Fever after peripheral blood stem cell infusion in haploidentical transplantation with post-transplant cyclophosphamide

Accepted Manuscript Fever After Peripheral Blood Stem Cell Infusion in Haploidentical Transplantation with Post-transplant Cyclophosphamide Marcos Arango, Juan F. Combariza PII: DOI: Reference:

S1658-3876(17)30031-6 http://dx.doi.org/10.1016/j.hemonc.2017.03.001 HEMONC 169

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Hematology/Oncology and Stem Cell Therapy

Received Date: Accepted Date:

21 December 2016 14 March 2017

Please cite this article as: M. Arango, J.F. Combariza, Fever After Peripheral Blood Stem Cell Infusion in Haploidentical Transplantation with Post-transplant Cyclophosphamide, Hematology/Oncology and Stem Cell Therapy (2017), doi: http://dx.doi.org/10.1016/j.hemonc.2017.03.001

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Fever After Peripheral Blood Stem Cell Infusion in Haploidentical Transplantation with Post-transplant Cyclophosphamide

Marcos Arango *, Juan F. Combariza

Hematology Department, Hospital Pablo Tobón Uribe, Medellín, Colombia

Received XXX, Received in revised form XXX, Accepted XXX

* Corresponding author. Hematology Department, Hospital Pablo Tobón Uribe, Medellín, Calle 78 B # 69-240, Medellín, Colombia. E-mail address: [email protected] (M. Arango).

Running title: Fever after peripheral blood stem cell infusion

Abstract

Objective/Background: Noninfection-related fever can occur after peripheral blood stem cell infusion in haploidentical hematopoietic stem cell transplantation with post-

transplant cyclophosphamide. The objective of this study was to analyze the incidence of fever and characterize some clinical features of affected patients. Methods: A retrospective case-series study with 40 patients who received haploidentical hematopoietic stem cell transplantation was carried out. Results: Thirty-three patients (82.5%) developed fever; no baseline characteristic was associated with its development. Median time to fever onset was 25.5 hours (range, 9.5– 100 hours) and median peak temperature was 39.0C (range, 38.1–40.5C). Not a single patient developed hemodynamic or respiratory compromise that required admission to the intensive care unit. Fever was not explained by infection in any case. Ninety-one percent of the febrile episodes resolved within 96 hours of cyclophosphamide administration. No significant difference in overall survival, event-free survival, or graft versus host disease-free/relapse-free survival was found in the group of febrile individuals after peripheral blood stem cell infusion. Conclusion: Fever after peripheral blood stem cell infusion in this clinical setting was common; it usually subsides with cyclophosphamide administration. The development of fever was not associated with an adverse prognosis.

Keywords:

cyclophosphamide,

fever,

haploidentical

hematopoietic

transplantation, peripheral blood stem cell transplantation, prognosis

stem

cell

1. Introduction

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has emerged as a readily available alternative for the treatment of patients with diverse hematological disorders that lack an HLA-matched sibling or unrelated donor.1,2 Post-transplant cyclophosphamide (PT-CY) for the prevention of graft versus host disease (GVHD) has allowed the widespread use of this procedure.3,4 Notably, outcomes with haplo-HSCT apparently are similar to those obtained with matched unrelated and umbilical cord blood transplantation in some clinical settings.5–7 Fever is a common event after the infusion of stem cells in recipients of haploHSCT.8,9 Even though it may represent the first manifestation of infection, alternative noninfectious etiologies should be kept in mind. Recently, it has been suggested that fever can be part of the presentation of the cytokine release syndrome (CRS), and a grading system adapted for the haplo-HSCT setting has been proposed.10 CRS is an entity commonly seen after chimeric antigen receptor T-cell therapy that may be linked to an adverse prognosis.11 The aim of this study was to analyze the incidence of fever in a relatively homogeneous patient population and characterize some of its associated clinical features. We also analyzed whether clinically relevant CRS was found in this group of individuals and the development of fever had an adverse prognosis on relevant outcomes.

2. Methods

2.1. Patients

All consecutive patients undergoing haplo-HSCT at Hospital Pablo Tobón Uribe (Medellín, Colombia) between March 2014 and August 2016 were included; there were no exclusion criteria. Pediatric as well as adult patients were part of the study population. Transplantation records were reviewed, and patients who had haplo-HSCT during the period of interest were identified and selected for further analysis. A retrospective chart review was carried out by the authors. The hematopoietic cell transplantation comorbidity index was used to assess the baseline health status of the patients.12 Likewise, the disease risk index was included when possible (i.e., adult patients with malignant disease).13 Acute GVHD was graded according to modified Glucksberg et al’s14 criteria. Chronic GVHD was diagnosed and graded per recent international working group recommendations.15 The ethics committee of the hospital where the study was conducted granted permission for the development of this investigation.

2.2. Transplantation procedures

Two conditioning regimens were used according to individual patient characteristics: a myeloablative conditioning regimen based on the combination of fludarabine (30 mg/m2/d during 3 days) and total body irradiation (12 Gy fractionated in 8 doses during 4 days) as previously described by Solomon et al,4 or a nonmyeloablative regimen based on cyclophosphamide (14.5 mg/kg/d during 2 days), fludarabine (30 mg/m2/d during 5 days), and total body irradiation (2 Gy in a single dose) according to the original Johns Hopkins protocol.3 Unmanipulated granulocyte-colony stimulating factor mobilized T-cell-replete peripheral blood stem cells (PBSCs) were the graft source for all patients. The backbone of GVHD prophylaxis was PT-CY (50 mg/kg/d) associated with MESNA on Day +3 and Day +4. Oral mycophenolate mofetil (MMF; 45 mg/kg/d divided in 3 doses) and continuous infusion of tacrolimus (initial dose 1 mg/24 h, target through level 5–15 ng/mL) were started on Day +5. As soon as clinically permissible, tacrolimus was switched to the oral presentation. MMF and tacrolimus were stopped on Day +35 and Day +180, respectively. High-dose methylprednisolone (2 mg/kg/d during 5 days with gradual taper and later switch to prednisone) was the first-line therapy for acute GVHD. Chronic GVHD was initially treated with prednisone (1 mg/kg/d with gradual taper). Neutrophil engraftment and platelet engraftment were defined as 3 consecutive days with an absolute count of > 500  109/L and of > 20  109/L (without transfusion support), respectively. Antimicrobial prophylaxis was administered with ciprofloxacin, trimethoprim– sulfamethoxazole, acyclovir, and fluconazole, as suggested in international guidelines.16

Individuals with a previous diagnosis of invasive aspergillosis received voriconazole suppressive therapy instead of fluconazole. Surveillance of invasive fungal infection was carried out with twice weekly monitoring of serum galactomannan antigen and appropriate imaging and additional tests as indicated. Cytomegalovirus quantitative plasma viral load (polymerase chain reaction—LightCycler 2.0; Roche Diagnostics) was monitored once weekly, and if positive, preemptive therapy was initiated. Granulocytecolony stimulating factor at a dose of 5 g/kg/d was started on Day +5 and continued until neutrophil engraftment.

2.3. Definition of fever and basic management

Fever was present when a single axillary temperature measurement was ≥ 38.3C or when the temperature was ≥ 38.0C for 1 hour or longer at any time during the first 5 days after stem cell infusion. At first recognition of fever, a diagnostic workup that included a minimum of two blood cultures (1 through the central catheter), a urine culture, a chest Xray, and other tests as clinically indicated was performed. Antibiotic therapy with piperacillin/tazobactam was initiated and administered at least until blood cultures were reported as negative (standard 96-hour incubation period). Acetaminophen was allowed as a rescue medication without exceeding established weight-based recommendations. It was given as needed to achieve symptomatic relief, regardless of the degree of fever. Systemic corticosteroids, tocilizumab, or any other medication (except for protocol-

indicated cyclophosphamide) that could potentially hamper the normal function of T cells was not administered to any patient during the first 4 days after PBSC infusion. CRS was defined and graded as recently suggested by Abboud et al.10 However, we considered it to be clinically relevant when the grade was 3 or higher.

2.4. Statistical analysis

No formal sample size calculation was made. Central tendency measures were presented as means or medians according to data distribution. The chi-square test (or Fisher’s exact test as required) was used for the comparison of categorical variables, while Wilcoxon’s test was used for comparing continuous variables. Cumulative incidence rates of acute GVHD (on Day +100) and chronic GVHD (on Day +365) were calculated. Overall survival, event-free survival, and GVHD-free/relapse-free survival were estimated with the nonparametric method of Kaplan–Meier, and a comparison of the probability of survival was carried out with the log-rank test.17 An association between independent variables and overall survival was determined through the hazard ratio using the Cox proportional hazards regression model. No specific cutoff value was used to select items for inclusion in this model. Clinically relevant variables selected for inclusion were conditioning regimen, disease relapse, fever, and acute GVHD. The threshold for statistical significance was set at p < .05. SPSS Statistics 23 (SPSS Inc., Chicago, IL, USA) was the software used for data analysis.

3. Results

3.1. Patient and transplant characteristics

Forty consecutive patients underwent haplo-HSCT and were included in this study. Median age of the whole group was 17.5 years (range, 1–59 years), and most patients had a diagnosis of acute leukemia. The disease risk index could not be estimated in 17 individuals; one of them had aplastic anemia, and the remainder were children with acute lymphoblastic leukemia (8 cases, all of them beyond 1st remission or with active disease), acute myeloid leukemia (7 cases, 5 of them beyond 1st remission or with active disease), or juvenile myelomonocytic leukemia (1 case with active disease). Sixteen patients (40%) received a myeloablative conditioning regimen, and the remaining 24 (60%) patients received a nonmyeloablative conditioning regimen. No clinical characteristic was significantly different in the group of individuals who developed fever after PBSC infusion when compared with those who did not (Table 1).

3.2. Transplant outcomes

For the entire cohort, the median follow-up was 245 days (range, 34–886 days). Table 2 summarizes the major transplant-related outcomes. Cumulative incidence of acute GVHD of any grade and Grade III–IV at 100 days, and chronic GVHD (any grade) at 1 year was 32.5%, 10%, and 20%, respectively. Overall, 15 (37.5%) patients relapsed and 17 (42.5%) patients died during follow-up; three (7.5%) deaths were considered to be treatment related, while the rest were attributed to disease progression. Median overall survival of the entire cohort was 17.2 months (95% confidence interval [CI], 13.1–21.3), median event-free survival was 15.7 months (95% CI, 11.4–19.9), and median GVHD-free/relapsefree survival was 13.6 months (95% CI, 9.4–17.9).

3.3. Fever, characteristics, and outcomes

Thirty-three patients (82.5%) developed fever in the first 5 days after stem cell infusion. The median time to fever onset was 25.5 hours (range, 9.5–100 hours) and the median peak temperature was 39.0C (range, 38.1–40.5C). Not a single patient fulfilled criteria for Grade 3 or higher CRS. Notably, 91% of the individuals who experienced fever responded to cyclophosphamide administration, and temperature returned to normal by Day 7 after stem cell infusion. Despite extensive testing, only one patient had a microbiological specimen isolated. However, clinical relevance was questionable and definite infection was not established in any case. Table 3 summarizes some characteristics of febrile episodes.

No baseline variable was significantly associated with the development of fever in univariate analysis. Overall survival (18.7 months vs. 9.9 months, p = .12; Figure 1), eventfree survival (16.8 months vs. 9.2 months, p = .23), or GVHD-free/relapse-free survival (14.5 months vs. 8.7 months, p = .32) was not significantly different when comparing febrile and afebrile individuals. Finally, in a multivariable analysis, the development of fever after PBSC infusion was not associated with a higher risk of death (hazard ratio 0.6; 95% CI, 0.2–2.9).

4. Discussion

Fever is a common event after stem cell infusion in haplo-HSCT with PT-CY. We found that it occurs regardless of the patient´s age, baseline diagnosis, number of CD34+ cells administered, or intensity of the conditioning regimen used, among other characteristics. Despite extensive microbiological testing, no definite infectious etiology was found for any febrile episode. In addition, clinically relevant CRS was not seen in this group of individuals. Most importantly, the development of fever was not associated with an adverse clinical prognosis. This study included a group of patients treated homogeneously. All of them received PT-CY as the backbone of GVHD prophylaxis, but also had tacrolimus and MMF as described in the original protocols.3,4 This is important as patients included in a recently published paper, which suggested that fever may be part of the CRS, received MMF alone

after PT-CY for GVHD prevention.10 Even though CRS is not exclusively a T-cell-mediated condition, as other cellular populations and soluble mediators are involved in its pathogenesis, it is also clear that T lymphocytes play a key role.11 In this regard, one can speculate that the blockade of T-cell function provided by tacrolimus could be important to avoid the development of CRS. The difference in clinically relevant CRS incidence between our study and the aforementioned series (0% vs. 12%) could also be due to the higher age (17.5 years vs. 49 years, median) and comorbidity burden (1 vs. 4 hematopoietic cell transplantation comorbidity index score, median) of the patients in the latter group.10 Thirty percent of patients included in a large haplo-HSCT series from China experienced fever during the 1st day after stem cell infusion.9 However, comparing their results with ours can be difficult, as they used antithymocyte globulin as part of the preparative regimen and the graft source was a combination of PBSCs and granulocytecolony stimulating factor-primed bone marrow. Furthermore, they allowed the early use of corticosteroids to manage febrile episodes. In our series, 33 (82.5%) patients developed fever. This is similar to what has been described elsewhere using a GVHD prophylaxis based on PT-CY and a PBSC graft.18 Nevertheless, the onset of fever occurred earlier among the group of patients included in the present report (~1 day vs. 2.5 days, median). The early but not immediate onset of febrile episodes after stem cell infusion suggests that this phenomenon is not mediated by soluble elements already contained in the product and further supports the theory that fever is associated with the initial proliferation of alloreactive donor T cells exposed to host antigens.1,8 Although the peak

temperature was high, it was not associated with immediate clinical consequences, including seizures, in adult or pediatric patients. Perhaps, the most reassuring clinical finding was the resolution of most cases of fever (30/33, 91%) in the 96-hour time frame following the administration of cyclophosphamide. Although this cutoff is arbitrary, we selected it to assess the true effect of this medication regarding the resolution of fever. The three cases that fell outside this margin were individuals with late-onset fever (i.e., beyond the 72nd hour after stem cell infusion), and all of them experienced defervescence by Day +9. The use of systemic corticosteroid therapy or any T-cell-directed medication during the first 4 days after PBSC infusion was not allowed to avoid any potential interference with the process of cell activation. As a matter of fact, there was no clinical indication for any specific therapy besides cyclophosphamide, since not a single patient developed significant hemodynamic or respiratory dysfunction while febrile. The general outcomes experienced by our group of patients were roughly similar to what has been described elsewhere,4,18–20 as expected high-risk disease was common. A key finding was the lack of a negative impact on relevant outcomes associated with the development of fever. Albeit we grouped together all causes of death for statistical analysis, due to the restricted number of individuals one can hypothesize that fever is simply a reflection of the T-cell activation and proliferation that occurs early after PBSC infusion, and that this process is crucial to ensure that PT-CY is effective (i.e., selectively suppressing alloreactive clones) so that the whole transplantation procedure is successful. Further studies with a larger patient population may look specifically for a relationship

between fever defervescence after cyclophosphamide administration and GVHD development or other outcomes such as transplant-related mortality. The fact that this was a single institution study may limit the external validity of our results. However, our findings reflect real-life transplant practice in a resource-limited country. Owing to economic limitations, we do not perform T-cell dose quantification in the grafts and we were not able to assess its potential relevance. Finally, we acknowledge that patient follow-up may have been relatively short to assess some outcomes (e.g., chronic GVHD) and that the small patient number may limit the statistical power of this study. In summary, we provide a description of general features of febrile episodes after PBSC infusion in haplo-HSCT with PT-CY setting. Fever was common, regardless of baseline patient characteristics, but we did not find an adverse prognosis linked with it. Medication that could lead to impairment of T-cell activation was avoided in the first days after transplantation without compromising patient safety, and fever resolved with cyclophosphamide administration in most cases.

Conflicts of interest

There are no conflicts of interest to report. The authors have no financial disclosures to report.

References

1. Kanakry C, Fuchs E, Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol 2016;13:10–24. 2. Raiola A, Dominietto A, di Grazia C, Lamparelli T, Gualandi F, Ibatici A, et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant 2014;20:1573–9. 3. Luznik L, O’Donnell P, Symons H, Chen A, Leffell M, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008;14:641–50. 4. Solomon S, Sizemore C, Sanacore M, Zhang X, Brown S, Holland H, et al. Total body irradiation based myeloablative haploidentical stem cell transplantation is a safe and effective alternative to unrelated donor transplantation in patients without matched sibling donors. Biol Blood Marrow Transplant 2015;21:1299–307. 5. Bashey A, Zhang X, Sizemore C, Manion K, Brown S, Holland H, et al. T-cell-replete HLAhaploidentical hematopoietic transplantation for hematologic malignancies using posttransplantation cyclophosphamide results in outcomes equivalent to those of

contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol 2013;31:1310–6. 6. Kanate A, Mussetti A, Kharfan-Dabaja M, Ahn K, DiGilio A, Beitinjaneh A, et al. Reducedintensity transplantation for lymphomas using haploidentical related donors vs HLAmatched unrelated donors. Blood 2016;127:938–47. 7. Ruggeri A, Labopin M, Sanz G, Piemontese S, Arcese W, Bacigalupo A, et al. Comparison of outcomes after unrelated cord blood and unmanipulated haploidentical stem cell transplantation in adults with acute leukemia. Leukemia 2015;29:1891–900. 8. O'Donnell P, Raj K, Pagliuca A. High fever occurring 4 to 5 days post-transplant of haploidentical bone marrow or peripheral blood stem cells after reduced-intensity conditioning associated with the use of post-transplant cyclophosphamide as prophylaxis for graft-versus-host disease. Biol Blood Marrow Transplant 2015;21:197–8. 9. Chen Y, Huang X-J, Wang Y, Liu K, Chen H, Chen Y, et al. Febrile reaction associated with the infusion of Haploidentical peripheral blood stem cells: incidence, clinical features, and risk factors. Transfusion 2015;55:2023–31. 10. Abboud R, Keller J, Slade M, DiPersio J, Westervelt P, Rettig M, et al. Severe cytokine release syndrome following T-cell replete peripheral blood haploidentical donor transplant is associated with poor survival and anti-IL6 therapy is safe and well tolerated. Biol Blood Marrow Transplant 2016;22:1851–60. 11. Lee D, Gardner R, Porter D, Louis C, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124:188–95.

12. Sorror M, Maris M, Storb R, Baron F, Sandmaier B, Maloney D, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912–9. 13. Armand P, Kim H, Logan B, Wang Z, Alyea E, Kalaycio M, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 2014;123:3664–71. 14. Glucksberg H, Storb R, Fefer A, Buckner C, Neiman P, Clift R, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLAmatched sibling donors. Transplantation 1974;18:295–304. 15. Jagasia M, Greinix H, Arora M, Williams K, Wolff D, Cowen E, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graftversus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389–401. 16. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009;15:1143–238. 17. Holtan S, DeFor T, Lazaryan A, Bejanyan N, Arora M, Brunstein C, et al. Composite end point

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conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant 2012;18:1859–66. 19. Sugita J, Kawashima N, Fujisaki T, Kakihana K, Ota S, Matsuo K, et al. HLAhaploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide after busulfan-containing reduced-intensity conditioning. Biol Blood Marrow Transplant 2015;21:1646–52. 20. Raj K, Pagliuca A, Bradstock K, Noriega V, Potter V, Streetly M, et al. Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant 2014;20:890–5.

Table 1 Patient and Graft Characteristics Overall

Fever after

No fever after

population

infusion

infusion

p

No. of patients

40

33

7

Age (y), median (range)

17.5 (1–59)

18 (1–59)

11 (3–48)

.38

Adult patients, n (%)

24 (60)

21 (64)

3 (42)

.30

Diagnosis, n (%)

.45

ALL

20 (50)

17 (52)

3 (43)

AML

15 (37.5)

12 (36)

3 (43)

Other

5 (12.5)

4 (12)

1 (14)

DRI score, n (%)

.92

Low

1 (2.5)

1 (3)

0

Intermediate

7 (17.5)

6 (18)

1 (14)

High

15 (37.5)

13 (39.5)

2 (29)

Not applicable

17 (42.5)

13 (39.5)

4 (57)

Disease status at transplant, n (%)

.28

Remission

33 (82.5)

28 (85)

5 (71.5)

Active

6 (5)

4 (12)

2 (28.5)

Not applicable

1 (2.5)

1 (3)

0

1 (0–4)

1 (0–4)

1 (0–2)

HCT-CI score, median (range)

.35

Donor relationship, n (%)

.94

Parent

22 (55)

18 (55)

4 (57)

Sibling

15 (37.5)

12 (36)

3 (43)

Other

3 (7.5)

3 (9)

0

11 (27.5)

9 (27)

2 (28.5)

ABO mismatch, n (%)

.90

CMV serological status, n (%)

.70

Donor+/receptor+

37 (92.5)

30 (91)

7 (100)

Other

3 (7.5)

3 (9)

0

Sex mismatch, n (%)

11 (27.5)

9 (27)

2 (28.5)

.90

Full haplotype mismatch, n (%)

26 (65)

22 (67)

4 (57)

.63

CD34+ per 106/kg cell dose, median (range)

5.6 (2.8–13.6)

5.4 (2.8–13.6)

6.1 (3.3–13.6)

.42

Myeloablative conditioning, n (%)

16 (40)

11 (33)

1 (14)

.31

Note. ABO = ABO blood group; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CMV = cytomegalovirus; DRI = disease risk index; HCT-CI = hematopoietic cell transplantation comorbidity index; y= year..

Table 2 Transplant Outcomes Overall

Fever after

No fever after

p

population

infusion

infusion

No. of patients

40

33

7

Engraftment failure, n (%)

6 (15)

5 (15)

1 (14)

.95

Neutrophil engraftment day, median (range)

15 (11–22)

14 (11–22)

15 (11–22)

.83

Platelet engraftment day, median (range)

18 (11–33)

15 (11–33)

18 (13–31)

.55

Engraftment syndrome, n (%)

3 (7.5)

2 (6)

1 (14)

.45

Overall survival, median (95% CI)a

17.2 (95% CI,

18.7 (95% CI,

9.9 (95% CI,

.12

13.1–21.3)

14.2–23.2)

3.4–16.4)

15.7 (95% CI,

16.8 (95% CI,

9.2 (95% CI,

11.4–19.9)

12.1–21.5)

2.1–16.2)

13.6 (95% CI,

14.5 (95% CI, 9.8–

8.7 (95% CI,

9.4–17.9)

19.2)

0.9–16.5)

Event-free survival, median (95% CI)a

GVHD-free/relapse-free survival, median (95% CI)a

Note. CI = confidence interval; GVHD = graft versus host disease. a

Overall survival, event free survival and GVHD free/relapse free survival are given in months.

Table 3 Characteristics of Febrile Episodes Time to fever onset (h), median (range)

25.5 (9.5–100)

Peak temperature (C), median (range)

39.0 (38.1–40.5)

Rash associated with fever, n (%)

13/33 (39)

Peak CRP value (mg/L), median (range)

100.6 (10.3–310.4)

Fever resolution with cyclophosphamide, n (%)

30/33 (91)

ICU admission for hemodynamic or respiratory support, n (%)

0/33 (0)

Note. CRP = C-reactive protein; h = hour; ICU = intensive care unit.

.23

.32

FIGURE 1. Overall survival according to the development of fever Note. mo = months.