Mycoses
Conditions
Keywords
Allo-HSCT, rhGM-CSF, Systemic fungal infection (SFI)
Brief summary
We conducted a prospective, multicenter, open-label randomized trial to compare the antifungal effect of Recombinant Human Granulocyte-macrophage Stimulating Factor (rhGM-CSF), Recombinant Human Granulocyte Stimulating Factor (rhG-CSF) or a combination of rhGM-CSF and rhG-CSF for neutropenic patients undergoing allogeneic stem cell transplantation.
Detailed description
From Sept 2009 to Dec 2012, we recruited consecutive patients with hematological diseases undergoing allogeneic stem cell transplantation at 5 institutions in China. Recipients between ages of 14 to 60 years old were eligible. Eligible patients were randomized to receive once daily subcutaneous 5-7μg/kg/d GM-CSF (Molgramostim, TOPLEUCON®; Xiamen Amoytop Biotech Co., Ltd., China) (GM-CSF group), 5-7μg/kg/d G-CSF (G-CSF group), or a combination of 2-3μg/kg/d GM-CSF and 2-3μg/kg/d G-CSF each (G-CSF+GM-CSF group). Administration of CSFs was started on day 5 post-transplant and continued until recovery from neutropenia (absolute neutrophil count \[ANC\] \> 1.5×10(9)/L for 2 consecutive days). If absolute neutrophil count (ANC) decreased to \< 1.5×10(9)/L within 5 days after withdrawal of CSFs, the same CSF would be resumed until the absolute neutrophil count (ANC) reached 1.5×10(9)/L again. All patients received antimicrobial prophylaxis with oral levofloxacin 500 mg daily and antifungal prophylaxis with oral fluconazole 200 mg daily.
Interventions
DRUGrhGM-CSF group
subcutaneous rhGM-CSF 5-7μg/kg/d , started on day 5 post-transplant and continued until recovery from neutropenia (absolute neutrophil count \[ANC\] \> 1.5×10(9)/L for 2 consecutive days).
DRUGrhG-CSF+rhGM-CSF group
a combination of 2-3μg/kg/d rhGM-CSF and 2-3μg/kg/d rhG-CSF each after transplantation, started on day 5 post-transplant and continued until recovery from neutropenia (absolute neutrophil count \[ANC\] \> 1.5×10(9)/L for 2 consecutive days).
DRUGrhG-CSF group
subcutaneous rhGM-CSF 5-7μg/kg/d , started on day 5 post-transplant and continued until recovery from neutropenia (absolute neutrophil count \[ANC\] \> 1.5×10(9)/L for 2 consecutive days).
Sponsors
Shanghai Jiao Tong University Affiliated First People's Hospital
Xiamen Amoytop Biotech Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Age 14\ 60 years old * Allogenic hematological stem cell transplantation(HSCT) patients. * Cardiac ejection factor ≥ normal upper limit, Aspartate aminotransferase and/or Alanine aminotransferase \< 2 upper limit of normal, and/or total bilirubin \< 2.5 upper limit of normal, creatinine \< upper limit of normal. * Informed consent.
Exclusion criteria
* Evidence of proven, probable or possible fungal infection at the time of enrollment. * Patients were receiving anti-fungal treatment with proven SFI before transplantation. * A history of hypersensitivity to G-CSF or GM-CSF.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidences of Invasive Fungal Diseases (IFD) | 100 day post transplant | The incidence of proven and probable Invasive fungal diseases (IFD) within 100 days post transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Transplant Related Mortality | 100 days post transplant | Transplant related mortality within 100 days after Allogeneic Stem Cell Transplantation (Allo-HSCT). |
| Incidence of Ⅱ- Ⅳ Acute Graft Versus Host Disease (aGVHD) | 100 days post transplant | Incidence of Ⅱ- Ⅳacute graft versus host disease (aGVHD) within 100 days after allogeneic stem cell transplantation (Allo-HSCT).The severity of acute GVHD in the three main target organs (skin, liver, gastrointestinal tract) was assigned stage 1 to 4 based on accepted criteria (Consensus Conference on Acute GVHD Grading). |
| IFD Related Mortality | 3-1099 days | IFD-related mortalities after a median follow-up of 600 days. |
| Hematological Engraftment | 100 days post transplant | The median time of neutrophil and platelet recovery . |
| Graft Versus Host Disease (aGVHD) Related Mortality | 3-1099 days | Graft versus host disease (aGVHD) related mortality after a median follow-up of 600 days . |
| Hemorrhage Related Mortality | 3-1099 days | Hemorrhage related mortality after a median follow-up of 600 days |
| Infection Related Mortality | 3～1099 days) | Infection related mortality after a median follow-up of 600 days. |
| Relapse Related Mortality | 3～1099 days | Relapse related mortality after a median follow-up of 600 days. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| rhGM-CSF Group subcutaneous rhGM-CSF 5-7μg/kg/d , started on day 5 post-transplant and continued until recovery from neutropenia (absolute neutrophil count \[ANC\] \> 1.5×10(9)/L for 2 consecutive days). | 68 |
| rhG-CSF+ rhGM-CSF Group a combination of 2-3μg/kg/d rhGM-CSF and 2-3μg/kg/d rhG-CSF each after transplantation, started on day 5 post-transplant and continued until recovery from neutropenia (absolute neutrophil count \[ANC\] \> 1.5×10(9)/L for 2 consecutive days). | 69 |
| rhG-CSF Group subcutaneous rhG-CSF 5-7μg/kg/d , started on day 5 post-transplant and continued until recovery from neutropenia (absolute neutrophil count \[ANC\] \> 1.5×10(9)/L for 2 consecutive days). | 69 |
| Total | 206 |
Baseline characteristics
| Characteristic | Total | rhGM-CSF Group | rhG-CSF+ rhGM-CSF Group | rhG-CSF Group |
|---|---|---|---|---|
| Age, Categorical <=18 years | 22 Participants | 8 Participants | 5 Participants | 9 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 184 Participants | 60 Participants | 64 Participants | 60 Participants |
| Age, Continuous | 31.75 years | 30.68 years | 32.55 years | 32.04 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 206 Participants | 68 Participants | 69 Participants | 69 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 206 participants | 68 participants | 69 participants | 69 participants |
| Sex: Female, Male Female | 74 Participants | 17 Participants | 32 Participants | 25 Participants |
| Sex: Female, Male Male | 132 Participants | 51 Participants | 37 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 68 | 31 / 69 | 28 / 69 |
| serious Total, serious adverse events | 0 / 68 | 0 / 69 | 0 / 69 |
Outcome results
Primary
Incidences of Invasive Fungal Diseases (IFD)
The incidence of proven and probable Invasive fungal diseases (IFD) within 100 days post transplantation
Time frame: 100 day post transplant
Population: The number of intention-to-treat patients is 206. The incidence of invasive fungal infection analysis within 100 day is based on intention-to-treat (ITT)patients .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rhGM-CSF Group | Incidences of Invasive Fungal Diseases (IFD) | 11.76 percentage of partipants |
| rhG-CSF + rhGM-CSF Group | Incidences of Invasive Fungal Diseases (IFD) | 10.14 percentage of partipants |
| rhG-CSF Group | Incidences of Invasive Fungal Diseases (IFD) | 23.19 percentage of partipants |
Secondary
Graft Versus Host Disease (aGVHD) Related Mortality
Graft versus host disease (aGVHD) related mortality after a median follow-up of 600 days .
Time frame: 3-1099 days
Population: The number of intention-to-treat patients is 206. The IFD related mortality analysis is based on intention-to-treat (ITT) patients .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rhGM-CSF Group | Graft Versus Host Disease (aGVHD) Related Mortality | 8.82 percentage of participants |
| rhG-CSF + rhGM-CSF Group | Graft Versus Host Disease (aGVHD) Related Mortality | 4.35 percentage of participants |
| rhG-CSF Group | Graft Versus Host Disease (aGVHD) Related Mortality | 7.25 percentage of participants |
Secondary
Hematological Engraftment
The median time of neutrophil and platelet recovery .
Time frame: 100 days post transplant
Population: The number of intention-to-treat patients is 206. The hematological engraftment analysis within 100 day is based on intention-to-treat (ITT)patients .
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| rhGM-CSF Group | Hematological Engraftment | Median time for neutrophil recovery to 0.5×10(9)/L | 13 days |
| rhGM-CSF Group | Hematological Engraftment | Median time for platelet recovery to 50 × 10(9)/L | 18 days |
| rhG-CSF + rhGM-CSF Group | Hematological Engraftment | Median time for neutrophil recovery to 0.5×10(9)/L | 11 days |
| rhG-CSF + rhGM-CSF Group | Hematological Engraftment | Median time for platelet recovery to 50 × 10(9)/L | 19 days |
| rhG-CSF Group | Hematological Engraftment | Median time for neutrophil recovery to 0.5×10(9)/L | 11 days |
| rhG-CSF Group | Hematological Engraftment | Median time for platelet recovery to 50 × 10(9)/L | 25 days |
Secondary
Hemorrhage Related Mortality
Hemorrhage related mortality after a median follow-up of 600 days
Time frame: 3-1099 days
Population: The number of intention-to-treat patients is 206. The IFD related mortality analysis is based on intention-to-treat (ITT) patients .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rhGM-CSF Group | Hemorrhage Related Mortality | 5.88 percentage of participants |
| rhG-CSF + rhGM-CSF Group | Hemorrhage Related Mortality | 1.45 percentage of participants |
| rhG-CSF Group | Hemorrhage Related Mortality | 1.45 percentage of participants |
Secondary
IFD Related Mortality
IFD-related mortalities after a median follow-up of 600 days.
Time frame: 3-1099 days
Population: The number of intention-to-treat patients is 206. The IFD related mortality analysis is based on intention-to-treat (ITT) patients .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rhGM-CSF Group | IFD Related Mortality | 1.47 percentage of participants |
| rhG-CSF + rhGM-CSF Group | IFD Related Mortality | 1.45 percentage of participants |
| rhG-CSF Group | IFD Related Mortality | 11.59 percentage of participants |
Secondary
Incidence of Ⅱ- Ⅳ Acute Graft Versus Host Disease (aGVHD)
Incidence of Ⅱ- Ⅳacute graft versus host disease (aGVHD) within 100 days after allogeneic stem cell transplantation (Allo-HSCT).The severity of acute GVHD in the three main target organs (skin, liver, gastrointestinal tract) was assigned stage 1 to 4 based on accepted criteria (Consensus Conference on Acute GVHD Grading).
Time frame: 100 days post transplant
Population: The number of intention-to-treat patients is 206. The incidence of aGVHD analysis is based on intention-to-treat (ITT) patients .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rhGM-CSF Group | Incidence of Ⅱ- Ⅳ Acute Graft Versus Host Disease (aGVHD) | 30.88 percentage of partipants |
| rhG-CSF + rhGM-CSF Group | Incidence of Ⅱ- Ⅳ Acute Graft Versus Host Disease (aGVHD) | 24.64 percentage of partipants |
| rhG-CSF Group | Incidence of Ⅱ- Ⅳ Acute Graft Versus Host Disease (aGVHD) | 21.74 percentage of partipants |
Secondary
Infection Related Mortality
Infection related mortality after a median follow-up of 600 days.
Time frame: 3～1099 days)
Population: The number of intention-to-treat patients is 206. The IFD related mortality analysis is based on intention-to-treat (ITT) patients .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rhGM-CSF Group | Infection Related Mortality | 1.47 percentage of participants |
| rhG-CSF + rhGM-CSF Group | Infection Related Mortality | 5.8 percentage of participants |
| rhG-CSF Group | Infection Related Mortality | 14.50 percentage of participants |
Secondary
Relapse Related Mortality
Relapse related mortality after a median follow-up of 600 days.
Time frame: 3～1099 days
Population: The number of intention-to-treat patients is 206. The IFD related mortality analysis is based on intention-to-treat (ITT) patients .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rhGM-CSF Group | Relapse Related Mortality | 5.8 percentage of participants |
| rhG-CSF + rhGM-CSF Group | Relapse Related Mortality | 8.7 percentage of participants |
| rhG-CSF Group | Relapse Related Mortality | 4.35 percentage of participants |
Secondary
Transplant Related Mortality
Transplant related mortality within 100 days after Allogeneic Stem Cell Transplantation (Allo-HSCT).
Time frame: 100 days post transplant
Population: The number of intention-to-treat patients is 206. The transplant related mortality analysis within 100 day is based on intention-to-treat (ITT) patients .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rhGM-CSF Group | Transplant Related Mortality | 8.8 percentage of participants |
| rhG-CSF + rhGM-CSF Group | Transplant Related Mortality | 8.7 percentage of participants |
| rhG-CSF Group | Transplant Related Mortality | 21.7 percentage of participants |