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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.

You are potentially eligible for this study because you are 60 years of age or older and have recently been diagnosed with acute myeloid leukemia (AML) that is treatable with standard intensive chemotherapy.

The analysis of your leukemic cells has shown that they do not carry gene abnormalities that would have made you eligible for specific drugs in addition to chemotherapy.

You must receive standard intensive chemotherapy. This begins with a so-called “induction” course according to a “3+7” regimen, combining 3 days of treatment with short infusions of a chemotherapy drug called idarubicin and 7 days of treatment with a continuous infusion of cytarabine (also called aracytine).

The induction course aims to achieve complete remission, defined as the absence of visible leukemic cells on microscopic examination of your bone marrow and the restoration of normal bone marrow function. Even when they are no longer detectable under the microscope, rare residual leukemic cells may persist in the blood and bone marrow. More sophisticated laboratory tests (flow cytometry, molecular biology) are then required to enumerate them. These rare persistent leukemic cells constitute what is referred to as “residual disease.” Their elimination requires continuation of treatment after the induction chemotherapy course.

The research study in which we are offering you the opportunity to participate involves the addition of a drug called sulfasalazine to the standard “3+7” induction chemotherapy regimen. The study aims to evaluate, in patients aged 60 years or older who have recently been diagnosed with AML, whether the addition of this drug (sulfasalazine) is safe and whether it increases the rate of deep complete remission, defined as complete remission associated with so-called “negative” residual disease (undetectable leukemic cells or less than 0.1% of cells analyzed by flow cytometry).

Achieving complete remission with negative residual disease is often predictive of prolonged remission.

Sulfasalazine is not a new molecule. This medicinal product has been used (and has marketing authorization) for more than 40 years in the treatment of other conditions (certain inflammatory rheumatic diseases and chronic inflammatory bowel diseases). Within the framework of the research study being proposed to you, sulfasalazine is administered orally, in the form of tablets to be taken 2 to 4 times per day for 8 to 15 days.

Recent research has shown that sulfasalazine induces the death of AML cells and, moreover, enhances the anti-leukemic effect of 3+7-type chemotherapy regimens, particularly those of the anthracycline class (such as idarubicin). The mechanism of action of sulfasalazine has been characterized with precision. These findings have been presented at international medical congresses and are the subject of a publication in a scientific journal. If you have a background in cell biology, please do not hesitate to ask the physician proposing this study any questions regarding this work.

The research study in which we are offering you the opportunity to participate consists of two successive phases:

The anticipated duration of the research is approximately 3 years, and your participation will last 14 months.

After signing your consent, the conduct of the research will proceed as follows:

Selection phase
If you decide to participate in this study and sign and date the informed consent form, your physician will request a series of examinations, as follows:

• A clinical examination,
• An electrocardiogram (ECG) and a cardiac ultrasound,
• Blood tests, most of which will be performed as part of routine monitoring,
• A bone marrow aspiration (myelogram) to assess the biological characteristics of your AML (analysis of chromosomes and genes of acute myeloid leukemia, immunological typing of your leukemic cells). An additional 2 ml of bone marrow will be collected for research purposes.

Hospitalization and Treatment Phase
You will be hospitalized for several weeks during your induction course, until recovery from aplasia. During these hospitalizations, the following examinations will be performed once or several times per week:

• A record of any adverse events you have experienced,
• A record of the medications you are currently taking or have recently taken,
• A clinical examination,
• Monitoring of your vital signs (blood pressure, temperature),
• An ECG as part of routine monitoring on Day 1, and for research purposes on Day 4, Day 15, and at the end-of-induction visit,
• Blood tests. Most of these are performed as part of routine monitoring during a “3+7” induction chemotherapy course (assessment of your biological, biochemical, and coagulation functions), but an additional volume is collected for research purposes (cardiac monitoring by measuring troponin on Day 1, Day 4, Day 15, and at the end-of-induction visit, 5 mL each time). In addition, extra blood samples will be collected for research on Day 1 (45 mL in phase I, 10 mL in phase II), Day 2 (10 mL in phases I and II), Day 4 (45 mL in phase I), and Day 15 (30 mL in phase I only) to measure sulfasalazine levels and evaluate its biochemical effects.

A blood sample and a bone marrow aspiration will also be performed between Day 28 and Day 42, after recovery from aplasia—that is, when your neutrophil count is ≥ 1 G/L and your platelet count is ≥ 100 G/L, or on Day 42 if hematological recovery has not occurred—to assess treatment response and the progression of your AML. An additional 2 mL of bone marrow will be collected for research at this time.

Follow-up Visits after the Induction Course

Depending on the results of the evaluation of your bone marrow at the end of the induction course, your physician may propose rehospitalization for consolidation cycles and/or for hematopoietic stem cell transplantation, if applicable. Aplasia following consolidation chemotherapy and post-transplant aplasia are usually shorter than post-induction aplasia.

A study follow-up visit will take place at the end of each consolidation cycle, when your blood recovery and disease status are reassessed; then prior to transplantation, if it is scheduled more than one month after the last consolidation cycle; and subsequently every three months until your end-of-study visit. The end-of-study visit occurs one year after the completion of your induction course. A visit may also be scheduled by your physician at any time if a relapse of the disease is suspected.

This follow-up schedule does not require any hospitalization or visits beyond routine care.

During these visits, the study physician or a member of the study team may perform the following procedures to assess the effect of the study drug and/or monitor your health status:

• Record any adverse events you have experienced,
• Perform a clinical examination,
• Monitor your vital signs (blood pressure, temperature),
• Collect blood samples (to monitor your biological, biochemical, and coagulation functions) and, if deemed necessary by the investigator, perform a bone marrow aspiration, to be analyzed locally.

The expected benefit of the study treatment, sulfasalazine, in addition to standard induction chemotherapy, is an increased likelihood of achieving deep remission of AML (complete remission with negative residual disease) and, consequently, an improved chance of prolonged survival.

Even the lowest dose of sulfasalazine evaluated in this protocol during its first phase may have anti-leukemic activity.

Furthermore, by participating in this study, you will contribute to increasing knowledge about AML treatments and may also help other individuals affected by the same disease.

Certain medications are not permitted:

• Anti-leukemic treatments other than those described in Section 3 of this information sheet,
• Red blood cell growth factors (recombinant erythropoietin) or medications stimulating platelet production (thrombopoietin analogues).

Some medications are discouraged unless your investigator considers their use absolutely necessary for your care:

• Medications belonging to the “purine analogue” family, in particular azathioprine (Imurel®),
• Digoxin,
• Ion-exchange resins (such as sodium polystyrene sulfonate, Kayexalate®, or cholestyramine, Questran®).

Bone marrow samples will be sent to the Hematology Laboratory of Hôpital Saint-Louis for residual disease analysis by flow cytometry, performed as part of routine care.

Two types of samples are used in this research, directed to several central laboratories:

• Blood samples sent to:
  • The Pharmacology Laboratory of Hôpital Saint-Louis in Paris for pharmacokinetic studies,
  • The INSERM U944 Research Unit of the Saint-Louis Research Institute for pharmacodynamic studies.
• Bone marrow aspiration samples sent to the INSERM U944 Research Unit of the Saint-Louis Research Institute for pharmacodynamic and biomarker studies.

These analyses will allow the study organizers to investigate the effect of sulfasalazine on your disease and your body. The results will be used exclusively for research purposes. Since these tests are exploratory in nature, they will have no specific consequences for you or for medical conditions affecting your family.

Some samples prepared from the collections performed at study entry and at the end-of-induction treatment evaluation will be frozen and stored at the INSERM U944 unit under the responsibility of Prof. Raphaël Itzykson. At the end of the research, and after declaration to the Ministry of Research and the competent regional health authority (Article L. 1243-3 of the French Public Health Code), these samples may be stored for a maximum of 20 years before being destroyed. They may be used for future AML research to address questions or employ techniques that may emerge as scientific knowledge advances, which cannot be specified today.

The results of these tests will not be routinely communicated to you. However, upon your request, a specific consultation with the study physician may be arranged to share the results of these analyses if available at the time of your request, as well as the overall study results when they become available.

If you decide to withdraw from the study and revoke your consent, you may request in writing that your blood samples not be analyzed within this research. Blood and bone marrow samples will then be destroyed according to local procedures.

The results of these studies 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 used for future research or additional analyses, in collaboration with competent authorities or private or public partners, in France or in other countries, including outside the European Union, under conditions that ensure confidentiality and the same level of protection as European legislation. Your data and biological material may, for example, be used for the future development of new treatments, even after the end of this study. These data and materials may be utilized or valorized by the study organizers. You may object at any time to the future use of your data and biological material by contacting the physician overseeing your participation in this research.

You also have the right, at any time, to request from your study physician the destruction of these biological samples or to oppose any future use.

If you decide not to participate in this research, you would most likely receive the same standard treatment with induction chemotherapy (“3+7”), followed, after the end of your participation in the study, by the same treatments: consolidation chemotherapy cycles and/or allogeneic hematopoietic stem cell transplantation.

However, the effectiveness of standard AML treatment is variable, which justifies the exploration of new approaches, such as the addition of sulfasalazine to standard induction chemotherapy, with the aim of improving the rate of deep remissions in AML and, we hope, prolonging survival and potentially increasing the likelihood of cure.

Early termination of participation in the research:

• Your physician may decide at any time to discontinue your participation and will explain the reasons for this decision.

• If you decide to withdraw your consent from the research, treatment with sulfasalazine, if still ongoing, will be stopped, and you will no longer be followed within the framework of this study. No further information about you will be collected as part of the research.

Within the framework of the research in which you are invited to participate, your personal data will be processed by AP-HP, the sponsor of the research and data controller, to allow analysis of the study results.

This processing is necessary for the conduct of the research, which falls within the public interest mission of AP-HP as a public hospital-university institution.

For this purpose, your medical data will be transmitted to the Sponsor or to persons or partners acting on its behalf, in France or abroad. These data will be identified by a registration number. They may also be transmitted, under conditions ensuring confidentiality, to French health authorities.

Medical data concerning you that may document a file submitted to the competent authorities regarding the drug evaluated in this research may be transmitted to an industrial partner so that a larger number of patients can benefit from the research results. This transfer will be carried out under conditions that ensure confidentiality.

Your data may also be used for future research or additional analyses related to this study, in collaboration with private or public partners, in France or abroad, under conditions that ensure confidentiality and the same level of protection as required by European legislation.

AP-HP has taken all necessary measures to conduct this research in accordance with the provisions of the French Public Health Code applicable to research involving human participants.

AP-HP has obtained insurance (No. 0100518814033 220037) covering its civil liability and that of all personnel involved, through the company HDI–GERLING via BIOMEDICINSURE, located at Parc d’Innovation Bretagne Sud C.P.142, 56038 Vannes Cedex.

AP-HP received a favorable opinion from the Sud-Méditerranée II Ethics Committee for the Protection of Persons on 07/07/2022, and authorization from the French National Agency for the Safety of Medicines and Health Products (ANSM) on 10/08/2022.