TO THE EDITOR:
Unrelated donor allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with acute myeloid leukemia and relies on timely donor availability. Donor unavailability after high-dose myeloablative conditioning is a medical emergency because bone marrow function recovery is unlikely. We successfully used an HLA-mismatched, cryopreserved, off-the-shelf cadaveric bone marrow graft in this setting. A man, aged 34 years, with NPM1-, FLT3-TKD–, KRAS-, PTPN11-, WT1-, and RAD21-mutated acute myeloid leukemia in first complete remission began myeloablative fludarabine/busulfan conditioning in preparation for a 10 of 10 HLA-matched unrelated donor peripheral blood stem cell transplant. On day −3 of conditioning, we were notified that the donor would not be able to complete the donation. The recipient received 3 of the 4 planned doses of fludarabine (40 mg/m2 per day) and busulfan (131 mg/m2 per day).1 A haploidentical donor would be available 7 days beyond planned transplant day, whereas unrelated donors could be procured in ∼3 weeks. To facilitate faster receipt of an allograft, an emergency request for a cryopreserved bone marrow product from a deceased donor was submitted to Ossium Health. Within 24 hours of the request, a 6 of 8 HLA-matched, bidirectional ABO-mismatched bone marrow graft was chosen among 6 allograft options, and within 72 hours, the product was shipped to the treating institution. The deceased donor was a White woman aged 41 years. Bone marrow was recoved from the vertebral bodies and processed and cryopreserved via proprietary methods (Ossium Health, Inc, San Francisco, CA). The red cell–depleted product contained 5.57 × 106 CD34+ cells per kg, 4.58 × 107 CD3+ cells per kg, and 5.57 × 108 total nucleated cells per kg, with 110 white cell progenitors per 105 total nucleated cells, and 91.6% viability.
A fourth fludarabine dose of 40 mg/m2 was administered on day 1, and the bone marrow graft was infused uneventfully 48 hours after the planned transplant day. Graft-versus-host disease prophylaxis consisted of tacrolimus, mycophenolate mofetil, and posttransplant cyclophosphamide (50 mg/kg per day) on transplant days +3 and +4.2 Filgrastim was administered starting on day +1. By day +5, the patient had a white cell count of 0, with a platelet count of 6 × 103/μL. Neutrophil and platelet engraftment occurred on day +14 and day +16, respectively (Table 1). No cytokine release syndrome was observed. Donor-recipient–sorted CD3/CD33 peripheral blood chimerism data are presented in Table 2. Hospital discharge occurred on day +14 with a 26-day length of stay.
Table 1.
Engraftment kinetics
| Engraftment | Absolute neutrophil and lymphocyte count | Platelets | Hemoglobin |
|---|---|---|---|
| Graft function on day 14 (engraftment) | 1.7 K/μL/0.07 K/μL | 55 K/μL | 7.1 g/dL |
| Graft function on day 60 | 5.57 K/μL/0.42 K/μL | 157 K/μL | 11.8 g/dL |
Table 2.
Chimerism kinetics
| Chimerism | Donor | Recipient |
|---|---|---|
| CD3 cells | ||
| Day 14 | 6% | 94% |
| Day 30 | 61% | 39% |
| Day 60 | 90% | 10% |
| Day 100 | 87% | 13% |
| CD33 cells | ||
| Day 14 | 100% | 0% |
| Day 30 | 100% | 0% |
| Day 60 | 100% | 0% |
| Day 100 | 100% | 0% |
Grade 2 steroid-responsive acute upper gastrointestinal and skin graft-versus-host disease was diagnosed on day 27 and successfully treated with topical therapy. Day +30 bone marrow biopsy showed molecular and morphologic remission. By day 100, CD3 chimerism increased to 87% and CD33 chimerism remained at 100%. Day 100 bone marrow biopsy confirmed molecular and morphologic remission with donor-derived hematopoiesis.
Timely access to an off-the-shelf HLA-mismatched bone marrow product prevented catastrophic bone marrow failure or debilitating opportunistic infections. These results highlight the unique value of cadaveric bone marrow grafts as a readily available, high quality graft source, particularly in life-threatening, unusual situations when living donors become unavailable during or after myeloablative conditioning has been administered. A prospective study of off-the-shelf cadaveric bone marrow grafts as a primary graft option is underway (ClinicalTrials.gov identifier: NCT05589896).
Conflict-of-interest disclosure: S.V. serves on the advisory boards of Alexion and Omeros. G.S.-P. reports consulting fees from Gamida Cell and Bristol Myers Squibb. M.d.L. serves on the data and safety monitoring board of AbbVie; reports consulting fees from Pfizer, Autolus, and Kite; research collaboration with Pfizer and Miltenyi Biotec; and serves as a board member of GreenJay Therapeutics. The remaining authors declare no competing financial interests.
Acknowledgments
Contribution: S.V. and M.d.L. analyzed the data and wrote the manuscript; S.M. provided critical material; and K.L., S.W., S.M., and G.S.-P. contributed to the writing of the manuscript.
Footnotes
Data are available from the corresponding author, Sumithira Vasu (sumithira.vasu@osumc.edu), on request.
References
- 1.de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104(3):857–864. doi: 10.1182/blood-2004-02-0414. [DOI] [PubMed] [Google Scholar]
- 2.Luznik L, O’Donnell P, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol. 2012;39(6):683–693. doi: 10.1053/j.seminoncol.2012.09.005. [DOI] [PMC free article] [PubMed] [Google Scholar]