Stem Cell Transplant for Acute Lymphoblastic Leukemia

Recruiting at 141 trial locations

Overseen By Christina Peters, Prof. MD PhD

Age: < 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: St. Anna Kinderkrebsforschung

Disqualifiers: Non Hodgkin-Lymphoma, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

1800 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new stem cell transplant approaches to improve treatment for children and teens with acute lymphoblastic leukemia (ALL), a type of blood cancer. It seeks the best methods for patients in complete remission, meaning no cancer cells are present in the bone marrow or spinal fluid. The study includes various treatment plans that combine chemotherapy drugs, such as ATG Thymoglobulin (an immunosuppressive drug), Busulfan, Cyclophosphamide, Fludarabine, Grafalon, TBI (Total Body Irradiation), Thiotepa, Treosulfan, and VP16, along with radiation to prepare the body for the transplant. It seeks young patients diagnosed with ALL who are in remission and need a stem cell transplant but have not yet undergone one. As a Phase 2 trial, this study measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to advancements in ALL treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the safety of treatments in clinical trials can vary based on the drug combinations used. For the TBI/VP16 regimen, which includes total body irradiation and VP16, studies indicate it often improves survival rates for patients with high-risk leukemia. However, side effects may include damage to healthy cells, a common concern with radiation treatments.

The Bu/VP16/Cy regimen combines Busulfan, VP16, and Cyclophosphamide. It is generally considered safe and effective, with some studies showing it has similar safety to other common treatments. Patients might experience side effects typical of chemotherapy, such as nausea or low blood cell counts.

For the Flu/Thio/ivBu regimen, involving Fludarabine, Thiotepa, and intravenous Busulfan, research shows it's safe in certain situations, like when patients have partially matched donors. Some patients might experience fewer side effects compared to other regimens.

Lastly, the Flu/Thio/Treo regimen, combining Fludarabine, Thiotepa, and Treosulfan, has been linked to a relatively low rate of treatment-related deaths in children with blood cancers. This suggests it's well-tolerated, though some risks remain typical of chemotherapy, such as infections or organ damage.

When considering joining a trial, discussing these findings with a doctor is important. They can help explain the potential risks and benefits based on these safety records. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute lymphoblastic leukemia because they offer innovative conditioning regimens for stem cell transplants. Unlike traditional methods that typically focus on chemotherapy alone, these regimens combine chemotherapy drugs like Busulfan, Cyclophosphamide, and Fludarabine with Total Body Irradiation (TBI) or newer agents like Treosulfan and Thiotepa. This approach aims to optimize the preparation of the patient's body for receiving new stem cells, potentially improving transplant success rates and reducing relapse. Additionally, some treatments include ATG Thymoglobulin or Grafalon to better manage immune responses, especially in mismatched donor scenarios, which could lead to fewer complications. These novel combinations are paving the way for more personalized and effective leukemia treatments.

What evidence suggests that this trial's treatments could be effective for acute lymphoblastic leukemia?

Research has shown that Total Body Irradiation (TBI) with VP16, one of the treatment arms in this trial, effectively treats young patients with acute lymphoblastic leukemia (ALL), offering good results and a lower risk of developing other cancers later. Another treatment arm, the combination of Busulfan, VP16, and Cyclophosphamide (Bu/VP16/Cy), benefits high-risk ALL patients, particularly those with minimal residual disease after treatment. The combination of Fludarabine, Thiotepa, and Busulfan (Flu/Thio/ivBu), also tested in this trial, has shown promising results in adults with manageable side effects, making it a viable option. Additionally, the mix of Fludarabine, Thiotepa, and Treosulfan (Flu/Thio/Treo) is another treatment arm under study, effective in fighting cancer, especially in patients with previous transplants. These treatments prepare patients for stem cell transplants by removing cancer cells and reducing immune system activity to prevent rejection. ^{2 6 7 8 9}

Who Is on the Research Team?

Christina Peters, Prof. MD PhD

Principal Investigator

St. Anna Kinderspital, Vienna, Austria

Peter Bader, Prof. MD PhD

Principal Investigator

Goethe University

Franco Locatelli, Prof. MD PhD

Principal Investigator

Ospedale Pediatrico Bambino Gesù, Rome, Italy

Are You a Good Fit for This Trial?

This trial is for children and adolescents up to 21 years old with Acute Lymphoblastic Leukemia in complete remission, who need a stem cell transplant. They must not be pregnant, have had previous transplants, or suffer from severe diseases that could interfere with the treatment.

Exclusion Criteria

I have been diagnosed with Non-Hodgkin Lymphoma.

No consent is given for saving and propagation of anonymous medical data for study reasons

Severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion (e.g. malformation syndromes, cardiac malformations, metabolic disorders)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo myeloablative conditioning with either TBI/VP16 or chemotherapy-based regimens such as Flu/Thio/Treo or Flu/Thio/ivBu, depending on age and donor type

2-3 weeks

Transplantation

Participants receive allogeneic hematopoietic stem cell transplantation (HSCT) from matched or mismatched donors

1 week

Follow-up

Participants are monitored for safety, overall survival, event-free survival, and adverse events of special interest

Up to 10 years

What Are the Treatments Tested in This Trial?

Interventions

• ATG Thymoglobulin
• Busulfan
• Cyclophosphamide
• Fludarabine
• Grafalon
• TBI
• Thiotepa
• Treosulfan
• VP16

Trial Overview The study tests how well different myeloablative conditioning regimens work before a stem cell transplant. These include drugs like Fludarabine and Cyclophosphamide, as well as procedures such as Total Body Irradiation (TBI).

How Is the Trial Designed?

Group I: Flu/Thio/ivBu Experimental Treatment 6 Interventions

Fludarabine/Thiotepa/iV Busulfan is used as conditioning regimen for haematopoietic stem cell transplantation (HSCT) in patients with: * MSD (matched sibling donors) or MD (matched related or unrelated donors). In addition, patients undergoing MD HSCT will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) with CB (Cord blood) or TCD (T-Cell depletion) or CD34+ selection. In addition, these patients will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) patients receiving Post TX-Cyclophosphamide

Group II: Flu/Thio/Treo Experimental Treatment 5 Interventions

Fludarabine/Thiotepa/Treosulfan is used as conditioning regimen for haematopoietic stem cell transplantation (HSCT) in patients with: * MSD (matched sibling donors) or MD (matched related or unrelated donors). In addition, patients undergoing MD HSCT will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) with CB (Cord blood) or TCD (T-Cell depletion) or CD34+ selection. In addition, these patients will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) patients receiving Post TX-Cyclophosphamide

Group III: Bu/VP16/Cy Experimental Treatment 3 Interventions

Busulfan/VP16/Cyclophosphamide is an alternative conditioning arm that may optionally be used for HSCT with MSD/MD and MMD graft in patients aged 0-24 months. Patients undergoing MD HSCT will also receive ATG Thymo- or Grafalon.

Group IV: TBI/VP16 Active Control 4 Interventions

TBI (Total Body Irradiation) / VP16 is used as conditioning regimen for haematopoietic stem cell transplantation (HSCT) in patients older than 48 months with: * MSD (matched sibling donors) or MD (matched related or unrelated donors). In addition, patients undergoing MD HSCT will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) with CB (Cord blood) or TCD (T-Cell depletion) or CD34+ selection. In addition, these patients will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) patients receiving Post TX-Cyclophosphamide. Patients aged 24-48 months may optionally receive Total Body Irradiation (TBI).

ATG Thymoglobulin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Thymoglobulin for:

• Prevention and treatment of acute rejection in organ transplantation
• Treatment of aplastic anemia
• Preparation for hematopoietic stem cell transplantation

Approved in United States as Thymoglobulin for:

• Treatment of acute rejection in kidney transplant patients
• Preparation for hematopoietic stem cell transplantation

Approved in Canada as Thymoglobulin for:

• Prevention and treatment of acute rejection in organ transplantation
• Treatment of aplastic anemia

Who Is Running the Clinical Trial?

St. Anna Kinderkrebsforschung

Lead Sponsor

Trials

14

Recruited

7,300+

Swiss Pediatric Oncology Group

Collaborator

Trials

7

Recruited

7,400+

Australian & New Zealand Children's Haematology/Oncology Group

Collaborator

Trials

7

Recruited

6,900+

Dutch Childhood Oncology Group

Collaborator

Trials

8

Recruited

4,500+

ALL SCTped Forum

Collaborator

Trials

2

Recruited

2,800+

European Society for Blood and Marrow Transplantation

Collaborator

Trials

35

Recruited

17,200+

ALL-BFM Study Group

Collaborator

Trials

2

Recruited

2,400+

Assistance Publique - Hôpitaux de Paris

Collaborator

Trials

3,369

Recruited

57,400,000+

Published Research Related to This Trial

Chemotherapy alone cures only 25-45% of adult patients with acute lymphoblastic leukemia (ALL), highlighting the urgent need for new treatment strategies.

Novel agents like monoclonal antibodies (e.g., rituximab, blinatumomab) and chimeric antigen receptor therapies have shown promising results in improving outcomes for patients with relapsed or refractory ALL, potentially offering less toxic treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel targeted therapies in acute lymphoblastic leukemia. Portell, CA., Advani, AS.[2019]

In a study of 122 AML patients, reduced intensity conditioning (RIC) using busulfan/fludarabine/low-dose total body irradiation (TBI) resulted in significantly lower rates of severe acute graft-versus-host disease (aGVHD) compared to myeloablative conditioning (MAC) with busulfan/fludarabine (6.2% vs 26.1%).

Both RIC and MAC regimens showed similar long-term outcomes in terms of overall survival, chronic GVHD, relapse rates, and non-relapse mortality, indicating that thymoglobulin used for GVHD prophylaxis did not adversely affect survival with the RIC regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of myeloablative and reduced intensity conditioning unrelated donor allogeneic peripheral blood stem cell transplant outcomes for AML using thymoglobulin for GVHD prophylaxis. Modi, D., Singh, V., Kim, S., et al.[2021]

In a study involving five patients with severe aplastic anemia, a conditioning regimen of fludarabine, cyclophosphamide, and thymoglobulin resulted in complete donor type hematologic recovery for all participants, indicating high efficacy for bone marrow transplantation.

The combination treatment showed minimal complications, with only one case of mild acute graft-versus-host disease (GVHD) and no serious complications, suggesting a favorable safety profile for this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. Kang, HJ., Shin, HY., Choi, HS., et al.[2013]

Inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate, has been approved for treating adults with relapsed or refractory acute lymphoblastic leukemia (ALL) and shows improved response rates and survival compared to standard chemotherapy.

This treatment not only enhances the chances of achieving minimal residual disease negativity but also increases the likelihood of patients being eligible for allogeneic stem cell transplants, which can be crucial for their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. Williams, S., Kim, M.[2020]

The study found that sequential treatment with methotrexate (MTX) followed by 6-mercaptopurine (6MP) significantly increased apoptosis in a human T-cell leukemia line compared to using each drug alone, suggesting a more effective treatment strategy for childhood acute lymphoblastic leukemia.

Similarly, sequential exposure to tiazofurin (TF) followed by 6-thioguanine (TG) also resulted in a greater induction of apoptosis, indicating that the order of drug administration is crucial for maximizing therapeutic efficacy in leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy in childhood leukaemia: in vitro studies of thiopurines and inhibitors of purine metabolism on apoptosis. De Abreu, RA., Trueworthy, RC., van Kuilenburg, AB., et al.[2017]

In a phase II study involving 16 patients with hematologic malignancies, the addition of rabbit antithymocyte globulin (rATG) to the fludarabine and busulfan conditioning regimen showed low rates of acute and chronic graft versus host disease (GvHD), which is a positive safety outcome.

The study found significant interpatient variability in pharmacologic biomarkers related to busulfan and fludarabine, suggesting that further research is needed to optimize the conditioning regimen for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. McCune, JS., Woodahl, EL., Furlong, T., et al.[2021]

Thymoglobulin is a safe and effective treatment for preventing acute rejection in organ transplantation, with common side effects including cytokine release syndrome and thrombocytopenia, but recent studies suggest that antiviral prophylaxis can mitigate the risk of cytomegalovirus disease associated with its use.

Thymoglobulin may offer advantages over horse ATG in treating aplastic anemia and can reduce the incidence of acute and chronic graft-versus-host disease (GvHD) in patients receiving stem cell transplants, indicating its potential as a versatile immunosuppressant in various therapeutic contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thymoglobulin--new approaches to optimal outcomes. Moicean, AD., Popp, AM., Sinescu, I.[2021]

In a study of 24 children with refractory acute lymphoblastic leukemia (ALL), a treatment regimen including amsacrine, etoposide, and high-dose methylprednisolone led to significant responses in 11 out of 19 evaluable patients, with 8 achieving complete remission.

Among those who responded to the treatment and underwent stem cell transplantation, 5 out of 9 patients are alive after a median follow-up of 43 months, suggesting that the level of minimal residual disease before transplantation may help predict survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amsacrine combined with etoposide and high-dose methylprednisolone as salvage therapy in acute lymphoblastic leukemia in children. Horstmann, MA., Hassenpflug, WA., zur Stadt, U., et al.[2015]

In a study of 30 patients undergoing allogeneic hematopoietic stem cell transplantation, Thymoglobulin and ATG-F showed comparable outcomes in terms of overall survival, disease-free survival, and transplant-related complications after a median follow-up of 3.3 years.

Although adverse events were more frequently reported during Thymoglobulin infusion, the difference was not statistically significant, suggesting that both treatments are similarly safe and effective for preventing graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies. Paiano, S., Roosnek, E., Tirefort, Y., et al.[2020]

In a study of four adult patients with early T-cell precursor acute lymphoblastic leukemia (Pre-T-ALL), three did not respond to standard induction chemotherapy, indicating a poor response to conventional treatments.

All patients eventually relapsed within 13 months of diagnosis, highlighting that Pre-T-ALL should be classified as a high-risk subgroup within T-lineage ALL, necessitating alternative treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poor prognosis of prethymic phenotype acute lymphoblastic leukemia (pre-T-ALL). Digel, W., Schultze, J., Kunzmann, R., et al.[2015]

In a study of 54 adults undergoing matched related donor blood cell transplantation, pretransplantation anti-thymocyte globulin (ATG) significantly reduced the incidence of chronic graft-versus-host disease (cGVHD) from 96% in the control group to 55% in the ATG group, indicating improved safety and potential quality of life for survivors.

Patients receiving ATG also experienced lower non-relapse mortality rates at 100 days (4% vs. 17%) and at 4 years (9% vs. 34%), suggesting that ATG may enhance overall survival despite a trend towards higher relapse rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adult recipients of matched related donor blood cell transplants given myeloablative regimens including pretransplant antithymocyte globulin have lower mortality related to graft-versus-host disease: a matched pair analysis. Russell, JA., Turner, AR., Larratt, L., et al.[2013]

In a multicenter phase II study involving 77 patients undergoing HLA-matched peripheral blood stem cell transplantation (PBSCT), low-dose anti-thymocyte globulin (ATG) significantly reduced the incidence of severe acute graft-versus-host disease (GVHD) to just 1.4% at 100 days, well below the predefined threshold of 18%.

The study also reported a low incidence of chronic GVHD at one year, with only 15.3% of patients experiencing all-grade chronic GVHD and 5.6% experiencing moderate to severe cases, indicating that low-dose ATG is effective in minimizing both acute and chronic GVHD risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation. Shiratori, S., Sugita, J., Ota, S., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10807553/

Intensified conditioning regimens with total marrow irradiation ... This study reveals the benefits of TMLI‐VP16‐CY and BU‐VP16‐CY conditioning regimens in high‐risk ALL patients with CR and MRD‐positive status.

2. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/abs/10.1002/cam4.6897

Intensified conditioning regimens with total marrow ... This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status.

3. ovid.com ovid.com/journals/camed/pdf/10.1002/cam4.6897~intensified-conditioning-regimens-with-total-marrow

Intensified conditioning regimens with total marrow Abstract. Purpose: Among high- risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo- HSCT),.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4946459/

A Safety and Efficacy Study of Medium-Dose Etoposide ... Prognosis for adult patients with acute lymphoblastic leukemia (ALL) is poor, and 5-year survival rates were reported to be approximately 35% to 50%.

5. astctjournal.org astctjournal.org/article/S1083-8791(14)00568-0/fulltext

Favorable Outcome of Hematopoietic Stem Cell ... Our study demonstrated that HSCT using a targeted once-daily i.v. BuFluVP regimen showed favorable outcomes and could be an option for HSCT in pediatric and ...

6. researchgate.net researchgate.net/publication/377092074_Intensified_conditioning_regimens_with_total_marrow_irradiationetoposidecyclophosphamide_and_busulfanetoposidecyclophosphamide_overcome_the_impact_of_pre-transplant_minimal_residual_disease_on_outcome

(PDF) Intensified conditioning regimens with total marrow ... These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)‐etoposide (VP16)‐cyclophosphamide (CY) ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.22.00767

Busulfan Plus Cyclophosphamide Versus Total Body ... The BuCy regimen has noninferior efficiency and safety as TBI-Cy (4.5 Gy × 2) for patients with adult standard-risk B cell-ALL in CR1 undergoing HLA-matched ...

8. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT00005866?draw=2&rank=1

Study Details | NCT00005866 | S9920 Busulfan Compared ... PURPOSE: Randomized phase III trial to compare the effectiveness of busulfan with that of cyclophosphamide in patients undergoing total-body irradiation plus ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S1083879117308728

Intravenous Busulfan Compared with Total Body Irradiation ... This retrospective study analyzed TBI and Bu on outcomes of ALL patients 18–60 years old, in first or second complete remission (CR), undergoing HLA-compatible ...