To the Editor:
The fludarabine shortage is causing unease within the hematopoietic cell transplantation (HCT) and cell therapy community as most reduced intensity (RIC) platforms along with conditioning for engineered T cell products rely on fludarabine for lymphodepletion. A recent national survey drew attention to the significant impact of oncology drug shortages causing treatment delays and rising hospital costs . Due to manufacturing delays, access to fludarabine specifically has been disproportionately affected in 2022. In this correspondence, we aim to highlight the fludarabine-free RIC regimen that our group has used since 2015 as the backbone for 89 allogeneic RIC HCTs to date, for malignant and nonmalignant indications, in the context of clinical trials at the National Institutes of Health. In 2011, Mariotti et al. demonstrated equivalent T lymphodepletion by pentostatin and low-dose, hyperfractionated cyclophosphamide (PC) as compared to fludarabine plus low-dose cyclophosphamide, but increased functional immunosuppression by pentostatin in a murine model . These findings were translated to the bedside in nonmyeloablative HCT platforms, where effective T lymphodepletion was again demonstrated . In 2015, a novel, RIC allogeneic HCT platform combined a PC backbone with 2 days of pharmacokinetically-dosed busulfan (Bu2), T cell replete grafts, and post-transplantation cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis (clinicaltrials.org identifier NCT02579967). The intentions in designing the conditioning regimen were to intensify lymphodepletion by using pentostatin instead of fludarabine, while also avoiding toxicities incurred by total body irradiation and myeloablative doses of alkylating agents. The first 20 patients were described by Dimitrova et al. and included children and adults with various inborn errors of immunity, of whom 30% also had a hematologic malignancy [4, 5]. Results were remarkable for 1-year overall survival of 90%, low incidence of organ toxicity and acute GVHD but even more so the absence of any chronic GVHD, while 1-year graft failure incidence of 10% was comparable to fludarabine-containing RIC regimens [6, 7]. In approaches branching off from our original platform but using the same PC-Bu2 backbone, immunosuppression duration has been reduced with good success (n = 23 further RIC HCTs, NCT02579967) , and distal serotherapy with equine anti-thymocyte globulin added for enhanced lymphodepletion in patients with underlying T cell dysregulation (n = 17, NCT03663933) and/or T cell lymphoma (n = 29, NCT03922724) [9, 10], Table 1. We anticipate the regimen may also be appropriate for patients with myeloid disorders who cannot tolerate a myeloablative HCT, given early full donor myeloid chimerism in the majority of recipients. One drawback to our regimen is that the conditioning is longer than typical fludarabine-based regimens. However, it is also very well-tolerated and can be administered in the outpatient setting to avoid overly lengthy inpatient hospitalization. While other alternatives exist, such as clofarabine, pentostatin is associated with fewer infections, less nephrotoxicity, and less hepatotoxicity, and is less costly than clofarabine [11,12,13]. Thus, with fludarabine difficult to obtain or unavailable, our platform offers an excellent alternative that may prevent treatment delays for patients in need of RIC HCT while allowing fludarabine to be preserved for other oncologic uses.
McBride A, Hudson-DiSalle S, Pilz J, Hamm M, Boring B, Buie LW, et al. National survey on the effect of oncology drug shortages in clinical practice: a hematology oncology pharmacy association survey. JCO Oncol Pract. 2022;18:e1289-e1296.
Mariotti J, Taylor J, Massey PR, Ryan K, Foley J, Buxhoeveden N, et al. The pentostatin plus cyclophosphamide nonmyeloablative regimen induces durable host T cell functional deficits and prevents murine marrow allograft rejection. Biol Blood Marrow Transpl. 2011;17:620–31.
Mossoba ME, Halverson DC, Kurlander R, Schuver BB, Carpenter A, Hansen B, et al. High-dose sirolimus and immune-selective pentostatin plus cyclophosphamide conditioning yields stable mixed chimerism and insufficient graft-versus-tumor responses. Clin Cancer Res. 2015;21:4312–20.
Dimitrova D, Gea-Banacloche J, Steinberg SM, Sadler JL, Hicks SN, Carroll E, et al. Prospective study of a novel, radiation-free, reduced-intensity bone marrow transplantation platform for primary immunodeficiency diseases. Biol Blood Marrow Transpl. 2020;26:94–106.
Dimitrova D, Rose JJ, Uzel G, Cohen JI, Rao KV, Bleesing JH, et al. Successful bone marrow transplantation for XMEN: hemorrhagic risk uncovered. J Clin Immunol. 2019;39:1–3.
Klein OR, Bapty S, Lederman HM, Younger MEM, Zambidis ET, Jones RJ, et al. Reduced intensity bone marrow transplantation with post-transplant cyclophosphamide for pediatric inherited immune deficiencies and bone marrow failure syndromes. J Clin Immunol. 2021;41:414–26.
Allen CE, Marsh R, Dawson P, Bollard CM, Shenoy S, Roehrs P, et al. Reduced-intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies. Blood. 2018;132:1438–51.
Dimitrova D, Napier S, Sponaugle J, Stokes A, Hyder M, Uzel G, et al. Prospective Clinical Trial of Mycophenolate Mofetil (MMF) De-Escalation in Allogeneic Hematopoietic Cell Transplantation (HCT) for Primary Immunodeficiency (PID): MMF is dispensable in reduced-intensity conditioning, posttransplantation cyclophosphamide(PTCy)-based HCT. Transplant Cell Ther. 2022;28:S14–S6.
Dimitrova D, Napier S, Stokes A, Uzel G, Miljkovic M, Pittaluga S, et al. Distal Equine Anti-Thymocyte Globulin (ATG) As an Adjunct to Reduced Intensity Conditioning and Posttransplantation Cyclophosphamide (PTCy) for Allogeneic Hematopoietic Cell Transplantation (HCT) in patients with benign and malignant disorders of T cell proliferation or dysregulation. Transplant Cell Ther. 2021;27:S219–S20.
Rechache K, Dimitrova D, Feng X, Flomerfelt F, Napier S, Sponaugle J, et al. Distally-Timed Equine Antithymocyte Globulin (eATG) in Allogeneic Hematopoietic Cell Transplantation (HCT) conditioning – pharmacokinetics and the relationship between total E-ATG levels, pre-HCT absolute lymphocyte count, immune reconstitution, and graft-versus-host responses. Transplant Cell Ther. 2022;28:S80.
Maziarz RT, Diaz A, Miklos D, Shah NN. Perspective: An International Fludarabine shortage: supply chain issues impacting transplant and immune effector cell therapy delivery. Transplant Cell Ther. 2022;S2666-6367.
Clolar (clofarabine) [package insert]. Cambridge, MA: Genzyme Corporation; 2014.
Nipent (pentostatin) [package insert]. Lake Forest, IL: Hospira, Inc.; 2019.
We would like to thank the patients and families who participated in the trials, and the colleagues who helped provide clinical care and research support. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Dimitrova, D., Kanakry, J.A. Beyond fludarabine: pentostatin plus cyclophosphamide are a well-tolerated alternative in reduced intensity conditioning. Bone Marrow Transplant 57, 1837–1838 (2022). https://doi.org/10.1038/s41409-022-01819-y