Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide in Patients With Acquired Refractory Aplastic Anemia (HAPLO-EMPTY)

Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide in Patients With Acquired Refractory Aplastic Anemia: a Nationwide Phase II Study

Outcomes for patients with severe aplastic anemia (SAA) who are refractory to first-line immunosuppressive therapy (IST) and who lack a matched unrelated donor (MUD) remain poor. Recently, the use of eltrombopag (ELT) has shown blood count improvements in 40% of these patients. However, most refractory patients do not respond to ELT or other second-line treatment and are therefore exposed to life-threatening infections, and bleeding. During the past 2 decades, there has been a significant decrease in infection-related mortality in patients with SAA unresponsive to initial IST but clonal evolution including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) still occur in the long-term with a grim prognosis. Overall, the overall survival of such patients with acquired refractory SAA to ELT is about 60-70% at 2 years.

Hematopoietic stem cell transplantation (HSCT) using alternative donor sources (i.e., mismatched unrelated donors, cord blood (CBT), and haplo-identical family donors) may be curative in patients with refractory SAA, despite carrying much higher rates of complications than in transplantations from matched related or unrelated donors. Recently, our group showed that CBT is a valuable curative option for young adults with refractory SAA. However, not all patients have available CB and CBT treatment related mortality is high in adult patients. Haploidentical (haplo) related donor Stem Cell Transplantation (haplo-SCT) have improved dramatically outcomes using T-cell replete grafts with administration of post-transplantation cyclophosphamide (PTCy). Preliminary results in a little number of patients with refractory SAA at Kings college (London, UK) and John Hopkins (Baltimore, USA) seem promising. The investigators retrospectively analyzed data from 36 patients (median age 42 years) transplanted between 2010 and 2017 in Europe on behalf of the SAA working party of the European Blood and Marrow Transplantation group. The 1-year overall survival was about 80% suggesting that this approach might be a valid option in this particular poor clinical situation.

The main objective of this study is to demonstrate a benefit in term of the 2-year overall survival rate from 60% (historical rates in patients with acquired refractory idiopathic aplastic anemia) up to 80% using haplo-SCT with PTCy.

Study Overview

• Status: Not yet recruiting
• Conditions: Refractory Idiopathic Aplastic Anemia; Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation
• Intervention / Treatment: Other: Allogenic transplantation

• Study Type: Interventional
• Enrollment (Anticipated): 31
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Régis Peffault de Latour; Phone Number: +33142385073; Email: regis.peffaultdelatour@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged from 3 to 35 years old
• Suffering from refractory acquired idiopathic aplastic anemia (at least one course of immunosuppression with anti-thymocyte globulin)
• Absence of geno-identical donor or 10/10 matched donor
• With identification of a haploidentical donor (brother, sister, parents, adult children or cousin)
• Absence of donor specific antibody detected in the patient with a MFI ≥ 1500 (antibodies directed towards the distinct haplotype between donor and recipient)

• With usual criteria for HSCT :

  • ECOG(Eastern Cooperative Oncology Group) ≤ 2
  • No severe and uncontrolled infection
  • Cardiac function compatible with high dose of cyclophosphamide
• Adequate organ function: ASAT(aspartate transaminase) and ALAT (alanine aminotransferase) ≤ 2.5 N (the norm), total bilirubin ≤ 2N, creatinine < 150 μmol/L
• With health insurance coverage
• Contraception methods must be prescribed during all the duration of the research. Women and men of childbearing age must use contraceptive methods within 12 months and 6 months after the last dose of cyclophosphamide, respectively.
• Having signed a written informed consent (2 parents for patients aged less than 18)

Exclusion Criteria :

• With no morphologic evidence of clonal evolution (patients with isolated bone marrow cytogenetic abnormalities are also eligible).
• With uncontrolled infection
• With seropositivity for HIV or HTLV-1 (Human T cell Leukemia) or active hepatitis B or C defined by a positive PCR (polymerase chain reaction) HBV (hepatitis B virus) or HCV (hepatitis C virus) and associated hepatic cytolysis
• Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix)
• Pregnant (βHCG positive) or breast-feeding.
• Who received attenuated vaccine within 2 months before transplantation
• Uncontrolled coronary insufficiency, recent myocardial infarction <6 month, current manifestations of heart failure, uncontrolled cardiac rhythm disorders, ventricular ejection fraction <50%
• With heart failure according to NYHA (New York Heart Association) (II or more)
• Preexisting acute hemorrhagic cystitis
• Renal failure with creatinine clearance <30ml / min
• With urinary tract obstruction
• With contraindications to treatments used during the research
• Who have any debilitating medical or psychiatric illness, which preclude understanding the inform consent as well as optimal treatment and follow-up
• Under tutorship or curatorship

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Haploidentical allogeneic hematopoietic stem cell transplantation.; Conditioning regimen Fludarabine (30mg/m2/day i.v: day -6 to day -2), pre-transplant cyclophosphamide (14.5 mg/kg/day i.v: day -6 and day -5), and Total Body Irradiation (2 Gray on day-1); Stem cell source Bone Marrow; GVHD Prophylaxis Rabbit ATG dosed at 0.5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, Cyclophosphamide 50 mg/Kg/day at D+3 and D+4, Tacrolimus (residual 8-12 microg/L) and mycophenolate (MMF) from D+5. In absence of GvHD, MMF will be stopped at D35 and tacrolimus at day 365.; Prevention of EBV reactivation Rituximab 150mg/m2 intravenously at Day+5 post HSCT, Each infusion of Rituximab will be preceded by administration of anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine.

Other: Allogenic transplantation; Conditioning regimen Fludarabine (30mg/m2/day i.v: day -6 to day -2), pre-transplant cyclophosphamide (14.5 mg/kg/day i.v: day -6 and day -5), and Total Body Irradiation (2 Gray on day-1); Stem cell source Bone Marrow; GVHD Prophylaxis Rabbit ATG dosed at 0.5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, Cyclophosphamide 50 mg/Kg/day at D+3 and D+4, Tacrolimus (residual 8-12 microg/L) and mycophenolate (MMF) from D+5. In absence of GvHD, MMF will be stopped at D35 and tacrolimus at day 365.; Prevention of EBV reactivation Rituximab 150mg/m2 intravenously at Day+5 post HSCT, Each infusion of Rituximab will be preceded by administration of anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival rate	at 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival		at 12 months
Graft failure incidence		at 2 years
Neutrophils engraftment	3 consecutive days with neutrophiles >0.5 G/L	at day 100
Platelets engraftment	7 consecutive days with platelets >20 G/L	at day 100
Absolute numbers of neutrophils		at 1 month
Absolute numbers of neutrophils		at 2 months
Absolute numbers of neutrophils		at 3 months
Absolute numbers of neutrophils		at 6 months
Absolute numbers of neutrophils		at 12 months
Absolute numbers of neutrophils		through study completion, an average of 6 months
Absolute numbers of platelets		at 1 month
Absolute numbers of platelets		at 2 months
Absolute numbers of platelets		at 3 months
Absolute numbers of platelets		at 6 months
Absolute numbers of platelets		at 12 months
Absolute numbers of platelets		through study completion, an average of 6 months
Incidence of use of growth factors for poor hematopoietic reconstitution		up to one year
Acute graft-versus-host disease (GvHD) incidence		at 3 months
Chronic graft-versus-host disease (GvHD) incidence		at 24 months
Relapse incidence		at 12 months
Relapse incidence		at 24 months
Progression free survival		at 24 months
Incidence of cytomegalovirus (CMV) infection		at 12 months
Incidence of Epstein-Barr virus (EBV) infection		at 12 months
Severe infections (CTAE grade 3-4)		at 3 months
Severe infections (CTAE grade 3-4)		at 6 months
Severe infections (CTAE grade 3-4)		at 12 months
Severe infections (CTAE grade 3-4)		at 24 months
Non-relapse mortality		at 24 months
Incidence of cardiac toxicities		at 12 months
Overall survival		at 12 months
Quality of life questionnaire for adults	Quality of life will be assessed for adult using "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) " EORTC QLQ-C30-V3 questionnaire.The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	at 3 months
Quality of life questionnaire for minors	Quality of life will be assessed for minor using The Pediatric Quality of Life Inventory™ (PedsQL™) The 36-item PedsQL™ Family Impact Module is a parent-report instrument designed to assess the impact of pediatric chronic health conditions on parents and the family. It includes 6 subscales measuring parents' self-reported functioning. The scale has five Likert response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding to scores of 100, 75, 50, 25 and 0). Higher scores indicate better functioning.	at 3 months
Quality of life questionnaire for adults	Quality of life will be assessed for adult using "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire" EORTC QLQ-C30-V3 questionnaire.The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	at 6 months
Quality of life questionnaire for minors	Quality of life will be assessed for minor using The Pediatric Quality of Life Inventory™ (PedsQL™) The 36-item PedsQL™ Family Impact Module is a parent-report instrument designed to assess the impact of pediatric chronic health conditions on parents and the family. It includes 6 subscales measuring parents' self-reported functioning. The scale has five Likert response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding to scores of 100, 75, 50, 25 and 0). Higher scores indicate better functioning.	at 6 months
Quality of life questionnaire for adults	Quality of life will be assessed for adults using "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire" EORTC QLQ-C30-V3 questionnaire.The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	at 12 months
Quality of life questionnaire for minors	Quality of life will be assessed for minor using The Pediatric Quality of Life Inventory™ (PedsQL™) The 36-item PedsQL™ Family Impact Module is a parent-report instrument designed to assess the impact of pediatric chronic health conditions on parents and the family. It includes 6 subscales measuring parents' self-reported functioning. The scale has five Likert response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding to scores of 100, 75, 50, 25 and 0). Higher scores indicate better functioning.	at 12 months
Quality of life questionnaire for adults	Quality of life will be assessed for adult using "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire" EORTC QLQ-C30-V3 questionnaire.The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	at 24 months
Quality of life questionnaire for minors	Quality of life will be assessed for minor using The Pediatric Quality of Life Inventory™ (PedsQL™) The 36-item PedsQL™ Family Impact Module is a parent-report instrument designed to assess the impact of pediatric chronic health conditions on parents and the family. It includes 6 subscales measuring parents' self-reported functioning. The scale has five Likert response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding to scores of 100, 75, 50, 25 and 0). Higher scores indicate better functioning.	at 24 months
Proportion of patients with a donor chimerism of 90% or more		at 1 months
Proportion of patients with a donor chimerism of 90% or more		at 3 months
Proportion of patients with a donor chimerism of 90% or more		at 6 months
Proportion of patients with a donor chimerism of 90% or more		at 12 months
Proportion of patients with a donor chimerism of 90% or more		at 24 months
Immune reconstitution by analyzing T, B, natural killer (NK), regulatory T cell levels in the peripheral blood		at 3 months
Immune reconstitution by analyzing T, B, natural killer (NK), regulatory T cell levels in the peripheral blood		at 6 months
Immune reconstitution by analyzing T, B, natural killer (NK), regulatory T cell levels in the peripheral blood		at 12 months
Immune reconstitution by analyzing T, B, NK, regulatory T cell levels in the peripheral blood		at 24 months
Ferritin levels		at 3 months
Ferritin levels		at 6 months
Ferritin levels		at 12 months
Ferritin levels		at 24 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Anticipated): November 25, 2021
• Primary Completion (Anticipated): November 25, 2026
• Study Completion (Anticipated): November 25, 2026

Study Registration Dates

• First Submitted: October 15, 2021
• First Submitted That Met QC Criteria: November 8, 2021
• First Posted (Actual): November 19, 2021

Study Record Updates

• Last Update Posted (Actual): November 19, 2021
• Last Update Submitted That Met QC Criteria: November 8, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Acquired refractory idiopathic aplastic anemia; Haplo identical hematopoietic stem cell transplantation; Post-transplantation cyclophosphamide
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Bone Marrow Failure Disorders; Anemia; Anemia, Aplastic
• Other Study ID Numbers: APHP200004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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