key: cord-0774412-saav639i
authors: Mariotti, Jacopo; De Philippis, Chiara; Bramanti, Stefania; Sarina, Barbara; Tordato, Federica; Pocaterra, Daria; Casari, Erminia; Carlo‐Stella, Carmelo; Santoro, Armando; Castagna, Luca
title: Caspofungin for primary antifungal prophylaxis after T‐cell–replete haploidentical stem cell transplantation with post‐transplant cyclophosphamide
date: 2019-02-13
journal: Eur J Haematol
DOI: 10.1111/ejh.13214
sha: a90d619d526e3b78effd53c1d5b4deeacbf0adf1
doc_id: 774412
cord_uid: saav639i

OBJECTIVES: T‐cell–replete haploidentical stem cell transplantation (Haplo‐SCT) with post‐transplant cyclophosphamide (PT‐Cy) is at high risk of invasive fungal infections (IFI), and anti‐mold–active drug is required for primary antifungal prophylaxis (PAP) according to international guidelines. No data are available on the efficacy of caspofungin as PAP in this setting. METHODS: Here, we report our retrospective experience with 103 consecutive patients treated with caspofungin as PAP after Haplo‐SCT. Caspofungin was administered only during the pre‐engraftment phase. RESULTS: Hundred‐day cumulative incidence of proven‐probable IFI (PP‐IFI) was 8.7% and median day of onset was 19 post‐SCT. No patient died of PP‐IFI, and overall survival (OS) and non‐relapse mortality (NRM) hazard ratio (HR) for patients experiencing IFI were 1.02 (P = 0.9) and 0.7 (P = 0.7), respectively. Three‐year overall survival (OS) and 1‐year non‐relapse mortality (NRM) were 55% and 19%, respectively. By univariate analysis, duration of neutropenic phase and partial remission pre‐transplant disease status were associated with increased incidence of IFI, but were not confirmed by multivariate analysis. CONCLUSION: In summary, PAP with caspofungin is an effective strategy for preventing IFI in the context of Haplo‐SCT with PT‐Cy. Further efforts are required in order to identify more potent strategies able to avoid the occurrence of breakthrough infections.

Among risk factors for IFI, donor type is the only pre-transplant variable that is potentially useful to dictate the choice of primary antifungal prophylaxis (PAP). Both the prospective study from the Transnet database 3 

Trapianto Midollo Osseo (GITMO) 7 have described that incidence of PP-IFI is approximately twice as high after mismatched related donor (MMRD; 8.1%-8.8%) compared with matched related donor (MRD; 4.6%-5.8%). Other smaller retrospective studies, comprising different types of haploidentical transplant platforms, have consistently found a higher risk of IFI after haploidentical/MMRD transplant relative to MRD Allo-SCT. 8, 9 Antifungal prophylaxis was very heterogeneous in these studies ranging from fluconazole only to anti-mold-active agents. All these reports support the urgent need for a more stringent PAP after haploidentical transplant in order to reduce the occurrence of IFI and of IFI-related mortality that can be as high as 33%. 9 In addition, epidemiologic studies on fungal infection and prophylaxis in the last years have shown a shift from Candida (that remains the second major cause, comprising albicans and non-albicans) to Aspergillus species as the most frequent agents responsible for IFI after Allo-SCT. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Given this background, the ECIL-5 11 and GITMO 12 recommended to employ anti-mold prophylaxis for patients at higher risk of IFI based on donor type (haploidentical or cord blood), timing after transplant (pre-or post-engraftment phase), and occurrence of GVHD. Itraconazole, voriconazole, and posaconazole received a BI-BII level of recommendations by the last version of ECIL recommendation. 13 No data are available either to recommend or to contraindicate echinocandin as PAP. our Institution. The aim of this study was to analyze the efficacy of caspofungin as PAP both in terms of IFI incidence in the first 100 days after Allo-SCT and in terms of patients' long-term outcome.

This is a retrospective study comprising 103 consecutive patients with a hematologic malignancy receiving a T-cell-replete Haplo-SCT with PT-Cy at our Institution. A donor was defined haploidentical when donor and recipient had more than 2 HLA mismatch and share one haplotype. Our transplant strategy is based on the Baltimore study 14 where donor graft was not manipulated (T-cell-replete) and GVHD prophylaxis consisted of cyclosporine, mycophenolate, and high-dose cyclophosphamide. Patients provided informed consent for the retrospective collection of their data. The study was approved from the Institutional Review Board at both institutions.

Three main conditioning regimens were employed: (a) non-myeloablative (NMA) regimen comprising Cy 14.5 mg/kg on days −6 and −5, fludarabine 30 mg/m 2 from day −6 to day −2, and low-dose total body irradiation (TBI) (2 Gy) on day −1; (b) reduced intensity (RIC) regimen comprising either thiotepa 10 mg/kg on day −5, cyclophosphamide 30-60 mg/kg on day −4 and day −3, fludarabine 30 mg/m 2 on day −4 and day −3, thiotepa 5 mg/kg on day −5, busulfan 3.2 mg/ kg on day −4 and day −3, and fludarabine 50 mg/m 2 from day −4 to day −2; and (c) myeloablative (MAC) conditioning comprising thiotepa 5 mg/kg on day −7 and day −6, busulfan 3.2 mg/kg/die from day −5 to day −3, and fludarabine 40 mg/m 2 from day −5 to day −2.

Potential family members were typed at the HLA-A, HLA-B, and HLA-DRB1 loci at high level of resolution. Selected donors were also typed at the HLA-C locus at a high-resolution level. Graft source was represented either by bone marrow (BM) or by peripheral blood stem cells (PBSC). The target was a minimum of 4 × 10 6 CD34/kg. Unmanipulated BM and peripheral blood stem cells (PBSC) were used for stem cell support on day 0. Graft source at the beginning was mainly represented by bone marrow as in the Baltimore protocol. Thereafter, PBSC was mainly used due to the easier collection strategy.

High-dose cyclophosphamide (50 mg/kg) was administered on day +3 and day +4 after transplant. Cyclosporin A (CsA) was dosed at 3 mg/kg as a continuous infusion until discharge and was converted to an oral formulation thereafter. CSA dosages were adjusted based on respective range of activity, between 100 and 200 ng/mL. MMF was administered at 15 mg/kg po three times per day until day +35.

CsA and MMF were started on day +5. CsA was tapered by day +100. G-CSF was started on day +5 in all patients.

Neutrophil engraftment was defined as the first of three consecutive days with an absolute neutrophil count (ANC) of 0.5 × 10 9 /L after transplantation. Platelet engraftment was defined as a platelet count of 20 × 10 9 /L, with no transfusions during the preceding 7 days. Acute GVHD (aGVHD) was graded according to the Keystone criteria, 15 and chronic GVHD (cGVHD) was retrospectively graded following the NIH criteria. 16 

All patients were allocated in HEPA-filtered rooms from the beginning of the conditioning until neutrophil engraftment. They received a low microbial diet. As blood vessel access, a CVC was placed. All patients underwent microbiological surveillance, including cultures from stool and urine and swabs from the anal area, starting before the conditioning and then weekly until discharge. In case of fever (defined when the temperature was >38°C), the following exami- week from day +15 until day +100. No routine screening for IFI was performed before transplant.

Possible-probable-proven IFI (PPP-IFI) and PP-IFI were defined according to standard international criteria. 17 Onset of PPP-and PP-IFI was defined as the day of the first positive radiological examination, or positive culture or pathologic test. PPP-and PP-IFIs were recorded during the first 100 days after Allo-SCT.

The primary endpoint of this study was to investigate cumulative incidence of IFI infections in patients receiving PAP with caspofungin.

Secondary endpoints were long-term outcome parameters such as overall survival (OS) and non-relapse mortality (NRM). Categorical variables were expressed as proportions and continuous variables as medians with the respective range. The cumulative incidence of aGVHD was estimated considering death not related to aGVHD within a year post-transplant as a competing event. cGVHD was estimated only for patients alive at day +100, considering death not related to cGVHD within 2 years post-transplant as a competing event. 18 For the calculation of NRM, disease relapse or progression was treated as a competing event, whereas NRM was the competing event for the calculation of cumulative incidence of relapse or progression. The Kaplan-Meier method was used for the OS and progression-free survival (PFS) analyses. 19 Outcomes (and respective 95% confidence interval (CI)) were calculated from the date of transplantation. Comparisons between groups were made by log-rank and Gray tests whenever indicated. The cumulative incidence of PPP-and PP-IFI up to day 100 was estimated considering death for any other reason not related to IFI infection as a competing event.

Univariate Cox regression models 20 were used to identify significant moderators (independent covariates) on the occurrence of PP-IFI. IFI was treated as a time-varying explanatory covariate to account for its effect on OS and NRM. Hazard ratios (HRs) with 95% confidence intervals (CIs) are reported. An HR >1 denotes an unfavorable effect. A P value <0.05 was considered significant. SPSS version 19.0 (IBM, Armonk, NY, USA) and EZR ("Easy R"; R Institute for Statistical Computing, Vienna, Austria) were used.

From November 2013 to December 2017, 103 consecutive patients received a Haplo-SCT with PT-Cy at our Institution and were treated with caspofungin as PAP. Patient characteristics are shown in Table 1 . Median age was 52 (20-72), and the main underlying diagnoses were represented by lymphoma and acute myeloid leukemia. Conditioning consisted mainly of RIC and NMA regimens (82%).

Forty-one percent of the patients received a graft from BM cells and 59% from PBSC. In the first 40 days after transplant (GITMO early phase), most patients (65%) were in the high-risk category according to GITMO classification, mainly because they were treated with Haplo-SCT plus the presence of another adverse variable, such as prolonged neutropenia or recurrent CMV infection. Between day 40 and day 100 (GITMO late phase), a minority of cases (35%) was in the high-risk category (35%), mainly due to acute GVHD requiring systemic steroids, recurrent CMV infection, or disease.

During the first 100 days post-Haplo-SCT, cumulative incidence of PPP-IFI was 11% (95% CI: 6-17) (10 cases) ( Figure 1A ). PP-IFI occurred only in 8 patients for a 100-day cumulative incidence When we analyzed risk factors commonly associated with fungal infection by univariate analysis, we found ( Table 2 ) that the longer the post-SCT neutropenic phase, the higher the chance of experiencing a PP-IFI within the first 100 days. Because caspofungin prophylaxis was limited to the engraftment phase, and because most IFI occurred before day 40 (cumulative incidence 6%), we performed a subanalysis to study whether day 40-IFI correlate with GITMO earlyphase risk category, but we could not find any significant difference (standard risk: 3% vs high risk: 7%, P = 0.4). Of note, by multivariate analysis only high/very high disease risk index (DRI) retained an independent value for increased risk of IFI (HR: 21.1, P = 0.047).

However, the confidence intervals were very wide due to the small number of events; therefore, this result needs to be confirmed on a larger number of patients.

In addition, we compared the 100-day cumulative incidence of PP-IFI of our cohort with a historical group of patients (n = 66) that received iv itraconazole as PAP between April 2009 and October 2013 at our institution. The two groups differed for patients' characteristics since the cohort receiving caspofungin was older and had a higher frequency of high-risk HCT-CI, previous autologous transplant, and more intensive conditioning (Table S1 ). Taking these limits into consideration, we observed a trend for reduced 100-day cumulative incidence of PP-IFI after caspofungin relative to itraconazole prophylaxis: 8.7% (95% CI: 4-15) vs 16% (95% CI: 8-26) ( Figure 1C , P = 0.17).

Ninety-four out of 103 patients (91%) were evaluable: 7 patients died before engraftment, and 2 experienced graft failure. The median time to ANC ≥0.5 × 10 9 /mL was 21 days (range 15-73), and the median time to platelet count ≥20 × 10 9 /mL was 27 (range 12-390).

Of note, 45 patients (48%) had neutropenia lasting>21 days.

With a median follow-up for alive patients of 19 

On Table 3 , we reported all diagnosis of pneumonitis per- 

Haplo-SCT with PT-Cy that are at higher risk of mold infections relative to MRD counterparts. We found a 100-day cumulative incidence of PP-IFI of 8.7% that compares well with the ones reported in the literature in recipients of Haplo-SCT. 21 In the past few years, T-cell-replete Haplo-SCT has gradually re- intensified immunosuppressive regimen, described a higher incidence of IFI, 12.5% in the early phase followed by 7% in the late one. In the Baltimore platform, cumulative incidence of PP-IFI varies between 8% and 16%. 25 In the retrospective study by Raiola et al 26 where fluconazole was used as PAP, 16% of Haplo-SCT recipients experienced PP-IFI, with Aspergillus as the most frequent agent followed by Candida non-albicans and Fusarium species. In another report from the same group, where most of the patients received fluconazole and a minority caspofungin followed by itraconazole, cumulative incidence of PP-IFI was 8%. 27 In a recent experience, we reported that micafungin prophylaxis yielded a cumulative incidence of PP-IFI of 12%. 28 TA B L E 2 (Continued) itraconazole or voriconazole or posaconazole reduced the incidence of PP-IFI, whereas posaconazole and voriconazole seemed superior to oral itraconazole in order to reduce the incidence of invasive aspergillosis. 29 In details, cumulative incidence of PP-IFI was very low in these phase 3 studies, ranging between 1% and 5%. Of note, these studies included only patients receiving a matched related or matched unrelated donor; therefore, it is not well known the efficacy of voriconazole and posaconazole in the Haplo-SCT setting. In accordance with these findings, most recent updates of ECIL, 11,13 GITMO, 12 German, and Australian guidelines 30 groups (patients with caspofungin had more adverse pre-transplant features). Moreover, data on blood concentration of itraconazole are not available, even if all patients received iv itraconazole, thus reducing the risk of low blood levels as frequently observed with the oral formulation.

In conclusion, we found that PAP with caspofungin in the pre-engraftment phase results in a manageable incidence of PP-IFI in the platform of Haplo-SCT with PT-Cy. Larger and prospective studies are warranted in order to identify which agent may further reduce the cumulative incidence of proven/probable IFI in the context of Haplo-SCT with PT-Cy.

The authors have no conflict of interest to disclose.

Jacopo Mariotti https://orcid.org/0000-0001-6528-9296

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