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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 6  |  Page : 1137-1143
Mismatched related hematopoietic stem cell transplantation in primary immunodeficiency

1 Queen Rania Children Hospital, King Hussein Medical Center, Royal Medical Services, Amman, Jordan
2 Ministry of Health and Population, Mukalla M. C. H. Hospital, Yemen

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Date of Web Publication13-Nov-2013


Hematopoietic stem cell transplantation (HSCT) is the definitive therapy for a variety of primary immunodeficiency syndromes (PIDs). However, no more than 30% of the patients will have a human leukocyte antigen (HLA)-identical sibling. We retrospectively analyzed our results of ten patients with PID; severe combined immunodeficiency (SCID) (n = 7), hyper IgM (HIgM) (n = 1) and combined immunodeficiency (CID) (n = 2), who lacked a fully matched donor and underwent mismatched related HSCT during the period from 2008 to 2010. The median age at the time of transplantation ranged between 3 and 84 months (median 6.5 months). Peripheral blood stem cells (PBSC) were used in all HSCTs. The mean value of the peripheral CD34+ cells infused was 9.19 × 10 6 /kg recipient weight. Patients received different conditioning protocols. All patients received anti graft versus host disease (GVHD) prophylaxis and all were engrafted. Mixed chimerism (5-55%) was noticed. GVHD was observed in 50% of the patients. Post-transplant follow-up ranged from 3 weeks to 36 months (median 15 months). Five patients are still alive while one patient developed engraftment syndrome followed by graft slippage for which a second transplant with CD34+ stem cells 5.8 × 10 6 /kg recipient's weight was infused. The others died from sepsis and transplant-related complications. Immune reconstitution was noticed in four patients. In conclusion, HLA-haploidentical stem cell transplantation may be feasible, with appropriate GVHD prophylaxis, for patients with PID who lack a fully matched donor.

How to cite this article:
Wahadneh AM, Bin Dahman HA, Abu Shukear ME, Habahbeh ZM, Ajarmeh MA, Zyood RM, Habashneh MS. Mismatched related hematopoietic stem cell transplantation in primary immunodeficiency. Saudi J Kidney Dis Transpl 2013;24:1137-43

How to cite this URL:
Wahadneh AM, Bin Dahman HA, Abu Shukear ME, Habahbeh ZM, Ajarmeh MA, Zyood RM, Habashneh MS. Mismatched related hematopoietic stem cell transplantation in primary immunodeficiency. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2021 Apr 22];24:1137-43. Available from: https://www.sjkdt.org/text.asp?2013/24/6/1137/121269

   Introduction Top

Haploidentical hematopoietic stem cell transplantation (HSCT) is a treatment option for approximately 70% of patients who do not have an HLA-identical sibling donor. [1],[2] Almost all patients have a haploidentical parent, child, sibling or relative who can serve almost immediately as a donor, [1],[3] particularly in those patients with advanced or resistant disease in need of urgent HSCT. [4]

There are three major factors that may influence the pattern of immune reconstitution in haploidentical stem cell recipients. The first major factor is disparity of human leukocyte antigen (HLA) up to three major HLA-alleles between donor and host; the second is the high number of stem cells infused to allow for stable engraftment; and the third is the profound T-cell depletion by positive selection of donor peripheral stem cells to prevent graft versus host disease (GVHD). [5]

In this manuscript, we retrospectively reviewed ten patients with primary immunodeficiency syndromes (PIDs) who lacked a fully matched donor and received mismatched related donor (MMRD) HSCT instead.

   Methods Top

From 2008 to 2010, ten patients with PID (six male, four female), including seven patients with severe combined immunodeficiency (SCID), one patient with hyper IgM and two patients with combined immunodeficiency(CID), who lacked a fully matched related donor, underwent HSCT in the King Hussein Medical Center (KHMC) from a MMRD. The patients' ages ranged between 3 and 84 months (median 6.5 months) at the time of HSCT [Table 1]. The diagnosis was possibly made according to the diagnostic criteria of PID by the European Society of PID. Mutation analysis was not performed. The mother was a donor in nine patients, while one patient received the transplant from her brother.
Table 1: Transplantation data for ten patients who underwent mismatched related donor HSCT for PID.

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Conditioning regimen [Table 1]

The preparative regimen was myeloablative (oral busulphan 4 mg/kg/day for 4 days from Day -9 to Day -6 and intravenous cyclophosphamide 50 mg/kg/day for 4 days from Day -5 to Day -2) in three patients, reduced intensity conditioning (RIC) [fludarabine 30 mg/m 2 over 5 days and a single dose of melphalan 140 mg/m 2 with antithymocyte globulin (ATG) 2.5 mg/kg/day for 4 days] in one patient, one patient with fludarabine, low-dose cyclophosphamide (5 mg/kg/day for 4 days) and ATG, one patient with fludarabine, busulphan and ATG, while the other four patients received non-conditioned HSCT.

GVHD prophylaxis

In addition to CD34+ stem cell selection, all patients received cyclosporine [2.5 mg/kg/dose every 12 h (started on Day -1, trough level 50-100 ng/mL)] and low-dose corticosteroids [prednisolone or methylprednisolone (1 mg/ kg/day)], three patients were given mycophenolate mofetil (MMF ) (400 mg/m /dose every 12 h or 15 mg/kg/dose every 8 h) and two patients were given methotrexate (MTX) [10 mg/m 2 /day for two doses (Day +1 and Day +2).

Hematopoietic stem cell source

Peripheral blood stem cells (PBSCs) were used in all HSCTs from mismatched related relatives. Donor-recipient histocompatibility was determined by serology for A, B and DR. Donor peripheral blood stem cells were mobilized with subcutaneous granulocyte colony-stimulating factor (G-CSF) (10 μg/kg for 5 days) and positive selection of CD34 stem cells using the CliniMACS system (Miltenyi Biotech GmbH, Bergisch Gladbach, Germany) based on magnetic beads attached to an anti-CD34 antibody, enabling marked purification of the CD34 stem cells. [6] The mean value of the peripheral CD34+ cells infused was 9.19 × 10 6 /kg recipient's body weight and the mean CD3+ cell number was 3.47 × 10 4 /kg.

Supportive therapy All patients were nursed in positive-pressure double door sterile cubicles and received intravenous immunoglobulin (IVIG) (0.5 g/kg/week). Surveillance cultures of blood, stool and oropharynx were taken at the time of admission and then weekly until discharge; antimicrobial prophylaxis during the transplantation period consisted of sulphamethoxazole-trimethoprim 10 mg/kg/day for Pneumocystis carinii, intravenous acyclovir (1500 mg/m 2 /day) for cytomegalovirus (CMV), oral fluconazole (5 mg/ kg/day) for fungal infection and anti-tuberculosis prophylaxis (rifampicin 15-20 mg/kg/ day once daily, isoniazid 10-15 mg/kg/day once daily and clarithromycin 10 mg/kg/dose every 12 h) when indicated. Ganciclovir was the treatment for CMV infection and reactivation was detected by a real time-polymerase chain reaction (PCR) assay and febrile neutropenia was treated with broad-spectrum antibiotics. G-CSF was used as needed.

Post transplantation

Hematological engraftment was defined as the first day on which the absolute neutrophil count exceeded 0.5 × 10 9 /L for three consecutive days. Chimerism was assayed on peripheral blood using XY fluorescence in situ hybridization (FISH) (for sex-mismatched HSCT) and DNA-finger print (for sex-matched HSCT) when appropriate. GVHD and venoocclusive disease (VOD) were diagnosed and classified according to the Glucksberg grading and Baltimore [7] criteria, respectively. Immune reconstitution monitoring was restricted to lymphocyte subsets, immunoglobulin, isohemagglutinins and anti-tetanus toxoid IgG assay. T-cell in vitro function is not available at our institute.

   Results Top

Our study included ten patients with different PID who lacked a fully matched related donor. Evaluation of the pre-transplantation status showed viral pneumonitis in five patients (P1, P4, P5, P7, P8), disseminated BCGosis in one patient (P7) and sepsis due to Klebsiella, Candida, Acinetobacter and Staphylococcus aureus in three patients (P7, P8, P10). CMV infection seen in one patient (P6), which required treatment. Positive serology for EBV and CMV was found in one patient (P10). All patients underwent MMRD HSCT (nine from the mother, one from a brother). All patients were engrafted. Two patients with myeloablative conditioning achieved more than 0.5 × 10 9 peripheral blood neutrophils L at a mean of 12 days while the third one was as late as 44 days. The other three patients with reduced intensity conditioning were engrafted at a mean of 13.6 days, while those who were transplanted with no preparative treatment did not have neutropenia. Seven patients had mixed chimerism as early as 21 days, while one was as late as 55 days. Typical engraftment syndrome was noticed in one patient (P10) as early as Day +8 with 75% donor engraftment by FISH at Day +14 before his chimerism slipped off at Day +36 (FISH 100% XY recipient). He underwent a second transplant with PBSC (CD34+ stem cells 5.8 × 10 6 /kg recipient weight) at Day +60. At the time of the report, the patient showed myeloid and lymphoid autologus recovery with a delay in platelet recovery. GVHD of skin was observed in five patients (50%), one with grade III, one with grade II and three patients with grade I. Gastrointestinal tract (GIT) and liver GVHD were noticed in patients P3 and P9, respectively. Other infectious and non-infectious post-transplant complications are shown in [Table 1]. Evaluation of immune reconstitution was performed in the four still surviving patients between 6 and 36 months post-HSCT [the fifth alive patient (P10) is still 80 days post-HSCT]. There were only two patients who had satisfactory reconstitution; they had no complications and are not on IVIG replacement. The other two patients had only satisfactory T-cell reconstitution but are still on monthly IVIG with no complications. At the time of this report, the post-transplantation follow-up ranged from 3 weeks to 36 months (median follow-up 15 months) and five of the ten patients are currently alive; four patients with mixed chimerism (5-55%) and three patients are still on IVIG with no significant morbidity. A second transplant was needed in one patient (P10) who received non-conditioned CD34+ stem cells (from the same donor) for graft rejection. Regarding the deceased patients, one patient died as early as 16 days post HSCT with severe pneumonitis while the other four patients died 62, 120, 28, and 240 days post HSCT respectively. The causes of death were VOD and Acinetobacter sepsis, severe GVHD and disseminated CMV infection, severe pneumonitis, alveolar hemorrhage and bronchiolitis obliterans.

   Discussion Top

HSCT is the definitive therapy for a variety of rare PID syndromes diagnosed in children. [8] However, no more than 30% of the patients have an HLA-identical sibling, [1],[3],[9],[10] and the chance of receiving a transplant from phenotypically matched unrelated donor (MUD) varies with the race of the patient, ranging from approximately 50% for Caucasian to less than 10% for ethnic minorities, and often requires waiting for months to identify the donor and obtain the graft. [11]

Most of the PID syndromes benefit from early diagnosis and transplantation before the development of serious infections, which contribute to a significant increased risk of mortality following transplant. In the absence of matched sibling, parental haploidentical, MUD and cord blood stem cells have all been utilized with varying degrees of success and immune reconstitution. [8] In our study, we retrospectively analyzed the results of MMRD HSCT in ten patients with PID who lacked a matched related donor. The pre-transplant condition in PID was important and seemed to be correlated with the outcome. Three of the five deceased patients (P7, P8 and P9) had disseminated BCGosis, Klebsiella, and Candida and Acinetobacter sepsis respectively. The CMV serology was positive in one patient (P6) in both the pre- and the post-HSCT periods, while two patients developed PCR-positive CMV infection post-HSCT. Gancyclovir was used to treat CMV infection pre-transplant and then promptly and pre-emptively treating any CMV antigenemia after transplantation in order to decrease the incidence of lethal CMV disease. [4]

Related HLA mismatched HSCT is limited by the high risk of severe GVHD, graft rejection, life-threatening infections and relapse, [12],[13] which might be partially related to intensive immune suppressive therapy and T-cell depletion. Hale et al reported that bone marrow transplantation (BMT) with T-cell depleted bone marrow from a haploidentical donor often leads to the development of opportunistic infections, such as CMV disease, or lympho-proliferative disorders owing to EBV (EBV-LPD), [14],[15] and there may be a substantial loss of CD34+ cells due to the processing required. [16]

One way to avoid such problems is to transplant large numbers of CD34+ stem cells, [17] which can be harvested from the donor peripheral blood after mobilization with G-CSF, [18] although only about 80% of all grafts can reach the level of cell doses required. [19],[20] In our study, the mean value of peripheral CD34+ cells infused was 9.19 × 10 6 /kg recipient's body weight (range 5.1-12 × 10 6 /kg) and the mean CD3+ cell number was 3.47 × 10 4 /kg. Miflin's observation in unmanipulated peripheral blood stem cell transplant showed that higher doses of CD34+ cells (>4 × 10 6 /kg) gave faster neutrophil and platelet engraftment, [21] and it did appear that doses below 2 × 10 6 CD34+cells/kg resulted in a significant delay in neutrophil and platelet engraftment while doses above 5 × 10 6 CD34+ cells/kg were associated with particularly rapid platelet engraftment. [16] Handgretinger et al recommended a CD34+ dose in the range of 10-20 × 10 6 /kg in order to achieve rapid immunological reconstitution. [22]

The disadvantages of haploidentical stem cell transplantation are the immunological consequences of crossing the major histocompatibility barrier, namely GVHD, graft rejection and delayed or incomplete immune reconstitution. [1] Acute GVHD has been reported at a lower incidence (46-66%) after MMRD BMT. [23],[24] Eyal reported acute GVHD in 45% of the patients in their MMRD BMT group. [25] In full agreement, 50% of the patients in our study developed acute GVHD. Although the results of haploidentical transplant have improved in some centers, this approach is not useful in the setting of advanced disease. [3] However, survival of patients undergoing MMRD BMT has been reported to vary between 45% and 78%. [11],[26],[27] Others showed a 3-year survival of only 54% in SCID patients with MMRD BMT. Furthermore, in another study, careful analysis of survival according to the degree of HLA identity showed that frank haploidentical (half-matched) transplantation resulted in only 25-30% long-term survival in patients with primary immunodeficiency [28] and, indeed, in this study, we showed a survival rate of 50%. In SCID patients, the mortality rate was 100% in B- SCID, while it was only 50% in B+ SCID. It has been reported that B-phenotypes (presumably NK) of SCID have a significantly poorer 3-year survival (36%) compared with B+ phenotypes (64%). [23],[26] Haddad et al have also shown a worse long-term outcome in children with B- SCID (NK cell phenotype unknown), who were more likely to die during the first 6 months post-transplant (37%) compared with those who had B+ SCID (13%). [29] This poor survival has been attributed to a diminished rate of engraftment, increased severity of GVHD, higher incidence of chronic GVHD [30] and slower recovery of T-cell function. [26],[29] In relation to the conditioning regimen, the survival rate was better in the patients who received reduced intensity conditioning (100%) in contrast to the myeloablative group (33.3%) and those with non-conditioned haploidentical HSCT (25%). Handgretinger et al. concluded that RIC regimens in haploidentical transplantations are associated with a reduced transplant-related mortality (TRM) rate even in patients who would be considered as being at a high risk for TRM in a standard allogeneic transplantation approach. [31]

The small number of patients and short duration of follow up make this a preliminary study. But it shows that HLA-haploidentical Hematopoietic Stem Cell Transplant with CD34+ve stem cells selection is of benefit in some patients with severe PIDs who lack a matched related or unrelated donor.

   References Top

1.Spitzer TR. Haploidentical stem cell transplantation: The always present but overlooked donor. Hematology Am Soc Hematol Educ Program 2005;390-5.  Back to cited text no. 1
2.Lang P, Greil J, Bader P, et al. Long-term outcome after haploidentical stem cell transplantation in children. Blood Cells Mol Dis 2004;33:281-7.  Back to cited text no. 2
3.Hwang WY, Ong SY. Allogeneic haematopoietic stem cell transplantation without a matched sibling donor: Current options and future potential. Ann Acad Med Singapore 2009;38:340-5.  Back to cited text no. 3
4.Lu DP, Dong L, Wu T, et al. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood 2006;107:3065-73.  Back to cited text no. 4
5.Eyrich M, Lang P, Lal S, et al. A prospective analysis of the pattern of immune reconstitution in a paediatric cohort following transplantation of positively selected human leucocyte antigen-disparate haematopoietic stem cells from parental donors. Br J Haematol 2001;114:422-32.  Back to cited text no. 5
6.Hagin D, Reisner Y. Haploidentical bone marrow transplantation in primary immune deficiency: Stem cell selection and manipulation. Immunol Allergy Clin N Am 2010;30: 45-62.  Back to cited text no. 6
7.Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG. Veno-occlusive disease of the liver following bone marrow transplantation. Transplantation 1987;44:778-83.  Back to cited text no. 7
8.Dvorak CC, Cowan MJ. Hematopoietic stem cell transplantation for primary immunodeficiency disease. Bone Marrow Transplant 2008;41:119-26.  Back to cited text no. 8
9.Nagatoshi Y, Kawano Y, Okamura J. Comparison of the outcomes of allogeneic bone marrow transplantation from partially mismatched related donors, matched sibling donors, and matched unrelated donors in Japanese pediatric patients: A single center result. Pediatr Transplant 2004;8:260-6.  Back to cited text no. 9
10.Ruggeri L, Capanni M, Mancusi A, et al. Allo reactive natural killer cells in mismatched hematopoietic stem cell transplantation. Blood Cells Mol Dis 2004;33:216-21.  Back to cited text no. 10
11.Smogorzewska EM, Brooks J, Annett G, et al. T cell depleted haplo identical bone marrow transplantation for the treatment of children with severe combined immuno deficiency. Arch Immunol Ther Exp 2000;48:111-8.  Back to cited text no. 11
12.Bishop MR, Henslee-Downey PJ, Anderson JR, et al. Long-term survival in advanced chronic myelogenous leukemia following bone marrow transplantation from haploidentical related donors. Bone Marrow Transplant 1996; 18:747-53.  Back to cited text no. 12
13.Roosnek E, Hogendijk S, Zawadynski S, et al. The frequency of pretransplant donor cytotoxic T cell precursors with anti-host specificity predicts survival of patients transplanted with bone marrow from donors other than HLA-identical siblings. Transplantation 1993;56:691-6.  Back to cited text no. 13
14.Aversa F, Tabilio A, Velardi A, et al. Treatment of high risk acute leukemia with T-cell depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 1998;339:1186-93.  Back to cited text no. 14
15.Hale G, Waldmann H. Risks of developing Epstein-Barr virus-related lymphoproliferative disorders after T-cell depleted marrow transplants. CAMPATH Users. Blood 1998;91: 3079-83.  Back to cited text no. 15
16.Keever-Taylor CA, Klein JP, Eastwood D, et al. Factors affecting neutrophil and platelet reconstitution following Tcell-depleted bone marrow transplantation: Differential effects of growth factor type and role of CD341 cell dose. Bone Marrow Transplant 2001;27:791-800.  Back to cited text no. 16
17.Reisner Y, Martelli MF. Tolerance induction by 'megadose' transplants of CD34+ stem cells: A new option for leukemia patients without an HLA-matched donor. Curr Opin Immunol 2000;12:536-41.  Back to cited text no. 17
18.Blau IW, Basara N, Lentini G, et al. Feasibility and safety of peripheral blood stem cell transplantation from unrelated donors: Results of a single-center study. Bone Marrow Transplant 2001;27:27-33.  Back to cited text no. 18
19.Tabilio A, Falzetti F, Zei T, et al. Graft engineering for allogeneic haploidentical stem cell transplantation. Blood Cells Mol Dis 2004; 33:274-80.  Back to cited text no. 19
20.Aversa F, Reisner Y, Martelli MF. Hematopoietic stem cell transplantation from alternative sources in adults with high-risk acute leukemia. Blood Cells Mol Dis 2004;33:294-302.  Back to cited text no. 20
21.Miflin G, Russell NH, Hutchinson RM, et al. Allogeneic peripheral blood stem transplantation for haematological malignancies - an analysis of kinetics of engraftment and GVHD risk. Bone Marrow Transplant 1997;9:9-13.  Back to cited text no. 21
22.Handgretinger R, Klingebiel T, Lang P, et al. Mega dose transplantation of purified peripheral blood CD34 + progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant 2001;27:777-83.  Back to cited text no. 22
23.Lanfranchi A, Verardi R, Tettoni K, et al. Haploidentical peripheral blood and marrow stem cell transplantation in nine cases of primary immunodeficiency. Haematologica 2000;85 Suppl 11:41-6.  Back to cited text no. 23
24.Drobyski WR, Klein J, Flomenberg N, et al. Superior survival associated with transplantation of matched unrelated versus one-antigen-mismatched unrelated or highly human leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: Establishing a treatment algorithm for recipients of alternative donor grafts. Blood 2002;99:806-14.  Back to cited text no. 24
25.Grunebaum E, Mazzolari E, Porta F, et al. Bone marrow transplantation for severe combined immune deficiency. JAMA 2006;295: 508-18.  Back to cited text no. 25
26.Antoine C, Müller S, Cant A, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: Report of the European experience 1968-99. Lancet 2003;361:553-60.  Back to cited text no. 26
27.Buckley RH, Schiff SE, Schiff RI, et al. Hemato- poietic stem -cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999;340:508-16.  Back to cited text no. 27
28.Caillat-Zucman S, Le Deist F, Haddad E, et al. Impact of HLA matching on outcome of hematopoietic stem cell transplantation in children with inherited diseases: A single-center comparative analysis of genoidentical, haploidentical or unrelated donors. Bone Marrow Transplant 2004;33:1089-95.  Back to cited text no. 28
29.Haddad E, Landais P, Friedrich W, Gerritsen B, Cavazzana- Calvo M, Morgan G. Longterm immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: A European retrospective study of 116 patients. Blood 1998;91:3646-53.  Back to cited text no. 29
30.Bertrand Y, Landais P, Friedrich W, et al. Influence of severe combined immunodeficiency phenotype on the outcome of HLA non-identical, T-cell depleted bone marrow transplantation: A retrospective European survey from the European group for bone marrow transplantation and the European Society for Immunodeficiency. J Pediatr 1999;134:740-8.  Back to cited text no. 30
31.Handgretinger R, Chen X, Pfeiffer M, et al. Feasibility and out come of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci 2007;1106:279-89.  Back to cited text no. 31

Correspondence Address:
Adel M Wahadneh
Queen Rania Children Hospital, King Hussein Medical Center, Royal Medical Services, Amman
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DOI: 10.4103/1319-2442.121269

PMID: 24231474

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