Stem Cell Transplant for Acute Lymphoblastic Leukemia
Recruiting in Palo Alto (17 mi)
+117 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: St. Anna Kinderkrebsforschung
Disqualifiers: Non Hodgkin-Lymphoma, Pregnancy, others
No Placebo Group
Prior Safety Data
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.
12345Is 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.
24567What 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.
89101112Eligibility 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)
+4 more
Trial 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
Participant Groups
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).
4Treatment groups
Experimental Treatment
Active Control
Group I: Flu/Thio/ivBuExperimental Treatment6 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/TreoExperimental Treatment5 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/CyExperimental Treatment3 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/VP16Active Control4 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Alberta Children's Hospital Division of Pediatric OncologyCalgary, Canada
BC Children's HospitalVancouver, Canada
Montreal Children's HospitalMontral, Canada
CHU Sainte-Justine Hematology-Oncology DivisionMontreal, Canada
More Trial Locations
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Who Is Running the Clinical Trial?
St. Anna KinderkrebsforschungLead Sponsor
Swiss Pediatric Oncology GroupCollaborator
Australian & New Zealand Children's Haematology/Oncology GroupCollaborator
Dutch Childhood Oncology GroupCollaborator
ALL SCTped ForumCollaborator
European Society for Blood and Marrow TransplantationCollaborator
ALL-BFM Study GroupCollaborator
Assistance Publique - Hôpitaux de ParisCollaborator
References
Comparison of myeloablative and reduced intensity conditioning unrelated donor allogeneic peripheral blood stem cell transplant outcomes for AML using thymoglobulin for GVHD prophylaxis. [2021]A head-to-head comparison of outcomes of unrelated donor allogeneic peripheral blood stem cell transplantation for AML between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens using thymoglobulin for GVHD prophylaxis is limited. We evaluated outcomes of 122 AML patients who received either busulfan (Bu)/fludarabine (Flu)/low-dose total body irradiation (TBI) as RIC (n = 64, 52%) or Bu/Flu as MAC (n = 58, 48%), and thymoglobulin 4.5 mg/kg total dose between day - 3 to - 1 for GVHD prophylaxis. Grades III-IV acute GVHD (aGVHD) was lower with Bu/Flu/TBI compared with Bu/Flu (6.2% vs 26.1%, p = 0.009). At 1 year, Bu/Flu/TBI was associated with similar chronic GVHD (41.2% vs 44.8%, p = 0.75), OS (61.9% vs 56.9%, p = 0.69), relapse rate (29.9% vs 20.7%, p = 0.24), relapse-free survival (52.8% vs 50%, p = 0.80), non-relapse mortality (17.4% vs 29.3%, p = 0.41), and GVHD-free relapse-free survival (24.2% vs 27.5%, p = 0.80) compared with Bu/Flu. Multivariable analysis did not reveal any difference in outcomes between both regimens. In summary, thymoglobulin at 4.5 mg/kg did not have any adverse impact on survival when used with RIC regimen. Both Bu/Flu/TBI and Bu/Flu conditioning regimens yielded similar survival.
Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. [2013]Antithymocyte globulin (ATG) has been used in severe aplastic anemia (SAA) as a part of the conditioning regimen. Among the many kinds of ATG preparations, thymoglobulin had been found to be more effective in preventing GVHD and rejection of organ transplants. As the fludarabine-based conditioning regimens without total body irradiation have been reported to be promising for bone marrow transplantation (BMT) from alternative donors in SAA, thymoglobulin was added to fludarabine and cyclophosphamide conditioning to reduce GVHD and to allow good engraftment in unrelated BMT. Five patients underwent BMT with cyclophosphamide (50 mg/kg once daily i.v. on days -9, -8, -7 and -6), fludarabine (30 mg/m2 once daily i.v. on days -5, -4, -3 and -2) and thymoglobulin (2.5 mg/kg once daily i.v. on days -3, -2 and -1) from HLA-matched unrelated donors. Complete donor type hematologic recovery was achieved in all patients. No serious complication occurred during BMT. Only one patient developed grade I acute GVHD resolved spontaneously. Except for one who had rupture of hepatic adenoma 78 days after BMT, all the other four patients are still alive with median 566 days. Fludarabine, cyclophosphamide plus thymoglobulin conditioning allows for the promising results of good engraftment, tolerable toxicity and minimal GVHD.
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]Because pretransplantation anti-thymocyte globulin (ATG) seems to reduce graft-versus-host-disease (GVHD) and treatment-related mortality (TRM) after unrelated donor bone marrow transplantation (BMT), we investigated this agent in matched related donor (MRD) blood cell transplantation (BCT). Fifty-four adults receiving rabbit ATG, cyclosporine A, and methotrexate with myeloablative conditioning and undergoing first MRD BCT were matched for disease and stage with 54 patients not given ATG. Most ATG-treated patients had fludarabine with oral (7) or i.v. busulfan (46) with total body irradiation (TBI) in 10. Control patients largely received TBI with VP16 (28) or oral busulfan with cyclophosphamide (15) or fludarabine (7). The ATG was given at a total dose of 4.5 mg/kg over 3 d, finishing on day 0. Rates of acute GVHD (aGVHD) grade II-IV, aGVHD grade III-IV, and chronic GVHD (cGVHD) were 19 +/- 5% versus 32 +/- 6% (P = .1), 6 +/- 3% versus 13 +/- 5% (P = NS), and 55 +/- 8% versus 96 +/- 3% (P = .002) in the ATG and control groups, respectively. Patients given ATG had fewer sites involved by cGVHD compared with the control group (mean 2.1 +/- 0.2 versus 2.8 +/- 0.2, P = .04). Non-relapse mortality (NRM) with and without ATG, respectively, was 4 +/- 3% versus 17 +/- 5% at 100 d and 9 +/- 4% versus 34 +/- 7% at 4 yr (P = .002). Deaths were GVHD related in 3 ATG-treated patients versus 14 controls (P = .007). Despite a trend to more relapse with ATG (43 +/- 7% versus 22 +/- 7% at 4 yr, P = 0.05), survival was 66 +/- 7% in the patients given ATG versus 50 +/- 7% in the controls (P = 0.046). This study indicates that myeloablative regimens incorporating fludarabine and oral or i.v. busulfan with pretransplantation ATG given to recipients undergoing MRD BCT may result in less cGVHD, lower TRM, and probably improved quality of life in survivors compared with previous protocols.
A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. [2021]Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin(®)) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/(T)busulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients.
Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies. [2020]Different rabbit polyclonal antilymphocyte globulins (ATGs) are used in allogeneic hematopoietic stem cell transplantation (alloHSCT) to prevent graft-versus-host disease (GvHD). We compared 2 different ATGs in alloHSCT after reduced intensity conditioning (RIC) for hematological malignancies. We reviewed 30 alloHSCT for hematologic malignancies performed between 2007 and 2010 with fludarabine and i.v. busulfan as conditioning regimen. Patients alternatingly received Thymoglobulin or ATG-F. Median followup was 3.3 (2.5-4.5) years. Adverse events appeared to occur more frequently during Thymoglobulin infusion than during ATG-F infusion but without statistical significance (P = 0.14). There were also no differences in 3-year overall survival (OS), disease-free survival (DFS), relapse incidence, and transplant related mortality (TRM) in the Thymoglobulin versus ATG-F group: 45.7% versus 46.7%, 40% versus 33.7%, 40% versus 33.3%, and 20% versus 33.3%. The same held for graft failure, rejection, infectious complications, immune reconstitution, and acute or chronic GvHD. In patients transplanted for hematologic malignancies after RIC, the use of Thymoglobulin is comparable to that of ATG-F in all the aspects evaluated in the study. However due to the small number of patients in each group we cannot exclude a possible difference that may exist.
Thymoglobulin--new approaches to optimal outcomes. [2021]Thymoglobulin has a proven safety and efficacy profile both as treatment of acute rejection and as induction therapy in organ transplantation. The most common adverse events associated with Thymoglobulin are cytokine release syndrome, thrombocytopenia, and lymphopenia. Results of early studies showed an increased rate of cytomegalovirus disease associated with Thymoglobulin treatment, but recent studies indicate that routine administration of modern antiviral prophylaxis can reduce this risk. More research comparing Thymoglobulin with basiliximab will help individualize regimens by matching the choice of induction agent with the risk profile of each transplant recipient. The proven efficacy and safety profile of Thymoglobulin provides an excellent starting point for future investigations. Horse ATG (hATG) or Thymoglobulin + Cyclosporine are an efficacious treatment for aplastic anemia. Due to its higher potency Thymoglobulin may be superior to hATG, but further studies are required for confirmation. GvHD prophylaxis with Thymoglobulin may result in less acute and chronic GvHD, lower TRM, improved survival and quality of life in myeloablative or reduced intensity conditioning protocols in patients receiving hematopoietic stem cells from related or unrelated donors. Attributable to its polyclonal nature, Thymoglobulin provides multifaceted immunomodulation suggesting that its use should be included in the immunosuppressant therapeutic armamentarium to help reduce the incidence of organ rejection and GvHD, and for treatment of aplastic anemia.
Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation. [2021]Allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of severe acute and chronic graft-versus-host disease (GVHD) compared to bone marrow transplantation. Anti-thymocyte globulin (ATG) can reduce severe acute and chronic GVHD in PBSCT; however, an optimal dose of ATG remains undefined. We conducted a multicenter phase II study to investigate safety and efficacy of low-dose ATG (a total of 2 mg/kg Thymoglobulin) in patients undergoing HLA-matched PBSCT after myeloablative conditioning. The primary endpoint was grades III-IV GVHD at 100 days. Seventy-seven patients were enrolled and 72 patients with a median age of 46.5 years were eligible for analysis. The primary endpoint, cumulative incidence of grades III-IV acute GVHD at 100 days was 1.4% (95% CI, 0.1-6.7%), which was greatly less than our pre-defined statistical threshold value (18.0%). The incidence of chronic GVHD at 1 year was also low (all-grade; 15.3%, moderate to severe; 5.6%). Non-relapse mortality, relapse, overall survival, disease-free survival, and GVHD-free, relapse-free survival at 1 year were 4.2%, 20.8%, 84.7%, 75.0%, and 69.4%, respectively. Low dose thymoglobulin is promising to reduce severe acute and chronic GVHD in HLA-matched PBSCT following myeloablative conditioning.
Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. [2020]Despite initial complete remission rates of up to 90%, long-term, disease-free survival remains poor in patients with newly diagnosed acute lymphoblastic leukemia (ALL). Response to salvage chemotherapy is suboptimal; therefore, novel therapeutic agents are being investigated in order to improve outcomes in these patients. Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate recently approved by the US Food and Drug Administration for the treatment of adults with relapsed or refractory B-cell precursor ALL. Inotuzumab ozogamicin improves response rate, minimal residual disease negativity, and survival compared to standard chemotherapy in this population. In addition, it offers more opportunities to proceed to an allogeneic stem cell transplant in patients who otherwise may not be candidates.
Amsacrine combined with etoposide and high-dose methylprednisolone as salvage therapy in acute lymphoblastic leukemia in children. [2015]In a retrospective analysis of 24 children with refractory or multiply relapsed acute lymphoblastic leukemia (ALL), a salvage regimen comprising amsacrine, etoposide, and high-dose methylprednisolone AEP achieved a significant treatment response in 11 of 19 evaluable patients (8 complete and 3 partial remissions). Five of 9 AEP-responsive patients who underwent subsequent stem cell transplantation are alive (median follow-up: 43 months; range 10 to 91). The load of minimal residual disease prior to transplantation appears to be predictive for outcome in this very poor-prognosis subgroup of ALL.
Novel targeted therapies in acute lymphoblastic leukemia. [2019]Chemotherapy alone cures only 25-45% of adult patients with acute lymphoblastic leukemia (ALL), making novel treatment agents and strategies desperately needed. The addition of monoclonal antibodies (rituximab, alemtuzumab, epratzumab) to chemotherapy has demonstrated encouraging results in patients with newly diagnosed and relapsed ALL. The anti-CD22 immunoconjugate, inotuzumab ozogamicin, and the anti-CD19 BiTE(®) antibody, blinatumomab, have demonstrated impressive single agent activity in patients with relapsed or refractory B-ALL. Early reports of chimeric antigen receptor therapies have been promising in patients with relapsed ALL. Other agents targeting NOTCH1, FLT3, the proteasome and DNA methylation are early in development. These new agents hope to improve the outcome of ALL therapy with less toxicity. The challenge going forward will be to find safe and effective combinations and determine where in the treatment schema these agents will be most effective in ALL therapy.
Poor prognosis of prethymic phenotype acute lymphoblastic leukemia (pre-T-ALL). [2015]Pre-T-ALL is an important subgroup of ALL with clinical features different from adult T-ALL. Expression of intracytoplasmic CD3 represents the earliest marker for the prethymic phenotype. We studied four consecutive adult patients with this phenotype. Three of the four patients did not respond to the induction chemotherapy with vincristine, daunorubicin, prednisone and asparaginase. They reached a delayed remission only after chemotherapy with cyclophosphamide and cytosine arabinoside. All four patients relapsed 3, 9, 10 and 13 months after diagnosis. One patient died 2 months after relapse, another one 2 months after allogeneic BMT performed in second relapse. We conclude that patients with early T-cell precursor leukemia do not respond adequately to conventional chemotherapy and should be considered as a high-risk subgroup within the T-lineage ALL.
Combination therapy in childhood leukaemia: in vitro studies of thiopurines and inhibitors of purine metabolism on apoptosis. [2017]Methotrexate (MTX) followed by 6-mercaptopurine (6MP) is one of the best known combinations for the treatment of childhood acute lymphoblastic leukaemia. Tiazofurin (TF) and 6-thioguanine (TG) are also used as chemotherapy agents in the treatment of malignancies. We have examined the induction of apoptosis by combinations of these drugs to gain more insights into their efficacy in the treatment of malignancies.