Rare Disease Report

Familial Haploidentical Stem Cell Transplantation Improves Quality of Life & Neurocognition in Sickle Cell Disease Patients

DECEMBER 01, 2018
Krista Rossi
At the 60th ASH Annual Meeting & Exposition in San Diego, California, a team of investigators presented long-term data on the treatment of familial haploidentical stem cell transplantation (HISCT) and myeloablative that utilizes CD34 enrichment and MNC (CD3) addback in high risk sickle cell disease recipients.

Among the results, the treatments demonstrated improvements in long-term health-related quality of life and neurocognition in patients.

As a chronic and debilitating blood disease, sickle cell disease can result in chronic organ damage, such as cerebral vasculopathy, acute chest syndrome, pulmonary hypertension, and a significantly shortened life-span. Survivors face significant neurocognition defects, particularly in processing speed in addition to having poor health-related quality of life.
  
Currently, human leukocyte antigen (HLA) matched sibling AlloSCT, following either myeloablative or reduced toxicity conditioning, is the only recorded cure for sickle cell disease. However, only an approximate 15% of sickle cell patients have an unaffected HLA matched sibling donor.

While safety and efficacy of CD34 enrichment and mononuclear cell addback (2 x 105 CD3/kg) in pediatric matched unrelated donor recipients was previously demonstrated my investigators, the team sought to assess long-term results.

The patient population involved in the study included “sickle cell disease patients with 1 or more high risk features (cerebral vasculopathy, repetitive ACS, repetitive VOC, abnormal TCD requiring RBC TX) underwent myeloablative and parental HISCT consisting of hydroxyurea, azathioprine, fludarabine, busulfan, cyclophosphamide, thiotepa, r-ATG and TLI and PBSCT utilizing CD34 enrichment (10x106 CD34/kg) and MNC addback (2x105 CD3/kg) and tacrolimus AGVHD prophylaxis x 100 days.”

WBC and RBC (CD71) enriched fractions of donor chimerism were determined centrally, and the Glucksberg and NIH consensus criteria were used, respectively, to determine AGVHD & CGVHD.

At baseline and 2 years, transthoracic echocardiogram, TRJ velocity, PFTs, MRI/MRA were conducted as well as DIVERGT screening, which was used as neurocognitive testing. The CHRIS-General and CHRIs-HSCT was used at baseline and Days +45, 100, 180, 365 and 730 post HISCT, which composing the health-related quality of life testing.  

All above methods were previously described and/or reported.

Of the 19 patients administered HISCT—which had a mean±SEM age of 13.1±1.2 years (3.3-20.0) years and a ratio of 12/7 (male/female)—18 were parental haploidentical donors with a mean±SEM age of 41.3±1.8 (30-55) years and a gender ratio of 15/3 (female/male). “The mean±SEM CD34 enriched PBSC infused was 10.94±0.4x106/kg and MNC addback (2 x 105 CD3/kg).”

Day +9 and +19 was the median time to neutrophil and platelet engraftment, 97.1±1.4 and 96.4±2.0% was the 1-year mean±SEM whole WBC and RBC (CD71) mixed donor chimerism, and 6.2% and 6.7% was the cumulative incidence of grade II-IV AGVHD and CGVHD, respectively. Ninety percent included the probability of 1-year EFS (CI95 64-97%).

Compared from baseline to 2-year post HISCT, “PFTs were stable to improved with a significant improvement in conductance (sGAW) (p<0.026), cardiac SF and TRJ velocity were stable to improved, MRI/MRA showed no new overt and/or silent strokes and no new cerebral vasculopathy.”

Intellectual functioning, memory, language, and executive function were also stable to improved. 

“Most importantly, processing speed was significantly improved (p<0.026) (Figure 1B), emotional functioning (HRQL) (p<0.03) (Figure 1C) and physical functioning (HRQL) (p<0.01) (Figure 1D) were significantly improved at 2 years vs. pre-HISCT.”

From the gathered results, investigators concluded that in addition to being well tolerated, myeloablative and familial HISCT utilizing parental donors and CD34 enrichment and MNC addback (2 x 105 CD3/kg) in high-risk patients with sickle cell disease demonstrated rapid hematological reconstitution, long-term stable WBC and RBC (CD71) donor chimerism, low cumulative incidence of A+CGVHD, and stable to improved pulmonary and cardiac function.

Additionally, 2 years post HISCT, significant improvements in processing speed and emotional and physical health-related quality of life were observed.

The study, titled “Significantly Improved Long Term Health Related Quality of Life (HRQL) and Neurocognition Following Familial Haploidentical Stem Cell Transplantation (HISCT) Utilizing CD34 Enrichment and Mononuclear (CD3) Addback in High Risk Patients with Sickle Cell Di),” was presented at the 60th ASH Annual Meeting & Exposition.

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