Stem Cell Transplant for Acute Lymphoblastic Leukemia

Recruiting at 117 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

Trial Summary

What is the purpose of this trial?

The ALL SCTped 2012 FORUM is a multinational, multi-centre, controlled, prospective phase III study for the therapy and therapy optimisation for children and adolescents with ALL in complete morphological remission (CR, less than 5% bone marrow blasts, no blasts in cerebrospinal fluid, no other extramedullary leukemia), who have an indication for HSCT with a myeloablative conditioning regimen. The stratification of patients in first and following remissions according to the individual transplantation modalities rests upon an indication for allogeneic HSCT and the availability of a suitable donor within the individual transplantation groups.

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.

What data supports the effectiveness of the drug regimen including ATG Thymoglobulin, Busulfan, Cyclophosphamide, and Fludarabine for stem cell transplant in acute lymphoblastic leukemia?

Research shows that using antithymocyte globulin (ATG) like Thymoglobulin in combination with drugs such as fludarabine and busulfan can reduce complications like graft-versus-host disease (GVHD) and improve survival rates in similar transplant settings. This suggests potential benefits for patients undergoing stem cell transplants for conditions like acute lymphoblastic leukemia. ^{1 2 3 4 5}

Is stem cell transplant with thymoglobulin safe for humans?

Thymoglobulin has a proven safety profile in various treatments, including organ transplantation and stem cell transplants, with common side effects like cytokine release syndrome (a reaction to immune system activation), low platelet count, and low white blood cell count. Studies show it can reduce severe graft-versus-host disease (a condition where transplanted cells attack the body) and improve survival rates, with manageable side effects when used with antiviral medications. ^{2 4 5 6 7}

What makes the stem cell transplant treatment for acute lymphoblastic leukemia unique?

This treatment is unique because it combines multiple drugs, including ATG Thymoglobulin, Busulfan, Cyclophosphamide, and others, to prepare the body for a stem cell transplant, which can offer a chance for long-term remission in patients who do not respond well to standard chemotherapy. The combination of these drugs helps to suppress the immune system and eliminate cancer cells, making the body more receptive to the new stem cells. ^{8 9 10 11 12}

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

Eligibility Criteria

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.

Inclusion Criteria

Patients with ALL (except for patients with B-ALL) who fulfill the following criteria: age at diagnosis ≤ 18 years, Age at HSCT ≤ 21 years, indication for allogeneic HSCT, complete remission (CR) before HSCT, written consent of the parents (legal guardian) and, if necessary, the minor patient via 'Informed Consent Form', no pregnancy, no secondary malignancy, no previous HSCT, HSCT is performed in a study participating centre

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

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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]

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]

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]

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 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]

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]

References

1. Germany 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. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. [2013]

3. United States 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. [2013]

4. Germany pubmed.ncbi.nlm.nih.gov

A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. [2021]

5. Egypt pubmed.ncbi.nlm.nih.gov

Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies. [2020]

6. Romania pubmed.ncbi.nlm.nih.gov

Thymoglobulin--new approaches to optimal outcomes. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. [2020]

9. Italy pubmed.ncbi.nlm.nih.gov

Amsacrine combined with etoposide and high-dose methylprednisolone as salvage therapy in acute lymphoblastic leukemia in children. [2015]

10. United States pubmed.ncbi.nlm.nih.gov

Novel targeted therapies in acute lymphoblastic leukemia. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Poor prognosis of prethymic phenotype acute lymphoblastic leukemia (pre-T-ALL). [2015]

12. England pubmed.ncbi.nlm.nih.gov

Combination therapy in childhood leukaemia: in vitro studies of thiopurines and inhibitors of purine metabolism on apoptosis. [2017]