Collection of HSCs for the purpose of allogeneic transplantation is achieved mostly by either apheresis of peripheral blood after mobilization with G-CSF, or by direct BM aspiration.1 Potential donors are submitted to a thorough workup, including history questionnaire, physical examination and laboratory testing, as per published regulations.2 This workup aims at minimizing health risks related to the collection for the donor, and also at protecting the recipient from transmissible diseases. In the setting of unrelated donor registries, recommendations for deferral according to precise medical conditions have been issued by the World Marrow Donor Association.3 The same rigorous precautions should be applied to family donors, and an alternative source of HSCs is usually recommended if the donor suffers from a chronic medical condition that significantly increases collection-related health risks. However, a readily accessible alternative donor is not always immediately available. Related donors will sometimes request to proceed with HSC collection despite a heightened risk for themselves because of underlying medical conditions. Physicians need to consider these donor preferences.
We report the case of a 58-year-old male with end-stage renal disease (ESRD) who committed to donate HSCs to his HLA-identical brother referred for secondary acute myeloid leukemia in remission and requiring urgent transplantation.
ESRD was caused by chronic hypertension and type 2 diabetes mellitus, and was treated with maintenance hemodialysis (HD) three times per week for the last 2 years. Other medical conditions were considered stable: asymptomatic angina pectoris after percutaneous coronary intervention 2 years earlier, dyslipidemia, hypothyroidism, past smoking history and morbid obesity.
Pretransplant workup in the donor, including history and physical examination, revealed a Karnosfky performance status of 80%, marked obesity (body mass index of 54) and exertional dyspnea. No other symptom of coronary heart disease was reported. An arteriovenous fistula as well as a jugular tunneled cuffed catheter for HD access was in place. Physical examination did not reveal any signs of congestive heart failure. The donor was evaluated by his nephrologists and a consultant cardiologist. Exercise electrocardiogram testing was negative, though limited by deconditioning, and echocardiogram was normal with a left ventricular ejection fraction of 70%.
The Stem Cell Transplant Committee at our institution reviewed the case and accepted to proceed once the donor had been clearly informed of the heightened risk of complications due to his comorbidities. Ad hoc protocol deviation forms were approved by the donor, the recipient and the physician in charge. The donor received G-CSF (filgrastim, Neupogen, Amgen Canada Inc, Missauga, ON, Canada) at a dose of 5 mcg/kg/day s.c. for 5 days (body weight: 130 kg). The targeted cellular dose to collect was 4 × 106 CD34+ cells per kg of recipient weight. The first injection was administered on day 1 and the patient was seen on day 5 for the first collection. Blood counts on days 5 and 6 are detailed in the Table 1. The first collection yielded a total of 2.4 × 106 CD34+ cells/kg (12.7 × 108 total nucleated cells) after standard procedure: whole blood flow rate between 60 and 70 mL/min, and a total processed volume of 18 L. On day 6, a second collection yielded a total of 2.53 × 106 CD34+ cells/kg (12.6 × 108 total nucleated cells) after a similar procedure. Biochemistry panel on both consecutive days did not show any significant abnormality. The patient complained of mild fatigue and back pain, and physical examination was unchanged on collection days. HD occurred twice during G-CSF injection (days 2 and 4) and was resumed on day 6 after the second collection. Leukocyte count was back to normal on day +9. The graft was cryopreserved and remained unmanipulated until infusion. The donor has not experienced any late effect with a follow-up of 18 months after HSC collection.
The recipient received myeloablative conditioning, followed by infusion of the total amount of cells collected, that is, 4.93 × 106 CD34+ cells/kg. Neutrophil (0.5 × 109/L) and platelet (20 × 109/L) engraftment occurred on day +18 and day +21, respectively. Chimerism analysis revealed a full donor state in lymphocytes (performed on day +98). The recipient is still in CR at 456 days since transplantation.
The clinical use of G-CSF in ESRD is well documented mainly in the context of renal disease associated with multiple myeloma and other paraproteinemias requiring autologous HSC transplantation.4 No additional toxicity has been observed with ESRD in this setting. The metabolism of G-CSF is known to consist of metabolic degradation, but data on pharmacokinetics in the context of renal failure are scarce. A study in patients with ESRD has shown no effects of accumulation and Ab production, even though the mean t1,2 was prolonged to about twice that of healthy subjects.5 Furthermore, HD did not affect the pharmacokinetics in these patients, and no dose modification is suggested in renal failure by the manufacturer.6 Nevertheless, because of sparse data and donor comorbidities (ESRD and obesity) we chose to reduce the dose from our standard 10 mcg/kg/day, which proved to be successful.
The hemodynamics of the apheresis procedure should not be considered an obstacle to HSC mobilization in patients with ESRD, especially if they are familiar with HD, which induces larger amounts of volume shifts. The experience of autologous transplantation in this population has again demonstrated no additional hazard.4
To our knowledge, no cases to date have been reported describing allogeneic HSC collection in the ESRD setting. Our donor experienced only side effects (mild bone pain) that are very common in healthy subjects.
In conclusion, this case illustrates the feasibility of HSC collection after mobilization with G-CSF in allogeneic donors with ESRD. Ethical concerns, however, remain significant. A search for an alternate source of HSCs should always be considered before exposing a donor to a higher risk of complications. In this case, the urgency of transplantation for the recipient, and the clearly expressed desire of his sibling to donate were paramount. A thorough multidisciplinary evaluation allowed safe mobilization, collection and transplantation of HSCs with successful engraftment.