June 2022 Clinical Case of the Month
“To be a successful farmer one must first know the nature of the soil.” Xenophon, Oeconomicus, 400 B.C.
Title: Mesenchymal cells for poor graft function after allogeneic stem cell transplantation
Submitted by: Marta Peña Domingo
Physicians expert perspective: Annalisa Paviglianiti and Anna Sureda
A 59-year-old male with a history of high-risk unclassifiable myelodisplastic/myeloproliferative neoplasm with bone marrow fibrosis score 3 previously treated with hydroxyurea received an allogeneic hematopoietic stem cell transplantation (alloHCT) from a matched unrelated donor with 9/10 HLA compatibility conditioned with reduced-intensity thiotepa-busulfan-fludarabine conditioning. Graft-versus-host disease (GVHD) prophylaxis was post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil. During the pre-engraftment period the patient had the following complications: septic arthritis, febrile neutropenia, transplant-associated microangiopathy, grade 2 acute cutaneous GVHD which resolved before day+28. Neutrophil engraftment was achieved at day +25 but thrombocytopenia and anemia persisted up to day +60. A bone marrow biopsy showed absence of disease but bilineage aplasia with persistent bone marrow fibrosis. Peripheral blood granulocyte donor chimerism was 100%. Secondary causes of cytopenias were excluded (viral infections, immuno-mediated, GVHD, drug toxicities). Eltrombopag was started at day+ 98. No response was observed after 2 months of therapy. Meanwhile, the registry donor was contacted to know whether he was available to donate again with the aim of collecting a CD34+ boost but he was unwilling to proceed with the second donation. Thus, a second donor (haploidentical son) was considered for an urgent donation to perform a second alloHCT. In order to avoid the toxicity of a second transplant and considering the presence of fibrosis, we attempted mesenchymal stem cells (MSC) infusion instead. The patient received the first MSC dose at day +122 and the second one at day +137. Platelets transfusion independence was reached 7-10 days after the second infusion and anemia started improving after 1 month. The patient is currently at 6 months from transplant with complete resolution of cytopenias.
Which of the following is not a therapeutic intervention or potential therapy in the case of poor graft function?
A. CD34 selected infusion
B. Thrombopoietin agonists
C. Atorvastatin
D. N-acetyl cysteine
E. Interferon gamma
Expert Perspective by Annalisa Paviglianiti and Anna Sureda
The EBMT defined poor graft function (PGF) as two or three cytopenias, more than 2 weeks after day +28 in the presence of >95% donor chimerism (1). The clinical course of PGF varies from spontaneous recovery to death due to complications of persistent cytopenias (infection being the most frequent). Therefore, it represents a challenge for clinicians who are managing this complex problem. Several risk factors have been associated with PGF such as age, hyperferritinemia, ABO incompatibility, nonsibling donor, blood culture positivity, CMV viremia, and GvHD (2, 3, 4, 5, 6, 7). However, the pathophysiology of PGF is still not fully understood. Nevertheless, there are evidence based on the interplay of key components of bone marrow: HSCs, microenvironment and T cells and cytokines (8).
Mesenchimal cells are increasingly used for PGF based on previous studies supporting the critical role of nonhematological stromal cells for stem cell maintenance and engraftment post-alloHCT. This finding underlies the role of bone marrow microenvironment in regulating the balance between HSC replication and quiescence (9).
CD34-selected stem cell reinfusions by providing HSCs without an alloreactive T-cell component have been used as therapy in PGF with variable efficacy and toxicity, with the aim of re-establish or increase the hematopoiesis. Based on current literature, quantitative and qualitative HSC abnormalities may have a causative role in PGF, and low stem cell dose in the graft has been associated with PGF (10).
Thrombopoietin agonists have preclinical and clinical evidence of improving HSC function and restoring multilineage recovery after alloHCT; this finding was recently confirmed by a clinical phase 1-2 trial (11).
Among stromal cells, also endothelial cells (EC) have been associated with PGF. Atorvastatin and N-acetyl cysteine demonstrated to enhance the number of EC of subject with PGF in vitro through downregulation of the p38 MAPK pathway.
Proinflammatory cytokines such as interferon gamma (IFN-gamma) and TNF-alfa, are more prevalent in patients with PGF (13). The hypothesis is that under the influence of IFN-gamma, stromal tissue contributes to inflammation, resulting in dysfunction of the bone marrow microenvironment, HSC suppression, and development of PGF. Therefore, interferon gamma blockade could represent a possible therapy, requiring still further investigation. In this case mesenchimal cells infusions was finally used, before trying CD34+ boost, after no response to first treatment with TPO agonist and the
More data from prospective studies involving patients with PGF are needed to understand in detail the mechanisms of disease and appropriate tailored therapy in each patient.
Correct Answer – E
References
1. Carreras E, Dufour C, Mohty M, Kröger N. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. Cham, Switzerland: Springer Nature; 2019. Available at: https://www.ncbi.nlm.nih.gov/books/NBK553978/.
2. Xiao Y, Song J, Jiang Z, et al. Risk-factor analysis of poor graft function after allogeneic hematopoietic stem cell transplantation. Int J Med Sci. 2014;11(6):652-657.
3. Sun YQ, He GL, Chang YJ, et al. The incidence, risk factors, and outcomes of primary poor graft function after unmanipulated haploidentical stem cell transplantation. Ann Hematol. 2015;94(10):1699-1705.
4. Alchalby H, Yunus DR, Zabelina T, Ayuk F, Kröger N. Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis. Bone Marrow Transplant. 2016;51(9):1223-1227.
5. Zhao Y, Gao F, Shi J, et al. Incidence, risk factors, and outcomes of primary poor graft function after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25(9):1898-1907
6. Reich-Slotky R, Al-Mulla N, Hafez R, et al. Poor graft function after T cell-depleted allogeneic hematopoietic stem cell transplant. Leuk Lymphoma. 2020;61(12):2894-2899.
7. Prabahran A, Koldej R, Chee L, Wong E, Ritchie D. Evaluation of risk factors for and subsequent mortality from poor graft function (PGF) post allogeneic stem cell transplantation. Leuk Lymphoma. 2021;62(6):1482-1489.
8. Prabahran A, Koldej R, Chee L, Ritchie D. Clinical features, pathophysiology, and therapy of poor graft function post-allogeneic stem cell transplantation. Blood Adv. 2022 Mar 22;6(6):1947-1959
9. Pinho S, Frenette PS. Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol. 2019;20(5):303-320.
Contacts
Anna Sureda, MD
Head of the Hematology Department and Hematopoietic Stem Cell Transplant Programme
Institut Català d'Oncologia - Hospital Duran i Reynals
Barcelona
Email: asureda@iconcologia.net
Marta Peña Domingo, MD
Hematology Department and Hematopoietic Stem Cell Transplant Programme
Institut Català d'Oncologia - Hospital Duran i Reynals
Barcelona
Email: mpena@iconcologia.net
Annalisa Paviglianiti, MD
Hematology Department and Hematopoietic Stem Cell Transplant Programme
Institut Català d'Oncologia - Hospital Duran i Reynals
Barcelona
Email: annalisapaviglianiti@iconcologia.net
Future Clinical Case of the Month
If you have a suggestion for future clinical case to feature, please contact Anna Sureda.