Patients Type of CB

GvHD Prophylaxis

CD34+ cell dose median/range

Engraftment Myeloid ANC500 Platelet 20K/50K (Plt20K or 50K)

**Jaing et al. 2008 matched pair (MP) RCR CB ARM @ [32–34]**

58 Thal patients 10 RCR patients MP performed on 30 matched pairs 30 MC patients vs. 10 RCR patients

Pre-match 2.8 post-MP 2.8

Pre-match 1–12 post-MP 1–12

Pesaro Class 1 Pre-match 46% MP 57% Pre-match 50% MP 50% MC 27 RCR 6 Class 2 Pre Pre-match 20% MP 20% MC 17 RCR 2 Class 3 Pre Pre-match 10% MP 10% MC 0 RCR 2 N/A MC 35 RCR 2 Conditioning Multi-inst. Series Multi-inst. Series Multi-inst. Series Multi-inst.

> CSA MP

MP 4.4

≤4/6 matches MC 45 RCR 8 TNC dose median Pre-match 9.1 MP 9.1 Pre-match 8.9 MP 8.9 MC 9.8 RCR 8.7

N/A MC 3.6

% CB not washed N/A MC 89%; RCR 77%

(10%)

4–6 MP 4–6

Pre-match 2.3–19 MP 2.3–19

Regimens Mostly BU/CY/ATG Mostly BU/CY/ATG Mostly

HLA A/B/DR 6/6 Pre-match median 4.8 MP 4.5 Pre-match median 4.4

% DCBT Pre-match 11 (23%) MP 5 (17%) Pre-match 1 (10%) MP 1

Pre-Match ANC MC 96 ± 4% vs. RCR 75 ± 15% (RR = 1.31; p = 0.56) Pre-Match Plt50K MC 95 ± 5% vs. RCR 75 ± 15% (RR = 1.24; p = 0.64)

MP ANC MC 88 ± 12% vs. RCR80 ± 14% (RR = 1.05; p = 0.90; P = 

MP Plt50K MC 88 ± 12% vs. RCR 70 ± 17% (RR = 1.01; p = 0.98; P = 

**(RR = 0.31; p = 0.24; P = 0.04)**

5/6 Pre-match range 3–6 MP 3–6 Pre-match range

**Chow et al. 2012 MC CB ARM @ [35]**

MC 5.3 RCR 4.0

0.3–2 0.8–12

BU/CY/ATG

MC 21 RCR 1

MC 38 RCR 3

2–23.7 2–18.6

MC 20% RCR 8%

Multiinstitution series

0.4–10.3

**ANC 83.2% Plt20/50K 79/76%**

N/A

91 Thal. 79 MC CBT **Chow et al. 2012 RCR CB ARM [35]**

91 Thal. 12 RCR CBT

series

Mostly BU/CY/ATG

Multiinstitution series

RCR1.5 0.4–13.5 **Thal** = thalassemia major; **CB** = cord blood; **CBT** = cord blood transplant; **MC** = non-red blood cell reduced cord blood MaxCell; **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; **GvHD** = graft-versus-host disease; **Ltd** =  limited chronic GvHD; **Ext** = extensive chronic GvHD; **TNC** = total nucleated cells in ×107 /kg patient weight; **CD34**+ =  total CD34+ Cells in ×105 /kg patient weight; **CI** = cumulative incidence; **KM** = Kaplan-Meier estimator survival; **OS** =  overall survival; **DFS** = disease-free survival; **TRM** = transplant-related mortality; **M** = months; **Y** = year; **D** = days posttransplant; RR = relative risk; p = p value of MC versus RCR matched pair comparison; **P** = paired Prentice-Wilcoxon test p value; **F/U** = follow-up; \* = modified Pesaro (no liver biopsy), which may underestimate the disease severity; @ =  TC data audited by CIBMTR on site; **MP** = MC versus RCR CBT-matched pair analysis used a logistic regression model to find patients with similar characteristics to form 30 pairs, with three MC patients matched to each RCR patient (30 MC patients to 10 RCR patients). Factors matched for were age, weight, #HLA matches, TNC dose, transplant center experience. Univariate comparisons and paired Prentice-Wilcoxon test were performed for the matched pairs.

**Table 3.** Unrelated CB transplantation for thalassemia patients—comparison of MaxCell (MC) versus red cell-reduced CBT.

To further minimize patient population differences and selection bias, Chow's group performed a rigorous matched pair (MP) comparison analysis using a logistic regression model to find thalassemia patients with similar characteristics to form 30 pairs (**Table 3**), with three MaxCell patients matched to each of the available 10 RCR patients (30 MaxCell CBT patients matched to 10 RCR CBT patients) [32–33]. Factors matched were age, weight, TNC Dose, #HLA matches and transplant center experience. Since all available RCR patients were used in the MP study, and the best-matched MaxCell patients were used in the matched pair, differences in the matched factors were further minimized and selection biases were avoided. After matched pairing, age, disease severity, # HLA matches, TNC dose and usage of double CBT were quite similar between the two groups, with no significant differences. Univariate comparisons and paired Prentice-Wilcoxon test (PPW) were performed for the matched pairs. The matched pair study results in **Table 3** showed that though engraftment did not improve significantly, autologous recovery rate was significantly lower in the MaxCell group at 7 ± 5% versus 22 ± 14% (RR = 0.31; p = 0.04). Most importantly, 3-year OS (96 ± 4% versus 53 ± 18%; RR = 0.09; p = 0.03 univariate and p = 0.001 PPW), 3-year DFS (89 ± 6% versus 40 ± 15%; RR =  0.17; p = 0.01 univariate and p = 0.0001 PPW), and TRM (4 ± 4% versus 47 ± 18%; RR = 0.09; p =  0.03 univariate and p = 0.001 PPW) were all significantly improved for the MaxCell CBT group. It should be noted again that the RCR and MaxCell OS and DFS rates observed in this study were similar to that reported for previously thalassemia series using unrelated CBT [3, 5–7, 26, 35]. Lastly, the outcome data for MaxCell CBT recipients were rigorously audited by CIBMTR personnel on site at transplant centers using actual patient records and verified to be 97.3% accurate, with no errors for major variables, such as engraftment, survival, mortality, autologous recovery, etc.

In 2012, Chow's group reported a multicenter series of 91 thalassemia patients transplanted with unrelated CB between 1999 and 2011, 79 with MaxCell CB and 12 with RCR CB (**Ta‐ ble 3**), the largest series to date of unrelated CBT for thalassemia [35]. With 45% male recipients, patient median age was 5.6 years (range 0.3–20) and median weight was 18.8 kg (range 4–80). HLA matches were 23 cases at 6/6, 45 cases at 5/6, 54 cases at 4/6 and 3 cases at 3/6 HLA A/B/DR matches. Median pre-freeze TNC dose was 9.4 × 107 /kg and median pre-freeze CD34+ dose was at 3.2 × 105 /kg—unusually high due to the exclusive usage of MaxCell CB products and the patients' young age in the study. Three-quarters of the patients were Asian and 84% CB was infused directly without post-thaw wash/reconstitution. Seven patients received a second CBT due to graft failure. Acute GvHD grade II–IV and III–IV occurred in 76 and 24% of the patients, respectively, whereas 60% and only 5% of the patients exhibited limited and extensive chronic GvHD, respectively. Overall, cumulative incidence of myeloid, platelet 20 and 50K engraftment of 83, 79 and 76% were achieved, respectively. Median times to myeloid and platelet 20K engraftment were 17 and 47 days, respectively. Most importantly, 180-day OS, 1-year OS and 1-year DFS of 80, 74 and 61% were reported, respectively, with a median followup of 711 days. Again, it is important to reemphasize that the outcome data for MaxCell CBT recipients were audited by CIBMTR on site at transplant centers using actual patient records and verified to be error-free for major clinical outcome measurements.

In their 2011 multi-institutional study, combined data of Eurocord, NYBC and CIBMTR, Ruggeri et al. [3] reported on 35 thalassemia patients (**Table 2**). With median age of 4 years, and mostly Pesaro class 1 and 2 patients (11 out of 15), this study used a variety of conditioning regimens (30/35 myeloablative regimens) and mostly calcineurin inhibitor containing GvHD prophylaxis (65% cyclosporine). Myeloid engraftment was only 42.8%, with 57.2% patients suffering primary graft failure. Though 66% were alive, only 23% were alive and thalassemiafree, with OS and DFS at 2-year post-transplant as estimated by Kaplan-Meier method as 62  ± 9% and 21 ± 7%, respectively (**Table 2**). Referring to the Jaing et al. series [26], the authors concluded that "For UCB, only one group has reported 80% DFS at 2 years… DFS was not as good as previously reported by Jaing and colleagues." Besides the single-center versus multiinstitutional aspects of the two groups, the most obvious differences were the significantly higher TNC dosage in the Jaing/Chow series [4, 6, 26, 31–33], caused by the exclusive utilization of RCR CB units in the Ruggeri et al. series [3] versus 100% MaxCell CB products used in the Jaing/Chow series. In a similar multi-institutional setting, using exclusively MaxCell CB products with 38% thalassemia patients, Petz et al. [5] reported 3-year OS at 79 ± 4% and DFS at 70 ± 6% (**Table 3**). As discussed above, Chow et al. [35] showed that in 91 thalassemia patients, employing MaxCell CB in 86.8% of the recipients, higher OS (73%) and DFS (61%) were also achieved compared to patients from the Ruggeri et al. series who received RCR CB units exclusively (**Table 3**).

The matched pair study results in **Table 3** showed that though engraftment did not improve significantly, autologous recovery rate was significantly lower in the MaxCell group at 7 ± 5% versus 22 ± 14% (RR = 0.31; p = 0.04). Most importantly, 3-year OS (96 ± 4% versus 53 ± 18%; RR = 0.09; p = 0.03 univariate and p = 0.001 PPW), 3-year DFS (89 ± 6% versus 40 ± 15%; RR =  0.17; p = 0.01 univariate and p = 0.0001 PPW), and TRM (4 ± 4% versus 47 ± 18%; RR = 0.09; p =  0.03 univariate and p = 0.001 PPW) were all significantly improved for the MaxCell CBT group. It should be noted again that the RCR and MaxCell OS and DFS rates observed in this study were similar to that reported for previously thalassemia series using unrelated CBT [3, 5–7, 26, 35]. Lastly, the outcome data for MaxCell CBT recipients were rigorously audited by CIBMTR personnel on site at transplant centers using actual patient records and verified to be 97.3% accurate, with no errors for major variables, such as engraftment, survival, mortality, autolo-

In 2012, Chow's group reported a multicenter series of 91 thalassemia patients transplanted with unrelated CB between 1999 and 2011, 79 with MaxCell CB and 12 with RCR CB (**Ta‐ ble 3**), the largest series to date of unrelated CBT for thalassemia [35]. With 45% male recipients, patient median age was 5.6 years (range 0.3–20) and median weight was 18.8 kg (range 4–80). HLA matches were 23 cases at 6/6, 45 cases at 5/6, 54 cases at 4/6 and 3 cases at 3/6 HLA

and the patients' young age in the study. Three-quarters of the patients were Asian and 84% CB was infused directly without post-thaw wash/reconstitution. Seven patients received a second CBT due to graft failure. Acute GvHD grade II–IV and III–IV occurred in 76 and 24% of the patients, respectively, whereas 60% and only 5% of the patients exhibited limited and extensive chronic GvHD, respectively. Overall, cumulative incidence of myeloid, platelet 20 and 50K engraftment of 83, 79 and 76% were achieved, respectively. Median times to myeloid and platelet 20K engraftment were 17 and 47 days, respectively. Most importantly, 180-day OS, 1-year OS and 1-year DFS of 80, 74 and 61% were reported, respectively, with a median followup of 711 days. Again, it is important to reemphasize that the outcome data for MaxCell CBT recipients were audited by CIBMTR on site at transplant centers using actual patient records

In their 2011 multi-institutional study, combined data of Eurocord, NYBC and CIBMTR, Ruggeri et al. [3] reported on 35 thalassemia patients (**Table 2**). With median age of 4 years, and mostly Pesaro class 1 and 2 patients (11 out of 15), this study used a variety of conditioning regimens (30/35 myeloablative regimens) and mostly calcineurin inhibitor containing GvHD prophylaxis (65% cyclosporine). Myeloid engraftment was only 42.8%, with 57.2% patients suffering primary graft failure. Though 66% were alive, only 23% were alive and thalassemiafree, with OS and DFS at 2-year post-transplant as estimated by Kaplan-Meier method as 62  ± 9% and 21 ± 7%, respectively (**Table 2**). Referring to the Jaing et al. series [26], the authors concluded that "For UCB, only one group has reported 80% DFS at 2 years… DFS was not as good as previously reported by Jaing and colleagues." Besides the single-center versus multiinstitutional aspects of the two groups, the most obvious differences were the significantly higher TNC dosage in the Jaing/Chow series [4, 6, 26, 31–33], caused by the exclusive utilization

/kg—unusually high due to the exclusive usage of MaxCell CB products

/kg and median pre-freeze CD34+

A/B/DR matches. Median pre-freeze TNC dose was 9.4 × 107

194 Umbilical Cord Blood Banking for Clinical Application and Regenerative Medicine

and verified to be error-free for major clinical outcome measurements.

gous recovery, etc.

dose was at 3.2 × 105

In 2012, using exclusively unrelated MaxCell CB, Jaing's group transplanted 35 thalassemia patients, with 12 patients receiving double CBT (**Table 2**) [6]. The authors explained that their initial approach of using oral busulfan resulted in five primary and one secondary graft failures due to high pharmacokinetic variability exhibited with oral busulfan, necessitating six retransplants. In this series, 88% of the transplants (35 first and 5 second transplants combined) achieved neutrophil engraftment. Five-year OS was 88.3 ± 6.7% and 5-year DFS was 85.7% (30 of 35 patients) in this exclusive MaxCell CBT series. The 85.7% 5-year DFS of this experience is in contrast to the 21 ± 7% 2-year DFS obtained by Ruggeri et al. [3] and compares very favorably with the 80 ± 5% 6-year DFS for HLA-identical related CBT reported for Locatelli series in 2013 [25].
