Sequential Conditioning with Thiotepa in T Cell- Replete Hematopoietic Stem Cell Transplantation for the Treatment of Refractory Hematologic Malignancies: Comparison with Matched Related, Haplo-Mismatched, and Unrelated Donors

Rémy Duléry; Anne-Lise Ménard; Sylvain Chantepie; Jean El-Cheikh; Sylvie François; Jérémy Delage; Federica Giannotti; Annalisa Ruggeri; Eolia Brissot; Giorgia Battipaglia; Florent Malard; Ramdane Belhocine; Simona Sestili; Anne Vekhoff; François Delhommeau; Oumédaly Reman; Ollivier Legrand; Myriam Labopin; Marie-Thérèse Rubio; Mohamad Mohty

doi:10.1016/j.bbmt.2018.01.005

Sequential Conditioning with Thiotepa in T Cell- Replete Hematopoietic Stem Cell Transplantation for the Treatment of Refractory Hematologic Malignancies: Comparison with Matched Related, Haplo-Mismatched, and Unrelated Donors

Biol Blood Marrow Transplant. 2018 May;24(5):1013-1021. doi: 10.1016/j.bbmt.2018.01.005. Epub 2018 Jan 11.

Authors

Rémy Duléry¹, Anne-Lise Ménard², Sylvain Chantepie³, Jean El-Cheikh⁴, Sylvie François⁵, Jérémy Delage⁶, Federica Giannotti⁷, Annalisa Ruggeri⁸, Eolia Brissot¹, Giorgia Battipaglia⁹, Florent Malard¹, Ramdane Belhocine⁸, Simona Sestili⁸, Anne Vekhoff⁸, François Delhommeau¹⁰, Oumédaly Reman³, Ollivier Legrand¹, Myriam Labopin¹¹, Marie-Thérèse Rubio⁸, Mohamad Mohty¹²

Affiliations

¹ Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France; UMRS 938, Inserm, Paris, France; Université Pierre et Marie Curie Paris VI, Sorbonne University, Paris, France.
² Department of Hematology, Henri Becquerel Center, Rouen, France.
³ Department of Hematology, Caen University Hospital, Caen, France.
⁴ Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
⁵ Department of Hematology, Angers University Hospital, Angers, France.
⁶ Department of Hematology, University Hospital of Montpellier, Montpellier, France.
⁷ Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France; Université Pierre et Marie Curie Paris VI, Sorbonne University, Paris, France.
⁸ Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.
⁹ Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France; Department of Hematology and Marrow Transplantation, Federico II University, Naples, Italy.
¹⁰ Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France; UMRS 938, Inserm, Paris, France; Université Pierre et Marie Curie Paris VI, Sorbonne University, Paris, France; Department of Biological Hematology, Saint Antoine and Armand-Trousseau Hospitals, AP-HP, Paris, France.
¹¹ Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France; UMRS 938, Inserm, Paris, France; Université Pierre et Marie Curie Paris VI, Sorbonne University, Paris, France; Paris Study Office/CEREST-TC, European Group for Blood and Marrow Transplantation, Paris, France.
¹² Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France; UMRS 938, Inserm, Paris, France; Université Pierre et Marie Curie Paris VI, Sorbonne University, Paris, France. Electronic address: mohamad.mohty@inserm.fr.

PMID: 29337223
DOI: 10.1016/j.bbmt.2018.01.005

Abstract

The results of conventional allogeneic stem cell transplantation (SCT) in refractory hematologic malignancies are poor. Sequential strategies have shown promising results in refractory acute myelogenous leukemia (AML), but have not been validated in a haploidentical (Haplo) transplant setting. We have developed a new sequential approach combining chemotherapy with broad antitumor activity (thiotepa 10 mg/kg, etoposide 400 mg/m², and cyclophosphamide 1600 mg/m² from day -15 to day -10), followed after 3 days of rest by a reduced-intensity conditioning regimen (fludarabine 150 mg/m², i.v. busulfan 6.4 mg/kg, and thymoglobulin 5 mg/kg from day -6 to day -2). High-dose post-transplantation cyclophosphamide was added in cases with Haplo donors. Seventy-two patients (median age, 54 years) with a refractory hematologic malignancy (44 with acute myelogenous leukemia, 7 with acute lymphoblastic leukemia, 15 with myelodysplastic syndrome/myeloproliferative neoplasms, and 6 with lymphomas) were included in this retrospective multicenter study. Donors were Haplo (n = 27), matched related (MRD; n = 16), and unrelated (UD; n = 29). With a median follow-up of 21 months, the 2-year overall survival (OS) and event-free survival (EFS) were 54.7% and 49.3%, respectively, in recipients of Haplo transplants, 49.2% and 43.8%, respectively, in recipients of MRD transplants, and 37.9% and 28%, respectively, in recipients of UD transplants. Compared with UD, the outcomes were improved in Haplo in terms of the incidences of acute grade II-IV graft-versus-host disease (GVHD) (11.1% versus 41.4%; P < .001) and GVHD-free, relapse-free survival (44.4 versus 10.3%; P = .022). These results support the safety and efficacy of a thiotepa-based sequential approach in allogeneic SCT with a Haplo donor with post-transplantation immune modulation. Thus, in patients with refractory hematologic malignancies, there seems to be no benefit in searching for a UD when a Haplo donor is readily available.

Keywords: Antithymocyte globulin; Conditioning; Haploidentical transplantation; Refractory hematologic malignancy.

Publication types

Comparative Study
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Alkylating / therapeutic use
Female
Hematologic Neoplasms / mortality
Hematologic Neoplasms / therapy*
Histocompatibility Testing
Humans
Male
Middle Aged
Retrospective Studies
Salvage Therapy / methods*
Salvage Therapy / mortality
Survival Analysis
Thiotepa / therapeutic use*
Tissue Donors
Transplantation Conditioning / methods*
Transplantation, Haploidentical
Unrelated Donors

Substances

Antineoplastic Agents, Alkylating
Thiotepa