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Double cord blood transplantation

R. Angarano, I. Donnini, B. Bartolozzi, A. Bosi

Ematologia, Azienda Ospedaliera Universitaria Careggi, Università di Firenze, Italy

stem cells (HSC) for transplant. The presence of relatively mature hema-topoietic progenitor cells (HPC) in hu-man umbilical cord blood (UCB) was demonstrated by Knudtzon in 1974 (2). About ten years later, Ogawa and col-leagues documented the presence of primitive HPC in UCB (3). However, it was not until 1989 that experimen-tal and clinical studies were published indicating that human UCB could be used in clinical settings. Broxmeyer et al. showed experimental evidence that UCB was a rich source of hema-topoietic stem/progenitor cells (HSPC) (4),and in the same year Gluckman et al. reported the first hematopoietic cell transplant in which UCB from an hu-man leukocyte antigen (HLA)-identical sibling donor was used as a source of hematopoietic cells in a child with Fan-coni anemia (5). Since then, there has been a growing interest in the use of UCB as an alternative source of HSPC for transplantation.

Correspondence: Alberto Bosi

Ematologia, Università degli Studi di Firenze U.O. di Ematologia,

Azienda Ospedaliera Careggi Largo Brambilla, 3 - Firenze, Italy E-mail: alberto.bosi@unifi.it

Key words: allogeneic transplantation,

double cord blood transplantation, graft-versus-host disease, total nucle-ated cells, human leukocyte antigen matching.

SUMMARY

In the last twenty years, the possibilities for transplantation have increased considerably with the introduction of alternative stem cell sources such as cord blood. The biggest benefits are the increase in availability of cord blood and the possibility to transplant units with more than one human leukocyte antigen mismatch, even if the dose cell limi-tation is critical, especially in adult transplants. The use of double cord blood units is one of the potential strategies that seem to overcome the cell dose limitation, improving engraftment and final transplant outcome.

◗◗◗ INTRODUCTION

Hematopoietic stem cell transplan-tation (HSCT) using peripheral blood, cord blood, or bone marrow is used to treat a wide variety of genetic and immunological disorders and hema-tologic and solid organ malignancies (1). Cord blood (CB) has been increas-ingly used in the last ten years as an alternative source of hematopoietic

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The biggest benefits are the increased availability of cord blood and the pos-sibility of transplanting units with more than one HLA mismatch, even if the dose cell limitation is critical, especially in adult transplants.

The experience gained and advanc-es in supportive care have led to an improvement in outcomes after UCB transplantation (UCBT). In the setting of myeloablative conditioning regimens, large retrospective analyses showed comparable outcomes in UCBT and adult unrelated donor peripheral blood stem cell or bone marrow (BM) transplantation for adult patients with hematologic malignancies (6). Impor-tant advantages of UCB include a low incidence of graft-versus-host disease (GVHD), despite a high degree of HLA mismatch (7-10); acute GVHD occurs with lower frequency after UCBT com-pared with that observed after HLA-matched marrow from unrelated do-nors (11).

Retrospective and prospective stud-ies have shown that unrelated donor UCBT:

1. reconstitutes hematopoiesis and achieves sustained engraftment, but with delayed myeloid recovery; 2. is associated with a low incidence

of GVHD;

3. does not result in a higher relapse risk and has similar survival rates to other sources of allogeneic HSCT. Because GVHD has been linked to re-lapse (12), there were initial concerns regarding the graft-versus-leukemia (GVL) potency of UCB. However, this has largely been resolved by single institution and registry studies, demon-strating a similar relapse risk compared with other HSC sources, including BM

and PB (6, 12-14). Several studies have shown that cell dose is a critical de-terminant of hematopoietic recovery, transplant-related mortality (TRM), and overall survival after UCB transplant, which translates into increased risk of graft failure (15), delayed hematopoi-etic engraftment (13-16), and delayed immune reconstitution (17-18).Almost all series concerning UCBT in children and adults from unrelated donors have demonstrated the profound impact of cell dose, measured as pre-freeze or infused total nucleated cells (TNC), colony-forming cells, and CD34+ cells on engraftment, transplant-related events, and survival. Transplantation of a single UCB unit containing a pre-freeze cell dose of 2.5x107 nucleated cells per kilogram, or an infused CD34 cell dose of 1.7x105 nucleated cells per kilogram, has been associated with poor engraftment, high non-relapse mortality (NRM) and poor survival (19). The cumulative incidence of non-en-graftment after UCB transplantation varies from 10% to 20% and the median time to neutrophil recovery varies from 22 to 27 days. There is growing consen-sus that a UCB cell dose of 2.5x107/kg represents the threshold of cryopre-served nucleated cells necessary for consistent engraftment (8, 9, 14). Al-though this cell dose is achievable with a single UCB unit for children, it is often not possible for adult recipients.

Many different approaches have been explored to improve the engraft-ment. Examples include injecting cord blood cells directly into the bone mar-row (20), in vivo o ex vivo amplification of cord blood cells (21, 22), use of re-duced intensity conditioning (RIC) reg-imen (23, 25), co-infusion with a haploi-dentical T-cell depleted graft (26, 27)

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or mesenchymal stem cells (28), and use of double unit UCB transplantation (29).

◗◗◗ DOUBLE CORD BLOOD TRANSPLANTATION

Given that cell dose and HLA dispari-ties are important and independent factors associated with outcomes, it has been suggested that both factors interact mutually on engraftment and on other outcomes. Thus, a higher cell dose in the graft could partially over-come the negative impact of HLA for each level of HLA disparity, but this hy-pothesis has not been yet fully demon-strated.18 The use of double cord blood units is one of the potential strategies that seems to overcome the cell dose limitation, improving engraftment and final transplant outcome. The meth-od of transplanting 2 partially HLA-matched UCB units to overcome the cell-dose barrier was pioneered at the University of Minnesota (24, 29)and ad-opted by others to extend the applica-tion of UCB transplantaapplica-tion.

Multiple reports confirm high rates of engraftment and promising survival outcomes after double UCB trans-plantation (23, 24, 29-33). Rates of sustained engraftment of 85-100% are reported after double UCBT, both after myeloablative and non-myeloablative conditioning regimens. The number of adult patients transplanted with UCBT has increased following the use of RIC regimen and double CB transplants. The Minnesota group has evaluated the efficacy of UCB in the setting of a non-myeloablative regimen consisting of fludarabine (200 mg/m2), cyclophos-phamide (50 mg/kg) and a single

frac-tion (200 cGy) of total body irradiafrac-tion with cyclosporin and mycophenolate mofetil for post-transplantation immu-noprophylaxis (23).The target cell dose for the UCB graft was 3x107 nucleated cells/kg, resulting in the selection of a second partially HLA-matched UCB unit in 85%. Data reported to the Center for International Blood and Marrow Trans-plant Research (CIBMTR) suggest that the numbers of double UCB transplan-tations being performed are increas-ing and that these now account for approximately 80% of UCB transplan-tations for adults in the United States. The decision to infuse 2 UCB units var-ies between institutions (34-36). Of the 947 cord blood transplants performed in Italy from 2000 to 2012, 908 were single and 39 were double (GITMO). In Europe, 9300 cord blood transplants were performed from 1988 to 2012, of which 1900 were derived from double cord blood units (Eurocord). These data underline the fact that, in Italy, 4% of cord blood transplants were per-formed using double units, while in Eu-rope this procedure has become more established, accounting for 20% of all cord blood transplants (Figure 1). Remarkably, sustained hematopoi-esis is usually derived from a single donor, and one of the CBUs disap-pears or does not engraft at all. In most patients, single-donor chimerism is generally documented within three months post transplantation, but may occur even earlier (23). The mecha-nism of predominance of a particular unit, however, has not yet been clari-fied. Several explanations have been brought forward, including immuno-logical rejection and insufficient cell viability. Some authors have shown that unit predominance may also be

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Figure 1 • Single and double cord blood (CB) transplantations carried out in Europe and in Italy. Europe CB transplantation 1988-2012 CB tot = 9300 CB double = 1900 (20%) Italy CB transplantation 2000-2012 CB tot = 947 CB single = 908 CB double = 39 (4%)

influenced by post-thaw viability (37), length of time between the infusion of the 2 UCB units (38), and ex vivo expansion (39, 40). Ramirez et al. sug-gest that, following dUCBT with 2 un-manipulated units of similar quality (as measured by viability) infused within a short interval (≤30 min), the main de-terminants of UCB predominance are CD3+ cell dose and, in the setting of nonmyeloablative conditioning, HLA-matching (41). Also T cells can medi-ate predominance after dUCBT as de-scribed in smaller numbers of patients (42-44). Gutman et al. showed that, after dUCBT, a subset of CD8+ memory T cells derived from the engrafting unit rapidly emerged after transplant and produced interferon-γ in response to the non-predominant UCB unit (47). Many factors, related to the UCB unit and environment, play a role in long-term unit predominance after dUCBT. Despite evidence suggesting an im-munologically mediated mechanism

underlying unit predominance, there are several questions that remain to be answered (41).

Incidence and severity of GVHD, re-lapse rate and TRM, both after standard myeloablative or reduced intensity regimen, in double UCB transplanta-tions versus single unit are matters of debate. Reports from a single institution suggest a higher risk of grade 2 acute GVHD and lower risk of relapse after double UCB transplantation in patients with acute leukemia (45)(Table 1) (15, 44-48). A potential mechanism for the observed increase in acuteGVHD after double UCBT may be the higher cell dose and the fact that the increased risk of acute GVHD was predominant-ly limited to the skin (44). While there was more stage III skin acute GVHD after double UCBT, incidences of liver and gastrointestinal tract acute GVHD were similar. Interestingly, the grade II acuteGVHDobserved in double UCBT in the MacMillan study was associated

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with lower TRM (44) (Table 1). While the mechanism for this is unclear, it is possi-ble that lower TRM is principally related to the higher cell dose associated with double UCBT with an effect that is in-dependent of acute GVHD.

So far, there have been several reports from single centers (30-33),and one multicenter phase II clinical trial (45), that demonstrate the potential effec-tiveness of double UCB transplanta-tion for adults with hematologic malig-nancies. Rocha and colleagues report lower risk of relapse after double UCB compared with single UCB transplan-tations for patients with acute leuke-mia in first but not in second CR (46) (Table 1). Double-unit UCB transplants after myeloablative conditioning regi-menshave been linked with lower re-lapse rates than other donor types, though they are also associated with longer time to hematopoietic engraft-ment and subsequent higher rates of NRM compared to reduced RIC. In a recent study, members of the

Euro-cord network showed that the use of double-unit UCB transplants was as-sociated also with an improved leu-kemia-free survival compared with single UCB transplants in the acute leukemia setting of patients using re-duced intensity conditioning regimen (47)(Table 1). Also Verneris and col-leagues report lower relapse risks in patients with acute myeloid leukemia or acute lymphoblastic leukemia who received transplants in first or second CR after double UCB compared with single UCB transplantation (45). How-ever, neither report (45, 46, 49) demon-strated differences in overall or leuke-mia-free survival (Table 1). These data suggest that the use of 2 UCB units is associated with an enhanced GVL ef-fect.

Although recipients of 2 UCB units re-ceived significantly more T cells than single-unit patients, neither T-cell dose nor age was associated with grade II-IV acute GVHD. Some authors specu-late that increased alloreactivity may TABLE 1 • Relapse rates and leukemia-free survival after double umbilical cord blood (UCB) compared with single UCB transplantation.

Single cord

blood unit Double cord blood unit References

aGvHD II-IV ↑ MacMillan et al., 2009 (44)

GVL effect ↑ Verneris et al., 2009 (45)

Incidence of relapse

at 2 years (CR1-CR2) ↑

=

Verneris et al., 2009 (45)

Saccardi et al., 2012 (15); Rocha, 2010 (46) (CR1 only); Rocha, 2013 (47)

Scaradavou, 2013 (48) 2γ-LFS in AL (RIC in CR1) ↑ Saccardi et al., 2012 (15)

TRM =

= Scaradavou, 2013 (48)

MacMillan et al., 2009 (44) (at 1 year)

aGvHD, graft-versus-host disease; GVL,graft-versus-leukemia; CR, complete response; LFS, leukemia-free survival; AL, acute leukemia; RIC, reduced intensity conditioning; TRM, transplant-related mortality.

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be induced by the graft-graft interac-tion between the 2 UCB units, and this may be responsible for the apparent reduction in the risk of relapse follow-ing double UCB transplantation. How-ever, the mechanism of this and the ef-fect or cell population remain unclear (45). These results may suggest that double UCB transplant results in better disease control than either single-unit UCB transplant or more conventional sources (i.e. BM or PB from unrelated donors). However, prospective clini-cal trials are required to confirm this. In contrast to what has been reported by others, Scaradavou et al. did not ob-serve significant differences in relapse risks or overall mortality after single and double UCB transplantations (Table 1), while mortality risks were higher for patients who received transplants in relapse and second or third CR com-pared to those who received trans-plants in first remission, showing that the most important determinant of sur-vival after transplantation of double or single UCB units was disease status at transplantation (48).

The risk of TRM was associated with the overall degree of HLA disparity. Only an estimated 25% of adults will be able to find a suitable single UCB unit, and studies on the safety and effectiveness of double UCB unit transplantations are underway to address the obstacle pre-sented by cell-dose. In the absence of a randomized clinical trial, when an 8/8 HLA-matched unrelated adult donor is not available and when a transplant is needed urgently, possible options are the use of 4-6/6 HLA matched unre-lated UCB or the infusion of 2 partially HLA-matched UCB units that could ef-fectively create an adequately dosed graft for patients lacking access to a

single UCB unit containing 2.5 107 TNC/ kg or more (50).

Having established that UCB is a suit-able alternative source, and that trans-plantation of 2 UCB units is a safe and efficient way to extend transplantation to the many adults with leukemia who lack a single UCB with an adequate TNC, early referral for transplantation will likely improve survival.

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