Haploidentical Stem Cell Transplantation for Children With Therapy Resistant Leukemia

NCT01025778 | Completed Phase 2

• 1 other identifier: BUS2009/1
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

Despite substantial progress in the treatment pediatric acute leukemia a significant number of children will experience primary or secondary resistance to the treatment. In other words it will be not possible to achieve remission using standard chemotherapy (primary resistance) or the patients will develop chemotherapy resistant relapse (secondary resistance). Children failing to achieve remission or children relapsing after previous allogeneic stem cell transplantation have short life expectancy and palliative treatment still remains the most reasonable option as the escalation of conventional chemotherapy is not longer effective. The role of Graft versus Leukemia effect was postulated as one of the mechanisms contributing to the leukemia control/eradication after transplantation of hematopoietic stem cells. In this study the investigators combine intensified multiagent Clofarabine containing chemotherapy with post-induction treatment intensification using reduced intensity conditioning followed by haploidentical hematopoietic stem cell transplantation. Introducing a new drug to the treatment of resistant leukemia the investigators want to achieve a response which allows us to proceed to immediate haploidentical transplantation. Using a haploidentical donor the investigators can avoid time consuming search for an unrelated donor and perform the transplantation at the optimal time-point. Combating therapy resistant leukemia the investigators would like to evoke and utilize potential Graft-versus-Leukemia effect which is much more pronounced in the haploidentical setting, as it is well documented that allogeneic transplantation with a matched donor is not effective in resistant disease. The use of best KIR mismatch donor and post-transplant donor lymphocyte infusion will be implemented in order to develop/intensify graft versus leukemia effect.

Conditions

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia

Keywords

Haploidentical hematopoietic stem cell transplantation; Graft versus host disease; Donor lymphocyte infusion; Graft versus leukemia effect; Immunological recovery; Bridge to transplant approach; Therapy resistant leukemia; Hematological malignancy

Outcome Measures

Primary Outcomes (1)

• Event free survival

  1 year from transplantation

Secondary Outcomes (4)

• Evaluation of induction efficacy by response rate and the number of children proceeding to transplant

  3 months from induction start

• Tolerance, safety and quality of life

  1 year from transplantation

• Hematological and immunological recovery

  100 days fron tranplantation

• Incidence of graft versus host disease

  100 days from transplantation

Study Arms (1)

Remission induction and haplo-SCT

EXPERIMENTAL

Remission induction with Clofaranie, Etoposide and Cyclophosphamide combination followed by haplidentical stem cella transplantation if remission achieved.

Drug: Clofarabine for remission induction; Drug: Etoposide for remission induction; Drug: Cyclophosphamide for remission induction; Drug: Clofarabine in conditioning before transplantation; Drug: Thiotepa in conditioning before transplantation; Drug: Melfalan in conditioning before transplantation; Procedure: Haploidentical transplantation of T-cell depleted graft; Procedure: Donor lymphocyte infusion

Interventions

Clofarabine for remission induction DRUG

Remission induction and haplo-SCT

Etoposide for remission induction DRUG

Remission induction and haplo-SCT

Cyclophosphamide for remission induction DRUG

Remission induction and haplo-SCT

Clofarabine in conditioning before transplantation DRUG

Remission induction and haplo-SCT

Thiotepa in conditioning before transplantation DRUG

Remission induction and haplo-SCT

Melfalan in conditioning before transplantation DRUG

Remission induction and haplo-SCT

Haploidentical transplantation of T-cell depleted graft PROCEDURE

Remission induction and haplo-SCT

Donor lymphocyte infusion PROCEDURE

Remission induction and haplo-SCT

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Target population
• Refractory acute lymphoblastic leukemia
• Chemoresistant isolated or combined bone marrow relapse
• Relapse after during/after conventional treatment
• Relapse ≥6 months after allogeneic stem cell transplantation
• Primary induction failure
• Isolated extramedullary relapse after previous HSCT (\>6 months)
• Refractory acute myeloblastic leukemia including sAML
• Chemoresistant relapse
• Relapse after during/after conventional treatment
• Relapse ≥6 months after allogeneic stem cell transplantation
• Primary induction failure
• Age ≥ 1 and ≤21 years
• Patients with previous HCST ≥ 6 m
• Provide signed written informed consent patients', and patients' parents /guardians

You may not qualify if:

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
• Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea.
• The patient must have recovered from all acute toxicities from any previous therapy.
• Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment.
• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Pregnant or lactating patients.
• Any significant concurrent malignant disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

Sponsors & Collaborators

• Lund University Hospital: lead

Study Sites (1)

Lund University Hospital

Lund, SE-22185, Sweden

Location

Related Publications (5)

• Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. doi: 10.1111/j.1365-2141.2009.07882.x. Epub 2009 Aug 29.

  PMID: 19747360 BACKGROUND

• Hijiya N, Gaynon P, Barry E, Silverman L, Thomson B, Chu R, Cooper T, Kadota R, Rytting M, Steinherz P, Shen V, Jeha S, Abichandani R, Carroll WL. A multi-center phase I study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia. Leukemia. 2009 Dec;23(12):2259-64. doi: 10.1038/leu.2009.185. Epub 2009 Sep 10.

  PMID: 19741725 BACKGROUND

• Stern M, Ruggeri L, Mancusi A, Bernardo ME, de Angelis C, Bucher C, Locatelli F, Aversa F, Velardi A. Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood. 2008 Oct 1;112(7):2990-5. doi: 10.1182/blood-2008-01-135285. Epub 2008 May 20.

  PMID: 18492955 BACKGROUND

• Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. doi: 10.1200/JCO.2005.03.8554.

  PMID: 16622268 BACKGROUND

• Toporski J, Krol L, Dykes J, Hakansson Y, Pronk C, Turkiewicz D. The combination of clofarabine, etoposide, and cyclophosphamide shows limited efficacy as a bridge to transplant for children with refractory acute leukemia: results of a monitored prospective study. Pediatr Hematol Oncol. 2021 Apr;38(3):216-226. doi: 10.1080/08880018.2020.1838012. Epub 2020 Nov 5.

  PMID: 33150834 RESULT

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Graft vs Host Disease; Hematologic Neoplasms

Interventions

Clofarabine; Remission Induction; Etoposide; Cyclophosphamide; Thiotepa; Melphalan

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides; Therapeutics; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Jacek Toporski, MD, PhD

  Lund University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Head, Section of Pediatric Oncology/Hematology

Study Record Dates

• First Submitted: December 3, 2009
• First Posted: December 4, 2009
• Study Start: December 1, 2009
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: February 21, 2021

Record last verified: 2021-02

Locations

SE (1)