Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (rhu GM-CSF) as Adjuvant Therapy for Invasive Fungal Diseases.

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an immunomodulatory cytokine produced by circulating and tissue-resident immune cells, as well as endothelial and alveolar epithelial cells. GM-CSF modulates multiple biological functions regulating hematopoiesis and immunomodulation [ 1–4 ]. This spectrum of biological activities, termed “cytokine pleiotropy,” and the ability of GM-CSF to link innate and adaptive immunity through effects on dendritic cell and T-lymphocyte function, highlight the central role of this cytokine in regulating the immune response.

GM-CSF also plays a central role in response to infection, including activation of macrophages, monocytes, and neutrophils [ 5 ]. GM-CSF augments phagocytosis, nonoxidative pathogen killing, and clearance by macrophages and peripheral blood monocytes, while also upregulating oxidative metabolism and microbicidal activity of neutrophils and signaling emergency hematopoiesis elicited by infection [ 6 ].

Sargramostim (yeast-derived, glycosylated recombinant human [rhu] GM-CSF) has been in clinical use in the United States for nearly 3 decades and is the only approved rhu GM-CSF. While sargramostim is used as a traditional hematopoietic growth factor, it is also utilized as adjunctive therapy for serious invasive fungal diseases. Although not commercially available, other rhu GM-CSF products include molgramostim (bacteria-derived) and regramostim (Chinese hamster ovary cell–derived), which differ in glycosylation profile and clinical toxicity compared with sargramostim. Molgramostim was approved by the European Medicines Agency but subsequently withdrawn from clinical use. Regramostim was never approved by a regulatory authority.

To our knowledge, there has been no systematic review of rhu GM-CSF for the treatment of invasive fungal diseases (IFDs). We therefore reviewed all available literature for rhu GM-CSF as adjuvant immunomodulatory therapy of IFDs in pediatric and adult patients. We also report 15 new cases of rhu GM-CSF used in the management of life-threatening mycoses in pediatric oncology patients in a retrospective cohort analysis.

METHODS

Definitions

Neutropenia : ANC <500 neutrophils/µL.

Invasive fungal disease (IFD) : defined by European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSG-ERC) criteria [ 7 ].

Refractory to antifungal therapy : lack of response to 7 or more days of antifungal therapy.

Adjunctive therapy : use of rhu GM-CSF in combination with antimicrobial therapy for treatment of IFDs.

Response to therapy :

Complete response : resolution of all signs, symptoms, and laboratory, microbiological, and diagnostic imaging evidence of IFD.

Partial response : resolution of most signs and symptoms, improvement of attributable laboratory abnormalities, resolution of microbiological findings, and ≥50% reduction of diagnostic imaging evidence of IFD.

Stable: resolution of most signs and symptoms and improvement of attributable laboratory abnormalities, resolution of microbiological findings, and <50% reduction of diagnostic imaging evidence of IFD.

Progression: worsening of signs, symptoms, laboratory, microbiological, and diagnostic imaging evidence of IFD.

Success : complete or partial response to therapy.

Failure : stable or progression of IFD despite therapy.

Follow-up: time elapsed from completion of antifungal therapy to last clinical visit.

New Cases of IFDs Treated With Rhu GM-CSF

Original cases where rhu GM-CSF (sargramostim) was used in refractory IFDs were identified in a retrospective cohort analysis from the inpatient Pediatric Infectious Diseases Consultation Service, which has monitored all pediatric oncology patients with suspected and confirmed IFDs at a single institution (Miller Children's and Women's Hospital, Long Beach, CA, USA) from 2009 through 2022. Data collected included demographic features, type of infection, antimicrobial therapy, use of rhu GM-CSF, and outcome.

Published Cases

A comprehensive literature search of the PubMed and Embase electronic databases was performed ( Figure 1 ). Search terms consisted of “granulocyte-macrophage colony-stimulating factor” OR “GM-CSF” OR “recombinant granulocyte-macrophage colony-stimulating factor” OR “sargramostim” OR “molgramostim” OR “regramostim” AND “fungal infection” OR “mycosis” AND “case report” to identify case reports published in the English language between January 1, 1990, and March 1, 2022, that evaluated use of rhu GM-CSF as adjunctive therapy in patients with IFDs. Additional studies identified on review of pertinent literature were also included. All cases in which the pathogen, treatment, and efficacy could be fully assessed were included; cases were excluded if no infectious organism was identified. Cases involving rhu GM-CSF for treatment of bacterial, viral, or parasitic infections were excluded.

RESULTS

New Case Studies of Sargramostim for IFD

Tables 1 and 2 detail and summarize, respectively, 15 contemporary, original cases of sargramostim as adjunctive therapy in the treatment of IFDs, including those caused by Candida spp., Aspergillus spp., Rhizopus sp., Lichtheimia sp., Scedosporium spp., and Trichosporon spp., in pediatric patients (1–20 years of age). A majority (80%) were neutropenic at baseline, and 12 patients (80%) were considered refractory to prior therapy. Sargramostim was administered adjunctively, with standard antifungal therapy and surgical debridement where appropriate, at a dosage of 250 µg/m 2 /d once daily if the ANC was <500 cells/µL, then reduced to immunomodulatory dosing of 100 µg/m 2 /d thrice weekly when the ANC exceeded 500 cells/µL.

Among the 15 patients, 12 completed treatment and were evaluable for response; 3 patients were still receiving therapy at the time of publication. Among the 12 evaluable patients, 8 (67%) achieved a complete response (resolution of infection), 3 (25%) attained a partial response, and 1 (8%) had a stable response. The remaining 3 patients who are continuing to receive antifungal and adjunctive sargramostim therapy are responding favorably, with continued improvement of signs, symptoms, and laboratory and imaging evidence of IFD. Importantly, with the addition of sargramostim, 11 patients were able to successfully complete scheduled chemotherapy, and 3 were able to restart chemotherapy. In 1 patient treated for 7 months with chemotherapy plus sargramostim, 1 additional month of sargramostim was administered after completion of chemotherapy and infection resolution to enhance further immune recovery and response.

Among the 3 patients still undergoing therapy, 1 with invasive aspergillosis had complete resolution of intracranial and pulmonary lesions but continues on antifungal therapy with sargramostim until completion of maintenance chemotherapy given the high risk of recurrence. One with sino-orbital-cerebral and pulmonary mucormycosis continues on antifungal therapy and immunomodulatory dosing of sargramostim (100 μg/m 2 thrice weekly) while undergoing staged surgical reconstruction of the face and continuing on modified maintenance chemotherapy with blinatumomab. Repeat cultures from serial debridements have been negative, and pulmonary lesions continue to decrease in size on serial imaging. One with pulmonary and hepatosplenic mucormycosis remains on antifungal therapy and immunomodulatory dosing of sargramostim while on maintenance chemotherapy with demonstrated gradual decrease in size of the hepatic lesions on serial imaging.

In these new cases, treatment-related adverse events were infrequent with sargramostim. Three (20%) of 15 patients experienced bone pain, including 1 with bruising from local injection and 1 with fever. There also were no cases of fluid shifts leading to third-spacing. No new safety concerns were identified, and no one discontinued sargramostim therapy due to adverse events.

Published Cases of Rhu GM-CSF for Treatment of IFDs

Published case reports on the use of rhu GM-CSF in IFDs are detailed and summarized in Tables 3 and 4 , respectively [ 8–45 ]. Among the 50 cases of IFDs, 15 were caused by Candida spp., 13 by Mucorales, 11 by Aspergillus spp., and 11 by less common organisms. Twenty (40%) had baseline neutropenia, and 36 (72%) were considered to be refractory to standard therapy before rhu GM-CSF administration. Complete response was reported in 40 (80%) patients and partial response in 1 (2%) patient, with 9 (18%) patients classified as failure to respond.

DISCUSSION

This systematic review is, to our knowledge, the largest reported series of patients treated adjunctively with rhu GM-CSF for IFDs. This report includes 15 newly described pediatric patients who were treated adjunctively with sargramostim for IFDs in the setting of hematologic malignancies. Patients with IFDs were treated both in neutropenic and non-neutropenic states. This paper also reviewed 50 previously published cases of IFDs that were adjunctively managed with rhu GM-CSF. The outcome measures of 50 previously published cases mirrored those of the 15 prospectively managed pediatric patients presented in this report. Overall (complete and partial) response rates for the newly reported pediatric oncology patients and cases from the systematic literature review were similar: 92% and 82%, respectively. These favorable outcomes may be related both to the hematopoietic properties of rhu GM-CSF and to its broad immunomodulatory effects on innate host defenses against fungi. These results support consideration of adjunctive treatment with sargramostim for IFDs in pediatric and adult patients with hematologic malignancies and other immunocompromised conditions, given the limited treatment options for refractory mycoses.

While there are no randomized controlled clinical trials of GM-CSF for treatment of refractory IFDs in immunocompromised patients, there is a critical need for new strategies to augment host response in this patient population. Given the limited options available to such patients, the supportive preclinical laboratory data, the impact on significantly preventing infections in GM-CSF-treated patients, and the successes reported in individual cases with documented IFDs, the careful use of GM-CSF in this patient population seems tenable.

In addressing toxicity, one needs to distinguish between the yeast-derived, glycosylated form of GM-CSF (sargramostim) and the bacteria-derived nonglycosylated form of GM-CSF (molgramostim). Although comparative studies have not been conducted, the nonglycosylated form of GM-CSF appears to be associated with greater systemic toxicity in clinical trials [ 47 ]. By comparison, sargramostim has consistently shown a favorable safety profile. Beveridge et al., in 137 patients receiving sargramostim or filgrastim, showed no significant differences in the incidence or severity of systemic adverse events, with the exception of a slightly higher incidence of grade I fever (<38.1°C) [ 48 ]. Rowe and colleagues, in a randomized, placebo-controlled phase 3 study, compared the toxicity of induction chemotherapy with daunorubicin and cytarabine with sargramostim vs placebo and found that the overall treatment toxicity was reduced in the sargramostim arm ( P = .049) [ 49 , 50 ].

As pediatric patients are often considered to be therapeutic orphans in the development of new immunomodulatory strategies, we consider that treatment of this carefully monitored cohort of patients is an important advance that may inspire further studies in children and adults. The patients with hematological malignancies at Miller Children's and Women's Hospital Long Beach are managed in a seamless, well-organized system of supportive care through a multidisciplinary team, including Infectious Diseases and Hematology/Oncology.

Among the 15 new pediatric oncology cases of IFD reported here, 7 had disseminated candidiasis, 6 of which were refractory to initial antifungal therapy. GM-CSF upregulates the oxidative metabolism of neutrophils and increases microbicidal activity against Candida spp. in vitro, as well as augments nonoxidative killing by monocytes and macrophages [ 6 , 51–53 ]. Sargramostim, in the 6 neutropenic patients with invasive candidiasis, was initially administered to induce hematopoiesis, then continued after neutropenia resolution to augment innate host response. Favorable outcomes among these pediatric cases are consistent with those described in individual case reports [ 8 ].

Among 50 previously published cases of IFDs adjunctively managed with rhu GM-CSF, 3 patients had disseminated candidiasis. Of these 3, 2 had chronic disseminated candidiasis that complicated neutropenia and necessitated extended courses of antifungal therapy (range, 2 months to 1.5 years) [ 8 , 9 ]. Chronic disseminated candidiasis reflects a Th1/Th2 dysimmunoregulation. Upon recovery from neutropenia in disseminated candidiasis, an ineffective inflammatory response modulated by Th2 cytokines results in fever and progressive lesions in the liver, spleen, and other tissues [ 54 , 55 ]. In these settings, rhu GM-CSF upregulates the microbicidal activity of monocytes, macrophages, and neutrophils, which may contribute to favorable responses in cases unresponsive to antifungal therapy alone. As this disease has been proposed to be a form of immune reconstitution syndrome [ 4 , 56 ], use of rhu GM-CSF may also serve as an immunomodulator that may regulate an aberrant host response.

Sargramostim also was used in 6 of the newly described pediatric patients as adjunctive treatment of invasive disease caused by Aspergillus spp., Rhizopus spp., and Scedosporium apiospermum/boydii , as well as another patient with sino-orbital-cerebral disease caused by Lichtheimia corymbifera . All patients demonstrated reduction or stabilization of disease following initiation of sargramostim. These findings are consistent with the known in vitro activity of GM-CSF-mediated augmentation of hyphal damage by neutrophils against Aspergillus spp. [ 57 ], Mucorales [ 53 , 58 ], and Scedosporium [ 59 ] spp., as well as the favorable responses observed in individual cases [ 20–24 , 27–30 , 33 , 35–37 , 46 ]. Moreover, the favorable outcomes observed in patients with invasive aspergillosis in this study are also compatible with those of Kasahara et al. who reported that administration of recombinant GM-CSF enhanced neutrophil NADPH oxidase response, augmented conidiacidal activity, and reduced residual fungal burden in lung tissue in a murine model of pulmonary aspergillosis [ 60 ].

A beneficial effect of rhu GM-CSF on invasive mold diseases caused by aspergillosis, mucormycosis, and fusariosis may be related both to upregulation of functional innate host response and hematopoietic growth properties that hasten recovery from neutropenia [ 4 , 61 ]. Recovery from neutropenia is essential for successful treatment of IFDs in neutropenic hosts [ 62 ]. At the same time, GM-CSF may also upregulate or protect innate host responses in non-neutropenic oncology patients receiving immunosuppressive therapies, such as in those with refractory IFDs and acute lymphoblastic leukemia who are receiving maintenance chemotherapy. Little is known, however, about the role of GM-CSF in nononcology patients receiving immunosuppressive therapies.

Of 49 published cases with reported baseline neutropenia data, 20 (40.8%) patients had neutropenia before antifungal treatment. Of these, fungal infections resolved in 17 (85%) patients following the addition of rhu GM-CSF to standard antifungal therapy. Similarly, 5 patients with non-neutropenic rhinocerebral mucormycosis were treated with rhu GM-CSF, 3 of whom had failed to respond to prior antifungal therapy. These infections resolved in 4 patients, and no recurrence was observed over a follow-up period of 2 to 4 years [ 33 , 35 , 46 ].

Among the newly described pediatric patients, 1 patient with acute myeloid leukemia developed pulmonary trichosporonosis while receiving prophylactic micafungin. This patient received sargramostim during neutropenia and throughout subsequent cycles of chemotherapy in conjunction with isavuconazole or posaconazole until complete resolution of all pulmonary nodules. A second patient had hepatic trichosporonosis during persistently profound neutropenia caused by chemotherapy-related myelodysplasia. Although the hepatic lesion remained stable, the molecular signal from the metagenomic assay decreased from 31 molecules/mL to below the threshold level of detection. Previous in vitro studies demonstrated that GM-CSF augments neutrophil and monocyte microbicidal and phagocytic activity, respectively, against Trichosporon asahii [ 63 , 64 ]. This antifungal activity may be related to reversal of the immunosuppressive effects of Trichosporon glucuronylxylomannan [ 65 , 66 ].

In addition to the effects of augmenting innate and adaptive host responses, sargramostim may also protect against infections by enhancing mucosal barrier immunity. In support of this concept, GM-CSF knockout mice demonstrated enhanced susceptibility to P. jirovecii and group B Streptococcus pneumonia, impaired alveolar macrophage function, reduced pulmonary clearance of surfactant proteins and lipids in the alveolar space, and lymphoid hyperplasia surrounding airways and lung vasculature [ 62 , 67–69 ]. Conversely, enhanced pulmonary expression of GM-CSF confers protection against postinfluenza tracheobronchial bacterial superinfection and P. jirovecii pneumonia [ 62 , 70 ].

Response to pulmonary infection may also be regulated by the pleiotropic effects of GM-CSF on macrophage mitochondrial function that underlie cellular proliferation and differentiation. Lack of GM-CSF signaling impairs amino acid biosynthesis, glycolysis, and the pentose phosphate pathway, suggesting the importance of GM-CSF in facilitating mitochondrial pathways crucial to macrophage differentiation and proliferation [ 66–71 ]. Macrophage efferocytosis and mitochondrial bioenergetics may also play a role in immune responses to infections [ 71 , 72 ]. GM-CSF also regulates alveolar macrophage population size via STAT5 phosphorylation [ 73 ].

Several small clinical studies indicate that inhaled delivery of rhu GM-CSF may be effective in improving pulmonary host defenses and clinical outcomes for several acute respiratory diseases [ 68–78 ]. Ongoing trials are further evaluating sargramostim in patients with COVID-19 and in those with sepsis [ 74–76 ].

Further supporting a respiratory mucosal protective role of rhu GM-CSF, a phase 2 trial evaluating sargramostim plus ipilimumab vs ipilimumab alone for metastatic melanoma showed a protective effect of sargramostim on pulmonary and gastrointestinal toxicity [ 77 ]. Such a protective effect on respiratory epithelia might also be beneficial in early IFD [ 79 , 80 ]. Based upon its pleiotropic effects on the phagocytic and respiratory epithelium in augmenting pulmonary and systemic innate host defenses, additional clinical studies of sargramostim should be considered for patients at risk for progression of IFD.

Based on our direct experience and previously published cases, some guidance can be made regarding the dosage, timing of initiation, and duration of sargramostim for treatment of IFDs. In the new cases presented here, patients with baseline neutropenia initially received sargramostim at a dosage of 250 µg/m 2 /d to promote recovery from neutropenia and were transitioned to a dosage of 100 µg/m 2 3 times weekly when the ANC exceeded 500 cells/µL. In contrast, those without baseline neutropenia were initiated on a lower initial dosage of 100 µg/m 2 3 times weekly. The initial sargramostim dose was therefore adjusted to each patient's hematologic profile in order to avoid a supraphysiological neutrophilic response in those without neutropenia. In the published case studies of rhu GM-CSF, dosing varied widely. Most patients were treated with a dosage of 250 to 300 μg/m 2 /d, with dose and frequency often reduced during the maintenance phase. In most of the new cases, sargramostim was added to existing antifungal therapy, and the combination regimen was continued until resolution of infection. This approach also was used in the majority of published cases, although some patients with treatment-resistant infections were treated successfully with rhu GM-CSF alone or in combination with interferon-γ [ 8 ]. For our new cases presented, duration of sargramostim therapy ranged from 4 to 124 weeks, facilitating stabilization or resolution of infection and allowing completion of chemotherapy or hematopoietic cell transplantation in most patients.

As reduction or elimination of concomitant immunosuppressive therapies is a cornerstone of successful treatment of IFDs, immunosuppressive corticosteroid therapy was discontinued or not administered where possible, in conjunction with modified doses of maintenance chemotherapy. GM-CSF also reduces the immunosuppressive effects of corticosteroids on pulmonary alveolar macrophages and elutriated human monocytes by preserving pro-inflammatory and Th1 cytokine responses to Aspergillus conidia, increasing IκB degradation, and enhancing NF-κB translocation to allow macrophage-mediated release of pro-inflammatory molecules and augmentation of innate host response to invasive aspergillosis [ 78–82 ].

In assessing the risk/benefit ratio of sargramostim in the treatment of refractory IFDs, several considerations bear note. There exists a clear potential for augmenting host response when other therapeutic options are ineffective. As sargramostim is well tolerated with minimal fever, flu-like symptoms, or bone pain in some patients, the therapeutic benefits appear to outweigh minimal risks. When considering the administration of sargramostim for earlier treatment of IFDs before they become refractory, the same analysis applies but warrants further investigation.

There are several limitations to this study. The published cases presented varied widely in dose and duration of rhu GM-CSF, use of concomitant antifungal agents, causes of IFDs, and types of comorbidities. More favorably responding cases treated with rhu GM-CSF may have been published, reflecting selection bias. Yet the overall response rate of 82% in published cases was similar to that of 92% in the newly reported cases. Also, conclusions about the efficacy of rhu GM-CSF for specific pathogens may be hindered due to the limited case numbers for some pathogens. While a fungal pathogen was identified in most cases, these laboratory diagnoses may not always be accurate. Finally, increased use of newer antifungal agents, as well as emergence of more resistant infections, complicates determination of the efficacy of rhu GM-CSF, particularly when comparing more recent results with older studies. Continued investigations of the immunoregulatory effect mechanisms of sargramostim will help to elucidate further the immunology underlying its benefit and allow for more rapid evaluation of the effects of rhu GM-CSF against specific pathogens.

Based on these data, several potential pathways exist for further evaluation of sargramostim as an adjunct to antifungal therapy. A classical approach would involve the design of a prospective clinical trial to enroll pediatric oncology patients with refractory IFDs. Given the challenges of completing such a study of uncommon fungal diseases, alternative approaches for demonstrating substantial improvements over available therapies for these serious life-threatening infections could be considered, including innovative designs with easily interpreted end points and well-defined case controls from registries, contemporaneous cases, and literature reviews.

Acknowledgments

The authors thank Pillar Medical Communications and Larry Rosenberg, PhD, for assistance with research and manuscript preparation.

Financial support. T.J.W. was supported in part for this work by the Henry Schueler 41 & 9 Foundation and the Save Our Sick Kids Foundation. P.Z. was supported for this work through a Hellenic/American Scholarship/Mentorship. This work was supported in part by Partner Therapeutics, Inc., which provided for research assistance, professional medical writing, graphical design, and publication fees. T.K.C. received funding from the Luke Tatsu Johnson Foundation and Save Our Sick Kids Foundation to support the analysis and writing of this manuscript.

Author contributions. Tempe Chen, Thomas Walsh: conceptualization, methodology, data curation, supervision, writing—original draft and multiple revised drafts; Jagmohan Batra, David Michalik, Jacqueline Casillas, Ramesh Patel, Maritza Ruiz, Harneet Hara, Bhavita Patel, Meena Kadapakkam, James Ch'Ng: supervision, writing—reviewing and editing; Catherine Small, Panagiotis Zagaliotis, Emmanuel Roilides: methodology, writing—reviewing and editing; Carolyn Ragsdale: conceptualization, methodology, data curation, writing—reviewing and editing; Luis Leal: conceptualization, methodology, writing—reviewing and editing.

Patient consent. Due to the retrospective nature of this case series in conjunction with the systematic review, patient consent was not required by the institutional review board of the authors (T.C., J.B., D.E.M., J.C., R.P., M.R., H.H., B.P., M.K., and J.C.).

Contributor Information

Tempe K Chen, Department of Pediatric Infectious Diseases, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Department of Pediatrics, Division of Infectious Diseases, University of California Irvine School of Medicine, Irvine, California, USA.

Jagmohan S Batra, Department of Pediatric Infectious Diseases, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Department of Pediatrics, Division of Infectious Diseases, University of California Irvine School of Medicine, Irvine, California, USA.

David E Michalik, Department of Pediatric Infectious Diseases, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Department of Pediatrics, Division of Infectious Diseases, University of California Irvine School of Medicine, Irvine, California, USA.

Jacqueline Casillas, Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.

Ramesh Patel, Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.

Maritza E Ruiz, Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.

Harneet Hara, Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.

Bhavita Patel, Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.

Meena Kadapakkam, Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.

James Ch'Ng, Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.

Catherine B Small, Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, New York, New York, USA.

Panagiotis Zagaliotis, Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, New York, New York, USA; Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece; Department of Pharmacology and Therapeutics, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Carolyn E Ragsdale, Partner Therapeutics, Inc., Lexington, Massachusetts, USA.

Luis O Leal, Partner Therapeutics, Inc., Lexington, Massachusetts, USA.

Emmanuel Roilides, Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece.

Thomas J Walsh, Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, New York, New York, USA; Center for Innovative Therapeutics and Diagnostics, Richmond, Virginia, USA.

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