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. 2024 Aug 13;8(15):3946-3960.
doi: 10.1182/bloodadvances.2023011642.

Modified Delphi panel consensus recommendations for management of severe aplastic anemia

Daria V Babushok  1 , Amy E DeZern  2 , Carlos M de Castro  3 , Zora R Rogers  4 , David Beenhouwer  5 , Michael S Broder  5 , Suzanne R Fanning  6 , Sarah N Gibbs  5 , Rabi Hanna  7 , Jaroslaw P Maciejewski  8 , Bart L Scott  9 , Srinivas K Tantravahi  10 , Marcin W Wlodarski  11 , Irina Yermilov  5 , Bhumika J Patel  6
Affiliations

Modified Delphi panel consensus recommendations for management of severe aplastic anemia

Daria V Babushok et al. Blood Adv. .

Abstract

Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 experts on adult and pediatric aplastic anemia was assembled and, using the RAND/University of California, Los Angeles modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here, we present the panel's recommendations to rule out inherited bone marrow failure syndromes, on supportive care before and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant vs medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors have completed International Committee of Medical Journal Editors Disclosure of Interest forms. D.V.B. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis; reports research grants from the National Institutes of Health and the American Society of Hematology (ASH); reports payment or honoraria for participation in Highlights of ASH from the American Society of Hematology; and reports stock or stock options from Carisma Inc. A.E.D. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis; reports consulting fees from Geron, Regeneron, Sobi, Caribou, Apellis, Bristol Myers Squibb, and Novartis. C.D. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis; reports consulting fees from Novartis for a steering committee; reports payment or honoraria from Alexion and Apellis; and reports participation on a data safety monitoring board or advisory board from Regeneron. Z.R.R. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis; reports honoraria for lecture on Bone Marrow Failure for Sub-specialty Board Review Course (2021) from the American Society of Pediatric Hematology/Oncology; reports payment or honoraria from UpToDate as author of Schwachman Diamond Topic Card; reports payment or honoraria from WebMD (formerly Medscape) as author of Pearson’s Syndrome Topic; reports participation on a data safety monitoring board or advisory board as a panel member for the Federal Data Safety Monitoring Board (DSMB #1) for the National Institutes of Health/the National Heart, Lung, and Blood Institute Bone Marrow Transplant Clinical Trials Network; reports leadership as past chair, with review of AAP hematology-related issues unpaid for the American Academy of Pediatrics Section on Hematology Oncology executive committee; and reports other financial or nonfinancial interests for programmatic review/grant review panel member as the chair from 2023 from the Bone Marrow Failure Research Program of the Congressionally Mandated Research Program. D.B. is an employee of Partnership for Health Analytic Research, which was paid by Novartis to conduct the research described in this manuscript, and by Akcea, Amgen, BioMarin Pharmaceuticals, Bristol Myers Squibb, Celgene, Delfi Diagnostics, Dompe, Eisai, Exact Sciences Corporation, Genentech, Gilead, GRAIL, Greenwich Biosciences, Ionis, Jazz, Nobelpharma, Novartis, Otsuka, Pfizer, Recordati, Regeneron, Sanofi US Services and Takeda Pharmaceuticals USA to conduct research related to the work described in this manuscript and outside of this submitted work. M.S.B. is an employee of Partnership for Health Analytic Research, which was paid by Novartis to conduct the research described in this manuscript, and by Akcea, Amgen, BioMarin Pharmaceuticals, Bristol Myers Squibb, Celgene, Delfi Diagnostics, Dompe, Eisai, Exact Sciences Corporation, Genentech, Gilead, GRAIL, Greenwich Biosciences, Ionis, Jazz, Nobelpharma, Novartis, Otsuka, Pfizer, Recordati, Regeneron, Sanofi US Services, and Takeda Pharmaceuticals USA to conduct research related to the work described in this manuscript and outside of this submitted work. S.F. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis; reports consulting fees from Genentech and Incyte; reports payment or honoraria from Takeda, Bristol Myers Squibb, and Sanofi; reports participation on a data safety monitoring board or advisory board from Genmab and AbbVie; and reports leadership or fiduciary role in other board, society, committee, or advocacy group paid or unpaid from South Carolina Oncology Society. S.N.G. is an employee of Partnership for Health Analytic Research, which was paid by Novartis to conduct the research described in this manuscript, and by Akcea, Amgen, BioMarin Pharmaceuticals, Bristol Myers Squibb, Celgene, Delfi Diagnostics, Dompe, Eisai, Exact Sciences Corporation, Genentech, Gilead, GRAIL, Greenwich Biosciences, Ionis, Jazz, Nobelpharma, Novartis, Otsuka, Pfizer, Recordati, Regeneron, Sanofi US Services, and Takeda Pharmaceuticals USA to conduct research related to the work described in this manuscript and outside of this submitted work. R.H. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis. J.P.M. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis; reports grants or contracts from National Institutes of Health, Leukemia and Lymphoma Society, and US Department of Defense; reports consulting fees for participation on an advisory board from Regeneron and Novartis, and consulting fees for MOS Registry from Bristol Myers Squibb, and consulting fees for PNH Registry from Alexion Pharmaceuticals; reports payment or honoraria for an online debate from Novartis; and reports participation on a data safety monitoring board or advisory board from Omeros. B.S. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis; reports consulting fees from Bristol Myers Squibb, Alexion, Novartis, and Incyte; reports payment or honoraria from Bristol Myers Squibb, Alexion, Novartis, and Jazz; reports participation on a data safety monitoring board or advisory board from Nektar, Alexion, and Bristol Myers Squibb; and reports leadership or fiduciary role in other board, society, committee, or advocacy group paid or unpaid from ASH Government Affairs. S.T. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis; reports grants or contracts from Karyopharm Therapeutics Inc as an investigator who initiated clinical trial and preclinical studies; reports consulting fees from consulting/advisory board from Karyopharm Therapeutics Inc, Novartis, AbbVie, MorphoSys, and CTI Biopharma; and reports support for attending meetings and/or travel from Karyopharm Therapeutics for 2023 AACR meeting. M.W.W. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis. I.Y. is an employee of Partnership for Health Analytic Research, which was paid by Novartis to conduct the research described in this manuscript, and by Akcea, Amgen, BioMarin Pharmaceuticals, Bristol Myers Squibb, Celgene, Delfi Diagnostics, Dompe, Eisai, Exact Sciences Corporation, Genentech, Gilead, GRAIL, Greenwich Biosciences, Ionis, Jazz, Nobelpharma, Novartis, Otsuka, Pfizer, Recordati, Regeneron, Sanofi US Services, and Takeda Pharmaceuticals USA to conduct research related to the work described in this manuscript and outside of this submitted work. B.J.P. reports support for the present manuscript for participation in the Delphi panel outlined in the manuscript by Novartis and to help write the manuscript, participation as the panel chair, being an active panelist and working on the manuscript with Novartis (note this was a blinded sponsored project, and payment was made to B.J.P.); and reports payment for training and education on Promacta with Novartis (payment was made to B.J.P.).

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Summary of Delphi panel Round 2 expert consensus ratings for diagnostic testing and initial therapy for SAA. (A) Summary plot of recommended testing to exclude inherited BM failure and “rule in” acquired AA in the evaluation of patients presenting with SAA of different ages. (B) Summary plot of recommended initial therapy in medically fit patients whose best available potential allogeneic donor options are MRD, MUD, mismatched unrelated or haploidentical donor (MMUD or haplo), or no donor available (or unknown). (C) Summary plot of recommended initial treatment for medically unfit patients. In all cases, data represent median score ± 95% confidence interval (CI). Scores in the range of 7 to 9 (green color) indicate treatments that would be highly appropriate. Scores in the range of 1 to 3 (red color) indicate treatments that would be less appropriate. Intermediate scores in the range of 4 to 6 (white color) indicate treatments that may be appropriate under selected circumstances.
Figure 2.
Figure 2.
Summary of Delphi panel Round 2 expert consensus ratings for subsequent therapy in patients refractory to initial treatment course. (A) Summary plot of recommended subsequent therapy in medically fit patients who are refractory to “triple IST” (horse ATG, CsA, or eltrombopag) based on the best available allogeneic donor option. (B) Summary plot of recommended subsequent therapy in medically fit patients who are refractory to standard IST administered without TPO-RA stratified based on the best available allogeneic donor option. (C) Summary plot of recommended subsequent therapy in medically unfit patients refractory to the initial treatment of CsA eltrombopag (CsA + eltrombopag), or to CsA monotherapy. In all cases, data represent median score ± 95% CI. Scores in the range of 7 to 9 (green color) indicate treatments that would be highly appropriate. Scores in the range of 1 to 3 (red color) indicate testing that would be less appropriate. Intermediate scores in the range of 4 to 6 (white color) may be appropriate under selected circumstances.
Figure 3.
Figure 3.
Summary of Delphi panel Round 2 expert consensus ratings for subsequent therapy in patients who relapse within 12 months of initial therapy and again develop severe cytopenias meeting the criteria for SAA. (A) Summary plot of recommended subsequent therapy in medically fit patients who relapse within 12 months of “triple IST” (horse ATG, CsA, or eltrombopag) based on the best available allogeneic donor option. (B) Summary plot of recommended subsequent therapy in medically fit patients who relapse within 12 months of standard IST administered without TPO-RA stratified based on the best available allogeneic donor option. (C) Summary plot of recommended subsequent therapy in medically unfit patients who relapse within 12 months of initial treatment of CsA eltrombopag (CsA + eltrombopag), or CsA monotherapy. In all cases, data represent median score ± 95% CI. Scores in the range of 7 to 9 (green color) indicate treatments that would be highly appropriate. Scores in the range of 1 to 3 (red color) indicate testing that would be less appropriate. Intermediate scores in the range of 4 to 6 (white color) may be appropriate under selected circumstances.
Figure 4.
Figure 4.
Summary of Delphi panel Round 2 expert consensus ratings for subsequent therapy in patients with late relapses (after 12 months of initial therapy) who again develop severe cytopenias meeting 3 criteria for SAA. (A) Summary plot of recommended subsequent therapy in medically fit patients who relapsed after 12 months of “triple IST” (horse ATG, CsA, or eltrombopag) based on the best available allogeneic donor option. (B) Summary plot of recommended subsequent therapy in medically fit patients who relapsed after 12 months of standard IST administered without TPO-RA stratified based on the best available allogeneic donor option. (C) Summary plot of recommended subsequent therapy in medically unfit patients who relapse after 12 months of initial treatment of CsA eltrombopag (CsA + eltrombopag), or CsA monotherapy. In all cases, data represent median score ± 95% CI. Scores in the range of 7 to 9 (green color) indicate treatments that would be highly appropriate. Scores in the range of 1 to 3 (red color) indicate testing that would be less appropriate. Intermediate scores in the range of 4 to 6 (white color) may be appropriate under selected circumstances.
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