Analysis of Risk Factors of Cord Blood Transplantation for Children

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1 Pediatr Blood Cancer 2013;60: Analysis of Risk Factors of Cord Blood Transplantation for Children Gal Goldstein, MD, 1 * Bella Bielorai, MD, 1 Jerry Stein, MD, 2 Polina Stepensky, MD, 3 Ronit Elhasid, MD, 4 Irena Zaidman, MD, 4 Angela Chetrit, MSc, 5 Isaac Yaniv, MD, 2 Arnon Nagler, MD, 6,7 and Amos Toren, MD, PhD 1 Background. As cord blood (CB) is being used frequently as a source for heamtopoetic stem cell transplantation defining risk factors for transplantation outcome is an important issue. Procedure. The data of all single unit CB transplantation preformed in Israel from 1992 to 2011 were collected. The risk factors for myeloid engraftment, event free survival (EFS) and overall survival (OS) were studied in 87 children. Results. There were 49 children with hematological malignancies and 38 with non-malignant diseases. Cumulative rate of neutrophil recovery was 78.3%, while median time to myeloid recovery was 26 days. The incidence of platelet engraftment at 150 days was 53%, and the median time to platelet recovery was 36 days. ABO blood group matching between CB unit and recipient was associated with superior myeloid engraftment. Acute graft versus host disease of grades II IV occurred in 33% of the patients. Chronic graft versus host disease occurred in 16% of patients. Probabilities of EFS and OS at 1 year were 45% and 57%, respectively. Factors associated with inferior OS were Rh major mismatch versus matched Rh and transplantation from unrelated donor versus related donor. Conclusions. These results indicate that matching of ABO blood groups is an important factor that affects engraftment, and also that Rh matching seem to have an impact on OS, which was not previously described in the setting of CB transplantation. Pediatr Blood Cancer 2013;60: # 2013 Wiley Periodicals, Inc. Key words: blood; children; cord; transplantation INTRODUCTION In the last three decades, cord blood (CB) has become a viable option as a graft source for hematopoetic stem cell transplantation (HSCT). The fact that a less stringent human leukocyte antigen (HLA) matching is required for transplantations from CB made it possible to use it as an alternative graft source when a suitable matched donor could not be found [1]. Since each CB unit contains limited amount of stem cells, transplantation from a single unit is usually reserved for children [2]. Using CB as a graft source for HSCT in children is considered feasible and safe both in malignant and non-malignant diseases [3 7]. Its main setbacks are relatively high rates of graft failure and delayed myeloid engraftment [8]. Both contribute to considerable treatment related mortality rates. Since the usage of CB as a graft source for HSCT is expanding rapidly, defining risk factors for such transplantation is of paramount importance. As in other graft sources, blood group incompatibilities between CB and host, may affect transplantation outcome. There is conflicting evidence regarding the importance of these incompatibilities [1,4]. We performed a retrospective analysis of all the HSCTs from CB that were done in children in Israel. Our aim was to analyze the risk factors for myeloid engraftment, event free survival (EFS) and overall survival (OS). Specifically we wanted to assess the importance of ABO and Rh matching as prognostic factor for transplantation outcome. PATIENTS AND METHODS Data were collected retrospectively from the medical records of the patients. The study was approved by the IRB committees of the participating centers. We included all the patients under the age of 18 year who underwent CB transplantation in Israel from July 1994 to June CB from unrelated donors was used when neither sibling donor nor matched unrelated bone marrow donor could be found within a reasonable frame of time, in accordance with the clinical condition of the patient. Although in some cases additional alleles were analyzed, we regarded the degree of matching of HLA only in A and B (either serology in a minority of CB units, or DNA typing in most of them), and in DR (DNA typing). C 2013 Wiley Periodicals, Inc. DOI /pbc Published online 26 August 2013 in Wiley Online Library (wileyonlinelibrary.com). Analysis End Points and Definitions Primary end points for analysis in this study included myeloid engraftment, graft versus host disease (GVHD), OS, and EFS. To be evaluable for myeloid engraftment, patients had to survive to day 30. Myeloid engraftment was defined as the first of 3 days of a sustained absolute neutrophil count >500/ml, and the time to platelet engraftment as the first of the seven consecutive days of platelet counts of /L or higher without platelet transfusion. Acute and chronic GVHD were defined according to standard criteria [9]. We defined severe acute GVHD as grades II IV. Patients that had neutrophil engraftment and survived to day 30 after transplant were evaluable for acute GVHD and those surviving beyond day 100 after transplant were evaluable for chronic GVHD. Events were defined as graft failure/rejection, leukemic relapse after engraftment or death. Secondary endpoints were association between pre-transplant parameters of patients, CB units, degree and types of mismatching between them, and conditioning regimens, to myeloid engraftment, EFS and OS. Major mismatch of ABO or Rh blood groups was defined as the existence of an antigen on the donor red blood cells with its absence on the recipient s cells. Minor 1 Department of Pediatric Hemato-Oncology and Bone Marrow Transplantation, The Edmond and Lily Safra Children s Hospital, Ramat Gan, Israel; 2 Department of Pediatric Hematology Oncology and Stem Cell Transplantation, Schneider Children s Medical Center of Israel, Petach Tikva, Israel; 3 Department of Pediatric Hemato- Oncology, Hadassah Medical Center, Jerusalem, Israel; 4 Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel Aviv, Israel; 5 Cancer and Radiation Epidemiology Unit, Gertner Institute for Epidemiology and Health Policy Research, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; 6 Hematology Division, Chaim Sheba Medical Center, Ramat Gan, Israel; 7 Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel Conflict of interest: Nothing to declare. Correspondence to: Gal Goldstein, Department of Pediatric Hemato- Oncology and Bone Marrow Transplantation, The Edmond and Lily Safra Children s Hospital, Israel. galgolds@gmail.com Received 2 December 2012; Accepted 18 April 2013

2 2008 Goldstein et al. mismatch was defined as the absence of an antigen on the donor cells with its existence on the recipient s cells. Bidirectional ABO mismatch was defined as the existences of an antigen on the donor red blood cells with its absence on the recipient s cells but, at the same time existence of an antigen on the recipient red blood cells with its absence on the donor s cells. Statistical Analysis Associations of categorical study parameters with engraftment were tested using the Chi-square statistic test or Fisher s exact test (when needed), while the unpaired t-test was used for continuous variables. The risk for engraftment by cell dose and ABO-mismatch and for OS by Rh-mismatch was calculated using Kaplan Meier survival analysis, and the difference between the survival curves was tested using the log-rank test. The Cox proportional hazard model was used to study variables that were significantly and independently associated with the outcomes. Variables found to be associated with the outcomes studied in the univariate analysis at a level of P-value of 0.15 or less, were entered into the multivariate analysis. Age and gender were included in the models regardless of their association with the outcome. All of the statistical analyses were done with Statistical Analysis System software version 9.1 (SAS Institute, Inc., Cary, NC). Statistical significance was set at P < 0.05, using two-tailed tests. TABLE I. Patient and Disease Characteristics (N ¼ 87) Characteristics No. % Age at transplantation Median 4 years Range 6 weeks to 14.5 years Male Recipient CMV positive Diagnosis at transplantation Malignant disease Acute lymphoblastic leukemia Acute myeloid leukemia Acute biphenotypic leukemia 3 3 Non-Hodgkin lymphoma 2 2 Chronic myeloid leukemia 1 1 Chronic eosinophilic leukemia 1 1 Juvenile myelo-monocytic leukemia 8 9 Myelodysplastic syndrome 2 2 Disease status at transplant (for acute leukemia and lymphoma only) CR CR CR3 2 6 Refractory disease 3 8 No data 1 3 Prior transplant Autologous 2 6 Haploidentical donor 1 3 Non-malignant disease Bone marrow failure Metabolic diseases Immune deficiencies Histiocytic disorders 3 3 Hemoglobinopathies 2 2 CMV, cytomegalo virus; CR, complete remission. RESULTS Pre-Transplantation Patient Characteristics A total of 89 children underwent CB transplantations from a single unit in five tertiary health care centers in Israel. Two of these patients were excluded because their data were not available. Patient and disease characteristics are summarized in Table I. Conditioning and GVHD Prophylaxis Regimens Graft and conditioning regimens are summarized in Table II. Conditioning regimens varied according to the transplant center. GVHD prophylaxis regimens were diverse and consisted mainly of combinations of cyclosporine alone or with mycophenolate, or prednisolone. No metothrexate was given as a GVHD prophylaxis. Median follow-up was 52 months. Myeloid and Platelet Engraftment The cumulative rate of neutrophil recovery by day 60 was 78.3%. Neutrophil recovery occurred at a median of 26 days (range 12 57). Platelet engraftment occurred at a median of 36 days (range 2 90). The incidence of platelet engraftment at 150 days was 53%. Seven patients died before day 30 without achieving neutrophil engraftment. In three cases, data was missing. Primary graft failure occurred in 23 patients (29.9%). Of these, 15 died, three are alive TABLE II. Donor, Graft and Transplant Characteristics (N ¼ 87) Characteristics No. % Donor Matched sibling Unrelated donor No. of HLA disparities 6/6 match /6 match /6 match No data 7 12 Cell dose, nucleated cells 10 7 /kg Median 6.1 Range Blood groups compatibility ABO matched ABO major mismatch ABO minor mismatch ABO bidirectional mismatch 6 7 Rh matched Rh major mismatch 9 10 Rh minor mismatch 6 7 Conditioning regimens Busulfan based TBI based Fludarabine based No conditioning (SCID patient) 1 1 Use of ATG ATG, anti-thymocytic globulin; SCID, severe combined immune deficiency.

3 Risk Factors in Cord Blood Transplantation 2009 TABLE III. Distribution of Study Characteristics by Myeloid Engraftment After Cord Blood Transplantation for Children Not engrafted Engrafted Variable # % # % Age (mean SD, years) Recepient gender Male Female Diagnosis Non-malignant Malignant Conditioning Non-myeloabltive Busulfan based TBI ATG Yes No Donor Sibling Unrelated Male Female No data HLA MM Full match MM MM No data Cell dose, 10 7 nucleated cell/kg > No data ABO mismatch Matched Major and minor MM Bidirectional 1 5 P-value after a second transplant, three are alive after their disease recurred (Chronic Granulomatous Disease, Gaucher, and Thalassemia), and two were lost to follow-up. Secondary graft failure occurred in one patient with Hurler syndrome and in eight patients with malignant diseases. Table III presents the univariate analysis of the study characteristics on myeloid engraftment. In a multivariate analysis an association between major ABO mismatch versus matched (Table IV) and lower incidence of myeloid engraftment (Fig. 1) was found. There was also an association of borderline statistical significance between cell dose of more than /kg compared to cell dose less than /kg (Table IV) and myeloid engraftment. In a multivariate analysis, no association was found between HLA matching and myeloid engraftment. Mortality Forty-one patients died. Fifteen of these died after primary graft failure, among them five after a second transplant. The main cause of death was graft failure. It occurred in the non-malignant diseases setting in seven cases. Twelve cases relapsed. The principal causes of treatment related mortality were infections (bacterial n ¼ 4, and fungal n ¼ 1) and GVHD (n ¼ 5). GVHD Seventeen (32.6%) and 14 (26.9%) of the 52 patients assessable had acute GVHD of grades II IVand III IV, respectively. Fifteen of the 43 patients assessable had chronic GVHD (34.8.6%). Seven had limited disease (16.2%) and eight had extensive chronic GVHD TABLE IV. Multivariate Analysis for Myeloid Engraftment After Cord Blood Transplantation for Children OR 95% CI P-value Recepient gender (male vs. female) Age (continuous) Cell dose (>3.5 vs NC/kg) ABO incompatibility Major MM vs. matched Minor MM vs. matched Bidirectional vs. matched

4 2010 Goldstein et al. Fig. 1. Myeloid engraftment according to ABO matching. Fig. 2. Overall survival according to Rh matching. (18.6%). Cumulative incidence of acute and chronic GVHD could not be evaluated due to absence of data. Survival The probability of EFS was 45% at 1 year and 40.5% at 2 years. No factor had a significant impact on EFS, but some showed a trend towards superior EFS. These were cell dose above nucleated cells (NC)/kg versus less than NC/ kg (HR 0.57, 95% CI ; P ¼ 0.09), and matched Rh versus major Rh mismatch (HR % CI ; P ¼ 0.1; Fig. 2). OS at 1 year was 56.1% and 54.6% at 2 years. Factors associated with inferior OS included: Rh major mismatch versus matched Rh (HR 2.89, 95% CI , P ¼ 0.01) and transplantation from unrelated donor versus related donor (HR 2.81, 95% CI , P ¼ 0.03). In a multivariate analysis, no associations were found between HLA matching and OS or EFS. DISCUSSION Our main findings in this retrospective multicenter study was that there was a better OS in CB transplantation of matched versus major Rh blood groups incompatibility. This is the first report of the impact that such blood group incompatibility has on CB transplantation outcomes. We have also found that matching of ABO was associated with improved myeloid engraftment and that there was a better OS in transplantation from related versus unrelated donor. There is evidence that major ABO incompatibility increases the risk for hemolytic events and red blood cell transfusion requirements post transplantation [10 11]. Although controversial, some studies have shown that ABO incompatibility also affects GVHD occurrence, myeloid engraftment, EFS, and OS [12 27]. ABO incompatibility is a significant negative factor for myeloid engraftment in unrelated CB transplantation and also in related donor CB transplantation for children [22]. This negative effect could be explained, as suggested by other authors, by the binding of anti A or B antibodies to the A or B antigens that were either adsorbed or expressed on myeloid precursors of the CB [23,27]. ABO major incompatibility has been described to be associated with decreased OS and DFS in CB transplantation for adults and children [12,4]. Such incompatibility was also found to be associated with higher treatment related mortality after reduced intensity conditioning-cb transplantation in adults with hematological malignancies [28]. The impact that ABO incompatibility may have on myeloid recovery in BM transplantation setting is a matter of debate. While there are several studies that did not find a correlation between ABO incompatibility and myeloid engraftment [11,14,29,30], others showed that major mismatch correlates with longer time to engraftment [16,31]. These were performed mostly on malignant, but also on non-malignant, diseases. The conditioning regimens were myeloablative, non-myeloablative and reduced intensity, and graft source was peripheral blood, bone marrow, and small numbers of CB. With regard to CB transplantation several studies did not show any effect of ABO incompatibility on transplantation outcome [1,32]. We can postulate that major ABO incompatibility may affect myeloid engraftment by stimulating cytokine production, as a consequence of a hemolytic event occurring shortly after graft transplantation. This may activate the remnants of the immune system of the host against myeloid precursors of the graft. Another interesting finding was the impact of major Rh incompatibility on transplantation outcome. Except for a single report of Erker et al. [33] this type of incompatibility usually is not considered to be a risk factor in HSCT. This finding was later challenged by Wirk et al. [34] that published a contradictory work. Although our work supports Erker et al. data, we could not find an explanation for it. In spite of the fact that there were only nine cases of major Rh incompatibility we believe that this question is relevant and should be studied further in larger cohorts of CB transplantation. As has been widely recognized in previous work, we found that low cell dose correlated to a trend of poor EFS [5,12,35 37]. In the group of the non-malignant diseases engraftment was achieved in 58% of the cases compared to 72% in the malignant diseases; however, survival was worse in latter group. We also found a statistically insignificant difference (P ¼ 0.3) in engraftment rate between the related group (79%) versus the unrelated CB group (60%). All the patients with the malignant diseases who received a graft from a sibling engrafted (n ¼ 8), with two cases of relapse, comparable to the unrelated group in which six relapses occurred. A graft from related CB was associated with better OS compared to unrelated CB. This is not surprising with respect to the HLA and minor antigens mismatch that every unrelated transplantation bears. These may interfere with

5 Risk Factors in Cord Blood Transplantation 2011 engraftment, pose a greater risk due to immune suppression and increase the likelihood of severe GVHD. Although not statistically significant in univariate analysis we have noticed a higher engraftment rate in the malignant disease group compared to the non-malignant group (P-0.1). There was a relatively high rate of graft failure in the non-malignant group (40%). This could be explained by the fact that 16 of 30 (44%) evaluable CB units in that group had a cell dose below the threshold recommended by Eurocord for CB transplantation in the nonmalignant disease setting NC/kg [8]. In comparison in only 12% of the transplantations in the malignant diseases group cell dose was below a dose of NC/kg. Although most patients of the unrelated group were mismatched with their CB donors at one or two HLA loci (45% and 20%, respectively), the incidence of acute GVHD II was comparable with that reported in several other studies on children [1,22,35]. The occurrence of chronic GVHD was slightly higher than reported in some of the studies of CB transplantation. Of note is the fact that some of these studies included only patients with extensive GVHD while others did not state if limited disease was also included. In 25 of the transplantations in this study, the conditioning regimens used were not myeloablative. We noted a similar engraftment, GVHD, EFS, and OS in this group of patients. The different conditioning regimens limited our ability to identify a preferable preparative regimen. Our study has some limitations, mostly related to the fact that it is retrospective. The wide variety of diseases, different conditioning, and GVHD prophylaxis regimens, limit the ability to draw precise conclusions. Our study reiterates the importance of a minimum cell dose in CB transplantation. The superior results of related versus unrelated CB transplantation in our study may stress the importance of CB collection from a sibling in families in which an offspring has a disease that is potentially treatable by HSCT. Our results indicate that matching of Rh blood groups is important in CB transplants. This observation will need to be studied in a larger cohort of patients. REFERENCES 1. Gluckman E, Rocha V. Donor selection for unrelated cord blood transplants. Curr Opin Immunol 2006;5: Davey S, Armitage S, Rocha V, et al. The London Cord Blood Bank: Analysis of banking and transplantation outcome. Br J Haematol 2004;125: Michel G, Rocha V, Chevret S, et al. Unrelated cord blood transplantation for childhood acute myeloid leukemia: A Eurocord Group analysis. 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