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Minimal Residual Disease

Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease

Leukemia volume 28, pages 658–665 (2014)Cite this article

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Abstract

The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)neg pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27–52) vs 35% (95% CI 27–44); P=0.62). Patients MRDpos pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRDpos (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRDneg status is preferred pre-HCT.

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Acknowledgements

This work was supported in part by Novartis providing the grant to CIBMTR for supplemental data collection. The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24 CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement U10 HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research; and grants from Allos Therapeutics, Inc.; Amgen, Inc. Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; the Leukemia and Lymphoma Society; the Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; TerumoBCT; Teva Neuroscience, Inc.; THERAKOS, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense or any other agency of the US Government.

Author contributions

VB, DJW: designed the study, assisted in supplemental data collection, interpreted data and wrote the manuscript. DIM: assisted in data interpretation, analysis and writing the manuscript. HW; M-JZ: collected and analyzed data, performed statistical analysis. Other authors reviewed the analyses, modified and approved the final manuscript.

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Authors and Affiliations

  1. Blood and Marrow Transplant Program, University of Minnesota Medical Center, Minneapolis, MN, USA

    V Bachanova & D J Weisdorf

  2. Bristol Adult BMT Unit, Bristol Children’s Hospital, Bristol, UK

    D I Marks

  3. Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin, Milwaukee, WI, USA

    M-J Zhang, H Wang & W Saber

  4. Seidman Cancer Center, University Hospitals Case Medical Center, Cleveland, OH, USA

    M de Lima & H M Lazarus

  5. Department of Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

    M D Aljurf

  6. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    M Arellano

  7. Department of Hematology and Oncology, University of Chicago Medicine, Chicago, IL, USA

    A S Artz

  8. Klinik und Poliklinik fur Stammzelltransplantation, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany

    U Bacher

  9. Department of Hematology, University Hospital, Grenoble, France

    J-Y Cahn

  10. Department of Bone Marrow Transplantation, Massachusetts General Hospital, Boston, MA, USA

    Y-B Chen

  11. Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA

    E A Copelan

  12. Medical College of Wisconsin, Milwaukee, WI, USA

    W R Drobyski

  13. Division of Experimental Medicine, Department of Medicine, Imperial College, Section of Hematology, London, UK

    R P Gale

  14. Department of Hematology and Stem Cell Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA

    J P Greer & B N Savani

  15. Princess Margaret Hospital, Toronto, Ontario, Canada

    V Gupta

  16. Department of Pediatric Hematology and Oncology, All Children’s Hospital, St Petersburg, FL, USA

    G A Hale

  17. Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA

    P Kebriaei & B Oran

  18. Department of Haematology and Bone Marrow Transplant Unit, Royal Adelaide Hospital/SA Pathology, Adelaide, South Australia, Australia

    I D Lewis

  19. Department of Hematology and Oncology, Alberta Children’s Hospital, Calgary, Alberta, Canada

    V A Lewis

  20. Department of Hematology and Oncology, Strong Memorial Hospital, University of Rochester Medical Center, NY, Rochester, USA

    J L Liesveld

  21. Department of Hematology and Internal Medicine, Mayo Clinic Rochester, Rochester, MN, USA

    M R Litzow

  22. Department of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    A W Loren

  23. Department of Oncology, Baylor University Medical Center, Dallas, TX, USA

    A M Miller

  24. Department of Hematology and Oncology, Shands HealthCare and University of Florida, Gainesville, FL, USA

    M Norkin

  25. Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA

    J Pidala

  26. Department of Hematology, Rambam Medical Center, Haifa, Israel

    J M Rowe

  27. Department of Bone Marrow Transplantation and Leukemia, Barnes Jewish Hospital, Washington University School of Medicine, St Louis, MO, USA

    R Vij

  28. Bone Marrow and Stem Cell Transplant Center, Emory University Hospital, Atlanta, GA, USA

    E K Waller

  29. Our Lady of Mercy Medical Center, Bronx, NY, USA

    P H Wiernik

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Correspondence to V Bachanova.

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Scientific Subheading: Transplantation

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Bachanova, V., Marks, D., Zhang, MJ. et al. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. Leukemia 28, 658–665 (2014). https://doi.org/10.1038/leu.2013.253

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