Oral calcitriol in hematopoietic recovery and survival after autologous stem cell transplantation: a randomized clinical trial
Calcitriol, the active metabolite of vitamin D, is an essential regulator in the hematopoiesis and immunity. However, knowledge revealing its influence on the immune and hematologic reconstitution after hematopoietic stem cell transplantation (HSCT) in clinical trials is very limited.
The effects of calcitriol on short-term and long-term hematopoietic recovery, relapse-free survival (RFS) and overall survival (OS) in multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma following autologous peripheral blood HSCT were assessed.
Eighty patients (age: 18–68 years) in complete remission were allocated 1:1 to two groups by balanced block randomization. Calcitriol 0.25 μg or placebo capsule was administered three times daily from transplantation to day 30. Absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and platelet count (PC) were determined daily from transplantation to day 30. White blood cell count (WBC), PC, and hemoglobin concentration (HC) of days 180 and 365 were extracted from clinic files. A thorough examination for oral mucositis (OM) was completed daily during hospital stay. Adverse drug reactions (ADRs) as well as two-year RFS and OS were evaluated.
Median time to ANC engraftment (≥0.5 × 103/μl: 10.0 vs. 11.0 days; P = 0.98) and PC engraftment (≥20.0 × 103/μl: both 14.0 days; P = 0.58) was similar between groups. However, the median time to ALC recovery was significantly shorter in the calcitriol group (≥0.5 × 103/μl: 13.0 vs. 20.0 days; P < 0.001). Moreover, ALC recovery rates on day 15 (≥0.5 × 103/μl: 82.1% vs. 42.5%; P < 0.001) and on day 30 (≥1.0 × 103/μl: 91.7% vs. 57.5%; P = 0.001) was significantly higher with calcitriol. WBC, PC, and HC on days 180 and 365 were not significantly different between groups. None of the OM indices were modulated by calcitriol. All the ADRs were non-serious and mild, possibly or unlikely related to the intervention. In a median of 29 months follow-up, RFS was significantly better in the calcitriol group (77.0%, SE = 7.0% vs. 59.0%, SE = 8.0%; P = 0.03), albeit the OS was not affected (87.0%, SE = 5.0% vs. 92.0%, SE = 4.0%; P = 0.72).
Calcitriol could improve ALC recovery and RFS as a safe option post-HSCT.
KeywordsCalcitriol Engraftment Immune reconstitution Hematopoietic stem cell transplantation Hodgkin Lymphocyte Lymphoma Mucositis Multiple myeloma Survival Vitamin D
We greatly appreciate the participants without whom this investigational study would not be possible. We thank Ms. Ashraf Sadat Mousavi, Ms. Zahra Shahriari, BMT wards staff of Shariati Hospital, and Dr. Hamid Khoee (drug supply and randomization) for their kind assistances.
This study was funded through an educational grant to the researchers from the Hematology-Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 1.Relias V. Hematopoietic cell trasplantation. In: Zeind CS, Carvalho MG, editors. Applied therapeutics: the clinical use of drugs. 11th ed. Philadelphia: Lippincott Williams & Wilkins, Wolters Kluwer; 2018. p. 2102–6.Google Scholar
- 17.von Bahr L, Blennow O, Alm J, Björklund A, Malmberg KJ, Mougiakakos D, et al. Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation. Bone Marrow Transplant. 2015;50(9):1217–23. https://doi.org/10.1038/bmt.2015.123.CrossRefGoogle Scholar
- 23.Wallace G, Jodele S, Myers KC, Dandoy CE, El-Bietar J, Nelson A, et al. Vitamin D deficiency in pediatric hematopoietic stem cell transplantation patients despite both standard and aggressive supplementation. Biol Blood Marrow Transplant 2016;22(7):1271–4. https://doi.org/10.1016/j.bbmt.2016.03.026.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Hamidieh AA, Sherafatmand M, Mansouri A, Hadjibabaie M, Ashouri A, Jahangard-Rafsanjani Z, et al. Calcitriol for oral mucositis prevention in patients with Fanconi anemia undergoing hematopoietic SCT: a double-blind, randomized, placebo-controlled trial. Am J Ther. 2016;23(6):e1700–e8. https://doi.org/10.1097/MJT.0000000000000269.CrossRefPubMedGoogle Scholar
- 28.Caballero-Velazquez T, Montero I, Sanchez-Guijo F, Parody R, Saldana R, Valcarcel D et al. Immunomodulatory effect of vitamin D after allogeneic stem cell transplantation: results of a prospective multicenter clinical trial. Clin Cancer Res. 2016;22(23):5673-81. https://doi.org/10.1158/1078-0432.ccr-16-0238.CrossRefGoogle Scholar
- 32.NCCN guidelines. National Comprehensive Cancer Network, Plymouth Meeting, PA, USA. 2018. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed Jan 13 2019.
- 34.Calcitriol capsules 0.25 mcg capsule. DailyMed, National Library of Medicine, USA. 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bebefb2a-7365-48e2-9681-83ed4b41e26e. Accessed Jan 13 2019.
- 35.Calcitriol (systemic): drug information. In: Post T, editor. UpToDate. Waltham, MA, USA: UpToDate Inc., Wolters Kluwer; 2018.Google Scholar
- 36.The use of the WHO-UMC system for standardised case causality assessment. WHO–UMC, Uppsala, Sweden. 2000. https://who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf. Accessed Jan 13 2019.
- 38.FDA. What is a serious adverse event? FDA, USA. 2016. http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm. Accessed Jul 25 2019.
- 40.Antiinfectives for systemic use. WHO, Oslo, Norway. 2018. http://www.whocc.no/atc_ddd_index/?code=J. Accessed Jan 13 2019.
- 41.Dudakov JA, Perales MA, van den Brink MRM. Immune reconstitution following hematopoietic cell transplantation. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR, editors. Thomas’ hematopoietic cell transplantation. 5th ed. UK: Wiley; 2016. p. 161–2.Google Scholar
- 42.Skrobot A, Demkow U, Wachowska M. Immunomodulatory role of vitamin D: a review. Current Trends in Immunity and Respiratory Infections. Springer; 2018. p. 13–23.Google Scholar
- 45.Ota K, Dambaeva S, Kim MW, Han AR, Fukui A, Gilman-Sachs A, et al. 1,25-Dihydroxy-vitamin D3 regulates NK-cell cytotoxicity, cytokine secretion, and degranulation in women with recurrent pregnancy losses. Eur J Immunol. 2015;45(11):3188–99. https://doi.org/10.1002/eji.201545541.CrossRefPubMedGoogle Scholar
- 52.Hiwase DK, Hiwase S, Bailey M, Bollard G, Schwarer AP. Higher infused lymphocyte dose predicts higher lymphocyte recovery, which in turn, predicts superior overall survival following autologous hematopoietic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2008;14(1):116–24.CrossRefGoogle Scholar