Introduction

Allogeneic hematopoietic cell transplant (HCT) for patients with severe sickle cell disease (SCD) is potentially curative but not commonly utilized therapy due to complications such as graft failure (GF) and organ toxicity. Herein, we report our long-term outcome data of non-myeloablative (NMA) HCT in adults with severe SCD focusing on short and long-term toxicities.

Method

We retrospectively reviewed all SCD patients who were ≥ 14 years old and who underwent allogeneic HCT in our center from 2015 until 2022 to allow a follow up of more than 2 years post-transplant. The conditioning regimen was alemtuzumab and 300 cGy Total Body Irradiation. Graft versus host disease prophylaxis with sirolimus. Short and long-term toxicities, including secondary myeloid malignancies were documented and reported.

Result

A total of 200 patients were included with a median age of 26 (range: 14-43). Around 56% of patients were male and 177 (89%) were ≥18 years. The median follow up was 4.3 years (9.4 - 2.1) and the event free survival 90.5% and overall survival was 96%. A total of 8 patients died (6 due to GF and 2 from infections [one from VZV encephalitis and one from severe pneumococcal sepsis]). A total of 19 patients experienced GF; 3 as primary and 16 as secondary. Outcomes post-GF included recurrence of SCD in 9 (47%) and aplastic bone marrow in 10 (53%). Eleven (58%) of patients with GF underwent a second HCT of whom three died due to sepsis. Additionally, two (10%) patients underwent a third HCT, one of whom died from sepsis.

In general, acute toxicities were rare and of mild severity. Mucositis developed in 95 (47%) of patients, venous thrombosis in 14 (7%) of patients, PRES in 2 (1%) patients, mild sinusoidal obstruction syndrome in one patient, and transplant associated - thrombotic microangiopathy (TA-TMA) in none. Acute graft versus host disease (GvHD) grades I and II occurred in 7 (3.5%) cases, 4 patients with skin aGVHD and 3 with gut aGVHD. Four patients required systemic corticosteroid for one course only and responded completely with no additional therapies. The remaining patients were treated with topical corticosteroids. Time to aGvHD was between +48 and +113 days. Additionally, there was one case of moderate cutaneous chronic GvHD without prior acute GvHD started on day +212 post-HSCT. The patient received prolonged course of oral and topical corticosteroids for 8 months with complete response.

Infectious complications were relatively common especially viral infections. Clinically significant cytomegalovirus (CMV) infection requiring preemptive therapy occurred in 34 (17%) patients with no CMV disease. Herpes simplex virus infection was observed in 15 (8%) patients, VZV reactivation in 21 (11%) patients and parvovirus infection in 4 (2%) patients. One patient died from VZV encephalitis. Bacterial infection and febrile neutropenia was evident For in 109 (55%) patients, bacterial osteomyelitis in six (3%) patients and fungal infections in 12 (6%) patients.

For long-term complications, metabolic and sirolimus related adverse events were relatively common as following; elevated liver enzymes (transaminitis) in 193 (97%), hyperlipidemia in 143 (72%), acne in 84 (42%), proteinuria in 73 (37%), headache including migraine in 72 (36%), oral and GI ulcers in 50 (25%), hypertension in 35 (17.5%), and hyperglycemia / type 2 DM in 17 (8.5%).

Autoimmune disorders developed in 20 patients (10%) and this included 10 patients with autoimmune hemolytic anemia (AIHA), 1 patient with immune thrombocytopenia (ITP), 6 patients with Graves' disease, 1 patient with vitiligo, and 2 patients with psoriasis. Seventeen (8.5%) patients developed hypothyroidism and some of them were secondary to autoimmune thyroiditis.

Many of these metabolic and endocrine complications were reversible with time as following: 41% for DM, 34% for HTN, 100 % for AIHA and ITP, 41% for hypothyroidism, and 33% for hyperthyroidism.

Two patients developed stroke and one patient developed intracranial hemorrhage in the setting of moyamoya disease 2 years post-HCT.

With this relatively long follow up, none of the patients developed clonal or myeloid malignancies or secondary malignancy.

Conclusion

The transplant related complications were relatively common but with different profile of toxicities. In the majority of cases, they were of mild severity and reversible.

Disclosures

No relevant conflicts of interest to declare.

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2024
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