Cardiac safe hematopoietic stem cell transplantation for systemic sclerosis with poor cardiac function: a pilot safety study that decreases neutropenic interval to 5 days


We compared three fludarabine-based regimens for systemic sclerosis patients with a high-risk cardiac phenotype that according to EBMT criteria would be a contraindication for a high-dose cyclophosphamide (200 mg/kg) transplant regimen. All three regimens included fludarabine, ATG, and cyclophosphamide (60 mg/kg), while two regimens also included rituximab with or without IVIG. Treatment related mortality (TRM) was 2.4%. The mean number of days of neutropenia (ANC < 500) was 5.2, the mean number of platelet and red blood cell transfusions was 0.3 and 1.85, respectively. Skin score, forced vital capacity (FVC), and total lung capacity (TLC) improved with all three regimens. For patients whose regimen did not include rituximab versus those that included rituximab, 1-year overall relapse rate was higher 36% (5/14) versus 3.6% (1 of 28) (p = 0.01), secondary autoimmune diseases were higher 21% (3/14) versus 0% (0/28) (p = 0.03), and upper respiratory tract infections were higher 28% (4/14) versus 3.6% (1/28) (p = 0.04). In this safety study, a fludarabine-based regimen was relatively safe with a TRM of 2.4% and a neutropenic interval of only 5.2 days in systemic sclerosis patients with a high-risk cardiac phenotype. The addition of rituximab decreased 1-year relapse rate, risk of late secondary autoimmune diseases, and upper-respiratory tract infections.

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Fig. 1


  1. 1.

    Burt RK, Oliveira MC, Shah SJ, Moraes DA, Simoes B, Gheorghiade M, et al. Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis. Lancet. 2013;381:1116–24.

    Article  Google Scholar 

  2. 2.

    Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011;378:498–506.

    CAS  Article  Google Scholar 

  3. 3.

    van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014;311:2490–8.

    Article  Google Scholar 

  4. 4.

    Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378:35–47.

    Article  Google Scholar 

  5. 5.

    Burt RK, Shah SJ, Gheorghiade M, Ruderman E, Schroeder J. Hematopoietic stem cell transplantation for systemic sclerosis: if you are confused, remember: “it is a matter of the heart”. J Rheumatol. 2012;39:206–9.

    CAS  Article  Google Scholar 

  6. 6.

    Burt RK, Shah SJ, Schroeder J, Oliveira MC, Moraes DA, Simoes B, et al. Autologous HSCT for systemic sclerosis—authors’ Reply. Lancet. 2013;381(Jun):2080–1.

    Article  Google Scholar 

  7. 7.

    Burt RK, Oliveira MC, Shah SJ. Cardiac assessment before stem cell transplantation for systemic sclerosis. JAMA 2014;312:1803.

    Article  Google Scholar 

  8. 8.

    Farge D, Burt RK, Oliveira MC, Mousseaux E, Rovira M, Marjanovic Z, et al. Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners. Bone Marrow Transpl. 2017;52:1495–503. Epub 2017 May 22.

    CAS  Article  Google Scholar 

  9. 9.

    Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis. 2017;76:1897–905.

    Article  Google Scholar 

  10. 10.

    El-Gendy H, Shohdy KS, Maghraby GG, Abadeer K, Mahmoud M. Gastric antral vascular ectasia in systemic sclerosis: Where do we stand? Int J Rheum Dis. 2017;20:2133–9.

    Article  Google Scholar 

  11. 11.

    Ross L, Prior D, Proudman S, Vacca A, Baron M, Nikpour M. Defining primary systemic sclerosis heart involvement: a scoping literature review. Semin arthritis rheumatism. 2019;48:874–87.

    Article  Google Scholar 

  12. 12.

    Bulkley BH, Ridolfi RL, Salyer WR, Hutchins GM. Myocardial lesions of progressive systemic sclerosis. a cause of cardiac dysfunction. Circulation 1976;53:483–90.

    CAS  Article  Google Scholar 

  13. 13.

    Scully PR, Bastarrika G, Moon JC, Treibel TA. Myocardial extracellular volume quantification by cardiovascular magnetic resonance and computed tomography. Curr Cardiol Rep. 2018;20:15.

    Article  Google Scholar 

  14. 14.

    Burt RK, Farge D. Systemic sclerosis: autologous HSCT is efficacious, but can we make it safer. Nat Rev Rheumatol. 2018;14:189–91.

    Article  Google Scholar 

  15. 15.

    Hegde UP, Wilson WH, White T, Cheson BD. Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia. Blood. 2002;100:2260–2.

    CAS  Article  Google Scholar 

  16. 16.

    Elhai M, Boubaya M, Distler O, Smith V, Matucci-Cerinic M, Alegre Sancho JJ, et al. Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study. Ann Rheum Dis. 2019;78:979–87.

    CAS  Article  Google Scholar 

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Clinical trial registry: Identifier: NCT03593902

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Burt, R.K., Han, X., Quigley, K. et al. Cardiac safe hematopoietic stem cell transplantation for systemic sclerosis with poor cardiac function: a pilot safety study that decreases neutropenic interval to 5 days. Bone Marrow Transplant (2020).

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