Upload
jale-boral
View
4
Download
0
Embed Size (px)
DESCRIPTION
HSCT
Citation preview
latin
efril-Mnd Re
Key Words:Fanconi anemiaStem cell transplantationCyclophosphamideRadiation
tern of toxicity), andctors that may affect. We analyzed data& Research Centeract of different keyediatric FA patients.
PATIENTS AND METHODSPatients
A review of our data at KFSH&RC from 1993 to 2011 identied 94 FApatients who underwent related bone marrow HCT. Forty-six (48.9%) were
Financial disclosure: See Acknowledgments on page 1602.* Correspondence and reprint requests: Mouhab Ayas, MD, King Faisal
Specialist Hospital and Research Center, Department of Pediatric Hema-tology Oncology, PO Box 3354, MBC 53, Riyadh 11211, Saudi Arabia.
E-mail address: [email protected] (M. Ayas).
1083-8791/$ e see front matter 2014 American Society for Blood and Marrow Transplantation.http://dx.doi.org/10.1016/j.bbmt.2014.06.016
Biol Blood Marrow Transplant 20 (2014) 1599e1603
Biology of Blood andMarrow Transplantationjournal homepage: wwfor bone marrow failure in FA patients; HCT does not, how-ever, prevent the occurrence of solid tumors [10]. The use ofconditioning regimens based on reduced doses of cyclo-phosphamide (CY), either alone or together with limited eld
the reported outcomes (survival and patonly few studies have investigated the fathe eventual outcome of these patientsfrom King Faisal Specialist Hospital(KFSH&RC) database to evaluate the impvariables on outcome of related HCT in pFanconi anemia (FA) is a rare, genetically heterogeneous,inherited disorder clinically characterized by congenital ab-normalities, progressive bone marrow failure, and a pre-disposition to develop malignancies [1-4], especially acutemyeloid leukemia and squamous cell carcinoma, mostlyhead and neck [5-9]. Allogeneic hematopoietic cell trans-plantation (HCT) currently remains the only curativemodality
mocyte globulin (ATG), has resulted in restoration of normalhematopoiesis in a large proportion of patients, particularlythose who underwent transplantation from HLA-matchedrelated donors [11-25].
Despite the favorable overall outcome in recipients ofHLA-matched related HCT, variations in the preparatoryregimens still exist among different institutions, as well as inINTRODUCTIONbeen favorable, but only a few studies have scrutinized the factors that may affect the eventual outcome ofthese patients. This retrospective analysis of 94 pediatric patients with FAwho underwent related HCT at KingFaisal Specialist Hospital & Research Center was carried out to attempt to identify factors that may affectoutcome. Results showed overall survival (OS) probabilities of 92.5%, 89%, and 86% at 1, 5, and 10 years,respectively. In univariate analysis, use of higher dose cyclophosphamide (CY) (60 mg/kg) conditioning wasassociated with a better 10-year OS than lower dose CY (20 mg/kg) conditioning (91% versus 82%, respec-tively; P .035), and use of radiation-containing regimens was associated with a signicantly lower 10-yearOS than nonradiation regimens (76% versus 91%, respectively; P .005). Of the 4 regimens used in this study,the udarabine-based regimen was associated with the highest survival (95.2%; P .034). The use of thehigher dose CY (60 mg/kg) was associated with a signicantly increased incidence of hemorrhagic cystitis(HC) (20% versus 5.6% respectively; P .049). Three patients (3%) developed squamous cell carcinoma(2 oropharyngeal and 1 genitourinary), at 9.4, 5.4, and 13.3 years after HCT; 2 of them had radiation-containing conditioning. In conclusion, our data suggest that although using a higher dose CY (60 mg/kg)conditioning regimen may be associated with better survival, it is also associated with a signicantlyincreased risk of HC. The addition of udarabine to the low-dose CY (20 mg/kg) is associated with the bestsurvival. On the other hand, radiation-containing regimens are associated with signicantly lower survival.
2014 American Society for Blood and Marrow Transplantation.
or total body irradiation (TBI), and with or without antithy-Accepted 11 June 2014 and it is generally accepted that these patients should receive low-intensity conditioning because of theunderlying DNA repair defect in their cells. Outcomes for recipients of matched related HCT have generallyReceived 11 March 2014 Hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi Anemia (FA),Factors Affecting the Outcome of ReHematopoietic Cell TransplantationFanconi Anemia
Mouhab Ayas*, Khawar Siddiqui, Abdullah Al-JSamer Markiz, Hasan Shahin, Abdulrahman ADepartment of Pediatric Hematology Oncology, King Faisal Specialist Hospital a
Article history: a b s t r a c ted AllogeneicPatients with
, Hassan El-Solh, Ali Al-Ahmari, Ashraf Khairy,usa, Amal Al-Seraihysearch Center, Riyadh, Saudi Arabiaw.bbmt.org
male. Eleven had evidence of myelodysplasia and/or abnormal cytogeneticclone (MDS) in bone marrow before HCT, and 1 patient had acute myeloidleukemia, received chemotherapy, and was in remission at time of HCT.
Conditioning RegimensCY was used in the conditioning regimens in all patients; 1 of 2 doses of
CY was used according to the time period when the patient underwent HCT:a higher dose, CY 60 mg/kg, used with ATG with no other agents (n 40), ora lower dose, CY 20mg/kg, used in combinationwith ATG and radiation (TBI,n 11; or thoraco-abdominal irradiation [TAI], n 22), or used in combi-nation with ATG and udarabine (n 21); 1 of the patients in the lattergroup also received TBI. Graft-versus-host disease (GVHD) prophylaxis waswith cyclosporine. ATG was delivered after HCT to the 22 patients with CY/
2.2%), respectively. Chronic GVHD (cGVHD) developed in 8 of90 patients at risk (cumulative incidence, 8.5%; SE, 2.8%); 2had limited disease and 6 had extensive disease. Six of thosewho developed cGVHD were alive at the last follow-up.Cumulative incidence of secondary graft failure was 4.3%(SE, 2%) and for HC was 12.5% (SE, 3.2%). Mild self-limitingveno-occlusive disease developed in 6 patients (6.4%).
Univariate analysis revealed that the incidence of acuteGVHD was not affected by age at HCT, gender of recipientor donor, concomitant MDS, or use of higher-dose CY orudarabine-based regimens. However, the incidence of acuteGVHD grade II to IV and grade III to VI was higher in patientswho received the TBI-containing regimen; 25% (SE, 13%)versus 6% (SE, 2.6%) and 2.4% (SE, 1.4%) in those who did not(P .02 and P .001, respectively). Similarly, cGVHD inci-dence was 25% (SE, 13%) in recipients of the TBI-containingconditioning regimen versus 6.1% (SE, 2.6%) in the othergroup (P value .03). Also, the cumulative incidence ofsecondary graft failure was higher in the TAI recipientsgroup: 13.6% (SE, 7.1%) compared with 1.4% (SE, 10%) in theothers (P .01). More cases of HC were noted in recipients ofthe higher doses of CY (60 mg/kg), 20% versus 5.6% in allothers (P .049).
SurvivalProbabilities of OSwere 92.5%, 89%, and 86% at 1, 5, and 10
years, respectively (Figure 1). When OS was evaluated basedon the CY dose used, the 10-year OS was signicantly betteramong recipients of the higher dose CY conditioning regimen(91.4% versus 82%, P .035), and when OS was evaluatedbased on the existence of radiation in the conditioning, OS
Age group
M. Ayas et al. / Biol Blood Marrow Transplant 20 (2014) 1599e16031600TAI and to 20 patients who received the higher dose CY conditioningregimen (Table 1).
Endpoints and DenitionsThe primary outcome studied was survival. Patients were classied
according to the conditioning regimen received. Patients were considered tohave an event at time of death from any cause; survivors were censored atlast contact. Time to engraftment was calculated as the interval from trans-plantation to the rst of 3 consecutive days with an absolute neutrophilcount (ANC) of 500/mm3. Primary graft failure was dened as failure toachieve an ANC of 500/mm3 after HCT, and secondary graft failure wasdened as sustained loss of ANC (
was signicantly higher among recipients of nonradiation-
HCT since it was shown more than 3 decades ago to beassociated with increased survival [11,28]. Regimens have,however, continued to evolve, and the low dose of CY hassubsequently varied from 1 study to another, depending onwhat other agents were used concomitantly; doses as low as20 mg/kg and up to 80 mg/kg have been used with favorableoutcomes, particularly in recipients of matched related HCT[12,13,15-23].
The rst reports used a combination of CY (20 to 40 mg/kg) with reduced-dose TAI or TBI (400 to 450 cGy), and
Figure 1. Overall survival of all patients.
No .860 .045Yes .889 .105
SEM indicates standard error of mean.
M. Ayas et al. / Biol Blood Marrow Transplant 20 (2014) 1599e1603 1601containing conditioning regimens (90.6% versus 75.9%, P .005). Because CY 20mg/kgwas used inmore than 1 regimen,we also evaluated survival according to the 4 regimens(TAI-based, TBI-based, CY 60 mg/kg without radiation,udarabine-based); OS was highest in the recipients of theudarabine-based regimen (95.2%; P .034) (Figure 2,Table 3).
In univariate analysis, OS was not affected by any of thefollowing variables: age at HCT (
from fully matched related and unrelated donors. Biol Blood MarrowTransplant. 2006;12:712-718.
22. Ayas M, Al-Seraihi A, El-Solh H, et al. The Saudi experience inudarabine-based conditioning regimens in patients with Fanconianemia undergoing stem cell transplantation: excellent outcome inrecipients of matched related stem cells but not in recipients of un-related cord blood stem cells. Biol Blood Marrow Transplant. 2012;18:627-632.
23. George B, Mathews V, Shaji RV, et al. Fludarabine-based conditioningfor allogeneic stem cell transplantation for multiply transfused patientswith Fanconis anemia. Bone Marrow Transplant. 2005;35:341-343.
24. Dalle JH. HSCT for Fanconi anemia in children: factors that inuenceearly and late results. Bone Marrow Transplant. 2008;42(Suppl 2):S51-S53.
25. Peffault de Latour R, Porcher R, Dalle JH, et al. Allogeneic hematopoieticstem cell transplantation in Fanconi anemia: the European Groupfor Blood and Marrow Transplantation experience. Blood. 2013;122:4279-4286.
26. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index forgrading acute graft-versus-host disease: retrospective comparisonwith Glucksberg grade. Br J Haematol. 1997;97:855-864.
27. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-hostsyndrome in man. A long-term clinicopathologic study of 20 Seattlepatients. Am J Med. 1980;69:204-217.
28. Gluckman E, Devergie A, Dutreix J. Radiosensitivity in Fanconianaemia: application to the conditioning regimen for bone marrowtransplantation. Br J Haematol. 1983;54:431-440.
29. Gluckman E, Rocha V, Ionescu I, et al. Results of unrelated cord bloodtransplant in Fanconi anemia patients: risk factor analysis for engraft-ment and survival. Biol Blood Marrow Transplant. 2007;13:1073-1082.
30. Wagner JE, Eapen M, MacMillan ML, et al. Unrelated donor bonemarrow transplantation for the treatment of Fanconi anemia. Blood.2007;109:2256-2262.
31. Ayas M, Saber W, Davies SM, et al. Allogeneic hematopoietic celltransplantation for Fanconi anemia in patients with pretransplantationcytogenetic abnormalities, myelodysplastic syndrome, or acute leuke-mia. J Clin Oncol. 2013;31:1669-1676.
32. Guardiola P, Soci G, Li X, et al. Acute graft-versus-host disease inpatients with Fanconi anemia or acquired aplastic anemia undergoingbone marrow transplantation from HLA-identical sibling donors: riskfactors and inuence on outcome. Blood. 2004;103:73-77.
33. Dufour C, Rondelli R, Locatelli F, et al. Stem cell transplantation fromHLA-matched related donor for Fanconis anaemia: a retrospectivereview of the multicentric Italian experience on behalf of AIEOP-GITMO. Br J Haematol. 2001;112:796-805.
34. MacMillan ML, Wagner JE. Haematopoeitic cell transplantation forFanconi anaemia - when and how? Br J Haematol. 2010;149:14-21.
35. Guardiola P, Pasquini R, Dokal I, et al. Outcome of 69 allogeneic stemcell transplantations for Fanconi anemia using HLA-matched unrelateddonors: a study on behalf of the European Group for Blood and MarrowTransplantation. Blood. 2000;95:422-429.
36. Soci G, Schmoor C, Bethge WA, et al. Chronic graft-versus-host dis-ease: long-term results from a randomized trial on graft-versus-hostdisease prophylaxis with or without anti-T-cell globulin ATG-Frese-nius. Blood. 2011;117:6375-6382.
37. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-hostdisease prophylaxis with or without anti-T-cell globulin in haemato-poietic cell transplantation from matched unrelated donors: a rando-mised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855-864.
38. Ayas M, Al-Jefri A, Al-Seraihi A, et al. Second stem cell transplantationin patients with Fanconi anemia using antithymocyte globulin alonefor conditioning. Biol Blood Marrow Transplant. 2008;14:445-448.
39. McCann SR, Bacigalupo A, Gluckman E, et al. Graft rejection and secondbone marrow transplants for acquired aplastic anaemia: a report fromthe Aplastic Anaemia Working Party of the European Bone MarrowTransplant Group. Bone Marrow Transplant. 1994;13:233-237.
40. Champlin RE, Horowitz MM, van Bekkum DW, et al. Graft failurefollowing bone marrow transplantation for severe aplastic anemia: riskfactors and treatment results. Blood. 1989;73:606-613.
41. Pasquini R, Carreras J, Pasquini MC, et al. HLA-matched sibling he-matopoietic stem cell transplantation for Fanconi anemia: comparisonof irradiation and nonirradiation containing conditioning regimens.Biol Blood Marrow Transplant. 2008;14:1141-1147.
M. Ayas et al. / Biol Blood Marrow Transplant 20 (2014) 1599e1603 1603
Factors Affecting the Outcome of Related Allogeneic Hematopoietic Cell Transplantation in Patients with Fanconi AnemiaIntroductionPatients and MethodsPatientsConditioning RegimensEndpoints and DefinitionsStatistical Analyses
ResultsEngraftment, GVHD, HC, and Veno-Occlusive Disease of the LiverSurvivalSecondary Malignancy
DiscussionAcknowledgmentsReferences