Myelodysplastic Syndromes
Conditions
Keywords
MDS classified as IPSS low/int-1
Brief summary
There are currently no licensed drugs in the EU to treat thrombocytopenia in MDS patients classified as IPSS low/int-1. Prior studies with romiplostim (a TPO receptor agonist) in MDS found that baseline concentration of TPO as well as transfusion history were predictive of subsequent response in a retrospective model. The current prospective study has the aim to explore whether both pretreatment variables (endogenous TPO, TPO-level, platelet transfusion history) can predict the response to subsequent short-term treatment with romiplostim.
Detailed description
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies of the pluripotent hematopoietic stem cells characterized by clonal hematopoiesis, progressive bone marrow failure, and the propensity to transform to acute myeloid leukemia (AML) (Malcovati et al., 2013). There are currently no licensed drugs in the EU to treat thrombocytopenia in MDS patients classified as IPSS low/int-1. Prior studies with romiplostim (a TPO receptor agonist) in MDS found that baseline concentration of TPO as well as transfusion history were predictive of subsequent response in a retrospective model. Classically, MDS is associated with apoptosis and excessive proliferation, resulting in a combination of a hyper-cellular marrow and peripheral cytopenia. The rationale for using romiplostim in MDS is to stimulate normal progenitor cells to increase platelet counts. Upon correction of thrombocytopenia, responding MDS patients should have a decreased risk of bleeding and a reduction in platelet transfusions (Giagounidis et al., 2014). This reduction in platelet transfusions may in turn decrease the risks of alloimmunization and the resultant morbidity and costs associated with that condition.
Interventions
DRUGN-Plate / romiplostim
medical intervention in 3 patient groups (MDS patients with IPSS Low/Int-1) that are stratified according to their baseline TPO-Level and previous transfusions
Sponsors
Amgen
Gesellschaft fur Medizinische Innovation - Hamatologie und Onkologie mbH
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must meet the following inclusion/
Exclusion criteria
to be eligible for the study. * Must understand and voluntarily sign the informed consent form * Age older 18 years at the time of signing the informed consent form * Must be able to adhere to the study visit schedule and other protocol requirements * Diagnosis of MDS using the 2008 WHO classification for myeloid neoplasms as assessed during the screening period * Per MDS IPSS, low or intermediate-1 risk MDS as assessed during the screening period * The mean of the 2 platelet counts taken within 4 weeks prior to stratification must be: * ≤ 30 x 109/L (with no individual count \> 30 x 109/L during the screening period), with or without a history of bleeding associated with the diagnosis of MDS, OR * \< 50 x 109/L (with no individual count \>60 x 109/L during the screening period), with a history of bleeding associated with the diagnosis of MDS (A standard of care platelet count taken prior to Informed consent may be used as 1 of the 2 counts taken within 4 weeks prior to stratification) * Adequate liver function, as evidenced by ALT ≤ 3 times the laboratory normal range, AST ≤ 3 times the laboratory normal range and total bilirubin ≤ 2 times the laboratory normal range * Bone marrow aspirate (central diagnostics) with cytogenetics (local) within 8 weeks of starting first dose of investigational product * Female subjects of childbearing potential† must: * Agree to use, and be able to comply with, effective contraception without interruption, 4 weeks before starting study drug, throughout study drug therapy and for 4 weeks after the end of study drug therapy, even if she has amenorrhoea. This applies unless the subject commits to absolute and continued abstinence confirmed on a monthly basis. Male patients who wish to participate in the study and their partner may become pregnant must agree also to reliable contraception during the study and for three months thereafter. The following are effective methods of contraception\* * Implant, - Levonorgestrel-releasing intrauterine system (IUS), Medroxyprogesterone acetate depot, Tubal sterilization, Sexual intercourse with a vasectomised male partner only; Ovulation inhibitory progesterone-only pills (i.e., desogestrel) * Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml not more than 3 days before the start of study medication once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hematologic Improvement of Platelets (HI-P) After 4 Months on Therapy | after 4 months on therapy (week 16) | The primary efficacy endpoint was the rate of HI-P defined as an absolute increase of platelet count to ≥ 30/nL for patients starting at \> 20/nL or an increase of platelets from \< 20/nL to \> 20/nL and by at least 100%, according to IWG 2006 criteria lasting for ≥ 8 weeks after at least 16 Weeks of romiplostim treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Incidence of Disease Progression to Higher Stage MDS or AML | week 16 | The incidence of disease progression to higher stage MDS or AML according to WHO (increase in blast percentage of ≥ 20 %) |
| Increase of Peripheral Blasts During Therapy | week 16 | — |
| Cumulative Hematologic Improvement | week 16 | Cumulative rate of hematologic improvement of platelets (HI-P), erythrocytes (HI-E) and neutrophil granulocytes (HI-N). None of the patients achieved simultaneous response of HI-P, HI-E and HI-N. |
| Incidence of Bleeding Events | up to 12 months | — |
| Type, Incidence and Severity of All Adverse Events Including Clinically Significant Changes in Laboratory Values | up to 12 months | — |
| Association of the Presence of Certain Mutations With Disease Progression in a Retrospective Analysis | week 16 | — |
Countries
France, Germany
Participant flow
Recruitment details
From May 2015 through July 2019, a total of 125 patients were screened at 19 study sites in France, 9 study sites in Germany and 1 study site in Czech Republic. Of them, 77 were eligible for study participation.
Pre-assignment details
77 patients were assigned into two different model groups at the time of screening based on previous platelet transfusion events (PTE) and centrally assessed TPO serum levels. 51 patients were assigned to Group A (TPO \< 500 ng/L and PTE \< 6 units/past year) and 26 patients to Group B+C (TPO \> 500 ng/L, and/or PTE ≥ 6 units/past year).
Participants by arm
| Arm | Count |
|---|---|
| Model Group A Starting dose 750 µg of romiplostim once a week (7d ± 2d), subcutaneous injection, 4 months maximum duration for responders treatment period was extended for up to 1 year (8 months extension period). The dose was adjusted based on the subject's platelet count. | 51 |
| Model Groups B+C Starting dose 750 μg of romiplostim once a week (7d ± 2d), subcutaneous injection, 4 months maximum duration for non-responders. The dose was adjusted based on the subject's platelet count. | 26 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | increase blasts | 2 | 0 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Physician Decision | 5 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Model Group A | Model Groups B+C | Total |
|---|---|---|---|
| Age, Continuous | 72.6 years STANDARD_DEVIATION 10.3 | 71.2 years STANDARD_DEVIATION 8.3 | 72.1 years STANDARD_DEVIATION 9.6 |
| Body Mass Index (BMI) | 26.46 kg/m^2 STANDARD_DEVIATION 3.99 | 28.03 kg/m^2 STANDARD_DEVIATION 4.44 | 26.97 kg/m^2 STANDARD_DEVIATION 4.18 |
| Race/Ethnicity, Customized Caucasian | 49 Participants | 23 Participants | 72 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Female | 18 Participants | 10 Participants | 28 Participants |
| Sex: Female, Male Male | 33 Participants | 16 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 1 / 26 |
| other Total, other adverse events | 10 / 51 | 5 / 26 |
| serious Total, serious adverse events | 12 / 51 | 8 / 26 |
Outcome results
Primary
Hematologic Improvement of Platelets (HI-P) After 4 Months on Therapy
The primary efficacy endpoint was the rate of HI-P defined as an absolute increase of platelet count to ≥ 30/nL for patients starting at \> 20/nL or an increase of platelets from \< 20/nL to \> 20/nL and by at least 100%, according to IWG 2006 criteria lasting for ≥ 8 weeks after at least 16 Weeks of romiplostim treatment.
Time frame: after 4 months on therapy (week 16)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Model Group A | Hematologic Improvement of Platelets (HI-P) After 4 Months on Therapy | 71.75 platelets (/nL) |
| Model Groups B+C | Hematologic Improvement of Platelets (HI-P) After 4 Months on Therapy | 18.75 platelets (/nL) |
Secondary
Association of the Presence of Certain Mutations With Disease Progression in a Retrospective Analysis
Time frame: week 16
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Model Group A | Association of the Presence of Certain Mutations With Disease Progression in a Retrospective Analysis | no | 69 Participants |
| Model Group A | Association of the Presence of Certain Mutations With Disease Progression in a Retrospective Analysis | yes | 8 Participants |
Secondary
Cumulative Hematologic Improvement
Cumulative rate of hematologic improvement of platelets (HI-P), erythrocytes (HI-E) and neutrophil granulocytes (HI-N). None of the patients achieved simultaneous response of HI-P, HI-E and HI-N.
Time frame: week 16
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Model Group A | Cumulative Hematologic Improvement | yes | 0 Participants |
| Model Group A | Cumulative Hematologic Improvement | no | 51 Participants |
| Model Groups B+C | Cumulative Hematologic Improvement | yes | 0 Participants |
| Model Groups B+C | Cumulative Hematologic Improvement | no | 26 Participants |
Secondary
Incidence of Bleeding Events
Time frame: up to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Model Group A | Incidence of Bleeding Events | 0.263 bleeding events per patient week | Standard Deviation 0.476 |
| Model Groups B+C | Incidence of Bleeding Events | 0.249 bleeding events per patient week | Standard Deviation 0.363 |
Secondary
Increase of Peripheral Blasts During Therapy
Time frame: week 16
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Model Group A | Increase of Peripheral Blasts During Therapy | 5%-10% | 0 Participants |
| Model Group A | Increase of Peripheral Blasts During Therapy | 10%-20% | 0 Participants |
| Model Group A | Increase of Peripheral Blasts During Therapy | > 20% | 0 Participants |
| Model Group A | Increase of Peripheral Blasts During Therapy | missing | 20 Participants |
| Model Group A | Increase of Peripheral Blasts During Therapy | < 5% | 31 Participants |
| Model Groups B+C | Increase of Peripheral Blasts During Therapy | < 5% | 15 Participants |
| Model Groups B+C | Increase of Peripheral Blasts During Therapy | missing | 11 Participants |
| Model Groups B+C | Increase of Peripheral Blasts During Therapy | 10%-20% | 0 Participants |
| Model Groups B+C | Increase of Peripheral Blasts During Therapy | 5%-10% | 0 Participants |
| Model Groups B+C | Increase of Peripheral Blasts During Therapy | > 20% | 0 Participants |
Secondary
The Incidence of Disease Progression to Higher Stage MDS or AML
The incidence of disease progression to higher stage MDS or AML according to WHO (increase in blast percentage of ≥ 20 %)
Time frame: week 16
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Model Group A | The Incidence of Disease Progression to Higher Stage MDS or AML | yes | 6 Participants |
| Model Group A | The Incidence of Disease Progression to Higher Stage MDS or AML | no | 45 Participants |
| Model Groups B+C | The Incidence of Disease Progression to Higher Stage MDS or AML | yes | 2 Participants |
| Model Groups B+C | The Incidence of Disease Progression to Higher Stage MDS or AML | no | 24 Participants |
Secondary
Type, Incidence and Severity of All Adverse Events Including Clinically Significant Changes in Laboratory Values
Time frame: up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Model Group A | Type, Incidence and Severity of All Adverse Events Including Clinically Significant Changes in Laboratory Values | 499 events |
| Model Groups B+C | Type, Incidence and Severity of All Adverse Events Including Clinically Significant Changes in Laboratory Values | 159 events |