Bone Marrow Transplantation (2008) 42, S109–S113 & 2008 Macmillan Publishers Limited All rights reserved 0268-3369/08 $30.00
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REVIEW
Hematopoietic stem cell transplantation in Oman D Dennison, S Al Kindi, A Pathare, S Daar, N Nusrat, J Ur Rehman, F Zia, H Khan, M Irfan Khan, A Alghazaly, S Al Zadjali, M Tauro, AT Al Lawatia and SS Ganguly Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman
Hematopoietic SCT (HSCT) is an integral part of the management of patients with hematologic disorders. The Sultanate of Oman, with a population of 2.3 million, has an HSCT program based in the Sultan Qaboos University (SQU) hospital. Initiated in 1995, this two-bed unit continues to be the only program in the country. Between June 1995 and August 2006, a total of 128 patients underwent HSCT in this center, averaging about 10–12 transplants per year. The median age of these patients was 11 years (2 months to 45 years). Hematologic malignancies (49%) and inherited disorders (42%) constituted the major transplant indications, whereas BM failure accounted for the remaining. The majority of transplants carried out so far have been HLA-matched sibling-donor allogeneic HSCTs. Among the inherited disorders, homozygous beta-thalassemia and primary immunodeficiency are important transplant indications in this center. The approximate cost of an uncomplicated transplant in this center is US$50 000. The success of this program has now led to the initiation of a new and larger HSCT complex to provide the opportunity for more patients to benefit from this treatment modality within the country. Bone Marrow Transplantation (2008) 42, S109–S113; doi:10.1038/bmt.2008.131 Keywords: Oman; transplant; allogeneic; inherited; thalassemia; immunodeficiency
Introduction Over the past three decades, hematopoietic SCT (HSCT) has become a vital therapeutic modality in the management of a variety of hematologic malignancies and inherited disorders.1,2 Once confined mainly to highly advanced centers in the United States and Europe, HSCT is now available in many centers worldwide. The Sultanate of Oman, with a population of 2.3 million (Omani 1.78 million, expatriate 0.56 million),3 started its program in 1995 as an initiative of the hematology department at SQU Hospital. It began as a one-bed unit, which was expanded
Correspondence: Dr D Dennison, Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman. E-mail:
[email protected]
to two beds in 2000. The program currently has the infrastructure to perform approximately 15 allogeneic transplants per year. We are recent members of the European BMT group. This paper describes the experience of HSCT in the Sultanate of Oman over the past decade.
Patients and methods Between June 1995 and August 2006, a total of 128 patients underwent 132 HSCT procedures in this center, the last few years averaging approximately 15 transplants per year. The median age was 11 years, ranging from 44 days to 45 years.
Transplant program The transplant unit consists of two transplant beds in positive pressure, high-efficiency particulate air-filtered rooms and two step-down beds in standard isolation rooms. Concomitant with the growth of the clinical transplant program has been the development of state-ofthe-art transplant laboratory facilities. The major components of this include a molecular biology section for chimerism and minimal residual disease analysis, a Clinimax machine for T-cell depletion and a BU pharmacokinetic laboratory. Ninety-five per cent of patients (121/ 128) transplanted in this center were Omani nationals. HSCTs in Oman were performed for a wide spectrum of disorders as shown in Figures 1 and 2, with a fairly equal proportion of patients with hematologic malignancy and inherited disorders. The major categories of inherited disorders included thalassemia major and primary immunodeficiency syndromes. In total, 128 transplants (97%) were allogeneic and four (3%) were autologous (Table 1). We were able to obtain HLA-matched siblings in approximately 40% of our patients. Two patients received T-celldepleted haplo-identical transplants for SCID syndrome (SCIDS). We currently have a waiting list of more than 100 patients, most of whom have thalassemia. The approximate cost of an uncomplicated allogeneic HSCT here is US$50 000. The Sultan Qaboos University (SQU) has an impressive infrastructure for research, and research grants are made available in both clinical and basic sciences. One of our major research interests in HSCT has been the role of BU pharmacokinetics in transplant conditioning and its relation to chimerism and toxicity.4,5 We established the oxidative burst assay by flow cytometry in our laboratory for the diagnosis of chronic granulomatous disease (CGD)
Hematopoietic SCT in Oman D Dennison et al
S110 Inherited disorders 57 (45%)
Hematological malignancy 62 (48%)
Bone marrow failure 9 (7%) Figure 1
Indications for hematopoietic SCT transplantation in Oman.
HLA class II deficiency: 1 (1.8%) Interferon gamma receptor deficiency: 1 (1.8%) Blackfan diamond syndrome: 1 (1.8%) Severe combined immunodeficiency syndrome: 2 (3.5%) Hemophagocytic lymphohistiocytosis: 2 (3.5%) Fanconi's anemia: 2 (3.5%) Sickle cell anemia: 2 (3.5%) Glanzmanns thrombasthenia: 2 (3.5%) Chronic granulomatous disease: 3 (5.3%)
Total number: 57
Figure 2
Table 1
Thalassemia major: 41 (71.9%)
Hematopoietic SCT for inherited disorders in Oman.
Type of transplant and source of stem cells
Type of transplant Allogeneic HLA-matched sibling donor Allogeneic HLA-matched parent Allogeneic HLA-haploidentical parent Autologous Source of stem cells for allogeneic transplants Marrow PBSC PBSC+marrow Cord blood+marrow T-cell depleted PBSC
n
%
125 1 2 4
94.6 0.8 1.5 3
96 24 5 1 2
75 18.8 3.9 0.8 1.6
and used this technique to monitor chimerism in these patients.6 Direct sequencing to analyze the mutations in patients with HLH (perforin, munc13-4 and syntaxin11) and CGD (genes involved in the NADPH oxidative system) is carried out routinely both for diagnosis and research. The HLH and CGD work have formed the basis of a PhD and Master’s theses, respectively, for two of our molecular biologists.7,8
Conditioning regimens A combination of BUu and Cy (Bu/Cy120) was the conditioning regimen used for hematologic malignancy, whereas Bu/Cy200 with or without antithymocyte globulin (ATG) was the main regimen used for thalassemia. Since Bone Marrow Transplantation
2003, the dose of BUu is individualized by first or test-dose pharmacokinetics to target a steady-state concentration (Css) between 700 and 800 ng/ml.9 The next major change in conditioning was the modification of the Bu/Cy120 regimen for hematologic malignancy to Bu/Flu where fludarabine is used instead of Cy.10 This same myeloablative regimen along with ATG (Fresenius Biotech, Grafelfing, Germany), Bu/Flu/ATG, is now currently used for patients with thalassemia. Reduced-intensity conditioning using low-dose Bu, fludarabine and ATG (LDBu/Flu/ATG) is our regimen of choice for selected categories of patients with primary immunodeficiency and the elderly with AML. For the autologous transplants, BEAM (BCNU, etoposide, Ara-C and melphalan (Mel)) is used for lymphoma, and Mel 200 mg/m2 is the regimen used in myeloma.
GVHD prophylaxis and treatment The standard GVHD prophylaxis was CYA and shortcourse methotrexate. Tacrolimus was used instead of CYA in two patients. Methylprednisolone at the dose of 2–5 mg/ kg/day was the first-line therapy for established acute GVHD (aGVHD). Our recent approach for steroid refractory GVHD has been to use the tumor necrosis factor a soluble receptor, eternacept. For chronic GVHD (cGVHD), the main line of management is with prednisolone, CYA or azathioprine. Source of stem cells, cryopreservation and cord blood bank BM was the main source of stem cells in over 75% of our patients. However, we are increasingly using PBSC in hematologic malignancy and selected infants with primary immunodeficiency. In 2005, we set up a cryopreservation facility for autologous transplantation and cord blood banking. The cord blood program is mainly to establish an unrelated donor bank, but we also store sibling donor cord blood when indicated. Post-transplant follow-up All of our patients, including the approximately 60 patients transplanted abroad, are followed up in the transplant outpatient clinic and day care unit. Patients are followed up at specific periods post transplant for post-transplant care, including re-immunization, monitoring of graft and minimal residual disease, managing GVHD and tapering of immunosuppression.
Results Hematologic malignancy A total of 62 patients underwent HSCT for a variety of malignant hematologic disorders (Table 2). The median age of these patients was 16 years, ranging from 3 to 45 years. AML The total number of patients with AML was 25, with a median age of 13 years (3–45 years). Sixty percent (15/25) of patients were in first CR at the time of transplant. Seventysix percent (19/25) received Bu/Cy120 as conditioning,
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Hematological malignancy: types of disorders and
Disease
n
AML ALL CML Myelodysplastic syndrome Multiple myeloma Lymphoma Neuroblastoma
25 24 5 3 2 2 1
Age (years) 13 15 25 25
(3–45) (4–31) (11–39) (16–45)
36, 44 18, 36 7
EFS (%)
Follow-up (months)
64 54 60 67
57+ (14–121) 32+ (12–119) 128+ (115–143) 73–98+
100 100 0
21–27+ 29–35+ Progressive disease
Abbreviation: EFS ¼ event-free survival.
whereas four received myeloablative Bu/Flu. One patient received reduced-intensity conditioning with LDBu/Flu/ ATG. Sixty-four percent (16/25) of patients are well and disease-free, with a median follow-up period of 5 years (14 months to 10 years). Thirty-two percent (8/25) of patients died, the majority being due to relapsed disease. Nonrelapse mortality was 8% (2/25), the causes being interstitial pneumonia1 and chronic pulmonary GVHD.1
ALL In total, 24 patients received transplants for ALL. As in AML, many were adolescents and children with a median age of 15 years (4–31 years). Half of these patients (12/24) were considered high risk and in first CR at the time of transplant. Non-TBI-based conditioning regimens were used in all patients owing to the nonavailability of TBI in the country until very recently. Specifically, 58% (14/24) received Bu/Cy120. Three patients were conditioned with Bu/Mel and the last consecutive seven received Bu/Flu. There was a higher incidence of aGVHD (82%) in this group of patients when compared to AML. Fifty-four percent (13/24) of patients are well and free from leukemia with a median follow-up of close to 3 years (1–10 years). Relapse and persistent disease accounted for all the transplant failures. The overall mortality was 38% (9/24). CML A total of five patients underwent HSCT for CML, the last patient being transplanted in 2002. The median age was 25 years, ranging from 11 to 39 years. One patient was in accelerated phase, whereas the other four were in first chronic phase. None of these patients had received imatinib prior to transplant. Overall disease-free survival was 60% with a median follow-up period of 11 years (9–12 years). Both patients who relapsed presented in lymphoid blast crisis 3–8 years following transplant. Miscellaneous hematologic malignancy Other hematologic malignancy for which HSCTs were performed included multiple myeloma (two), lymphoma (large cell lymphoma one and Hodgkin’s disease one), myelodysplastic syndrome (three) and neuroblastoma (one). One patient with myelodysplastic syndrome died from grade IV aGVHD and the neuroblastoma patient succumbed to progressive disease. All the rest are well. One patient with multiple myeloma had standard high-dose
therapy with melphalan and PBSC rescue. The other patient, aged 36 years in PR, received high-dose therapy with Mel followed by a reduced-intensity allogeneic transplant using Flu/LDBu/ATG as conditioning. The M-band, which was present at the time of the second transplant, has since disappeared 18 months later.
BM failure Eleven patients underwent HSCT for BM failure. The median age of these patients was 10 years, ranging from 2 to 34 years. All patients had received numerous blood component transfusions prior to coming to this hospital, many of which were nonleukocyte-depleted or irradiated. Idiopathic aplastic anemia Nine patients received transplants for idiopathic aplastic anemia. The first four patients received Cy and ATG as conditioning. Our current protocol, which is fludarabine, Cy and ATG (Flu/Cy120/ATG), was used in four patients. One of these four patients received a syngeneic graft. One patient with paroxysmal nocturnal hemoglobinuria and aplastic anemia received LDBu/Flu/ATG. None of the nine patients developed GVHD. Four patients (80%) were cured with a median follow-up of almost 6 years (1.3–12 years). The patient with paroxysmal nocturnal hemoglobinuria had poor graft function but continues to be a complete chimera, and is transfusion independent with a hemoglobin level of 10 g and mild thrombocytopenia. Fanconi’s anemia Two patients aged 3 and 10 years, respectively, received transplants for Fanconi’s anemia using Flu/Cy20/ATG as conditioning. This conditioning has been shown to be useful in multiple transfused patients with Fanconi’s anemia.11 Both patients are well and disease-free with a follow-up period of 5 years. Thalassemia In total, 41 patients with thalassemia underwent HSCT in this center. The median age was 9 years, ranging from 2 to 16 years. Fifty-six percent of patients (23/41) were Lucarelli class II. Ninety percent (37/41) were conditioned with Bu/Cy200 with or without ATG. The last four patients received myeloablative Bu/Flu/ATG12 with targeted-dose BU, which is our current protocol for thalassemia. Marrow was the source of stem cells for all patients except one, who received a combination of cord blood and BM. The incidence of aGVHD and cGVHD was 45 and 13%, respectively. Thirtysix patients (88%) are well and disease-free at a median of 6 years (1–12 years) following HSCT. Graft rejection occurred in three patients (7%). Overall mortality was 10% (4/41). Two patients died following second transplants for rejection, and the other two died from hemorrhage and sepsis. Primary immunodeficiency A total of nine patients underwent HSCT for primary immunodeficiency in this center. The median age was 3.5 years (44 days to 21 years). Bone Marrow Transplantation
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Phagocyte disorders Four patients with phagocyte disorders, three with CGD and one with IFN gamma receptor deficiency, were transplanted in this center, their median age being 13 years (4–21 years). All three patients had recurrent life-threatening infections. We used myeloablative conditioning with ivBu/Cy for the first patient with CGD. For all the others, including the patient with IFN gamma receptor deficiency, we used reduced-intensity conditioning with Flu/LDBu/ ATG with PBSC as the source of stem cells. All three patients are free from disease at a median of 3.5 years (17 months to 5.8 years) following HSCT. Familial hemophagocytic lymphohistocytosis We have transplanted two patients with HLH, both with perforin gene mutations. For the first patient aged 5 months (weight 5.3 kg), we used Bu/Cy/etoposide as myeloablative conditioning. She is cured with a follow-up of more than 6 years post-HSCT, but the regimen proved to be very toxic. The second patient who was 1.8 years old received reduced-intensity conditioning with Flu/Bu/ATG with very good results. This child is a stable mixed chimera and is well 17 months post-HSCT.
Infectious disease issues The spectrum of infection in our transplant population is not different from that reported in the literature. Very severe invasive pulmonary aspergillus and disseminated cerebral and pulmonary zygomyces seen in two patients were successfully treated with aggressive systemic antifungal therapy. Of the two patients with thalassemia who rejected their grafts and died owing to aplasia, one had documented central nervous system toxoplasmosis, whereas the other had clinical evidence of invasive fungal infection. Routine monitoring of blood by CMV PCR and pre-emptive therapy with ganciclovir has been our usual approach to CMV infection. GVHD The overall incidence of aGVHD and cGVHD was 30–40 and 10–15%, respectively. This is not different from the reported literature in the context of matched-sibling donor allogeneic transplants. At this point in time, our transplant numbers are too small to analyze differences in the incidence of GVHD with regard to the source of stem cells.
Discussion SCIDS Two patients with SCIDS aged 44 days and 3 months, respectively, underwent HSCT. Both had the autosomal recessive form of SCIDS and were typed as T-cell negative, B-cell positive and natural killer-cell positive. They received T-cell depleted, haploidentical HSCTs, the parents being the donors. T-cell depletion was carried out using a positive selection of CD34 cells. Myeloablative conditioning (ivBu/ Cy/ATG) was used in both cases with PBSC as the stem cell source. The first patient is now close to 5 years following transplant. She is free from infection and is no longer on Ig replacement therapy. The second patient expired 4 months post-HSCT from interstitial pneumonia. HLA class II deficiency This rare disorder was diagnosed when the patient presented with major recurrent opportunistic infections, diarrhea and failure to thrive. This clinical presentation, along with his immunological profile including the absence of HLA-DR on B cells by flow cytometry, clinched the diagnosis. The child was moribund, but with intensive supportive care and total parenteral nutrition, he finally underwent a matched-sibling HSCT. Reduced-intensity conditioning with Flu/ivBu/ATG and PBSC was used. He is thriving well, growing and free from infection now 2 years post-HSCT. Miscellaneous inherited disorders Other inherited disorders for which HSCT was performed in our center include Glanzmann’s thrombasthenia (two), sickle cell disease (two) and Blackfan–Diamond syndrome (one). The only death in this group was our first patient with sickle cell anemia who expired on day þ 15 owing to sepsis. All other patients are cured from their disease 5.5 years (5–6 years) post transplant. Bone Marrow Transplantation
The HSCT program in the Sultanate of Oman began in June 1995. The first patient, an Omani child with AA, received a matched-sibling allogeneic HSCT and is now well and cured more than 12 years post transplant. Since then, 127 more patients received HSCTs in this center and we have a large number of patients on the waiting list. The success of this program has now led to a major initiative by the university hospital and the national government to expand the current infrastructure to offer more patients curative therapy with HSCT within the country. The high prevalence of potentially curable inherited diseases of the blood in the country prompted us to take special interest in this group of patients. Our focus on thalassemia and primary immunodeficiency has paid great dividends. The conventional management of both these groups of patients is expensive, owing to the long-term cost of transfusion and chelation therapy in one group and antimicrobial and aggressive supportive care in the other. Our experience in transplanting such patients has been remarkable with an excellent outcome for most. Approximately 88% (36/41) of patients with thalassemia and 89% (8/9) of patients with primary immunodeficiency are cured. HSCT offers a cost-effective alternative and, more importantly, a cure for many. Two very contemporary themes have been our main research interests over the past decade, the first being BU pharmacokinetics and its role in conditioning, especially in the pediatric population. Initiated in 2000 as part of a research project investigating the use of oral versus intravenous BU in thalassemia conditioning, we now utilize BU pharmacokinetics in all our patients to scientifically target a steady-state concentration of this drug. The second is our focus on reduced-intensity conditioning for primary immunodeficiency transplants, which stemmed from our first patient with familial HLH who was transplanted at a
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time when the published literature suggested the use of Bu, Cy and etoposide as conditioning.13 Even though this patient is cured, we found it to be far too toxic. We subsequently used a reduced-intensity conditioning regimen with Flu/LDBu/ATG for our next patient with HLH with minimal toxicity and an excellent outcome as well. This regimen has now been used in our center with great success in phagocyte disorders and in our only patient with HLA class II deficiency. The use of this regimen for CGD and HLH has recently been published14,15 and we can confirm its efficacy in our small group of patients. Acute leukemias constituted the majority of hematologic malignancies transplanted in this center, and although our numbers are small, the results appear to be the best one can expect. As in many centers, relapse is the major cause for transplant failure. We have traditionally used Bu/Cy120 as myeloablative conditioning regimens for both AML and ALL. However, from 2005, we have switched to targeted-dose BU and fludarabine. With the recent availability of irradiation facilities within the country, we now have plans to incorporate TBI in the conditioning for patients with ALL. Peripheral blood is increasingly being used as the source of stem cells for patients transplanted for hematologic malignancy, the exception being small donors for whom PBSC harvesting may be technically difficult. However, we continue to use BM alone for thalassemia transplants owing to our concerns of cGVHD in these patients. Over the next few years, we plan to expand our autologous transplant program. These data have shown that Oman has a small, viable and successful HSCT program with results comparable to those of the best centers in the world. The wealth of experience gained over the past decade, especially in the field of thalassemia and primary immunodeficiency, is remarkable and will form the foundation for further improvement and research. Although with the current existing infrastructure this program is not sufficient to cater to the needs of the entire country, we have been able to provide state-of-the-art curative therapy for many patients with excellent results. The near future will see an expansion of this program with less of the country’s citizens needing to be sent abroad for this treatment.
Acknowledgements We specifically acknowledge the following for their invaluable contribution to the success of this program: Dr Mammen Chandy from the CMC Hospital in Vellore for initiating this program on his sabbatical from Vellore in 1995, Dr R Krishnamoorthy, Hospial Robert Debre, Paris, for his efforts in setting up the transplant laboratory, Dr Paul Veys from the Great Ormond Street Hospital in London for his advice and encouragement in HSCT for primary immunodeficiency, our dedicated nursing and laboratory staff and all the allied specialties and support services of the Sultan Qaboos University Hospital.
Conflict of interest Dr Daar has received lecture fees from ApoPharma. None of the other authors declared any financial interests.
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