Otolog Hematopoetik Kök Hücre Nakli Yapılan Multiple Myelom Hastalarında Kemik İliği Fibrozisinin Nakil Sonuçlarına Etkisi

Öz

Amaç: Yeni tanı multiple myelomda kemik iliğinde fibrozis %8-57 arasında görülmektedir. Bu retrospektif çalışmamızda, kemik iliğinde fibrozis olan multiple myelom hastalarının klinik ve demografik özellikleri ile kemik iliği fibrozisinin otolog hematopoetik kök hücre nakli sonrası engrafmana ve nakil sonuçlarına etkisini araştırmayı amaçladık. Gereç ve Yöntem: Çalışmamıza, Ağustos 2016 ile Temmuz 2023 tarihleri arasında merkezimizde multiple myelom tanısı ile indüksiyon tedavisi verilen ve otolog hematopoetik kök hücre nakli yapılan 78 hasta dahil edildi. Bulgular: Hastaların 37’sinde (%47,5) kemik iliğinde grade I-III fibrozis saptanmıştır. Kemik iliğinde fibrozis saptanan hastalarda kemik iliği plazma hücre oranı anlamlı daha yüksek tespit edilmiştir (%50 vs %35, p=0,007). Fibrozisi olan ve olmayan multiple myelom hastalarının diğer klinik ve demografik özellikleri benzerdir. Otolog hematopoetik kök hücre naklinde verilen CD34(+) kök hücre miktarları ve melfalan dozları da her iki grup arasında benzerdir. Otolog hematopoetik kök hücre nakli sonrası, nötrofil ve trombosit engrafmanı, kemik iliğinde fibrozis olan grupta anlamlı olarak daha uzun tespit edilmiştir (Medyan nötrofil engrafman günü: 14 vs 13 gün, (p=0,005), medyan trombosit engrafman günü: 16 vs 13.gün, (p=0,004). Otolog hematopoetik kök hücre nakli sonrası hastanede kalış süresi, kemik iliğinde fibrozis olan grupta anlamlı daha uzun tespit edilmiştir (22 gün vs 19 gün, p=0,047). Hastaların nötrofil ve trombosit engrafman günü üzerine etki edebilecek diğer hasta, hastalık ve transplant ilişkili diğer faktörler açısından anlamlı fark tespit edilememiştir. Sonuç: Çalışmamız sonucunda, kemik iliğinde fibrozis tespit edilen, yeni tanı multiple myelom hastalarında otolog hematopoetik kök hücre nakli sonrası nötrofil ve trombosit engrafman günü ile hastanede kalış süresi daha uzun saptanmıştır. Bu hasta grubunda optimal CD34(+) kök hücre miktarının belirlenmesi, destek tedavilerin ve büyüme faktörlerinin daha etkin kullanımı ile ilgili daha geniş prospektif çalışmalara ihtiyaç duyulmaktadır.

Anahtar Kelimeler

• Multiple Myeloma
• Otolog Kök Hücre Nakli
• Kemik İliği Fibrozisi
• Nötrofil Engrafmanı
• Trombosit Engrafmanı

Destekleyen Kurum

Yok

Etik Beyan

Çıkar Çatışması: Yazarlar olarak, herhangi bir çıkar çatışması olmadığını beyan ederiz. Finansal Destek: Bu Klinik araştırma, kamu, ticari veya kar amacı gütmeyen sektörlerdeki finansman kuruluşlarından herhangi bir finansal destek ya da özel hibe almamıştır. Etik Kurul onayı: 22.08.2023 tarihli ve 2023-312 numaralı Sağlık Bilimleri Üniversitesi Gülhane Tıp Fakültesi Etik Kurulu tarafından onaylanmıştır. Çalışmaya dahil edilen tüm bireysel katılımcılardan bilgilendirilmiş onam alınmıştır.

Teşekkür

Dr. Ahmet Kürşad Güneş

The Impact of Bone Marrow Fibrosis on Transplant Outcomes in Multiple Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation

Öz

Objective: In newly diagnosed multiple myeloma, bone marrow fibrosis is observed in 8-57% of cases. In this retrospective study, we aimed to investigate the clinical and demographic characteristics of multiple myeloma patients with bone marrow fibrosis, as well as the impact of bone marrow fibrosis on engraftment and transplant outcomes following autologous hematopoietic stem cell transplantation. Materials and Method: Our study included 78 newly diagnosed multiple myeloma patients who received induction therapy and underwent autologous hematopoietic stem cell transplantation at our center between August 2016 and July 2023. Results: Bone marrow fibrosis (grade I-III) was detected in 37 patients (47.5%). Patients with bone marrow fibrosis had a significantly higher percentage of bone marrow plasma cells compared to those without fibrosis (50% vs 35%, p=0.007). After autologous hematopoietic stem cell transplantation, time to neutrophil and platelet engraftment were significantly longer in the group with bone marrow fibrosis (Median time to neutrophil engraftment day:14 vs 13 days, p=0.005, Median time to platelet engraftment day:16 vs 13 days, p=0.004). The length of hospital stay after autologous hematopoietic stem cell transplantation was significantly longer in the group with bone marrow fibrosis (22 days vs 19 days, p=0.047). No significant differences were found regarding neutrophil and platelet engraftment days when considering clinical, demographic, and other transplant-related factors. Conclusion: In conclusion, our study found that newly diagnosed multiple myeloma patients with bone marrow fibrosis had longer neutrophil and platelet engraftment times and longer hospital stays after autologous hematopoietic stem cell transplantation. There is a need for larger prospective studies to determine the optimal amount of CD34 (+) stem cells and to explore more effective use of supportive therapies and growth factors in this patient group.

Anahtar Kelimeler

• Autologous Hematopoietic Stem Cell Transplantation
• Bone Marrow Fibrosis
• Multiple Myeloma
• Neutrophil Engraftment
• Platelet Engraftment

Kaynakça

1. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet. 2009;374(9686):324-39.
2. Rajkumar SV, Dimopoulos MA, Palumbo A ve ark. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-48.
3. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111(6):2962-72.
4. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.
5. Attal M, Lauwers-Cances V, Hulin C ve ark. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017;376(14):1311-20.
6. Dimopoulos MA, Moreau P, Terpos E ve ark. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up(dagger). Ann Oncol. 2021;32(3):309-22.
7. Duggan PR, Guo D, Luider J ve ark. Predictive factors for long-term engraftment of autologous blood stem cells. Bone Marrow Transplant. 2000;26(12):1299-304.
8. Reich-Slotky R, Makhani SS, Vasovic LV ve ark.. Comparison of time to engraftment between autologous patients receiving washed versus non-washed cryopreserved peripheral blood stem cell products. Leuk Lymphoma. 2018;59(12):2829-35.

9. Ippoliti C, Przepiorka D, Giralt S ve ark. Low-dose non-glycosylated rhGM-CSF is effective for the treatment of delayed hematopoietic recovery after autologous marrow or peripheral blood stem cell transplantation. Bone Marrow Transplant. 1993;11(1):55-9.
10. Khwaja A, Goldstone AH, Linch DC. Delayed neutrophil recovery after BEAM chemotherapy and autologous bone marrow transplantation for lymphoma is not associated with increased mortality from infection. Bone Marrow Transplant. 1995;15(2):313-5.
11. Balakumaran A, Robey PG, Fedarko N, Landgren O. Bone marrow microenvironment in myelomagenesis: its potential role in early diagnosis. Expert Rev Mol Diagn. 2010;10(4):465-80.
12. Babarovic E, Valkovic T, Stifter S ve ark. Assessment of bone marrow fibrosis and angiogenesis in monitoring patients with multiple myeloma. Am J Clin Pathol. 2012;137(6):870-8.
13. Furukawa Y, Kikuchi J. Molecular basis of clonal evolution in multiple myeloma. Int J Hematol. 2020;111(4):496-511.
14. de Jong MME, Kellermayer Z, Papazian N ve ark. The multiple myeloma microenvironment is defined by an inflammatory stromal cell landscape. Nat Immunol. 2021;22(6):769-80.
15. McCarthy DM. Annotation. Fibrosis of the bone marrow: content and causes. Br J Haematol. 1985;59(1):1-7.
16. Zahr AA, Salama ME, Carreau N ve ark. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies. Haematologica. 2016;101(6):660-71.
17. Rameshwar P, Chang VT, Thacker UF, Gascon P. Systemic transforming growth factor-beta in patients with bone marrow fibrosis--pathophysiological implications. Am J Hematol. 1998;59(2):133-42.
18. Bartl R, Frisch B, Fateh-Moghadam A, Kettner G, Jaeger K, Sommerfeld W. Histologic classification and staging of multiple myeloma. A retrospective and prospective study of 674 cases. Am J Clin Pathol. 1987;87(3):342-55.
19. Dolgikh TY, Domnikova NP, Tornuev YV, Vinogradova EV, Krinitsyna YM. Incidence of Myelofibrosis in Chronic Myeloid Leukemia, Multiple Myeloma, and Chronic Lymphoid Leukemia during Various Phases of Diseases. Bull Exp Biol Med. 2017;162(4):483-7.
20. Paul B, Zhao Y, Loitsch G ve ark. The impact of bone marrow fibrosis and JAK2 expression on clinical outcomes in patients with newly diagnosed multiple myeloma treated with immunomodulatory agents and/or proteasome inhibitors. Cancer Med. 2020;9(16):5869-80.
21. Palumbo A, Avet-Loiseau H, Oliva S ve ark. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-9.
22. Greipp PR, San Miguel J, Durie BG ve ark. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412-20.
23. Rajkumar SV. Multiple myeloma: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97(8):1086-107.
24. Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90(8):1128-32.
25. Kumar S, Paiva B, Anderson KC ve ark. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e46.
26. Koshiishi M, Kawashima I, Hyuga H ve ark. Presence of bone marrow fibrosis in multiple myeloma may predict extramedullary disease. Int J Hematol. 2022;116(4):544-52.
27. Soll E, Massumoto C, Clift RA ve ark. Relevance of marrow fibrosis in bone marrow transplantation: a retrospective analysis of engraftment. Blood. 1995;86(12):4667-73.
28. Buyukkurt N, ÖZSAN G, Ozkal S ve ark. Effects of bone marrow fibrosis and angiogenetic structure on autologous hematopoietic stem cell engraftment. Cukurova Medical Journal. 2017;42(3).
29. Scott BL, Storer BE, Greene JE, Hackman RC, Appelbaum FR, Deeg HJ. Marrow fibrosis as a risk factor for posttransplantation outcome in patients with advanced myelodysplastic syndrome or acute myeloid leukemia with multilineage dysplasia. Biol Blood Marrow Transplant. 2007;13(3):345-54.
30. Suyani E, Aki SZ, Yegin ZA ve ark. The impact of bone marrow fibrosis on the outcome of hematopoietic stem cell transplantation. Transplant Proc. 2010;42(7):2713-9.