Patients 1 2 3 CB

Age (yrs) median Range

HLA A/B/DR 6/6 5/6

≤4/6 matches

Engraftment Myeloid (ANC500) Platelet 20/50K

TNC dose Median Range

products [61, 62].

**Thal** = thalassemia major; **CB** = cord blood; **CBT** = cord blood transplant; **MaxCell** = non-red blood cell reduced cord blood; **RCR** = red cell reduced cord blood; **SCBT** = single cord blood transplantation; **DCBT** = double cord blood transplantation; **NW** = non-wash post-thaw processing; **N/A** = not available; **LGF** = late graft failure; **AR** = autologous recovery; **TI** = transfusion independent; **TNC** = total nucleated cells in ×107 /kg patient weight; **CD34**+ = total **CD34**+ Cells in ×105 /kg patient weight; **GvHD** = graft-versus-host disease; a**GvHD** = acute graft-versus-host disease; **Ltd** =  limited chronic GvHD; **Ext** = extensive chronic GvHD; **TRM** = transplant-related mortality; **M** = months; **3Y** = 3 Year; **1Y** = 1 Year; **D** = days post-transplant; **OS** = overall survival; **DFS** = disease-free survival; **EFS** = time interval from CBT to first event (death or autologous reconstitution or infusion of cryopreserved backup recipient hematopoietic stem cells); **RR** = relative risk; **F/U** = follow-up; **CI** = cumulative incidence; **KM** = Kaplan-Meier estimator survival. **SR** = Resolved with Steroids; **Thal** = Thalassemia.

**Table 1.** CBT using related donors and sibling-directed donor CB bank (SDCB) for patients with thalassemia.

In 2013, Locatelli et al. published their landmark study for hemoglobinopathies on the comparison of related HLA-identical HSCT with 66 thalassemia patients transplanted with CBT against 259 thalassemia patients transplanted with BMT (**Table 1**) [25]. The CBT cohort was younger (median age 6 versus 8 years; p = 0.02), had higher disease severity for the thalassemia patients (Pesaro 2–3 39 versus 44%; p < 0.01), and was transplanted more recently (median year 2001 versus 1999; p < 0.01), with a significantly higher percentage of BMT patients receiving methotrexate GvHD prophylaxis than CB product recipients. No patients were excluded except for patients who received a combination of CB and BM products. Most thawed CB products were thawed and washed per Rubinstein procedure [20], and no information was provided as to the type of CB processing employed for the units. Compared to BMT recipients, the patients given CBT had slower neutrophil engraftment, less acute GvHD and no extensive chronic GvHD. Graft failure occurred more commonly in CBT patients than recipients of BM grafts but not significantly (10.4 vs. 7.4%; p = 0.33). Eight of the patients who received CB graft experienced graft failure. Cumulative incidence of primary graft failure was 9 ± 4% and 6 ± 4% after CBT and BMT, respectively. Six patients experienced secondary graft failure after CBT at a median of day +151 (range day +51 to 202). The cumulative incidence of neutrophil engraftment was 90 ± 4% and 92 ± 1% (p = 0.01), and 83 ± 5% and 85 ± 5% for platelet engraftment after CBT and BMT, respectively. For patients who engrafted, the median time to neutrophil recovery was day +23 for CBT and day +19 for BMT, and day +38 and day +25 for CBT and BMT for platelet engraftment, respectively (p = 0.004). The proportion of long-term sustained mixed chimerism was significantly higher after CBT than for BMT (37 versus 22%; p = 0.01). Only 11% of CBT recipients experienced grade II–IV acute GvHD (no grade IV), versus 21% of BMT recipients (2% grade IV acute GvHD), with a cumulative incidence 10 ± 3% and 21 ±  2%, respectively (p = 0.04). Only six of 84 evaluable CB recipients experienced chronic GvHD with no extensive grade versus 42 of 355 (12 extensive) patients of BMT who survived past 100 days, with the cumulative incidence of chronic GvHD at 5 ± 3% and 12 ± 2%, respectively (p = 0.12), and extensive chronic GvHD at 0% and 5 ± 9%, respectively. Twenty-one patients expired from transplant-related causes—three after CBT and 18 after BMT. Most importantly, with a median follow-up of 70 months, the 6-year DFS was 80 and 86% for CB- and BMtransplanted patients, respectively, with no difference in multivariate analysis. This study proved that CBT using related donor for thalassemia is as efficacious and safe as related donor BMT, with potentially better long-term quality of life due to reduced chronic GvHD with minimal extensive grades. The authors point out that the quality of life for BMT patients with extensive chronic GvHD is worse than patients on medical therapy.

The author speculated that due to the higher nucleated cell dosage for most of the CB recipients, nucleated cell dosage was not shown to influence engraftment or disease-free survival. For CBT, methotrexate was shown in multivariate analysis negatively influencing DFS (HR 3.81, CI 1.40–10.87; p = 0.004), with 6-year DFS at 90 ± 4% if methotrexate was avoided versus 60 ± 11% (p < 0.001). Similar to previous studies, thiotepa-containing preparative regimen and Pesaro classification 1 were shown to correlate with better outcome after CBT. These series using related CBT demonstrate the efficacy and high margin of safety of related CB as a source of HSCT for thalassemia. The studies confirmed that even with persistent mixed chimerism, patients are still transfusion independent. Methotrexate GvHD prophylaxis was proven to be detrimental to favorable outcome and the addition of thiotepa to busulfan and cyclophosphamide conditioning regimen favored sustained donor engraftment.
