and radiological improvement accompanied by neutrophil recovery. Amphotericin B was then replaced by oral itraconazole 400 mg/day, excluding periods of recurrent neutropenia when therapeutic doses of amphotericin B were given. Three patients have also undergone surgical resection of a fungal mass prior their transplant (patients no. 1, 11, and 18). In 5 patients, fungal infection was still active on admission to transplant (based on clinical and radiological evidence of progression) (Table II, patients no. 10–14). Hematological disease status on admission to SCT was as follows: 8 patients were in complete remission (CR) of their hematological malignancy, 3 had early relapse (ER), 1 achieved partial remission (PR) with 8% blasts, and 6 had refractory relapse (patients no. 10–15). Antifungal Therapy During Transplantation

Amphotericin B (1 mg/kg/day), or liposomal amphotericin B (5 mg/kg/day) were restarted on admission to transplant and continued until neutrophil recovery (neutrophil count > 500/ml) occurred. Four of the pa-

tients who had active fungal infection on admission to transplant were treated with daily granulocyte transfusion, started when the neutrophil count decreased below 500/ml and continued until neutrophil engraftment occurred (patients no. 10 and 12–14). Outcome of Bone Marrow Transplantation (Table II)

Six patients underwent autologous SCT, and 12 underwent allogeneic SCT: 10 with matched sibling donor and 2 with haploidentical donor. At day 100 post-transplant eleven out of 18 patients were still alive (Table II). Six out of 6 autologous patients (patients nos. 1–6) survived the transplant, compared with 5/12 (41%) of the patients who had a sibling matched allogeneic/haploidentical SCT (P < 0.025). All autologous patients were transplanted in CR/ early relapse, with no evidence for active fungal infection, while 6/12 allogeneic patients were transplanted with refractory leukemia. Five of these 6 patients have also had an active invasive fungal infection. Eighty percent (4/5) of the allogeneic patients who survived had no evidence of active fungal infection nor active hematological disease on admission, where only 1/6 patients admitted with active leukemia/active fungal infection survived the transplant. Four out of 5 patients who had refractory leukemia accompanied with active fungal infection (patients no. 10–14) did not survive the transplant (patients no. 11–14). Two of these patients (no. 11 and 12) died of fulminant fungal infection, while the other two patients (no. 13 and 14) died of bacterial sepsis with no evidence for active fungal infection in open lung biopsies. Three more patients died, 2 with no evidence of active leukemia or fungal infection at transplantation (patients no. 16 and 17) and 1 with active leukemia but with no proof of fungal infection in tissue biopsy repeated pre-transplant (patient no. 15). Despite having no histological evidence for fungal infection on admission to transplant, this patient (no. 15) developed reactivation of previous Aspergillus infection while being treated with high-dose steroids for grade IV acute graft-versus-host disease and died of fulminant fungal infection. In summary, 3 patients only (17%) died of reactivation or progression of fulminant fungal infection following their transplant. Transplant Outcome Related to Treatment With Granulocyte Transfusions

Only one out of 4 patients who were treated with granulocyte transfusions for active fungal infection (patients no. 10, 12–14) survived the transplant. The three others died of fulminant fungal infection (patient no. 12) and severe bacterial sepsis with no evidence of fungal infection in lung biopsy (patients no. 13 and 14).

Stem Cell Transplantation Post Invasive Fungal Infection Is Feasible

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TABLE II. Complications and Outcome of Stem Cell Transplant*

Patient no.

Hematological disease status at SCT

Transplant conditioning regimen

Fungal infection status entering SCT

Type of transplant

Engraftment (in days) WBC

Outcome at 100 days post-transplant

1 2

CR ER

Bu + Cy Bu

NI NI

Auto Auto

8 40

Alive Alive

3 4 5 6

CR CR CR ER

Melphalan TBI + VP-16 NA Bu + Cy

NI NI NI NI

Auto Auto Auto Auto

11 10 NA 12

Alive Alive Alive Alive

7 8 9 10 11

PR CR ER Ab A

By + Cy NA NA ATG + F Bu + Cy

NI NI NI A A

Allo Allo Allo Haplo
20 Allo

17 NA NA 11 NE

12

A

TBI + VP-16

A

Allo

+18

13

A

Cy + TBI

A

Allo

15

14

A

ATG + F + CTX

A

Haplo

10

15

A

Bu + Cy

NI

Allo

+36

16

CR

BU + CY

NI

Allo

17

17 18

CR CR

TBI + VP16 BU + CY

NI NI

Allo Allo

NE +21

Alive Alive Alive Alive Died + 10 d lung hemorrhage, Aspergillus Died + 21 d Fusarium reactivation Died + 36 d. VOD, sepsis, respiratory failure Died + 44 d sepsis with respiratory failure Died + 45 d AGVHD Gr IV + lung Aspergillus Died + 38 d, Candida crusi sepsis, AGVHD, VOD Died + 10 days Alive

Follow-up (d, days; m, months) Dead + 4 m Dead relapsed AML + 3 ma Alive + 15 m Alive + 33 m Alive + 48 m Died 7 m ALL relapse Alive + 24 m Alive + 48 m Alive + 48 m Alive + 24 m Dead + 10 d

Died + 21 d Died + 36 d

Died + 44 d

Died + 45 d

Died + 38 d

Died + 10 d Alive + 9 m

*Abbreviations: A, active disease; CR, complete remission; ER, early relapse; NA, not available; PR, partial response; Bu, busulfan; Cy, cyclophosphamide; Melp, melphalan; F, fludarabine; ATG, anti-thymocyte globulin; VP-16, Etoposide; NI, no signs of active infection; NA, not available; Haplo, haploidentical bone marrow transplant; Allo, allogeneic bone marrow transplant; Auto, autologous bone marrow transplant; AML, acute myeloid leukemia; ALL, acute lymphocyte leukemia. a Developed reactivation of fungal infection when relapsed. b Had a first haploidentical BMT for refractory AML. Transplant was complicated with engraftment failure + systemic fungal infection. Received a second haploidentical BMT while fungal infection was still active.

DISCUSSION

In this report we present 18 patients with hematological malignancies who had stem cell transplantation after being treated for documented invasive fungal infection. Eleven out of 18 (61%) patients survived the transplant procedure with no reactivation of fungal infection procedure 100 days following their transplant. Activity of fungal infection and the hematological disease status both had a significant impact on transplant outcome. Hematologic Disease Status

Transplant outcome was significantly better in patients who entered transplant in complete remission

or with low marrow blast count. Only one out of 6 patients admitted with active leukemia survive the transplant, compared with 10/12 (83%) survival rate in patients in remission or with low blast count (P < 0.015). Stem cell transplantation with active leukemia has already been reported to be associated with a significantly higher mortality, even in patients without a previous fungal infection [15]. Controlled Fungal Infection Versus Nonresponsive, Active Infection

Four of the 5 patients transplanted with active fungal infection have died, compared with 3/13 (23%) patients transplanted without evidence of active fungal infection (P < 0.05). However, progressive

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Avivi et al.

fungal infection was the cause of death in 3 patients only: 2 with active fungal infection at admission to transplant and 1 with reactivation of previous fungal infection related to steroid therapy, given for acute GVHD. It is reasonable to assume that with the newer antifungal agents echinocandin derivatives, like caspofungin or improved triazoles like voriconazole that were unavailable to our patients at the time of the study, the outcome of the fungal infection might have been better. Several publications confirm a low rate of reactivation of fungal infection in patients transplanted with controlled fungal disease [10,11], suggesting previous fungal infection to be a relative contraindication only. Type of Transplant

All 6 autologous transplant patients survived, compared with 5 out of 12 allogeneic transplant patients. However, while all autologous patients had either CR or early relapsed disease and no evidence of active fungal disease, 6/12 allogeneic transplant patients had active leukemia, accompanied with active fungal infection in 5 of them. Four out of 6 patients who had undergone allogeneic SCT in CR/early relapse and with no evidence for active fungal infection have survived. Wang et al. recently reported the outcome in 7 patients who underwent allogeneic stem cell transplantation in 1st/2st CR, after having been successfully treated for documented invasive fungal infection [11]. None of the patients developed reactivation of fungal infection during transplant, supporting our observation that patients in CR who have no evidence for active fungal infection can be considered for allogeneic SCT [11]. Significance of Post-Transplant Neutropenic Period to Transplant Outcome

No correlation between the duration of neutropenic period (Table II) and SCT outcome has been seen in our study, which might reflect the small number of patients reported. However, since prolonged neutropenic period is a known risk factor for fungal infection [16–18], shortening its duration may have an advantage. Transplanting with peripheral blood stem cells (PBSC) compared with bone marrow stem cells (BMSC) [19] and both growth factors (granulocyte colony-stimulating factor [G-CSF] or granulocyte monocyte colonystimulating factor [GM-CSF]) post transplant [20] can be used to facilitate neutrophil engraftment. Patients who develop progression of infection while neutropenic may benefit from receiving granulocyte transfusions [21,22]. Fungal infection was successfully

controlled in three of our patients who had active infection when admitted to transplant and were therefore treated with granulocyte transfusion following transplant (confirmed histologically in two of them). The experience with granulocyte transfusion is too small to draw any conclusion. Prospective randomized trials are needed to support the routine usage of granulocyte infusions in these patients. In conclusion, patients with fungal infection should not be excluded from autologous or allogeneic stem cell therapy. Our experience suggests that at least 60% of patients may undergo transplant uneventfully. Only 17% of patients died due to reactivation/ progression of their fungal disease. Active hematological disease or active fungal infections are associated with a high mortality during SCT. By determining the status of fungal infection and hematological disease prior to SCT, one may predict the patient’s outcome. The lower survival rate observed in allografted patients compared with autografted patients is most probably reflecting the higher incidence of active fungal infection/active hematological disease observed in this group of patients. However, since this cohort of patients is small, caution is necessary in definitively describing risk factors and a multi-center study is warranted. REFERENCES 1. Offner F, Cordonnier C, Ljungman P, et al. Impact of previous aspergillosis on the outcome of bone marrow transplantation. Clin Infect Dis 1998;26:1098–1103. 2. Hovi L, Saarinen-Pihkala UM, Vettenranta K, Saxen H. Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years. Bone Marrow Transplant 2000;26:999–1004. 3. Pannuti CS, Gingrich RD, Pfaller MA, Wenzel RP. Nosocomial pneumonia in adult patients undergoing bone marrow transplantation: a 9-year study. J Clin Oncol 1991;9:77–84. 4. Schwartz RS, Mackintosh FR, Schrier SL, Greenberg PL. Multivariate analysis of factors associated with invasive fungal disease during remission induction therapy for acute myelogenous leukemia. Cancer 1984;1;53:411–419. 5. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis 1990;12:1147–1201. Review. 6. De Bock R. Epidemiology of invasive fungal infections in bone marrow transplantation. EORTC Invasive Fungal Infections Cooperative Group. Bone Marrow Transplant 1994;14(Suppl 5):S1–2. 7. McWhinney PH, Kibbler CC, Hamon MD, et al. Progress in the diagnosis and management of aspergillosis in bone marrow transplantation: 13 years’ experience. Clin Infect Dis 1993;17(3): 397–404. 8. Wade JC. Treatment of fungal and other opportunistic infections in immunocompromised patients (review). Leukemia 1997;11(Suppl 4): S38–9. 9. Noskin G, Pietrelli L, Gurwith M, Bowden R. Treatment of invasive fungal infections with amphotericin B colloidal dispersion in bone marrow transplant recipients (review). Bone Marrow Transplant 1999;23:697–703.

Stem Cell Transplantation Post Invasive Fungal Infection Is Feasible 10. Hoover M, Morgan ER, Kletzel M. Prior fungal infection is not a contraindication to bone marrow transplant in patients with acute leukemia. Med Pediatr Oncol 1997;28:268–273. 11. Wang JT, Yao M, Tang JL, Chang SC, Hung CC. Prior invasive fungal infection is not a contraindication for subsequent allogeneic bone marrow transplantation in adult patients with hematologic malignancies. J Clin Oncol 2001;19(1):4000–4001. 12. Michailov G, Laporte JP, Lesage S, et al. Autologous bone marrow transplantation is feasible in patients with a prior history of invasive pulmonary aspergillosis. Bone Marrow Transplant 1996; 17:569–572. 13. Rowe JM, Ciobanu N, Ascensao J, et al. Recommended guidelines for the management of autologous and allogeneic marrow transplantation. A report from the Eastern Cooperative Oncology Group. Ann Intern Med 1994;120:143–158. 14. Ascioglu S, Rex JH, de Pauw B, et al. on behalf of the Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002;34(1): 7–14. 15. Grigg AP, Szer J, Beresford J, et al. Factors affecting the outcome of allogeneic bone marrow transplantation for adult patients with refractory or relapsed acute leukaemia. Br J Haematol 1999;107: 409–418.

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16. Jantunen E, Ruutu P, Piilonen A, et al. Treatment and outcome of invasive Aspergillus infections in allogeneic BMT recipients. Bone Marrow Transplant 2000;26:759–762. 17. Johnson E, Gilmore M, Newman J, Stephens M. Preventing fungal infections in immunocompromised patients. Br J Nurs 2000;9: 1154–1156, 1158–1164. 18. Oren I, Haddad N, Finkelstein R, Rowe JM. Invasive pulmonary aspergillosis in neutropenic patients during hospital construction: before and after chemoprophylaxis and institution of HEPA filters. Am J Hematol 2001;66:257–262. 19. Larsson K, Bjo¨rkstrand B, Ljungman P. Faster engraftment but no reduction in infectious complications after peripheral blood stem cell transplantation compared to autologous bone marrow transplantation. Support Care Cancer 1998;6:378–383. 20. Trigg ME, Peters C, Zimmerman MB. Administration of recombinant human granulocyte-macrophage colony-stimulating factor to children undergoing allogeneic marrow transplantation: a prospective, randomized, double-masked, placebo-controlled trial. Pediatr Transplant 2000;4:123–131. 21. Catalano L, Fontana R, Scarpato N, et al. Combined treatment with amphotericin B and granulocyte transfusion from G-CSF-stimulated donors in an aplastic patient with invasive aspergillosis undergoing bone marrow transplantation. Haematologica 1997;82:71–72. 22. Peters C, Minkov M, Matthes-Martin S, et al. Leucocyte transfusions from rhG-CSF or prednisolone stimulated donors for treatment of severe infections in immunocompromised neutropenic patients. Br J Haematol 1999;106:689–696.