Pediatr Transplantation 2015: 19: 399–407
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12458
Matched related donor hematopoietic stem cell transplantation results in a long-term follow-up of a pediatric acquired severe aplastic anemia subset: A stem cell source perspective Hamidieh AA, Mozafari M, Noshad S, Alimoghaddam K, Behfar M, Ghavamzadeh A. (2015) Matched related donor hematopoietic stem cell transplantation results in a long-term follow-up of a pediatric acquired severe aplastic anemia subset: A stem cell source perspective. Pediatr Transplant, 19: 399–407. DOI: 10.1111/petr.12458. Abstract: HSCT has substantially improved pediatric acquired SAA patients’ outcomes. Retrospectively, we attempted to assess the outcome of MRD HSCT in 65 pediatric patients referred to a single center from 1992 to 2012. We were particularly interested to find out whether source of SC (PB, n = 40 and BM, n = 25) significantly impacts EFS and GVHD incidence. With a median follow-up of 45 months, total EFS was 87.7%; EFS for PB and BM groups was 87.5% and 88%, respectively. Acute GVHD (grades 3–4) occurred in 13 patients (PB, n = 10 [25%] and BM, n = 3 [12%]), acute GVHD (grades 2–4) occurred in 24 (PB, n = 16 [40%] and BM, n = 8 [32%]). Extensive chronic GVHD occurred in five patients (PB, n = 3 [7.5%] and BM, n = 2 [8%]). Cox regression revealed that elapsed time of 0.5 9 109/L and platelet recovery acknowledged as the primary happening of seven sequential days with a platelet count ≥20 9 109/L and no transfusion auspices. Donor chimerism is dubbed “complete” when ≥95% of donor cells are identified in the recipient’s BM or PB and when >5% and 20 units was the only significant predictor (p = 0.013). Of note, delayed diagnosis-to-transplant interval was also associated with extensive cGVHD incidence, but p value failed to reach statistical significance (p = 0.060). When placed in hazard regression models, neither were significant predictors of extensive cGVHD, however. As evident in Table 4, source of SC did not influence the probability of either aGVHD (grades 3–4) or extensive cGVHD occurrence (p = 0.121, and 0.487, respectively). Discussion
Once conferring survival to only half of its pediatric SAA affiliates (37), MRD-HSCT has produced much better figures globally as recent multiple reports show OS rates ranging from 79% to 100% (20, 24, 38, 39). Our pediatric acquired SAA subset exhibited an EFS (as OS = EFS in our subset) rate of 87.7%, which is in-sync with the aforementioned literature. The spurt noticed in these years regarding OS rates could be attributed to boosts of accessory care in terms of quality and application of cutting-edge conditioning regimens that have cornered malevolent situations such as GVHD and graft rejection (17). Some entities have been suggested by distinct authors to positively influence the survival derived from HSCT for SAA including shorter time-to-transplant interval, PB or BM as choice of SC, younger recipient age at HSCT, decremented pre-HSCT transfusions, no antecedent IST, MRD transplantation, excluding irradiation from preparative regimens, and CY+ ATG as the conditioning protocol (4, 12, 16, 20, 24, 40–43). Our study highlighted a 403
Hamidieh et al. Table 3. Comparison of effects of different variables on EFS (OS = EFS) of patients after transplant Event (Death)/total Patient age at transplant ≤10 yr 2/17 >10 yr 6/48 Diagnosis-to-transplant interval ≤10 months 3/48 >10 months 5/17 Patient sex Female 1/19 Male 7/46 IST prior to referral for HSCT Yes 5/50 No 3/15 Pretransplant packed cell transfusion ≤15 units 2/45 >15 units 6/20 Pretransplant platelet transfusion ≤40 units 3/47 >40 units 5/18 Source of SCs BM 3/25 PB 5/40 Infused MNC cells ≤3.5 9 108/kg 4/25 >3.5 9 108/kg 4/40 Infused CD34+ cells ≤2.5 9 106/kg 6/32 >2.5 9 106/kg 2/33 Time to neutrophil engraftment 12 days 5/41 Chimerism Full 6/60 Mixed 2/5 aGVHD No/Grades 1–3 6/60 Grade 4 2/5 cGVHD No/Limited 6/60 Extensive 2/5 Donor age ≤18 yr 5/32 >18 yr 3/33 Donor-recipient sex match Match 4/36 Mismatch 4/29 Donor-patient relationship Siblings 7/57 Other relatives 1/8 Donor-recipient major blood group match, n (%) Match 3/34 Mismatch 5/31 Donor-recipient Rh group match, n (%) Match 6/56 Mismatch 2/9
p value
0.969
0.007
0.293
0.199
0.005
0.036
0.938
0.284
0.164
0.557
0.171
0.051
0.051
0.077
0.457
0.710
0.905
0.303
0.377
diagnosis-to-HSCT interval of more than 10 months to significantly decline the chance of survival (Fig. 1b). Bacigalupo et al. have pro404
posed a “window period” of 114 days considering the length of time between diagnosis and HSCT for significant perturbation of OS, and Gupta et al. have set three months as the cutoff point (12, 41). In our study, patients transfused with more than 40 and 15 platelet and packed cell units, in order, obtained a significant reduction in EFS based on K–M analysis but these findings came short of duplicating in multivariate analysis, while an excess of 20 transfusions has been accompanied with a higher post-HSCT mortality rate. (44) Considering OS, two separate studies have acknowledged a negative role for pre-HSCT treatment (24, 40). Nonetheless, our assessment did not display any significant relation between IST prior to referral for HSCT and EFS, as Konopacki et al. disclosed the same outcome, and these researchers were not successful in reproducing a significant link between previous transfusions and OS, either (45). The interrelation between the source of SC applied in HSCT and OS, and GVHD risk is commonly reviewed in SAA-related works (12– 16). SAA patients 15 yr 2/25 Diagnosis-to-transplant interval ≤5 months 5/25 0.780 >5 months 8/40 Patient sex Female 5/19 0.453 Male 8/46 IST prior to referral for HSCT Yes 6/50 0.093 No 7/15 Pretransplant packed cell transfusion ≤20 units 9/50 0.496 >20 units 4/15 Pretransplant platelet transfusion ≤40 units 8/47 0.583 >40 units 5/18 Source of SCs BM 3/25 0.320 PB 10/40 Time to neutrophil engraftment 15 days 8/22 Donor age ≤18 yr 8/32 0.422 >18 yr 5/33 Donor-recipient sex match Match 6/36 0.344 Mismatch 7/29 Donor-patient relationship Siblings 11/57 0.753 Parents/Other relatives 2/8 Donor-recipient major blood group match, n (%) Match 5/34 0.164 Mismatch 8/31 Donor-recipient Rh group match, n (%) Match 13/56 0.139 Mismatch 0/9
were 20% and 26.15% (limited = 18.5% – extensive = 7.7%), in order, and comparable to above-cited articles. In our retrospective study, patients supplied with more than 20 packed cell units before HSCT were put at greater risk of extensive cGVHD, albeit with no significant repetition in multivariate analysis and this held true for other significant associations with GVHD in K–M. It should be noted that even though an inclination toward happening of grades 3–4 aGVHD and extensive cGVHD existed among ISTna€ıve patients (p = 0.199, p = 0.093 and p = 0.156, respectively), no statistical significance was established in our analyses. Like the fate of
OS, GVHD occurrence did not significantly correlate with previous treatment in Konopacki et al.’s study (45). A few notes are worth mentioning; first of all, as PB-HSCT is technically less troublesome and can provide a larger quantity of SCs comparing to BM-HSCT, these features pertaining to PBHSCT could have explained the superior numbers of PB-HSCTs in our center (40 PB-HSCTs vs. 25 BM-HSCTs). Second, we are a large, university-affiliated, referral center. Our center is the only center in the country that contains a specifically designed pediatric HSCT unit. Therefore, the number of HSCTs performed in our center regarding pediatric acquired SAA represents the total HSCTs carried out for eligible pediatric acquired SAA patients in the whole country with a good approximation. But, it should also be reiterated that the number of our patients is relatively small and this has limited our study and studies with larger number of patients can validate or reconfirm our results. Finally, aGVHD (grades 3–4) and extensive cGVHD are lethal forms of GVHD that should be focused on, aGVHD (grades 1–2) does not cause fatalities frequently and limited cGVHD effects diminish eventually, respective patients do not face serious problems, and quality of life is not altered. It is the extensive form of cGVHD that makes a significant clinical impact on pediatric acquired SAA patients, and in our analysis, we focused on extensive cGVHD, not limited cGVHD and maybe the difference witnessed between cGVHD numbers reported by us, and other authors could be related to the inclusion of limited cGVHD by these transplant specialists when reporting the cGVHD figures. Conclusively, we have provided an EFS rate of 87.7%, accompanied by a median follow-up span of 45 months for our SAA subset. We have also shown a longer than 10 months diagnosis-toHSCT interval to be associated with a higher mortality rate. This finding must be validated via large sample-size clinical trials that are randomized, multicenter, and prospective in nature. Based on our observation, no significant difference existed between PB-HSCT and BM-HSCT in terms of EFS and aGVHD (grades 3–4) and extensive cGVHD risk and this finding should be further delved into via separate research teams. The latter finding can potentially alternate our attitude toward PB-HSCT in pediatric acquired SAA patients and given that PB-HSCT is practically less difficult compared to BM-HSCT, it should be an area of further debate and exchange of ideas among transplant specialists in the future. 405
Hamidieh et al. Acknowledgments We would also like to extend our thanks to the pediatric transplant nursing team for their invaluable assistance in this study.
17.
Conflict of interest
18.
Authors declare that they do not have any potential conflict of interests. 19.
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© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12458
Matched related donor hematopoietic stem cell transplantation results in a long-term follow-up of a pediatric acquired severe aplastic anemia subset: A stem cell source perspective Hamidieh AA, Mozafari M, Noshad S, Alimoghaddam K, Behfar M, Ghavamzadeh A. (2015) Matched related donor hematopoietic stem cell transplantation results in a long-term follow-up of a pediatric acquired severe aplastic anemia subset: A stem cell source perspective. Pediatr Transplant, 19: 399–407. DOI: 10.1111/petr.12458. Abstract: HSCT has substantially improved pediatric acquired SAA patients’ outcomes. Retrospectively, we attempted to assess the outcome of MRD HSCT in 65 pediatric patients referred to a single center from 1992 to 2012. We were particularly interested to find out whether source of SC (PB, n = 40 and BM, n = 25) significantly impacts EFS and GVHD incidence. With a median follow-up of 45 months, total EFS was 87.7%; EFS for PB and BM groups was 87.5% and 88%, respectively. Acute GVHD (grades 3–4) occurred in 13 patients (PB, n = 10 [25%] and BM, n = 3 [12%]), acute GVHD (grades 2–4) occurred in 24 (PB, n = 16 [40%] and BM, n = 8 [32%]). Extensive chronic GVHD occurred in five patients (PB, n = 3 [7.5%] and BM, n = 2 [8%]). Cox regression revealed that elapsed time of 0.5 9 109/L and platelet recovery acknowledged as the primary happening of seven sequential days with a platelet count ≥20 9 109/L and no transfusion auspices. Donor chimerism is dubbed “complete” when ≥95% of donor cells are identified in the recipient’s BM or PB and when >5% and 20 units was the only significant predictor (p = 0.013). Of note, delayed diagnosis-to-transplant interval was also associated with extensive cGVHD incidence, but p value failed to reach statistical significance (p = 0.060). When placed in hazard regression models, neither were significant predictors of extensive cGVHD, however. As evident in Table 4, source of SC did not influence the probability of either aGVHD (grades 3–4) or extensive cGVHD occurrence (p = 0.121, and 0.487, respectively). Discussion
Once conferring survival to only half of its pediatric SAA affiliates (37), MRD-HSCT has produced much better figures globally as recent multiple reports show OS rates ranging from 79% to 100% (20, 24, 38, 39). Our pediatric acquired SAA subset exhibited an EFS (as OS = EFS in our subset) rate of 87.7%, which is in-sync with the aforementioned literature. The spurt noticed in these years regarding OS rates could be attributed to boosts of accessory care in terms of quality and application of cutting-edge conditioning regimens that have cornered malevolent situations such as GVHD and graft rejection (17). Some entities have been suggested by distinct authors to positively influence the survival derived from HSCT for SAA including shorter time-to-transplant interval, PB or BM as choice of SC, younger recipient age at HSCT, decremented pre-HSCT transfusions, no antecedent IST, MRD transplantation, excluding irradiation from preparative regimens, and CY+ ATG as the conditioning protocol (4, 12, 16, 20, 24, 40–43). Our study highlighted a 403
Hamidieh et al. Table 3. Comparison of effects of different variables on EFS (OS = EFS) of patients after transplant Event (Death)/total Patient age at transplant ≤10 yr 2/17 >10 yr 6/48 Diagnosis-to-transplant interval ≤10 months 3/48 >10 months 5/17 Patient sex Female 1/19 Male 7/46 IST prior to referral for HSCT Yes 5/50 No 3/15 Pretransplant packed cell transfusion ≤15 units 2/45 >15 units 6/20 Pretransplant platelet transfusion ≤40 units 3/47 >40 units 5/18 Source of SCs BM 3/25 PB 5/40 Infused MNC cells ≤3.5 9 108/kg 4/25 >3.5 9 108/kg 4/40 Infused CD34+ cells ≤2.5 9 106/kg 6/32 >2.5 9 106/kg 2/33 Time to neutrophil engraftment 12 days 5/41 Chimerism Full 6/60 Mixed 2/5 aGVHD No/Grades 1–3 6/60 Grade 4 2/5 cGVHD No/Limited 6/60 Extensive 2/5 Donor age ≤18 yr 5/32 >18 yr 3/33 Donor-recipient sex match Match 4/36 Mismatch 4/29 Donor-patient relationship Siblings 7/57 Other relatives 1/8 Donor-recipient major blood group match, n (%) Match 3/34 Mismatch 5/31 Donor-recipient Rh group match, n (%) Match 6/56 Mismatch 2/9
p value
0.969
0.007
0.293
0.199
0.005
0.036
0.938
0.284
0.164
0.557
0.171
0.051
0.051
0.077
0.457
0.710
0.905
0.303
0.377
diagnosis-to-HSCT interval of more than 10 months to significantly decline the chance of survival (Fig. 1b). Bacigalupo et al. have pro404
posed a “window period” of 114 days considering the length of time between diagnosis and HSCT for significant perturbation of OS, and Gupta et al. have set three months as the cutoff point (12, 41). In our study, patients transfused with more than 40 and 15 platelet and packed cell units, in order, obtained a significant reduction in EFS based on K–M analysis but these findings came short of duplicating in multivariate analysis, while an excess of 20 transfusions has been accompanied with a higher post-HSCT mortality rate. (44) Considering OS, two separate studies have acknowledged a negative role for pre-HSCT treatment (24, 40). Nonetheless, our assessment did not display any significant relation between IST prior to referral for HSCT and EFS, as Konopacki et al. disclosed the same outcome, and these researchers were not successful in reproducing a significant link between previous transfusions and OS, either (45). The interrelation between the source of SC applied in HSCT and OS, and GVHD risk is commonly reviewed in SAA-related works (12– 16). SAA patients 15 yr 2/25 Diagnosis-to-transplant interval ≤5 months 5/25 0.780 >5 months 8/40 Patient sex Female 5/19 0.453 Male 8/46 IST prior to referral for HSCT Yes 6/50 0.093 No 7/15 Pretransplant packed cell transfusion ≤20 units 9/50 0.496 >20 units 4/15 Pretransplant platelet transfusion ≤40 units 8/47 0.583 >40 units 5/18 Source of SCs BM 3/25 0.320 PB 10/40 Time to neutrophil engraftment 15 days 8/22 Donor age ≤18 yr 8/32 0.422 >18 yr 5/33 Donor-recipient sex match Match 6/36 0.344 Mismatch 7/29 Donor-patient relationship Siblings 11/57 0.753 Parents/Other relatives 2/8 Donor-recipient major blood group match, n (%) Match 5/34 0.164 Mismatch 8/31 Donor-recipient Rh group match, n (%) Match 13/56 0.139 Mismatch 0/9
were 20% and 26.15% (limited = 18.5% – extensive = 7.7%), in order, and comparable to above-cited articles. In our retrospective study, patients supplied with more than 20 packed cell units before HSCT were put at greater risk of extensive cGVHD, albeit with no significant repetition in multivariate analysis and this held true for other significant associations with GVHD in K–M. It should be noted that even though an inclination toward happening of grades 3–4 aGVHD and extensive cGVHD existed among ISTna€ıve patients (p = 0.199, p = 0.093 and p = 0.156, respectively), no statistical significance was established in our analyses. Like the fate of
OS, GVHD occurrence did not significantly correlate with previous treatment in Konopacki et al.’s study (45). A few notes are worth mentioning; first of all, as PB-HSCT is technically less troublesome and can provide a larger quantity of SCs comparing to BM-HSCT, these features pertaining to PBHSCT could have explained the superior numbers of PB-HSCTs in our center (40 PB-HSCTs vs. 25 BM-HSCTs). Second, we are a large, university-affiliated, referral center. Our center is the only center in the country that contains a specifically designed pediatric HSCT unit. Therefore, the number of HSCTs performed in our center regarding pediatric acquired SAA represents the total HSCTs carried out for eligible pediatric acquired SAA patients in the whole country with a good approximation. But, it should also be reiterated that the number of our patients is relatively small and this has limited our study and studies with larger number of patients can validate or reconfirm our results. Finally, aGVHD (grades 3–4) and extensive cGVHD are lethal forms of GVHD that should be focused on, aGVHD (grades 1–2) does not cause fatalities frequently and limited cGVHD effects diminish eventually, respective patients do not face serious problems, and quality of life is not altered. It is the extensive form of cGVHD that makes a significant clinical impact on pediatric acquired SAA patients, and in our analysis, we focused on extensive cGVHD, not limited cGVHD and maybe the difference witnessed between cGVHD numbers reported by us, and other authors could be related to the inclusion of limited cGVHD by these transplant specialists when reporting the cGVHD figures. Conclusively, we have provided an EFS rate of 87.7%, accompanied by a median follow-up span of 45 months for our SAA subset. We have also shown a longer than 10 months diagnosis-toHSCT interval to be associated with a higher mortality rate. This finding must be validated via large sample-size clinical trials that are randomized, multicenter, and prospective in nature. Based on our observation, no significant difference existed between PB-HSCT and BM-HSCT in terms of EFS and aGVHD (grades 3–4) and extensive cGVHD risk and this finding should be further delved into via separate research teams. The latter finding can potentially alternate our attitude toward PB-HSCT in pediatric acquired SAA patients and given that PB-HSCT is practically less difficult compared to BM-HSCT, it should be an area of further debate and exchange of ideas among transplant specialists in the future. 405
Hamidieh et al. Acknowledgments We would also like to extend our thanks to the pediatric transplant nursing team for their invaluable assistance in this study.
17.
Conflict of interest
18.
Authors declare that they do not have any potential conflict of interests. 19.
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