Page 10 - Haematologica May 2020
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Editorials
Immunosuppression and growth factors for severe aplastic anemia: new data for old questions
David J. Young and Cynthia E. Dunbar
Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA E-mail: DAVID J. YOUNG - david.young2@nih.gov
   doi:10.3324/haematol.2020.246512
The arrival of a new patient with severe aplastic anemia (SAA) with severe cytopenias and accom- panying risks of bleeding and serious infections strikes fear into the hearts of even experienced hematol- ogists. In most cases, SAA is an acquired disorder driven by a potent autoimmune attack on the most primitive hematopoietic stem and progenitor cell (HSPC) compart- ment.1 Treatment requires elimination of the damaging immune response while supporting or replacing the dam- aged HSPC, either via allogeneic stem cell transplantation (SCT) or intensive immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine.2,3 Children or younger adults with available donors should undergo upfront allogeneic SCT, since IST does not reverse cytopenias in all patients and requires on average months to result in improvement of cell counts. In addi- tion, IST is associated with both relapse and progression to clonal hematopoietic disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplasia/acute myeloid leukemia in an appreciable fraction of patients followed long-term.4 In the current issue of Haematologica, Tichelli and colleagues present a new analysis of the SAA-granulocyte colony-stimulating factor (G-CSF) trial from the European Group for Blood and Marrow Transplantation (EBMT) Working Party on SAA.5 In their report, they revisit the use of adjuvant growth factors in SAA treatment and, in doing so, provide the longest fol- low-up of SAA patients treated with IST to date.
The development and optimization of effective IST for SAA in the late 1980s and early 1990s was punctuated by the identification and clinical availability of hematopoiet- ic cytokines such as G-CSF and erythropoietin. G-CSF was shown to decrease the duration and severity of chemotherapy-induced and inherited neutropenias, rap- idly inspiring widespread use in SAA. However, the most primitive HSPC lack the G-CSF receptor, thus at best G- CSF might be expected to accelerate or increase output from a limited number of remaining myeloid progenitor or precursor cells, without improving the underlying pro- found hematopoietic defects. In addition, early concerns arose that clonal progression could be accelerated or induced by addition of G-CSF to IST, based on retrospec- tive analyses of both children and adults treated with IST.6-8 A Japanese multicenter, randomized prospective trial that enrolled 101 patients examined the effects of G- CSF added to IST found no increase in progression to myelodysplastic syndromes.6 At 6 months, the response rate to IST was higher in the G-CSF arm (77% vs. 57%), but by the 1 year primary endpoint, response rates were identical and there was no difference in overall survival at 4 years. Interestingly, patients in the G-CSF arm showed fewer relapses (15% vs. 42%). In a European trial of 102 SAA patients, higher rates of complete response and 6-
month failure-free survival, and faster cell count recovery, were reported, but no significant differences in overall response, 5-year survival or progression to clonal abnor- malities could be detected.9 A number of smaller trials were carried out worldwide with varying designs, assess- ing the impact of G-CSF, granulocyte-macrophage colony-stimulating factor or erythropoietin, generally showing no consistent benefit or risk in SAA,10-12 also when pooled via meta-analyses.13
The EBMT strove to resolve the confusion by conduct- ing a large, multicenter, randomized trial using optimal IST with and without G-CSF, enrolling 192 patients between 2002 and 2008. The original report published in 2011 showed no impact of G-CSF on primary response or event-free, relapse-free or overall survival rates at 6 years.14 There was a small but statistically significant reduction in infections and hospitalizations in the G-CSF group. In this initial report, rates of clonal progression were low in both arms, with no apparent impact of G- CSF.
Tichelli and coworkers now provide very illuminating long-term follow-up results from this same EBMT trial.5 Even the initial report of this trial, as well as registry stud- ies have suggested that all relevant data on the risks and benefits associated with various treatments for SAA are not captured by a sole focus on initial hematologic response and relatively short-term overall survival. Across all ages, regardless of disease severity or treat- ment, event-free survival continues to decline years after treatment, with continuing increases in the rates of clonal disease and frank second malignancies. Consequently, long-term outcome data provide information on the nat- ural history of treated SAA regardless of the use of growth factors, potentially further informing decisions regarding the initial choice between IST and allogeneic SCT. The authors have been able to provide a median of almost 12 years follow-up in a large well-characterized cohort, an impressive feat in this rare disease. In terms of the original primary endpoints, there was still no impact of G-CSF on response, relapse (in contrast to some previ- ous smaller studies) or overall survival. The primary determinants of outcomes remained age and disease severity at the time of diagnosis, but in patients surviving to 1 year after IST, even these determinants became irrel- evant. Regarding clonal disease, the rates at 15 years were congruent with prior estimates, being 8% for cytogenetic abnormalities or myelodysplastic syndrome/acute myeloid leukemia and 10-13% for clinical paroxysmal nocturnal hemoglobinuria. Importantly, G-CSF did not increase the risk of clonal events, and total exposure to G- CSF did not correlate with risk of progression. While Tichelli et al. offer additional strong evidence that the addition of G-CSF to IST does not alter overall outcomes
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