Drug Trials Snapshots: GRAFAPEX
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the GRAFAPEX Prescribing Information for all the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
GRAFAPEX (treosulfan)
graf-uh-PECKS
Medexus Pharma, Inc.
Approval date: January 21, 2025
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
GRAFAPEX is a medicine that is indicated for use in combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation in adult and pediatric patients 1 year of age and older with acute myeloid leukemia (AML) as well as myelodysplastic syndrome (MDS).
How is this drug used?
GRAFAPEX is an injection. It is given by a healthcare professional directly into the vein (intravenous infusion) daily for three days, beginning on Day -4 prior to transplantation in combination with fludarabine.
Who participated in the clinical trials?
The FDA approved GRAFAPEX based on safety and efficacy from a clinical trial (MC-FludT.14/L Trial II; NCT00822393) of 570 adult patients with AML and MDS, with additional safety data from 111 pediatric patients treated with GRAFAPEX. The adult trial was conducted at 31 sites in five countries including France, Germany, Hungary, Italy, and Poland. The pediatric patients were treated at 26 sites in five countries including Czech Republic, Germany, Italy, Poland, and the United Kingdom.
How were the trials designed?
GRAFAPEX was evaluated in a single phase 3 clinical trial of 570 adult patients with AML and MDS (MC-FludT.14/L Trial II). The trial was a randomized active-controlled trial comparing GRAFAPEX to busulfan in combination with fludarabine. There were 280 patients randomized to the GRAFAPEX arm and 290 patients to the busulfan arm.
The safety of GRAFAPEX as part of transplant conditioning was also evaluated in pediatric patients.
How were the trials designed?
The efficacy and safety of GRAFAPEX were evaluated in MC-FludT.14/L Trial II. Eligible patients included adults 18 to 70 years old with AML in remission or MDS, and hematopoietic cell transplantation comorbidity index (HCT-CI) score >2 for those patients <50 years old. The benefit of GRAFAPEX was measured in 365 patients with AML and 205 patients with MDS. Patients were randomized to receive GRAFAPEX 10 g/m² daily on Day -4, -3, and -2 or busulfan 0.8 mg/kg every six hours on Day -4 and 3 in combination with fludarabine 30 mg/m² daily on Day -6, -5, -4, -3, and -2, and transplantation on Day 0. Efficacy was established based on overall survival, defined as the time from randomization until death from any cause.
Safety of GRAFAPEX in pediatric patients was evaluated in pediatric patients 1 year and older including patients with AML or MDS.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were enrolled in the clinical trial used to evaluate the efficacy of GRAFAPEX.
Figure 1. Baseline Demographics by Sex, Efficacy Population
Source: Adapted from FDA Review
Figure 2 summarizes how many patients by age were enrolled in the clinical trial used to evaluate the efficacy of GRAFAPEX.
Figure 2. Baseline Demographics by Age, Efficacy Population
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Baseline Demographics of Efficacy Trials by Age, Race, Sex, and Ethnicity
| Baseline Demographics | GRAFAPEX N=280 n (%) | Busulfan N=290 n (%) |
|---|---|---|
| Sex |
|
|
| Female | 109 (38.9) | 114 (39.3) |
| Male | 171 (61.1) | 176 (60.7) |
| Age, years |
|
|
| 18 to <65 | 204 (72.9) | 218 (75.2) |
| ≥65 | 76 (27.1) | 72 (24.8) |
| Race Unknown | 280 (100.0) | 290 (100.0) |
| Ethnicity Unknown | 280 (100.0) | 290 (100.0) |
Source: Adapted from FDA Review
What are the benefits of this drug?
In MC-FludT.14/L Trial II, patients with AML and MDS who received GRAFAPEX showed an improved overall survival compared to patients who received busulfan.
What are the benefits of this drug (results of trials used to assess efficacy)?
In MC-FludT.14/L Trial II, 570 patients were randomized to either the GRAFAPEX arm (N=280) or the busulfan arm (N=290) to be given with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation. Figure 3 summarizes efficacy results established based on overall survival, measured from the time of randomization until death from any cause.
Figure 3. Kaplan-Meier Curve for Overall Survival Since Time of Randomization, MC FludT.14/L Trial II
Source: GRAFAPEX Prescribing Information
Abbreviations: CI, confidence interval
The hazard ratio (HR) for overall survival (stratified by donor type and risk group) compared to busulfan was 0.67 (95% CI: 0.51, 0.90), in favor of GRAFAPEX. In patients with AML the HR for overall survival was 0.73 (95% CI: 0.51, 1.06), and in patients with MDS it was 0.64 (95% CI: 0.40, 1.02).
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: GRAPAFEX appeared to work better in males than in females.
- Race: Information on race of the patients was not collected. Therefore, differences in how GRAFAPEX worked among races could not be determined.
- Age: GRAPAFEX appeared to work better in patients 65 years of age and older than in patients who are younger than 65 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race and age groups?
The benefit of GRAFAPEX was consistent across age subgroups.
Table 2. Results by Sex and Age, Efficacy Population
| Subgroup | GRAFAPEX Survival Probability at 24 months % (95% CI) | Busulfan Survival Probability at 24 months % (95% CI) | GRAFAPEX Events/N (%) | Busulfan Events/N (%) | HR |
|---|---|---|---|---|---|
| Sex |
|
|
|
|
|
| Female | 69 (59, 77) | 70 (60, 78) | 36/109 (33) | 33/114 (29) | 1.02 (0.63, 1.64) |
| Male | 75 (67, 81) | 54 (46, 61) | 45/171 (26) | 79/176 (45) | 0.52 (0.36, 0.76) |
| Age, years |
|
|
|
|
|
| 18 to <65 | 72 (65, 78) | 64 (57, 70) | 59/204 (29) | 75/218 (34) | 0.78 (0.55, 1.09) |
| ≥65 | 75 (63, 84) | 49 (36, 61) | 22/76 (29) | 37/72 (51) | 0.43 (0.25, 0.75) |
Source: Adapted from FDA Review
Abbreviations: CI: confidence interval ; HR, hazard ratio (based on Cox proportional hazards model stratified by donor type and risk group)
What are the possible side effects?
GRAFAPEX causes severe and prolonged bone marrow suppression, therefore, hematopoietic stem cell transplantation is required, and hematologic laboratory parameters must be monitored.
GRAFAPEX may cause serious side effects including skin reactions, secondary cancer disease, seizures, and harm to an unborn baby. Using doses higher than the approved dose has resulted in early deaths and serious side effects.
The most common side effects (reported by greater than 20% of patients) include: body pain (arms, legs, back), joint and bone pain, stomatitis, fever, nausea, edema, infection, and vomiting.
What are the possible side effects (results of trials used to assess safety)?
Table 3 summarizes adverse reactions and Table 4 select grade 3 or 4 laboratory abnormalities that occurred within 30 days after hematopoietic stem cell transplantation reported by greater than 10% of patients who were treated with GRAFAPEX or the comparator Busulfan.
Table 3. Adverse Reactions in ≥10% of Patients Through Transplant Day +30 in Study MC-FludT.14/L Trial II, Safety Population
| Adverse Reaction* | All Grades | Grades 3 or 4 | ||
|---|---|---|---|---|
GRAFAPEX N=270 % | Busulfan N=283 % | GRAFAPEX N=270 % | Busulfan N=283 % | |
| Musculoskeletal pain | 39 | 27 | 5 | 2 |
| Stomatitis | 38 | 48 | 6 | 7 |
| Pyrexia | 34 | 36 | 1 | 3 |
| Nausea | 33 | 41 | 3 | 6 |
| Edema | 29 | 18 | 0.7 | 1 |
| Infection1 | 23 | 18 | 12 | 6 |
| Vomiting | 22 | 19 | 1 | 1 |
| Rash | 17 | 13 | 1 | 1 |
| Diarrhea | 17 | 18 | 1 | 1 |
| Headache | 16 | 18 | 1 | 1 |
| Febrile neutropenia | 15 | 11 | 15 | 11 |
| Abdominal pain | 15 | 13 | 3 | 2 |
| Hypertension | 14 | 21 | 8 | 10 |
| Hemorrhage | 14 | 14 | 1 | 1 |
| Fatigue | 13 | 15 | 1 | 0.4 |
| Constipation | 12 | 12 | 0.4 | 0 |
| Tachycardia | 10 | 5 | 1 | 2 |
| Hepatotoxicity | 10 | 8 | 4 | 3 |
Source: GRAFAPEX Prescribing Information
Grading based on Common Terminology Criteria for Adverse Events Version 4.03
* Includes grouped terms
1 Includes fatalities: n=6 in the GRAFAPEX arm and n=2 in the busulfan arm
Table 4. Selected Grades 3 or 4 Laboratory Abnormalities through Transplant Day +30 in Study MC-FludT.14/L Trial II
| Laboratory Abnormality | GRAFAPEX % | Busulfan % |
|---|---|---|
| Gamma glutamyl transferase Increased | 16 | 28 |
| Bilirubin increased | 6 | 5 |
| Alanine aminotransferase increased | 6 | 4 |
| Aspartate aminotransferase increased | 4 | 1 |
| Creatinine increased | 3 | 0.7 |
Source: GRAFAPEX Prescribing Information
Grading based on Common Terminology Criteria for Adverse Events Version 4.03
Were there any differences in side effects among sex, race and age?
- Sex: The occurrence of side effects was similar in females and males.
- Race: Information on race of the patients was not collected. Therefore, the occurrence of side effects in different races could not be determined.
- Age: In pediatric patients treated with GRAFAPEX, the incidence of liver and gastrointestinal adverse reactions was higher than in adults. The occurrence of side effects was similar in adult patients across age groups.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 5. Adverse Reactions ≥10% Through Transplant Day +30 by Sex, Safety Population
| Adverse Reaction* | All Grades | |
|---|---|---|
GRAFAPEX Female N=107 n (%) | GRAFAPEX Male N=163 n (%) | |
| Any AE | 100 (93.5) | 150 (92.0) |
| Musculoskeletal pain | 42 (39.3) | 63 (38.7) |
| Stomatitis | 45 (42.1) | 57 (35.0) |
| Pyrexia | 36 (33.6) | 57 (35.0) |
| Nausea | 41 (38.3) | 48 (29.4) |
| Edema | 35 (32.7) | 42 (25.8) |
| Infection | 22 (20.6) | 41 (25.2) |
| Vomiting | 35 (32.7) | 24 (14.7) |
| Rash | 16 (15.0) | 30 (18.4) |
| Diarrhea | 22 (20.6) | 23 (14.1) |
| Headache | 21 (19.6) | 23 (14.1) |
| Febrile neutropenia | 15 (14.0) | 25 (15.3) |
| Abdominal pain | 12 (11.2) | 28 (17.2) |
| Hypertension | 17 (15.9) | 21 (12.9) |
| Hemorrhage | 13 (12.1) | 24 (14.7) |
| Fatigue | 12 (11.2) | 22 (13.5) |
| Constipation | 17 (15.9) | 16 (9.8) |
| Tachycardia | 11 (10.3) | 16 (9.8) |
| Hepatotoxicity | 6 (5.6) | 21 (12.9) |
| Alanine aminotransferase increased | 11 (10.3) | 12 (7.4) |
| Renal impairment | 6 (5.6) | 18 (11.0) |
Source: Adapted from FDA Review
* Includes grouped terms
Abbreviations: AE, adverse event
Table 6. Adverse Reactions ≥10% of Patients through Transplant Day +30 by Age, Safety Population
| Adverse Reaction* | All Grades | |
GRAFAPEX 18 to <65 Years N=197 n (%) | GRAFAPEX ≥65 Years N=73 n (%) | |
| Any AE | 185 (93.9) | 65 (89.0) |
| Musculoskeletal pain | 73 (37.1) | 32 (43.8) |
| Stomatitis | 78 (39.6) | 24 (32.9) |
| Pyrexia | 66 (33.5) | 27 (37.0) |
| Nausea | 67 (34.0) | 22 (30.1) |
| Edema | 59 (29.9) | 18 (24.7) |
| Infection | 40 (20.3) | 23 (31.5) |
| Vomiting | 40 (20.3) | 19 (26.0) |
| Rash | 32 (16.2) | 14 (19.2) |
| Diarrhea | 30 (15.2) | 15 (20.5) |
| Headache | 33 (16.8) | 11 (15.1) |
| Febrile neutropenia | 30 (15.2) | 10 (13.7) |
| Abdominal pain | 30 (15.2) | 10 (13.7) |
| Hypertension | 29 (14.7) | 9 (12.3) |
| Hypotension | 11 (5.6) | 8 (11.0) |
| Hemorrhage | 26 (13.2) | 11 (15.1) |
| Fatigue | 22 (11.2) | 12 (16.4) |
| Constipation | 24 (12.2) | 9 (12.3) |
| Tachycardia | 18 (9.1) | 9 (12.3) |
| Hepatotoxicity | 19 (9.6) | 8 (11.0) |
| Alanine aminotransferase increased | 15 (7.6) | 8 (11.0) |
| Aspartate aminotransferase increased | 15 (7.6) | 8 (11.0) |
| Renal impairment | 16 (8.1) | 8 (11.0) |
| Decreased appetite | 14 (7.1) | 10 (13.7) |
Source: Adapted from FDA review
* Includes grouped terms
Abbreviations: AE, adverse event
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.