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As part of the standard care for your disease or as part of a protocol, your doctor has offered you a treatment based on azacitidine, combined with either venetoclax or ivosidenib depending on the characteristics of your disease, with the aim of achieving remission. The clinical efficacy of these treatments has been established. They are internationally recognized standard treatments for your disease. However, it has been established that even when the first course of treatment is maximally effective, some residual leukemia cells remain, requiring further cycles of treatment after complete remission has been achieved.

The research proposed as part of the DREAM study aims to determine whether it is possible, based on laboratory analysis of blood or bone marrow samples, to predict the effectiveness of treatment, but also to improve biological knowledge about the minority of residual leukemia cells in order to identify ways to improve these treatments.

To do this, the DREAM study relies on new technologies available at the Leukemia Institute, which enable leukemia cells to be cultured in vitro to determine their response to treatment, or to study how diseased cells react to treatment using a blood or bone marrow sample (a technology known as “single-cell sequencing”).

To answer the question posed in the research, this bicentric study with minimal risks and constraints planned to include 120 people newly admitted to the St Louis Hospital and Avicenne Hospital for AML.

Before starting the first course of treatment, then during the administration period of this first course (4 to 10 days), and finally when evaluating the response to the first and sixth cycles (generally between 21 and 56 days after the start of the cycle), your doctor will prescribe various biological tests (cellular, molecular, protein, and microbiological) of your blood and bone marrow at regular intervals in order to better characterize the disease, monitor its progression during treatment, and monitor the effects of the disease and its treatment on your health.

In the proposed research, we will conduct biological studies on additional blood or bone marrow samples at certain key moments during treatment:

• just before treatment begins
• in the first few hours after administration
• on the 2nd and 7th days of the cycle
• then when evaluating the response to the first cycle and after six cycles)

This study aims to validate an in vitro drug response test as a “biomarker” of treatment response. It also aims to refine our understanding of the molecular consequences of these drugs’ action on leukemia cells, and in particular to determine the heterogeneity of response from one cell to another. It is therefore conducted purely for research purposes and will not result in any changes to the treatments your doctor will administer to you. The results of these biological studies will be obtained after your medical treatment has been completed and will have no impact on it.

These additional tests may require up to 6 additional blood tubes (30 mL) to be drawn, most often during a blood draw already scheduled for your monitoring. It is possible that adherence to the study blood draw schedule may result in an additional blood draw. Similarly, an additional 2 mL of bone marrow will be collected during a bone marrow puncture performed at the start of treatment, during the first cycle, and then during the reassessment at the end of the first cycle. While it is standard practice to perform a bone marrow puncture after the first cycle of treatment, an additional intermediate puncture will be performed around the 7th day of treatment as part of this study. This will be crucial in enabling the research physicians to understand the mechanism of action of the treatments, with a view to ultimately improving their efficacy.
Finally, if you give your specific consent, your doctor will perform a biopsy under local anesthesia instead of a simple bone marrow aspiration before starting treatment. This procedure, which is part of the routine tests for certain blood and bone marrow diseases, is generally performed if the aspiration fails.

With your specific consent, this examination will be performed immediately, and if necessary during the reassessment. In addition to the diagnostic information usually obtained with a fine needle aspiration, it will provide information on their spatial organization that only a needle biopsy can provide. New technologies (spatial transcriptomics) will enable medical researchers to better understand how diseased cells are distributed in the bone marrow and with which normal cells in the body (immune system cells, support cells known as “stromal” cells) they interact. This will ultimately lead to the development of new treatment options.

The estimated duration of the study is 38 months, and your participation will be 56 days. After signing your consent form, the study will proceed as follows:

• As soon as the initial assessment of the disease has been completed, the following will be performed:
  – A 2 mL bone marrow sample will be taken during the initial myelogram assessment of the disease.
  – Optionally, if you have specifically consented to it, this myelogram (puncture-aspiration) will be replaced by a puncture-biopsy (“bone marrow biopsy”) under local anesthesia.
  – A 30 mL blood sample will be taken before any anti-leukemia treatment, preferably on the same day as the initial myelogram.
• A new 30 mL blood sample will then be taken
  – On the evening of Day 1 of the first cycle, between 6 and 12 hours after the first dose of venetoclax (or ivosidenib) was administered (“lysis assessment”),
  – On Day 2 of the first cycle, before the second dose of venetoclax (or ivosidenib)
  – On the day of remission assessment (between Day 21 and Day 56 after the start of the first cycle).
• A new 2 mL bone marrow sample will then be taken
  – Around the 7th day of the cycle (between the 4th and 10th day)
  – During the evaluation myelogram of the first and 6th cycles (between the 21st and 56th day after the start of the cycle).
  – Optionally, if you have specifically consented to it, this myelogram (aspiration) will be replaced by a biopsy (“bone marrow biopsy”) under local anesthesia.

By participating in this research, you will contribute to a better understanding of how leukemia treatments work.

As part of this academic research, no financial compensation is provided in return for your participation.

The limitations of this study are related to the need to take samples at a fixed time or on a fixed day, and to make it mandatory to perform an intermediate reassessment myelogram. These limitations are minimal because blood samples can usually be taken during the blood tests required for the routine management of your disease, without the need for additional venipuncture, and because the addition of an intermediate evaluation myelogram has no impact on medical management. Blood and bone marrow samples may cause a temporary discomfort at the time of the puncture, as well as a bruise at the puncture site.

If you agree to participate, you must comply with the following points:

• Attend appointments. If you are unable to attend, please contact your doctor as soon as possible.
• Follow your doctor’s recommendations regarding your participation in the study.
• Inform the research doctor of any treatment you are receiving and any events that occur during the study (hospitalization, pregnancy, blood tests performed in the last month).
• Be affiliated with a social security system or be a beneficiary of such a system.

After being collected, blood and bone marrow samples will be separated into plasma, cells, and tissue sections (for biopsies). Some of these samples will be cryopreserved at the INSERM U944 unit at Saint-Louis Hospital (Institut de Recherche Saint-Louis) for future use. This biological collection will be reported to the Ministry of Research and the Regional Health Agency (Article L. 1243-3 of the Public Health Code). Another part will be used directly for molecular and/or cellular analyses (RNA and/or DNA sequencing on single cells, flow cytometry, plasma protein assays). Most of these analyses will be conducted at the Hôpital Saint-Louis (Institut de Recherche Saint-Louis).

However, it is possible that certain specific analyses of biological samples or their derivatives (RNA, DNA, proteins, cells, etc.) may be conducted by external academic partners in France, Europe, or elsewhere in the world, or may be outsourced to biotechnology companies in France, Europe, or elsewhere in the world. Where applicable, such shipments will be subject to obtaining an export authorization for biological samples derived from human beings issued by the Ministry of Research, in accordance with Articles R.1235-7 et seq. of the Public Health Code.

At the end of the study, unused samples will be stored for future research on the pathology studied. The biological collection obtained as part of this study will be unique due to the availability of samples obtained during treatment, and not just at diagnosis.

The stored samples and anonymized data will be accessible to THEMA investigators. Access (transfer or assignment) by academic research partners may be requested on the basis of annual calls for projects at the end of this research, and scientific projects must be approved by the DREAM study Steering Committee.

Biological samples will be labeled “THEMA – DREAM biobank” and stored for a maximum period of 25 years (20 years after the end of this research) in the INSERM U944 unit of the Saint-Louis Research Institute. Raw data from correlative biological analyses will be stored securely on the server in the MEARY building at the Saint-Louis Hospital. Secondary data (biomarkers) from this research will be compiled in the eTHEMA study’s clinical data collection and managed by the Clinical Research Unit at Saint-Louis Hospital. This data will be stored for 25 years after the start of the DREAM study.

The DREAM study involves analyzing the somatic genetic characteristics of leukemia cells, excluding any constitutional genetic characteristics, i.e., those that could potentially be passed on to offspring. If a biological analysis of these samples were to suggest the study of transmissible genetic characteristics, you would be asked to provide a new, specific consent form.

You may at any time ask the physician supervising you in the context of the research to destroy these biological samples or to object to any further use of them.

If you do not participate in this study, your treatment will remain unchanged, as will the monitoring of blood tests during treatment and the bone marrow assessment at the beginning and end of the first treatment cycle.

At the end of your participation in the DREAM study, your medical care will continue unchanged, as will your participation in the eTHEMA registry, unless you also decide to end your participation in this registry. Your doctor may decide at any time to end your participation and will explain the reasons for doing so.

As part of the research in which you are being asked to participate, your personal data will be processed by AP-HP, the research sponsor and data controller, in order to analyze the results.

This processing is necessary for the research to be carried out, which is in line with the public interest mission entrusted to AP-HP as a public university hospital.

To this end, your medical data will be sent to the Sponsor or to people or partners acting on its behalf, in France or abroad. This data will be identified by a registration number and labeled “THEMA – DREAM database.” This data may also be sent to French health authorities, under conditions that ensure its confidentiality.
In addition to the sponsor and the investigators at the THEMA center, the only recipients of your coded personal data will be the following two subcontractors:
• The provider of the data collection software, hosted in France (the latter may not distribute or analyze the data).
• The study’s data management and biostatistics department, which is part of the THEMA center.

Your medical data that may be used to document a file for the competent authorities may be transmitted to a manufacturer so that a greater number of patients can benefit from the results of the research. This transmission will be carried out under conditions that ensure confidentiality.

Your data may be used for further research or analyses complementary to this research in collaboration with private or public partners, in France or abroad, under conditions that ensure their confidentiality and the same level of protection as European legislation.

You may object at any time to the further use of your data by the physician who is treating you as part of this research.

Your data will only be stored for as long as is strictly necessary and proportionate to the purpose of the research. It will be stored in the data controller’s information systems for up to ten years after the last publication of the research results.

Your data will then be archived in accordance with current regulations.
The computer file used for this research is implemented in accordance with French regulations (amended Data Protection Act) and European regulations (General Data Protection Regulation – GDPR). You have the right to access, rectify, restrict, and object to the processing of data covered by professional secrecy used in the context of this research. These rights can be exercised by contacting the physician in charge of the research, who is the only person who knows your identity (identified on the first page of this document).

If you decide to stop participating in the research, the data collected prior to this decision will be used in accordance with the regulations and exclusively for the purposes of this research. This is because deleting this data could compromise the validity of the research results. In this case, your data will not be used at any time in the future or for any other research.

If you encounter difficulties in exercising your rights, you can contact the AP-HP Data Protection Officer at the following address: protection.donnees.dsi@aphp.fr, who will be able to explain the remedies available to you through the CNIL. You may also exercise your right to lodge a complaint directly with the CNIL (for more information on this subject, please visit www.cnil.fr).

The AP-HP has taken all necessary measures to conduct this research in accordance with the provisions of the Public Health Code applicable to research involving human subjects.
The AP-HP has taken out insurance (0100518814033 230094) covering its civil liability and that of all parties involved with the company HDI–GERLING through BIOMEDICINSURE, whose address is Parc d’Innovation Bretagne Sud C.P.142 56038 Vannes Cedex.

The AP-HP obtained a favorable opinion from the Committee for the Protection of Persons for this research (Comité de protection des personnes Ile de France III) on September 12, 2023.

Your participation in this research is entirely voluntary. Your decision will not affect the quality of care and treatment you are entitled to expect.

Throughout the research, you may ask your doctor for information about your health and explanations about how the research is being conducted.
You may withdraw from the study at any time without justification, without any impact on the continuation of your treatment or the quality of care you receive, and without any impact on your relationship with your doctor. After withdrawing, you may continue to be treated by the same medical team. In this case, the data collected up to the time of withdrawal will be used for the analysis of the study results.

You may at any time ask the doctor supervising your research to destroy these biological samples or object to their further use.

Your medical file will remain confidential and may only be consulted under the responsibility of the doctor treating you, as well as by the health authorities and persons duly authorized by the AP-HP for research purposes and subject to professional secrecy.

At the end of the study and after analysis of the data relating to this study, you may be informed of the overall results by asking the doctor who is treating you as part of this study.

You may also access all of your medical data directly or through a doctor of your choice in accordance with the provisions of Article L 1111-7 of the Public Health Code.

After reading all this information, discussing all aspects with your doctor, and taking time to reflect, if you agree to participate in the research, you will be required to sign and date the informed consent form at the end of this document.

It is important that you read these pages carefully, as they will provide you with the necessary information on the various aspects of this study. Do not hesitate to ask your doctor any questions you deem useful.
Your participation is entirely voluntary, and we need your consent.
This study aims to record and collect some of your health data necessary for the management of your illness. It is strictly observational and therefore does not require any additional action on your part, other than those required for the diagnosis, treatment, and routine monitoring of your illness.
The Assistance Publique – Hôpitaux de Paris AP-HP (Clinical Research and Innovation Department [DRCI], Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75010 Paris) is the sponsor of this study. It is responsible for it and is organizing it as part of the National Center for Precision Medicine on Leukemia (THEMA) project. This THEMA center, supported by the National Agency for Research as part of the government’s Future Investment Plan, brings together doctors, biologists and researchers from three AP-HP hospitals (Saint-Louis, Robert Debré, Avicenne) conducting research on leukemia and related diseases with the ongoing aim of improving the understanding and management of these diseases.

You have just learned that you have leukemia or a blood disorder that can promote the development of leukemia (myelodysplastic syndrome, myelofibrosis).

In these diseases, abnormal cells accumulate in the bone marrow and sometimes in the blood.
This can lead to a failure to produce normal blood cells, such as red blood cells (their reduction causes anemia that can require blood transfusions), white blood cells (their reduction causes frequent and/or serious infections, particularly bacterial infections, and therefore fever), and platelets (their reduction causes bleeding).
These diseases form a heterogeneous group, which can now be characterized in each individual patient by studying their cellular and molecular characteristics in the laboratory. Therapeutic management depends on these characteristics, but also on your age and general condition, as well as your medical history and associated illnesses. Depending on these various factors, your doctor may suggest treatments of varying intensity, often based on chemotherapy drugs, possibly followed by a hematopoietic stem cell transplant.
At this stage, your hematologist has diagnosed your disease. They have sufficiently specified the subtype to be able to offer you appropriate treatment, although a more detailed characterization of your disease will need to be continued in the laboratory. They will decide as a team, during a multidisciplinary consultation meeting (RCP), which treatment is best suited to your disease and your health status, among the various options available. The study in which we are inviting you to participate does not impose any choice of treatment among these options; there is no direct comparison between treatment groups, nor is there any random selection.

This study involves establishing a clinical and biological cohort of leukemias and related diseases. It is considered non-interventional because it does not involve the use of new drugs, medical devices, or new tools. Its objective is to establish a prospective registry documenting the characteristics of these diseases, the treatments used, as well as the outcomes and experiences of the patients treated.
This study will assess the following in a large cohort of patients:
– Short- and long-term patient outcomes
– Quality of life assessed by your own responses to a specific questionnaire
– The treatments offered, among the various validated and authorized options currently available
– The precise biological characteristics of different cases of leukemia and related diseases, based on the study of bone marrow or blood cells, or their molecular components (DNA, RNA, and proteins). The collection, study, and preservation of biological material thus allows not only to optimally choose the treatment proposed to you and monitor its effectiveness, but also to advance general knowledge about these diseases and identify patients eligible for future research.
More generally, this cohort will allow us to better understand the mechanisms underlying leukemia, confirm or discover new risk factors, and conduct so-called “correlative” biological studies conducted in the laboratory using cells and serum collected from your blood and bone marrow during your routine examinations, or their components (DNA, RNA, or proteins).
Once again, participation in this study will not change the choice or nature of the treatment proposed to you. It does not require any specific tests or additional visits, particularly no additional blood tests or bone marrow samples, which would not be performed as part of the routine monitoring of your disease and treatment. However, whenever these tests are necessary for your care, during your initial treatment or follow-up, an additional volume of blood and bone marrow may be collected to perform additional biological research. This research will include, in particular, analyzing the sensitivity of leukemia cells to the various available drugs (functional cytometry platform at Saint-Louis Hospital), with the aim of advancing our treatment options for future patients. However, these volumes will not exceed 50 ml of blood and 4 ml of bone marrow in total.
These additional volumes of blood and bone marrow will also allow us to develop a collection of biological material: serum, cells, and nucleic acid (DNA and RNA) from these cells. This biological material will be stored, after freezing, in the Biological Resource Center of Saint-Louis Hospital or Robert Debré Hospital, under the responsibility of Professors Jean Soulier and Hélène Cave, respectively.
It should be noted that the studies conducted using nucleic acids (DNA/RNA) will allow us to explore gene mutations associated with your disease. These analyses are not intended to identify “constitutional” genetic abnormalities (present in all cells of your body, from birth, and sometimes hereditary). If your doctor had reason to suspect a constitutional genetic abnormality that predisposed you to the disease, they would not be able to look for it as part of this study and would then contact you to propose a genetic study and ask for your consent.

Approximately 2,500 to 3,000 patients are expected to participate in this cohort.
Your individual participation in the study is for 15 years, allowing us to document your long-term outcomes and those of your disease.
The study is expected to remain open to patient inclusion for a period of 5 years.

By participating in this cohort study, you will contribute to a better understanding of leukemia and related diseases, their biological characteristics, the choice of treatments and the treatments actually received, as well as the outcomes of patients treated, including long-term outcomes and their quality of life.
Your participation is not likely to provide you with any direct benefit other than participating in research that ensures standardized care and the precise study of the characteristics of your disease, according to the best current standards.
Subsequently, the data collected in this study may provide a more precise understanding of the characteristics of the disease and its patients, leading to the development of more individualized and effective treatments that will benefit new patients.
Your participation in this study is voluntary. Furthermore, you are free to discontinue your participation in the study at any time. This will in no way affect your relationship with your physician or the quality of care provided to you.

As part of this study, your personal data will be processed by the Clinical Research and Innovation Department (DRCI) of the AP-HP, sponsor of the study and responsible for data processing, to enable analysis of the results within the framework of the THEMA center.

This processing is necessary to conduct research, which fulfills the public interest mission entrusted to the AP-HP as a public university hospital.
The categories of data collected for this observatory are health data.
The purpose of the processing of personal data is medical research on leukemia and blood diseases that can promote the development of leukemia (myelodysplastic syndrome, myelofibrosis).
The legitimate interest of the THEMA center and the AP-HP, which is medical research on these diseases, represents the legal basis for the processing of this data.

Their processing
The personnel involved in the study are bound by professional secrecy. Your personal data required for the study will be transmitted after encryption for computer processing and analysis. Your data will be collected in “pseudonymized” form, i.e., identified by a code number and the first letter of your first and last name. In addition to the medical and clinical research team, a representative of the sponsor, such as an auditor, a clinical research technician, or a representative of the French or foreign health authorities, bound by professional secrecy, may have access to your file to verify the compliance of the data collected. In addition to the sponsor and investigators at the THEMA center, the recipients of your encrypted personal data will be the two subcontractors mentioned below:

• The data collection software provider, hosted in France
• The data management and biostatistics department

The computer file used for this research is implemented in accordance with French regulations (the “Informatique et Libertés” law of January 6, 1978, revised following Ordinance No. 2018-1125 published in the Official Journal on December 13, 2018) and European regulations (General Data Protection Regulation – GDPR).
You have the right to access, rectify, limit, and object to the processing of data covered by professional confidentiality used in this research. These rights can be exercised by contacting the physician in charge of the research, who alone knows your identity (identified on the front page of this document).
If you decide to stop participating in the research, the data collected prior to this will be used. in accordance with regulations, and exclusively for the purposes of this research. Indeed, their deletion would likely compromise the validity of the research results. In this case, your data will absolutely not be used subsequently or for other research.

Their use
Your data will be used solely for scientific research purposes with the aim of improving the understanding and management of leukemia and related diseases.
The results of this study may be published in a book or medical journal or used for educational purposes. However, your data will remain confidential; neither your name nor any information that could directly identify you will be used in any publication or educational material. Your data and biological material may be the subject of subsequent research or additional analyses by public or private partners in France or in other countries, including outside the European Union, in collaboration with the competent authorities and under conditions ensuring their confidentiality and the same level of protection as European legislation.

Your data and biological material may, for example, be used for the further development of new treatments, even after the end of this study.
You may object at any time to the further use of your data by contacting the physician treating you as part of this research.

Retention

Your data and biological material will only be kept for a period strictly necessary and proportionate to the purpose of the research.
In accordance with current regulations, your data and biological material will be kept for a maximum period of 25 years by the sponsor and in the study’s biological resource center.
Your data will then be archived in accordance with current regulations.

Your participation in this research study is entirely free and voluntary. Your decision will not affect the quality of care and treatment you are entitled to. If you do not wish to participate in the research, simply inform your doctor.
You will be able to request information about your health and an explanation of the research process from your doctor throughout and at the end of the research study.

Research Rights

You have the following rights regarding your personal data: right to transparency, right of access, right to modification, right to object, right to be forgotten, right to restriction, right to portability. The processing of your data does not involve automated individual decision-making.
These rights may be exercised with the center’s physician, who alone knows your identity. They may also be exercised with the study sponsor’s data protection officer, whose contact details are provided above.
Your medical records will remain confidential and may only be accessed under the responsibility of the physician overseeing your treatment, as well as by individuals duly authorized by the sponsor for the research and bound by professional confidentiality.
At the end of the research and after analysis of the data relating to this research, you may be informed of the overall results by the physician treating you as part of this research. You can also access all of your medical data directly or through a doctor of your choice in accordance with the provisions of Article L 1111-7 of the Public Health Code.

Withdrawal rights

You may withdraw from the research study at any time without justification, without impact on the continuation of your treatment or the quality of care provided to you, and without any impact on your relationship with your physician. Following this withdrawal, you may be monitored by the same medical team. In this case, the data collected up to the time of your withdrawal will be used to analyze the research results. You may also refuse to participate in the aforementioned biological collection and request the destruction of your samples at any time or object to their use.

If you decide to stop participating in the research study, the data collected prior to this withdrawal will be used in accordance with regulations and exclusively for the purposes of this research study. Indeed, their deletion would likely compromise the validity of the research results. In this case, your data will absolutely not be used subsequently or for any other research study.

Recourse

If you have any difficulty exercising your rights, you can contact the AP-HP Data Protection Officer at the following address: protection.donnees.dsi@aphp.fr, who will be able to explain the avenues of appeal available to you with the CNIL.
You can also exercise your right to complain directly to the CNIL either by mail: 3 Place de Fontenoy TSA 80715, 75334 PARIS CEDEX 07 or by telephone at 01 53 73 22 22 (for more information on this subject, visit www.cnil.fr).

The sponsor has taken all necessary measures to conduct this research in accordance with the provisions of the French Health Code applicable to research involving human subjects.
The sponsor received a favorable opinion for this research from the EST I Committee for the Protection of Persons on September 9, 2021.