Haploidentical bone marrow transplantation improves cerebral hemodynamics in adults with sickle cell disease
Authors: Lori C. Jordan, Meher R. Juttukonda, Adetola A. Kassim, Michael R. DeBaun, Larry T. Davis, Sumit Pruthi, Niral J. Patel, Chelsea A. Lee, Spencer L. Waddle, Manus J. Donahue
Journal: American Journal of Hematology (2019)

We read with interest the paper by Krishnamurti et al.1 on safety and feasibility of bone marrow transplantation (BMT) for adults with severe sickle cell disease (SCD), in which 20 of 22 enrolled participants survived at 1 year follow-up, and ≥70% had event-free survival. Interestingly, the majority of participants had magnetic resonance imaging (MRI) of the brain at baseline and follow-up (n = 17), all of which were described as stable. BMT is increasingly utilized in SCD for secondary stroke prevention, but outcomes have largely been evaluated by coarse indicators such as all-cause mortality with limited additional physiologic evidence of improved cerebral hemodynamics. In SCD, cerebral blood flow (CBF; mL blood/100 g tissue/min) and oxygen extraction fraction (OEF; ratio of oxygen consumed to oxygen delivered) are generally increased to maintain oxygen delivery to brain tissue in the setting of chronic anemia and reduced oxygen carrying capacity. These hemodynamic profiles have been associated with prior stroke and clinical impairment.2 As a proof of principle that BMT improves cerebral hemodynamics via a decline or normalization in CBF and OEF, (Supporting Information Figure 1A) as is seen after blood transfusion with increased hematocrit (Hct),3, 4 we performed anatomical and hemodynamic MRI before and after haploidentical bone marrow transplant (haplo-BMT) in adults with SCD and healthy adults without SCD scanned twice without interval interventions. Equally important, we had central adjudication of infarct recurrence and formal neurological examination to assess for progression of neurological morbidity. Adults with SCD (phenotype HbSS) undergoing haplo-BMT on a consortium protocol5 (age range = 18-40 years) provided informed, written consent for this institutional review board-approved imaging study. Age- and race-matched controls without sickle trait were enrolled for comparison. Participants underwent standardized neurological examination by a neurologist and non-contrast brain MRI and magnetic resonance angiography (MRA) of the head and neck (3.0T Philips Achieva, Best, The Netherlands) within 30 days prior to, and approximately 12 months after, haplo-BMT. Control participants received MRI and MRA on two separate days, less than 1 year apart. Time-of-flight MRA of the head and neck assessed for intracranial and cervical vasculopathy; MRI of the brain, including axial and coronal T2-weighted fluid attenuated inversion recovery (FLAIR), axial diffusion-weighted imaging, and T2-weighted and T1-weighted imaging, evaluated for new or progressive cerebral infarcts. Infarcts were judged to be silent based on history and detailed neurological examination. For OEF measurement, T2-relaxation-under-spin-tagging (TRUST) data were acquired with a spatial resolution of 3.4 × 3.4 × 5 mm3, refocusing pulse interval of 10 ms, effective echo time of 0, 40, 80, and 160 ms, repetition time/echo time of 1978/3.6 ms, and average of 6, as previously performed in adults with SCD.2 For CBF measurement, pseudo-continuous arterial spin labeling was applied (post-labeling delay = 1.9 seconds; spatial resolution = 3 × 3 × 7 mm3) as recently optimized for adults with SCD.6 Two neuroradiologists independently evaluated for cerebral infarcts and vasculopathy and reached consensus. Infarct was defined as T2-weighted FLAIR hyperintensity visible on two imaging planes and ≥3 mm in one plane. Vasculopathy was defined as stenosis of a major cervical or intracranial vessel >50%. For OEF quantification, T2 values from TRUST-MRI were converted to venous oxygen saturation (Yv) using previously characterized calibration curves.2 Yv and arterial oxygenation saturation (Ya) were used to calculate OEF as the fractional difference of blood oxygenation in the arteries and veins, OEF = (Ya − Yv)/Ya. CBF was calculated as previously optimized for adults with SCD.6 The subject-specific arterial blood T1, calculated using measured Hct, was also included in the model. Statistical analyses were performed on hemodynamic variables using the Wilcoxon signed-rank test with two-tailed P < 0.05 required for significance. Data are presented as line graphs and continuous variables as mean ± SD. Healthy age- and race-matched adult controls were scanned at two time-points (interval = 202.4 ± 67.7 days; n = 7; age = 26.1 ± 6.2 years; Hct = 42.2 ± 6.8%). In controls, when measured at two time-points, OEF and CBF were not significantly different (OEF = 34.6 ± 8.1% vs 33.8% ± 6.9%, P = 0.50; CBF = 48.3 ± 10.1 vs 50.2 ± 7.7 mL blood/100 g tissue/minute, P = 0.22). Four adults with SCD (Table 1; age = 33 ± 8.9 years) completed the protocol. Two participants had a history of overt strokes and unilateral moyamoya vasculopathy (one had prior revascularization surgery); one participant had multiple new silent cerebral infarcts (SCIs), and one participant had recurrent pain crises and acute chest syndrome as a transplant indication with normal brain MRI/MRA. All received pretransplant conditioning with thymoglobulin, thiotepa, fludarabine and low dose total body irradiation (200 cGy), and graft versus host disease (GVHD) prophylaxis with sirolimus, mycophenolate mofetil, plus posttransplant cyclophosphamide.5 All participants were fully engrafted (100% myeloid donor cells) at the time of 1-year follow-up imaging. All adults with SCD had elevated CBF and OEF prior to haplo-BMT when compared to controls (P < 0.01). OEF reduced from a mean of 53.1 ± 11.8% (median = 52.8%) pretransplant to 37.6 ± 8.6% (median = 40.4%) posttransplant, P = 0.04 (Supporting Information Figure 1, panels B and C). Pretransplant CBF was 110.3 ± 14.4 mL blood/100 g tissue/minute (median = 106.2 mL blood/100 g tissue/minute) and declined to 63.7 ± 31.9 mL blood/100 g tissue/minute (median = 60.1 mL blood/100 g tissue/minute) posttransplant, P = 0.03. Pretransplant hemoglobin was 7.15 ± 1.7 g/dL (median = 7.05 g/dL) and improved to 12.3 ± 1.54 g/dL (median = 12.05 g/dL) posttransplant. On posttransplant imaging, one of the four participants (Table, participant 4) had a new SCI ipsilateral to moyamoya vasculopathy with no change in intracranial stenosis degree by MRA or change in neurological examination. Main complications posttransplant in participants were asymptomatic viral reactivation and infection, similar to other published haploidentical BMT studies.7, 8 Participant 2 developed HHV6 viremia and encephalopathy. No participant developed acute or chronic GVHD. Participant 4 had a new SCI but did not have unusual complications of haplo-BMT. We extend recent findings showing BMT feasibility in SCD patients to provide evidence for the first time that compensatory changes in cerebral hemodynamic parameters associated with SCI in children with SCD9 and overt stroke or SCI in adults with SCD,2 OEF and CBF, improve following haplo-BMT in adults with SCD. Improvement in these markers of cerebral stress generally correlates with increased Hct3, 4 and may decrease the incidence of initial or subsequent cerebral infarcts; larger studies are necessary. The global OEF assessment methods used are reasonable as elevated OEF is attributable to globally reduced oxygen carrying capacity and anemia in SCD. However, intracranial stenosis may also reduce oxygen delivery, producing regional changes in OEF. In the two participants with unilateral moyamoya syndrome, regional changes in OEF might have been even more significant than global OEF. Regional OEF methods have been applied in this population as well.4 Our study highlights the importance of central neuroradiology adjudication of MRI and MRA of the brain10 and formal neurological evaluation pretransplant and posttransplant to determine the benefits and risks of transplant for primary and secondary stroke prevention. Without such a process, the rate of infarct recurrence, particularly SCI, is likely to be under-estimated following BMT. Biological factors such as moyamoya, unique conditioning regimens, or both may contribute to the ongoing risk of infarct recurrence following BMT. Future curative options such as gene therapy and further BMT trials should not only focus on cure, but also minimizing short and long term sequelae. This work represents proof of the concept that haplo-BMT improves cerebral hemodynamic parameters in adults with SCD; assessment of CBF and OEF before and after transplant is ongoing at our center along with efforts to make this work multicenter. This work was funded by an American Heart Association Collaborative Science Award and NIH 5R01NS097763-03. The AHA and NIH had no role in the study design, analysis, or reporting of results. The project was also supported by CTSA award UL1 TR002243 from the National Center for Advancing Translational Sciences. M.J.D. receives research related support from Philips North America and is a paid consultant for Global Blood Therapeutics. L.C.J., M.J. D., and M.R.D. designed the research and wrote the article. S.P. and L.T.D. reviewed the neuroimaging. M.R.J., S.L.W., and M.J.D. acquired and analyzed the imaging data. A.A.K. assisted with study design and patient recruitment. N.J.P. and C.A.L. recruited study participants and entered the data. All authors reviewed and critically revised the manuscript. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.