High Fever Occurring 4 to 5 Days Post-Transplant of Haploidentical Bone Marrow or Peripheral Blood Stem Cells after Reduced-Intensity Conditioning Associated with the Use of Post-Transplant Cyclophosphamide as Prophylaxis for Graft-versus-Host Disease

Recently, two multicenter reports in the May and June issues of Biology of Blood and Marrow Transplantation showed that peripheral blood stem cells (PBSCs) can be used safely and effectively as the graft source for transplantation from haploidentical donors after reduced-intensity conditioning for treatment of high-risk hematologic malignancies [1Castagna L. Crocchiolo R. Furst S. et al.Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post-transplantation cyclophosphamide.Biol Blood Marrow Transplant. 2014; 20: 724-729Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 2Raj K. Pagliuca A. Bradstock K. et al.Peripheral blood stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced intensity conditioning.Biol Blood Marrow Transplant. 2014; 20: 890-895Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. Both reports used post-transplant cyclophosphamide (PTCy) to eliminate alloreactive T cells as previously described [3Luznik L. O'Donnell P.V. Symons H.J. et al.HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, post transplantation cylophosphamide.Biol Blood Marrow Transplant. 2008; 14: 641-650Abstract Full Text Full Text PDF PubMed Scopus (1207) Google Scholar]. Our own publication [2Raj K. Pagliuca A. Bradstock K. et al.Peripheral blood stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced intensity conditioning.Biol Blood Marrow Transplant. 2014; 20: 890-895Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar] was a 4-center study of 55 patients with acute leukemias or lymphomas with a 17-month median follow-up. Of note, a preliminary report of our first 29 patients was reported in abstract form at the Tandem BMT Meetings of 2012 [4Raj K. Streetly M. Kazmi M. et al.Peripheral blood progenitor cell (PBPC) transplantation from haploidentical donors following reduced intensity conditioning (RIC) for high-risk hematolgic malignancies.Biol Blood Marrow Transplant. 2012; 18S (abstr. 343): 331Abstract Full Text Full Text PDF Google Scholar]. In the setting of haploidentical transplantation of PBSCs after an ablative conditioning regimen and use of PTCy as graft-versus-host disease (GVHD) prophylaxis, Solomon et al. [5Solomon S.R. Sizemore C.A. Sanacore M. et al.Haploidentical transplantation using T-cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial.Biol Blood Marrow Transplant. 2012; 18: 1859-1866Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar] and Grosso et al. [6Grosso D. Carabasi M. Filicko-O'Hara J. et al.A two-step approach to myeloablative haploidentical stem cell transplantation: a phase I/II trial performed with optimised T-cell dosing.Blood. 2011; 118: 4732-4739Crossref PubMed Scopus (61) Google Scholar] reported that high fever was commonly observed at 4 to 5 days post-transplant. In the absence of documented infection, it was hypothesized that the fever was likely a cytokine-mediated phenomenon associated either with initial proliferation of alloreactive T cells or from the actual destruction of alloreactive T cells by PTCy given per protocol on days +3 and +4. Here, we report that a similar incidence of high fever at 4 to 5 days post-transplant also was observed in our recently reported study of haploidentical PBSCs [2Raj K. Pagliuca A. Bradstock K. et al.Peripheral blood stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced intensity conditioning.Biol Blood Marrow Transplant. 2014; 20: 890-895Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. A similar finding of high fever post-transplant also was observed in patients who had undergone bone marrow transplantation from haploidentical donors [7Brunstein C.G. Fuchs E.J. Carter S.L. et al.Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts.Blood. 2011; 118: 282-288Crossref PubMed Scopus (442) Google Scholar]. The median Tmax of patients transplanted with PBSCs (39.7°C) was significantly higher than the Tmax of patients transplanted with bone marrow (38.6°C, P = .007), possibly reflecting the 5- to 10-fold greater content of T cells in PBSC allografts from haploidentical donors [2Raj K. Pagliuca A. Bradstock K. et al.Peripheral blood stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced intensity conditioning.Biol Blood Marrow Transplant. 2014; 20: 890-895Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. At the time of the febrile episodes, hemodynamic instability was not observed in any patient. It does not appear that the high fevers were associated strictly with use of PTCy as GVHD prophylaxis because high fevers were not observed (median T max of 37°C) in a sample of 10 patients who had undergone bone marrow transplantation from HLA-matched related or unrelated donors after conditioning with a busulfan–fludarabine conditioning regimen and use of PTCy as the only GVHD prophylaxis [8Kanakry C. O'Donnell P. Furlong T. et al.Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning.J Clin Oncol. 2014; 32: 3497-3505Crossref PubMed Scopus (188) Google Scholar]. As more centers begin to use the novel approach of PTCy as GVHD prophylaxis, physicians should be aware that high fevers early post-transplant are a common feature after transplantation of haploidentical bone marrow or PBSCs regardless of conditioning intensity but not after transplantation of bone marrow from HLA-matched donors. Fever usually resolves spontaneously by post-transplant days +5 to +6 and does not require treatment with glucocorticoids. Although the fevers at post-transplant days +4 to +5 may be predominantly noninfectious, patients may be neutropenic secondary to the myelosuppressive effect of agents used in different conditioning regimens and so are likely be treated empirically for infection in any event. Financial disclosure: This research was supported, in part, by grant CA 18029-37 from the National Cancer Institute and LLR funding. Conflict of interest statement: There are no conflicts of interest to report. Peripheral Blood Hematopoietic Stem Cells for Transplantation of Hematological Diseases from Related, Haploidentical Donors after Reduced-Intensity ConditioningBiology of Blood and Marrow TransplantationVol. 20Issue 6PreviewIn a multicenter collaboration, we carried out T cell–replete, peripheral blood stem cell (PBSC) transplantations from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplantation cyclophosphamide (Cy) as graft-versus-host disease (GVHD) prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50 mg/kg i.v. on days 3 and 4 after infusion of PBSC (mean, 6.4 × 106/kg CD34+ cells; mean, 2.0 × 108/kg CD3+ cells). The median times to neutrophil (500/μL) and platelet (>20,000/μL) recovery were 17 and 21 days respectively.