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RESEARCH ARTICLE
Outcomes and management strategies for graft failure after umbilical cord blood transplantation Harshabad Singh,1 Sarah Nikiforow,2 Shuli Li,3 Karen K. Ballen,4 Thomas R. Spitzer,4 Robert Soiffer,2 Joseph H. Antin,2 Corey Cutler,2 and Yi-Bin Chen4* Graft failure is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Graft failure is more prevalent after umbilical cord blood transplantation (UCBT) compared with conventional adult stem cell sources. We identified 21 consecutive patients who experienced graft failure after UCBT at our center between 2004 and 2013 and describe their treatment strategies and outcomes. Two patients experienced early death. Seven patients had return of autologous hematopoiesis including 1 patient who was given previously collected autologous stem cells. Twelve patients received a second early HSCT, six from separate UCB units and six from a haploidentical donor. With a median follow-up of 33.2 months for surviving patients, 3-year PFS is 23% and 3-year OS is 37%. Of the six long-term survivors without relapse, four received a second HSCT from a haploidentical donor with post-HSCT high-dose cyclophosphamide based GVHD prophylaxis. This strategy appears safe and merits further investigation in this setting. C 2014 Wiley Periodicals, Inc. Am. J. Hematol. 00:000–000, 2014. V
䊏 Introduction Graft failure is an important and life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Graft failure can be due to immunological rejection of donor cells by residual host lymphocytes, the presence of donor specific anti-HLA antibodies, or nonimmunologic mechanisms such as poor stem cell viability and viral infections [1,2]. Graft failure is more prevalent after umbilical cord blood transplantation (UCBT) due to inherently low stem cell doses, HLA mismatch, relative immaturity of UCB lymphocytes, and the increasing use of reduced intensity conditioning (RIC) with UCBT. Multiple strategies have been employed after graft failure including the use of recombinant growth factors, autologous stem cell reinfusion (if available), waiting for recovery of autologous hematopoiesis and, most commonly, a second HSCT [3–11]. Here, we describe the outcomes and treatment of patients who experienced graft failure after UCB transplantation performed at our institutions (Dana-Farber Cancer Institute and Massachusetts General Hospital) between 2004 and 2013.
䊏 Methods This study was approved by the Institutional Review Board of the Dana-Farber Harvard Cancer Center (DF/HCC). All adult patients who developed primary or secondary graft failure after undergoing UCBT between January 1, 2004 and December 30, 2013 at Dana-Farber/Brigham and Women’s Cancer Center and Massachusetts General Hospital Cancer Center were included. The majority of patients (18/22) received fludarabine-based RIC. The most common conditioning regimen used consisted of fludarabine (30 mg/m2/day for 5 days)/melphalan (100 mg/m2 for 1 day)/anti-thymocyte globulin (ATG; 1.5 mg/kg for 4 days), and this was given in 14 of 21 patients. Four patients received myeloablative conditioning with cyclophosphamide and total body irradiation with or without fludarabine. GVHD prophylaxis was tacrolimus/sirolimus in 15 patients, cyclosporine/mycophenolate in 4 patients and tacrolimus/mycophenolate in 2 patients. Total donor chimerism was assessed from peripheral blood and bone marrow samples at the judgment of the treating physician or based on protocol requirements. Our routine practice is to check chimerism from peripheral blood starting two weeks after UCBT and repeat serially every 1–2 weeks until engraftment is clearly present. In patients with prolonged cytopenias, chimerism testing was sent when clinically indicated from the peripheral blood and when bone marrow aspiration was performed. Chimerism was determined using recipient PB or BM samples collected in EDTA. “Total donor cell” chimerism was performed on buffy coat leukocytes. “T-cell” chimerism was on Ficoll Hypaque separated lymphocytes from which purified CD31 T cells were isolated using immunomagnetic beads (Stem Cell Technologies). Pretransplantation PB samples were R kit with the ABI 3130 capillary used to determine the donor and recipient genotypes based on 9 CODIS Short Tandem Repeat loci using the Applied Biosystems Profiler PlusV genetic analyzer to determine the alleles at each locus. Informative alleles unique to either donor or recipient were used to calculate % donor chimerism at each locus using the median peak intensity of amplicons attributable to donor divided by the sum of all amplicons at that locus. In cases where there were only unique recipient amplicons, % donor chimerism was calculated as (100% recipient chimerism); 95% confidence interval for chimerism was 65%. Disease risk was defined by the Disease Risk Index as described by Armand et al. [12]. Primary graft failure was defined as failure to achieve ANC > 500/ml by day 142 after UCBT. Primary graft failure with autologous reconstitution was defined as achievement of ANC > 500/ml but with predominantly host hematopoiesis (> 50% all cell chimerism). Secondary graft failure was defined as development of persistent neutropenia with ANC < 100/ml or gradual decrease in donor cell chimerism after initial donor engraftment with subsequent return of host hematopoiesis, death without count recovery, or recommendation of a second HSCT by the treating physician. 1 Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; 2Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts; 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; 4Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
Conflicts of Interest: The authors have no relevant conflicts of interest to disclose. *Correspondence to: Yi-Bin Chen, MD, Bone Marrow Transplant Unit, Cox 108, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E-mail: [email protected] Received for publication: 23 July 2014; Revised: 1 September 2014; Accepted: 2 September 2014 Am. J. Hematol. 00:00–00, 2014. Published online: 5 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23845 C 2014 Wiley Periodicals, Inc. V
doi:10.1002/ajh.23845
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Singh et al. TABLE I. Patient Characteristics Variable Median age (years) Gender M:F Diagnosis AML/ALL MDS/MDS-MPN PV/MF HD NHL/CLL AA Disease Risk Indexb High Intermediate Low Median lines of therapy prior to UCBT Median Total nucleated cell/kg 3 107 Median CD341 cell/kg 3 105 Donor HLA-specific antibodies
Conditioning Regimen Myeloablative Flu/Cy/TBIc Cy/TBI Reduced intensity Flu/Mel/ATG Flu/Mel/TBI Flu/Bu/ATG GVHD prophylaxis Tacrolimus 1 Sirolimus Tacrolimus 1 Mycophenolate Cyclosporine 1 Mycophenolate Median time from UCB to GF in days Median time between first and second allogeneic HSCT in daysd
N 5 21 51 (range: 20–68) 12:9 8/1 2/2 1 1 2/1 3a 16 3 1 1 (range: 0–4) 2.33 (range: 1.6–3.98) 1.89 (range: 0.59–10.71) Present in 7 patients Absent in 13 patients Data unavailable for 1 patient 3 1 14 2 1
15 2 4 41 (range: 32–88) 41 (range: 31–64)
a Two patients with AA later developed secondary MDS, which factored into decision for transplant. b One patient with AA could not be characterized by the DRI. c One patient with AA received ATG in addition. d 212 patients received early second allogeneic HSCT. Abbreviations: AA: aplastic anemia; ALL: acute lymphoid leukemia; AML: acute myeloid leukemia; ATG: antithymocyte globulin; CML: chronic myelogenous leukemia; Cy: cyclophosphamide; Flu: fludarabine; GF: graft failure; HD: Hodgkin’s disease; MDS: myelodysplastic syndrome; Mel: melphalan; MF: myelofibrosis; MPN: myeloproliferative neoplasm; NHL: non Hodgkin lymphoma; PV: polycythemia vera; TBI: total body irradiation
Patient clinical characteristics were summarized descriptively. Progression-free survival (PFS) was defined as the time from initial UCB infusion to relapse, disease progression or death from any cause. Overall survival (OS) was defined as time from initial UCB infusion to death from any cause. The Kaplan-Meier method was used to estimate PFS and OS.
䊏 Results During the period 2004–2013, there were 192 UCBTs performed at our centers. We identified 21 patients with graft failure (Table I), making the overall incidence of graft failure after UCBT 10.9%. For the patients who experienced graft failure, the median age at time of UCBT was 51 years (range: 20–68). Two of the 21 patients experienced secondary graft failure, and the remaining 19 had primary graft failure. AML was the most common diagnosis, present in 8 of 21 patients; 7 out of the 8 patients with AML were in CR1 and the last patient was in CR2 at the time of UCB transplant. One patient with ALL was also in CR1 at the time of UCB transplant. Sixteen of the 21 patients were categorized as high risk according to the Disease Risk Index. Twenty patients received two UCB units while one patient received a single UCBT on a clinical trial. The median total nucleated cell/kg and CD341cells/kg doses were 2.33 3 107 (range: 1.6–3.98) and 1.89 3 105 (range: 0.59–10.71), respectively. 2
American Journal of Hematology, Vol. 00, No. 00, Month 2014
Figure 1. Progression-free and OS for patients (n 5 21) who experienced graft failure after UCBT.
The median follow-up for the eight survivors was 33.2 months (range: 10.9–97.7 months). The median PFS and OS were 13.6 and 20 months, respectively, for the entire cohort. OS for all patients with graft failure was 67% (95% CI: 43–83%) and 37% (95% CI: 16–59%) at 1 and 3 years, respectively. PFS for all patients was 57% (95% CI: 33–75%) and 23% (95% CI: 7.5–44%) at 1 and 3 years, respectively (Fig. 1). Different therapies pursued after graft failure therapy, based on the clinical judgment of the treating physician, are described in Fig. 2 and Table II. Two patients underwent no additional therapy and died within 45 days after transplant. Another patient experienced secondary graft failure 88 days after his UCB transplant in the setting of withdrawal of immunosuppression to control disseminated adenovirus and subsequently underwent reinfusion of previously collected autologous stem cells. Six patients experienced independent autologous recovery without additional therapy, and 12 patients received a second allogeneic HSCT from either a UCB or haploidentical source. In the six patients who experienced autologous recovery of host hematopoiesis after graft failure, the median PFS and OS were 15.5 and 93 months, respectively (Fig. 2). Five of these patients ultimately experienced disease relapse. Two of them subsequently underwent a second HSCT at 305 and 444 days, respectively, relative to initial UCB transplant. A matched unrelated donor was found for the first patient with high-risk B-ALL in CR1; the other patient received a haploidentical HSCT in CR2 after relapse of AML. Both remain alive and in remission. The most common treatment strategy undertaken was a second HSCT, which was performed for twelve patients (Table II). The median interval between the two transplants was 41 days (range: 31– 64). The median PFS and OS of this group were 12.8 and 17.8 months, respectively, with only one case of observed disease relapse. Six patients received a graft from a haploidentical donor, five patients received double UCB units, and one patient received infusion of a single UCB unit without further conditioning. Of these 12 patients who underwent early second HSCT, 5 patients are alive and free of disease with median follow-up of 22.8 months (range: 10.9–36.7). Among these 5 survivors, one patient had underlying aplastic anemia, two patients had MDS develop from long standing aplastic anemia, one patient had high risk AML and the other had MPN/MDS. Four of these five patients received bone marrow grafts from a haploidentical donor after reduced-intensity conditioning and then followed by post-transplant high-dose cyclophosphamide-based GVHD doi:10.1002/ajh.23845
RESEARCH ARTICLE
Graft Failure After UCBT
Figure 2. Outcomes after graft failure (n 5 21).
prophylaxis [13]. In these four patients, neutrophil engraftment occurred between 17 and 25 days after BMT with one patient each developing acute and chronic GVHD, respectively. Two additional patients received a second HSCT from haploidentical donors without post-BMT cyclophosphamide-based platforms. Both of these patients had successful donor engraftment, but both experienced acute GVHD. One patient died from complications of acute GVHD and the other from infectious complications. Six patients received a second UCBT for early rescue therapy, only three of which successfully engrafted (22, 34, and 39 days after second UCBT). One patient with AA/MDS who received two new UCB units with alemtuzumab-based conditioning is alive and in remission now 8.3 years after second UCBT. Three patients (High risk AML, MDS/MPN, and extranodal NK-T cell lymphoma) who received a second dUCBT died within 100 days of their first dUCBT from primary graft failure and infectious complications of the second UCBT. One of the remaining two patients who had anaplastic large cell lymphoma received a second dUCBT and engrafted. She experienced a cutaneous relapse 240 days after transplant and died of acute GVHD after a third-party unrelated donor lymphocyte infusion. The final patient with high risk MDS was in complete remission after her second dUCBT but unfortunately succumbed to multiple infections complicating chronic GVHD 18 months after second UCBT.
䊏 Discussion Graft failure is an important and potentially fatal complication after UCBT. In this descriptive report, we illustrate that some patients who experience graft failure after UCBT are able to achieve long-term disease-free survival, either through recovery of autologous hematopoiesis or with second HSCT. For those who undergo second HSCT, we describe the first successful reports of using RIC followed by haploidentical bone marrow transplant with post-transplant high-dose cyclophosphamide based GVHD prophylaxis in the setting of GF doi:10.1002/ajh.23845
after UCBT. We did not analyze the risk factors for graft failure after UCBT, as to do so accurately, would require a larger number of events and sample size. Several recent series have described other centers’ outcomes after graft failure complicating UCBT with second HSCT being the most common therapeutic strategy undertaken. The majority of these recipients lack well matched related or unrelated donor options for second HSCT. Furthermore, the time delay and logistics required in unrelated donor transplantation often makes using unrelated donors an unrealistic option. In contrast, UCB and haploidentical donor sources are readily available and, thus, the most common sources for second HSCT. Previously, Chan et al. described outcomes of 110 pediatric patients who underwent UCBT, of whom 13 had experienced graft failure [3]. Of those, 10 patients received a second UCBT and 6 were alive after a median follow-up of 38 months. Waki et al. described RIC UCBT as salvage therapy for graft failure in 80 patients and described an OS rate of 33% at 1 year [11]. Approximately 74% of those patients had received UCB units for the first HSCT illustrating that a second UCB is a feasible option for graft failure after a first UCBT. It is important to point out that the majority of patients described in the series above underwent single UCBT, and the relatively smaller size of recipients in the pediatric and Asian populations, likely allowed the easier identification of adequate UCB units for use in second HSCT. In regards to second HSCT using haploidentical donors after UCBT, Fuji et al. retrospectively analyzed Japanese registry outcomes of 220 patients with graft failure after UCBT who received a second HSCT [5]. While a second UCB unit was the donor source for the second HSCT in 180 patients, they did demonstrate that using peripheral blood cells from a haploidentical donor was associated with higher rates of engraftment and OS in multivariable analysis. Recently, Modscardo et al. reported a 36% OS at 2 years for 11 single UCB recipients with graft failure using a T-cell-depleted haploidentical HSCT regimen for second HSCT [13]. American Journal of Hematology, Vol. 00, No. 00, Month 2014
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4
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AA/CMML
AML
MDS/MPN
AML
AML
AA / MDS
AML
MDS/MPN
MDS
ALCL
EN NK TCL
30
51
53
66
55
30
42
47
62
57
54
High
High
High
High
High
Int
High
High
High
High
High
–
DRI
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/ATG
Cy/TBI
Flu/Cy/TBI
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/TBI
Flu/Cy/ATG/TBI
Conditioning regimen
Tacro/Siro
Tacro/Siro
Tacro/Siro
Tacro/Siro
Tacro/Siro
CSA/MMF
CSA/MMF
Tacro/MMF
Tacro/MMF
Tacro/Siro
Tacro/Siro
Tacro/Siro
GVHD ppx
3.29
3.7
1.6
3.71
3.98
1.88
2.3
1.77
1.66
2.3
2.75
2.3
TNC 3 107/kg
2.2
5.09
9.65
2.45
1.89
2.04
1.61
1.03
3.01
0.7
1.48
3.1
CD34 3 105/kg
CR1
CR2
Progressive MDS Residual
CR2
Untreated
CR1
CR1p
Residual
CR1
Residual
Untreated
Disease at time of UCBT
Dead (Infection)
Dead (GVHD)
Dead (GVHD, infection, PRES)
Dead (Graft failure, Infection) Dead (Graft failure)
Alive
Dead (GVHD and infection) Dead (Infection)
Alive
Alive
Alive
Alive
Alive/Dead (COD)
42
33
43
31
64
48
39
41
39
39
40
41
Days btwn HSCTs
dUCB
dUCB
dUCB
dUCB
sUCB
dUCB
Haplo
Haplo
Haplo
Haplo
Haplo
Haplo
HSCT2 Donor
N
Y
Y
N
N
Y
Y
Y
Y
Y
Y
Y
HSCT2 engraft?
Flu/Cy/ Alemtuzumab/ TBI 200 Flu/Cy/ Alemtuzumab/ TBI 200 Flu/Cy/TBI 200
ATG
Flu/Cy/ Alemtuzumab Flu/Cy/ Alemtuzumab/ TBI 200 –
Flu/Bu
Flu/Cy/TBI 200
Flu/Cy/TBI 200
Flu/Cy/TBI 200
Flu/Cy/TBI 200
Conditioning HSCT2
Tacro/Siro
Tacro/Siro
Tacro/Siro
–
Tacro/Siro
CSA/MMF
CSA/MMF
Hi-Cy/Tacro/ MMF Hi-Cy/Tacro/ MMF Hi-Cy/Tacro/ MMF Hi-Cy/Tacro/ MMF Tacro/MTX/ATG
GVHD ppx HSCT#2
Abbreviations: AA: aplastic anemia; aGVHD: acute graft versus host disease; ALCL: anaplastic large cell lymphoma; AML:-acute myeloid leukemia; ATG: antithymocyte globulin; CML: chronic myelogenous leukemia; Cy: cyclophosphamide; Dz: disease; EN NK TCL: extranodal NK T cell lymphoma; Flu: fludarabine; HHV6: human herpes virus 6; Hi-Cy: high-dose cyclophosphamide; MDS: myelodysplastic syndrome; MMF: mycophenolate mofetil; MPN: myeloproliferative neoplasm; PRES: posterior reversible encephalopathy syndrome; TBI: total body irradiation.
AA
Dx
20
Age
TABLE II. Early Second HSCT
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Graft Failure After UCBT
To our knowledge, using a RIC regimen with haploidentical HSCT followed by post-HSCT high-dose cyclophosphamide based GVHD prophylaxis has not been described in this setting. Developed by colleagues at Johns Hopkins University, the post-HSCT high-dose cyclophosphamide platform with haploidentical bone marrow transplantation has been shown to engender high rates of engraftment, adequate immune reconstitution, low rates of acute and chronic GVHD, and low rates of transplant-related mortality [14]. Two recent series have also shown the safety of using haploidentical peripheral blood stem cells as the graft source [15,16] thereby, making donor logistics more convenient which is especially advantageous in the setting of prolonged aplasia from graft failure. While our small numbers obviously limit the ability to draw any firm conclusions, haploidentical HSCT with post-HSCT high-dose cyclophosphamide appears to be a feasible and promising strategy for patients with graft failure after UCBT, given considerations of safety, rapidity of engraftment, and relative logistics of other available donor sources.
䊏 References
1. Cutler C, Kim HT, Sun L, et al. Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation. Blood 2011;118:6691–6697. 2. Olsson R, Remberger M, Schaffer M, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant 2013;48: 537–543. 3. Chan KW, Grimley MS, Taylor C, Wall DA. Early identification and management of graft failure after unrelated cord blood transplantation. Bone Marrow Transplant 2008;42:35–41. 4. Davies SM, Weisdorf DJ, Haake RJ, et al. Second infusion of bone marrow for treatment of graft failure after allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;14: 73–77. 5. Fuji S, Nakamura F, Hatanaka K, et al. Peripheral blood as a preferable source of stem cells for salvage transplantation in patients with graft failure after cord blood transplantation: A retrospective analysis of the registry data of the Japanese Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2012;18:1407–1414. 6. Guardiola P, Kuentz M, Garban F, et al. Second early allogeneic stem cell transplantations for graft failure in acute leukaemia, chronic myeloid
doi:10.1002/ajh.23845
7.
8.
9.
10.
11.
12.
Due to the relatively high incidence of graft failure with UCBT and encouraging outcomes with early second HSCT, we recommend that all patients undergoing UCBT have an identified rescue strategy in the event of graft failure. This is especially true for patients who have conditions such as MDS or aplastic anemia or for those who are being treated with higher intensity conditioning regimens where recovery of autologous hematopoiesis will likely not occur. In this descriptive report, we illustrate that patients who experience graft failure after UCBT can be salvaged with haploidentical donor grafts with post-transplant cyclophosphamide, and we have observed achievement of long term disease free survival with this strategy.
䊏 Author Contributions HS and YC performed the research study, designed the research, analyzed the data, and wrote the article. SL analyzed the data and wrote the article. SN, KKB, TRS, RS, KHA, and CC contributed to writing the article.
leukaemia and aplastic anaemia. French Society of Bone Marrow Transplantation. Br J Haematol 2000;111:292–302. Mehta J, Powles R, Singhal S, et al. Outcome of autologous rescue after failed engraftment of allogeneic marrow. Bone Marrow Transplant 1996;17:213–217. Nemunaitis J, Singer JW, Buckner CD, et al. Use of recombinant human granulocytemacrophage colony-stimulating factor in graft failure after bone marrow transplantation. Blood 1990;76:245–253. Rondon G, Saliba RM, Khouri I, et al. Longterm follow-up of patients who experienced graft failure postallogeneic progenitor cell transplantation. Results of a single institution analysis. Biol Blood Marrow Transplant 2008;14:859– 866. Schriber J, Agovi MA, Ho V, et al. Second unrelated donor hematopoietic cell transplantation for primary graft failure. Biol Blood Marrow Transplant 2010;16:1099–1106. Waki F, Masuoka K, Fukuda T, et al. Feasibility of reduced-intensity cord blood transplantation as salvage therapy for graft failure: Results of a nationwide survey of adult patients. Biol Blood Marrow Transplant 2011;17:841–851. Armand P, Gibson CJ, Cutler C, et al. A disease risk index for patients undergoing allogeneic
13.
14.
15.
16.
stem cell transplantation. Blood 2012;120:905– 913. Moscardo F, Romero S, Sanz J, et al. T-cell depleted related HLA-mismatched peripheral blood stem cell transplantation as salvage therapy for graft failure after single unit unrelated donor umbilical cord blood transplantation. Biol Blood Marrow Transplant 2014;20:1060–1063. Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity conditioning: Results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 2011;118:282–288. Castagna L, Crocchiolo R, Furst S, et al. Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post-transplantation cyclophosphamide. Biol Blood Marrow Transplant 2014;20:724–729. Raj K, Pagliuca A, Bradstock K, et al. Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant 2014;20:890–895.
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Outcomes and management strategies for graft failure after umbilical cord blood transplantation Harshabad Singh,1 Sarah Nikiforow,2 Shuli Li,3 Karen K. Ballen,4 Thomas R. Spitzer,4 Robert Soiffer,2 Joseph H. Antin,2 Corey Cutler,2 and Yi-Bin Chen4* Graft failure is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Graft failure is more prevalent after umbilical cord blood transplantation (UCBT) compared with conventional adult stem cell sources. We identified 21 consecutive patients who experienced graft failure after UCBT at our center between 2004 and 2013 and describe their treatment strategies and outcomes. Two patients experienced early death. Seven patients had return of autologous hematopoiesis including 1 patient who was given previously collected autologous stem cells. Twelve patients received a second early HSCT, six from separate UCB units and six from a haploidentical donor. With a median follow-up of 33.2 months for surviving patients, 3-year PFS is 23% and 3-year OS is 37%. Of the six long-term survivors without relapse, four received a second HSCT from a haploidentical donor with post-HSCT high-dose cyclophosphamide based GVHD prophylaxis. This strategy appears safe and merits further investigation in this setting. C 2014 Wiley Periodicals, Inc. Am. J. Hematol. 00:000–000, 2014. V
䊏 Introduction Graft failure is an important and life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Graft failure can be due to immunological rejection of donor cells by residual host lymphocytes, the presence of donor specific anti-HLA antibodies, or nonimmunologic mechanisms such as poor stem cell viability and viral infections [1,2]. Graft failure is more prevalent after umbilical cord blood transplantation (UCBT) due to inherently low stem cell doses, HLA mismatch, relative immaturity of UCB lymphocytes, and the increasing use of reduced intensity conditioning (RIC) with UCBT. Multiple strategies have been employed after graft failure including the use of recombinant growth factors, autologous stem cell reinfusion (if available), waiting for recovery of autologous hematopoiesis and, most commonly, a second HSCT [3–11]. Here, we describe the outcomes and treatment of patients who experienced graft failure after UCB transplantation performed at our institutions (Dana-Farber Cancer Institute and Massachusetts General Hospital) between 2004 and 2013.
䊏 Methods This study was approved by the Institutional Review Board of the Dana-Farber Harvard Cancer Center (DF/HCC). All adult patients who developed primary or secondary graft failure after undergoing UCBT between January 1, 2004 and December 30, 2013 at Dana-Farber/Brigham and Women’s Cancer Center and Massachusetts General Hospital Cancer Center were included. The majority of patients (18/22) received fludarabine-based RIC. The most common conditioning regimen used consisted of fludarabine (30 mg/m2/day for 5 days)/melphalan (100 mg/m2 for 1 day)/anti-thymocyte globulin (ATG; 1.5 mg/kg for 4 days), and this was given in 14 of 21 patients. Four patients received myeloablative conditioning with cyclophosphamide and total body irradiation with or without fludarabine. GVHD prophylaxis was tacrolimus/sirolimus in 15 patients, cyclosporine/mycophenolate in 4 patients and tacrolimus/mycophenolate in 2 patients. Total donor chimerism was assessed from peripheral blood and bone marrow samples at the judgment of the treating physician or based on protocol requirements. Our routine practice is to check chimerism from peripheral blood starting two weeks after UCBT and repeat serially every 1–2 weeks until engraftment is clearly present. In patients with prolonged cytopenias, chimerism testing was sent when clinically indicated from the peripheral blood and when bone marrow aspiration was performed. Chimerism was determined using recipient PB or BM samples collected in EDTA. “Total donor cell” chimerism was performed on buffy coat leukocytes. “T-cell” chimerism was on Ficoll Hypaque separated lymphocytes from which purified CD31 T cells were isolated using immunomagnetic beads (Stem Cell Technologies). Pretransplantation PB samples were R kit with the ABI 3130 capillary used to determine the donor and recipient genotypes based on 9 CODIS Short Tandem Repeat loci using the Applied Biosystems Profiler PlusV genetic analyzer to determine the alleles at each locus. Informative alleles unique to either donor or recipient were used to calculate % donor chimerism at each locus using the median peak intensity of amplicons attributable to donor divided by the sum of all amplicons at that locus. In cases where there were only unique recipient amplicons, % donor chimerism was calculated as (100% recipient chimerism); 95% confidence interval for chimerism was 65%. Disease risk was defined by the Disease Risk Index as described by Armand et al. [12]. Primary graft failure was defined as failure to achieve ANC > 500/ml by day 142 after UCBT. Primary graft failure with autologous reconstitution was defined as achievement of ANC > 500/ml but with predominantly host hematopoiesis (> 50% all cell chimerism). Secondary graft failure was defined as development of persistent neutropenia with ANC < 100/ml or gradual decrease in donor cell chimerism after initial donor engraftment with subsequent return of host hematopoiesis, death without count recovery, or recommendation of a second HSCT by the treating physician. 1 Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; 2Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts; 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; 4Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
Conflicts of Interest: The authors have no relevant conflicts of interest to disclose. *Correspondence to: Yi-Bin Chen, MD, Bone Marrow Transplant Unit, Cox 108, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E-mail: [email protected] Received for publication: 23 July 2014; Revised: 1 September 2014; Accepted: 2 September 2014 Am. J. Hematol. 00:00–00, 2014. Published online: 5 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23845 C 2014 Wiley Periodicals, Inc. V
doi:10.1002/ajh.23845
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RESEARCH ARTICLE
Singh et al. TABLE I. Patient Characteristics Variable Median age (years) Gender M:F Diagnosis AML/ALL MDS/MDS-MPN PV/MF HD NHL/CLL AA Disease Risk Indexb High Intermediate Low Median lines of therapy prior to UCBT Median Total nucleated cell/kg 3 107 Median CD341 cell/kg 3 105 Donor HLA-specific antibodies
Conditioning Regimen Myeloablative Flu/Cy/TBIc Cy/TBI Reduced intensity Flu/Mel/ATG Flu/Mel/TBI Flu/Bu/ATG GVHD prophylaxis Tacrolimus 1 Sirolimus Tacrolimus 1 Mycophenolate Cyclosporine 1 Mycophenolate Median time from UCB to GF in days Median time between first and second allogeneic HSCT in daysd
N 5 21 51 (range: 20–68) 12:9 8/1 2/2 1 1 2/1 3a 16 3 1 1 (range: 0–4) 2.33 (range: 1.6–3.98) 1.89 (range: 0.59–10.71) Present in 7 patients Absent in 13 patients Data unavailable for 1 patient 3 1 14 2 1
15 2 4 41 (range: 32–88) 41 (range: 31–64)
a Two patients with AA later developed secondary MDS, which factored into decision for transplant. b One patient with AA could not be characterized by the DRI. c One patient with AA received ATG in addition. d 212 patients received early second allogeneic HSCT. Abbreviations: AA: aplastic anemia; ALL: acute lymphoid leukemia; AML: acute myeloid leukemia; ATG: antithymocyte globulin; CML: chronic myelogenous leukemia; Cy: cyclophosphamide; Flu: fludarabine; GF: graft failure; HD: Hodgkin’s disease; MDS: myelodysplastic syndrome; Mel: melphalan; MF: myelofibrosis; MPN: myeloproliferative neoplasm; NHL: non Hodgkin lymphoma; PV: polycythemia vera; TBI: total body irradiation
Patient clinical characteristics were summarized descriptively. Progression-free survival (PFS) was defined as the time from initial UCB infusion to relapse, disease progression or death from any cause. Overall survival (OS) was defined as time from initial UCB infusion to death from any cause. The Kaplan-Meier method was used to estimate PFS and OS.
䊏 Results During the period 2004–2013, there were 192 UCBTs performed at our centers. We identified 21 patients with graft failure (Table I), making the overall incidence of graft failure after UCBT 10.9%. For the patients who experienced graft failure, the median age at time of UCBT was 51 years (range: 20–68). Two of the 21 patients experienced secondary graft failure, and the remaining 19 had primary graft failure. AML was the most common diagnosis, present in 8 of 21 patients; 7 out of the 8 patients with AML were in CR1 and the last patient was in CR2 at the time of UCB transplant. One patient with ALL was also in CR1 at the time of UCB transplant. Sixteen of the 21 patients were categorized as high risk according to the Disease Risk Index. Twenty patients received two UCB units while one patient received a single UCBT on a clinical trial. The median total nucleated cell/kg and CD341cells/kg doses were 2.33 3 107 (range: 1.6–3.98) and 1.89 3 105 (range: 0.59–10.71), respectively. 2
American Journal of Hematology, Vol. 00, No. 00, Month 2014
Figure 1. Progression-free and OS for patients (n 5 21) who experienced graft failure after UCBT.
The median follow-up for the eight survivors was 33.2 months (range: 10.9–97.7 months). The median PFS and OS were 13.6 and 20 months, respectively, for the entire cohort. OS for all patients with graft failure was 67% (95% CI: 43–83%) and 37% (95% CI: 16–59%) at 1 and 3 years, respectively. PFS for all patients was 57% (95% CI: 33–75%) and 23% (95% CI: 7.5–44%) at 1 and 3 years, respectively (Fig. 1). Different therapies pursued after graft failure therapy, based on the clinical judgment of the treating physician, are described in Fig. 2 and Table II. Two patients underwent no additional therapy and died within 45 days after transplant. Another patient experienced secondary graft failure 88 days after his UCB transplant in the setting of withdrawal of immunosuppression to control disseminated adenovirus and subsequently underwent reinfusion of previously collected autologous stem cells. Six patients experienced independent autologous recovery without additional therapy, and 12 patients received a second allogeneic HSCT from either a UCB or haploidentical source. In the six patients who experienced autologous recovery of host hematopoiesis after graft failure, the median PFS and OS were 15.5 and 93 months, respectively (Fig. 2). Five of these patients ultimately experienced disease relapse. Two of them subsequently underwent a second HSCT at 305 and 444 days, respectively, relative to initial UCB transplant. A matched unrelated donor was found for the first patient with high-risk B-ALL in CR1; the other patient received a haploidentical HSCT in CR2 after relapse of AML. Both remain alive and in remission. The most common treatment strategy undertaken was a second HSCT, which was performed for twelve patients (Table II). The median interval between the two transplants was 41 days (range: 31– 64). The median PFS and OS of this group were 12.8 and 17.8 months, respectively, with only one case of observed disease relapse. Six patients received a graft from a haploidentical donor, five patients received double UCB units, and one patient received infusion of a single UCB unit without further conditioning. Of these 12 patients who underwent early second HSCT, 5 patients are alive and free of disease with median follow-up of 22.8 months (range: 10.9–36.7). Among these 5 survivors, one patient had underlying aplastic anemia, two patients had MDS develop from long standing aplastic anemia, one patient had high risk AML and the other had MPN/MDS. Four of these five patients received bone marrow grafts from a haploidentical donor after reduced-intensity conditioning and then followed by post-transplant high-dose cyclophosphamide-based GVHD doi:10.1002/ajh.23845
RESEARCH ARTICLE
Graft Failure After UCBT
Figure 2. Outcomes after graft failure (n 5 21).
prophylaxis [13]. In these four patients, neutrophil engraftment occurred between 17 and 25 days after BMT with one patient each developing acute and chronic GVHD, respectively. Two additional patients received a second HSCT from haploidentical donors without post-BMT cyclophosphamide-based platforms. Both of these patients had successful donor engraftment, but both experienced acute GVHD. One patient died from complications of acute GVHD and the other from infectious complications. Six patients received a second UCBT for early rescue therapy, only three of which successfully engrafted (22, 34, and 39 days after second UCBT). One patient with AA/MDS who received two new UCB units with alemtuzumab-based conditioning is alive and in remission now 8.3 years after second UCBT. Three patients (High risk AML, MDS/MPN, and extranodal NK-T cell lymphoma) who received a second dUCBT died within 100 days of their first dUCBT from primary graft failure and infectious complications of the second UCBT. One of the remaining two patients who had anaplastic large cell lymphoma received a second dUCBT and engrafted. She experienced a cutaneous relapse 240 days after transplant and died of acute GVHD after a third-party unrelated donor lymphocyte infusion. The final patient with high risk MDS was in complete remission after her second dUCBT but unfortunately succumbed to multiple infections complicating chronic GVHD 18 months after second UCBT.
䊏 Discussion Graft failure is an important and potentially fatal complication after UCBT. In this descriptive report, we illustrate that some patients who experience graft failure after UCBT are able to achieve long-term disease-free survival, either through recovery of autologous hematopoiesis or with second HSCT. For those who undergo second HSCT, we describe the first successful reports of using RIC followed by haploidentical bone marrow transplant with post-transplant high-dose cyclophosphamide based GVHD prophylaxis in the setting of GF doi:10.1002/ajh.23845
after UCBT. We did not analyze the risk factors for graft failure after UCBT, as to do so accurately, would require a larger number of events and sample size. Several recent series have described other centers’ outcomes after graft failure complicating UCBT with second HSCT being the most common therapeutic strategy undertaken. The majority of these recipients lack well matched related or unrelated donor options for second HSCT. Furthermore, the time delay and logistics required in unrelated donor transplantation often makes using unrelated donors an unrealistic option. In contrast, UCB and haploidentical donor sources are readily available and, thus, the most common sources for second HSCT. Previously, Chan et al. described outcomes of 110 pediatric patients who underwent UCBT, of whom 13 had experienced graft failure [3]. Of those, 10 patients received a second UCBT and 6 were alive after a median follow-up of 38 months. Waki et al. described RIC UCBT as salvage therapy for graft failure in 80 patients and described an OS rate of 33% at 1 year [11]. Approximately 74% of those patients had received UCB units for the first HSCT illustrating that a second UCB is a feasible option for graft failure after a first UCBT. It is important to point out that the majority of patients described in the series above underwent single UCBT, and the relatively smaller size of recipients in the pediatric and Asian populations, likely allowed the easier identification of adequate UCB units for use in second HSCT. In regards to second HSCT using haploidentical donors after UCBT, Fuji et al. retrospectively analyzed Japanese registry outcomes of 220 patients with graft failure after UCBT who received a second HSCT [5]. While a second UCB unit was the donor source for the second HSCT in 180 patients, they did demonstrate that using peripheral blood cells from a haploidentical donor was associated with higher rates of engraftment and OS in multivariable analysis. Recently, Modscardo et al. reported a 36% OS at 2 years for 11 single UCB recipients with graft failure using a T-cell-depleted haploidentical HSCT regimen for second HSCT [13]. American Journal of Hematology, Vol. 00, No. 00, Month 2014
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4
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AA/CMML
AML
MDS/MPN
AML
AML
AA / MDS
AML
MDS/MPN
MDS
ALCL
EN NK TCL
30
51
53
66
55
30
42
47
62
57
54
High
High
High
High
High
Int
High
High
High
High
High
–
DRI
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/ATG
Cy/TBI
Flu/Cy/TBI
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/ATG
Flu/Mel/TBI
Flu/Cy/ATG/TBI
Conditioning regimen
Tacro/Siro
Tacro/Siro
Tacro/Siro
Tacro/Siro
Tacro/Siro
CSA/MMF
CSA/MMF
Tacro/MMF
Tacro/MMF
Tacro/Siro
Tacro/Siro
Tacro/Siro
GVHD ppx
3.29
3.7
1.6
3.71
3.98
1.88
2.3
1.77
1.66
2.3
2.75
2.3
TNC 3 107/kg
2.2
5.09
9.65
2.45
1.89
2.04
1.61
1.03
3.01
0.7
1.48
3.1
CD34 3 105/kg
CR1
CR2
Progressive MDS Residual
CR2
Untreated
CR1
CR1p
Residual
CR1
Residual
Untreated
Disease at time of UCBT
Dead (Infection)
Dead (GVHD)
Dead (GVHD, infection, PRES)
Dead (Graft failure, Infection) Dead (Graft failure)
Alive
Dead (GVHD and infection) Dead (Infection)
Alive
Alive
Alive
Alive
Alive/Dead (COD)
42
33
43
31
64
48
39
41
39
39
40
41
Days btwn HSCTs
dUCB
dUCB
dUCB
dUCB
sUCB
dUCB
Haplo
Haplo
Haplo
Haplo
Haplo
Haplo
HSCT2 Donor
N
Y
Y
N
N
Y
Y
Y
Y
Y
Y
Y
HSCT2 engraft?
Flu/Cy/ Alemtuzumab/ TBI 200 Flu/Cy/ Alemtuzumab/ TBI 200 Flu/Cy/TBI 200
ATG
Flu/Cy/ Alemtuzumab Flu/Cy/ Alemtuzumab/ TBI 200 –
Flu/Bu
Flu/Cy/TBI 200
Flu/Cy/TBI 200
Flu/Cy/TBI 200
Flu/Cy/TBI 200
Conditioning HSCT2
Tacro/Siro
Tacro/Siro
Tacro/Siro
–
Tacro/Siro
CSA/MMF
CSA/MMF
Hi-Cy/Tacro/ MMF Hi-Cy/Tacro/ MMF Hi-Cy/Tacro/ MMF Hi-Cy/Tacro/ MMF Tacro/MTX/ATG
GVHD ppx HSCT#2
Abbreviations: AA: aplastic anemia; aGVHD: acute graft versus host disease; ALCL: anaplastic large cell lymphoma; AML:-acute myeloid leukemia; ATG: antithymocyte globulin; CML: chronic myelogenous leukemia; Cy: cyclophosphamide; Dz: disease; EN NK TCL: extranodal NK T cell lymphoma; Flu: fludarabine; HHV6: human herpes virus 6; Hi-Cy: high-dose cyclophosphamide; MDS: myelodysplastic syndrome; MMF: mycophenolate mofetil; MPN: myeloproliferative neoplasm; PRES: posterior reversible encephalopathy syndrome; TBI: total body irradiation.
AA
Dx
20
Age
TABLE II. Early Second HSCT
Singh et al.
RESEARCH ARTICLE
doi:10.1002/ajh.23845
RESEARCH ARTICLE
Graft Failure After UCBT
To our knowledge, using a RIC regimen with haploidentical HSCT followed by post-HSCT high-dose cyclophosphamide based GVHD prophylaxis has not been described in this setting. Developed by colleagues at Johns Hopkins University, the post-HSCT high-dose cyclophosphamide platform with haploidentical bone marrow transplantation has been shown to engender high rates of engraftment, adequate immune reconstitution, low rates of acute and chronic GVHD, and low rates of transplant-related mortality [14]. Two recent series have also shown the safety of using haploidentical peripheral blood stem cells as the graft source [15,16] thereby, making donor logistics more convenient which is especially advantageous in the setting of prolonged aplasia from graft failure. While our small numbers obviously limit the ability to draw any firm conclusions, haploidentical HSCT with post-HSCT high-dose cyclophosphamide appears to be a feasible and promising strategy for patients with graft failure after UCBT, given considerations of safety, rapidity of engraftment, and relative logistics of other available donor sources.
䊏 References
1. Cutler C, Kim HT, Sun L, et al. Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation. Blood 2011;118:6691–6697. 2. Olsson R, Remberger M, Schaffer M, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant 2013;48: 537–543. 3. Chan KW, Grimley MS, Taylor C, Wall DA. Early identification and management of graft failure after unrelated cord blood transplantation. Bone Marrow Transplant 2008;42:35–41. 4. Davies SM, Weisdorf DJ, Haake RJ, et al. Second infusion of bone marrow for treatment of graft failure after allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;14: 73–77. 5. Fuji S, Nakamura F, Hatanaka K, et al. Peripheral blood as a preferable source of stem cells for salvage transplantation in patients with graft failure after cord blood transplantation: A retrospective analysis of the registry data of the Japanese Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2012;18:1407–1414. 6. Guardiola P, Kuentz M, Garban F, et al. Second early allogeneic stem cell transplantations for graft failure in acute leukaemia, chronic myeloid
doi:10.1002/ajh.23845
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Due to the relatively high incidence of graft failure with UCBT and encouraging outcomes with early second HSCT, we recommend that all patients undergoing UCBT have an identified rescue strategy in the event of graft failure. This is especially true for patients who have conditions such as MDS or aplastic anemia or for those who are being treated with higher intensity conditioning regimens where recovery of autologous hematopoiesis will likely not occur. In this descriptive report, we illustrate that patients who experience graft failure after UCBT can be salvaged with haploidentical donor grafts with post-transplant cyclophosphamide, and we have observed achievement of long term disease free survival with this strategy.
䊏 Author Contributions HS and YC performed the research study, designed the research, analyzed the data, and wrote the article. SL analyzed the data and wrote the article. SN, KKB, TRS, RS, KHA, and CC contributed to writing the article.
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