Haploidentical Donor vs mMUD in Hematological Malignancies (HAMLET)

A Randomized Controlled Trial Comparing Outcome After Hematopoietic Cell Transplantation From a Partially Matched Unrelated Versus Haploidentical Donor

The goal of this trial is to compare the outcome after partially matched (single mismatch) unrelated donor transplantation with haploidentical transplantation in a randomized controlled setting.

Study Overview

• Status: Completed
• Conditions: AML; MDS; ALL
• Intervention / Treatment: Biological: Peripheral blood stem cells

Detailed Description

For patients with an indication for allogeneic HCT, the search for a stem cell donor is a challenge. 20% of patients who need an allograft have an HLA-identical sibling available, and for approximately 70% of the remaining patients, a suitable, HLA-well-matched (10/10), unrelated volunteer can be found. For the remaining patients, partially matched (single mismatch) unrelated donors or haploidentical donors are alternative options.

Recently published retrospective single center and registry studies suggest comparable outcomes for HCT from unrelated donors matched at HLA -A, -B, -C, and -DRB1 and haploidentical donors. The number of haploidentical HCT evaluated in these studies was still relatively small and a selection bias for the retrospective comparisons cannot be excluded.

The goal of this trial is to evaluate overall survival of patients with high-risk AML, ALL or MDS after partially matched unrelated or haploidentical donor transplantation..

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany, 53105
    • Universitätsklinikum Bonn
  • Dresden, Germany
    • Universitätsklinikum Dresden
  • Frankfurt am Main, Germany, 60595
    • Universitätsklinikum Frankfurt
  • Halle, Germany, 06120
    • Universitatsklinikum Halle (Saale)
  • Mannheim, Germany, 68167
    • Universitätsmedizin Mannheim
  • Münster, Germany, 48149
    • Universitätsklinikum Münster
  • Nürnberg, Germany, 90419
    • Klinikum Nürnberg Nord
  • Stuttgart, Germany, 70376
    • Robert-Bosch-Krankenhaus
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

1. Eligible diagnoses are listed below:

   AML with adverse risk genetic abnormalities (according to the ELN guidelines)1. AML with intermediate genetic abnormalities (according to ELN guidelines) either in first complete remission, after relapse, or by chemotherapy-refractory disease.

   AML with favourable genetic abnormalities (according to ELN guidelines) after relapse or by chemotherapy-refractory disease, except APL.

   AML with undefined genetic risk classification after relapse or with chemotherapy-refractory disease.

   AML arising from myelodysplastic syndrome (MDS) or a myeloproliferative neoplasia, except if favourable genetic abnormalities (according to ELN guidelines) are present.

   Therapy-related myeloid neoplasia except if favorable genetic abnormalities (according to ELN guidelines) are present.

   MDS with high risk or very high risk disease (according to the IPSS-R score)2.

   First CR of high-risk ALL, defined by one or more of these:

   • Early or mature T-ALL (CD1a negative).
   • Pro B-ALL with t(4v;11); KMT2A-rearrangements.
   • Presence of BCR-ABL and/or t(9;22).
   • Persistence of minimal residual disease after the second induction course. ALL with or without complete remission after salvage therapy following poor response to induction therapy.

   ALL after haematological or molecular relapse.

2. Fit for transplant according to physician judgement.
3. No history of cardiac disease and absence of active symptoms, otherwise, documented left ventricular ejection fraction ≥40%.
4. No history of chronic pulmonary disease and absence of dyspnea. Otherwise, documented diffusion lung capacity for carbon monoxide (DLCO) ≥40% or FEV1/FVC ≥ 50% despite appropriate treatment
5. Availability of ≥1 unrelated donor with a single allele or antigen mismatch at HLA-A, -B, -C, or -DRB1 and no concurrent DQB1 mismatch (9/10) shown by confirmatory typing.
6. Availability of at least one haploidentical donor meeting the following criteria:

Donor is a biologic parent / child of the patient, or haploidentity has been confirmed for patient's relatives by HLA-Typing.

The donor has expressed his/her will to donate and has no contraindications against a stem cell donation by medical history.

Donor age is ≥18 years and ≤75 years.

Exclusion criteria

1. Relapse or graft failure after a first allogeneic transplantation.
2. Thymic ALL in first complete remission.

3. Severe organ dysfunction defined by either of the following three criteria:

   Patients who receive supplementary continuous oxygen. Serum bilirubin >1.5 x ULN (if not considered Gilbert-Syndrome) or ASAT/ALAT >5 x ULN.

   Estimated Glomerular Filtration Rate (GFR) < 40 mL/min

4. Uncontrolled infection at the time of enrollment.
5. Pregnant or breast-feeding women.
6. An HLA-identical sibling donor or 8/8 (HLA-A, -B, -C, or -DRB1) matched unrelated donor is available and suitable to donate prior to randomization.
7. Men unable or unwilling to use adequate contraception methods from enrollment to minimum of six months after the last dose of chemotherapy.
8. Women of childbearing potential except those who fulfill the following criteria: Post-menopausal or post-operative or continuous and correct application of a contraception method with a Pearl Index <1% or sexual abstinence or vasectomy of the sexual partner.
9. Simultaneous participation in another clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Haploidentical donor; Peripheral blood stem cells from Haploidentical donor	Biological: Peripheral blood stem cells; Hematopoietic stem cell transplantation with PBSC; Other Names: PBSC
Active Comparator: partially matched unrelated donor; Peripheral blood stem cells from unrelated donor with a single allele or antigen mismatch at HLA-A, -B, -C, or -DRB1 and no concurrent DQB1 mismatch (9/10) shown by confirmatory typing	Biological: Peripheral blood stem cells; Hematopoietic stem cell transplantation with PBSC; Other Names: PBSC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival calculated from the time of randomization will be the primary endpoint of this trial. Death from any reason will be considered as event.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Engraftment rate	Engraftment	day 56
Immune-reconstitution rate	Immune-reconstitution rate	day56
Infections	Severe infections rate	2 months after HCT
Event Free Survival	Event Free Survival	1 year
Graft vs Host Disease	Graft vs Host Disease rate	1 year
Graft vs Host Disease-free survival	Graft vs Host Disease-free survival rate	1 year

Collaborators and Investigators

• Sponsor: DKMS gemeinnützige GmbH
• Investigators: Study Chair: Johannes Schetelig, Prof Dr med, Universtitätsklinikum Dresden

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Actual): April 13, 2024
• Study Completion (Actual): April 13, 2024

Study Registration Dates

• First Submitted: September 4, 2017
• First Submitted That Met QC Criteria: September 6, 2017
• First Posted (Actual): September 7, 2017

Study Record Updates

• Last Update Posted (Actual): August 7, 2024
• Last Update Submitted That Met QC Criteria: August 6, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Haploidentical; hematopoietic stem cell transplantation; mismatched unrelated donor; donor comparison
• Other Study ID Numbers: DKMS-16-01; 2015-005399-12 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No