Objectives: Over the past 2 decades, hematopoietic stem cell transplant has evolved from an experimental procedure to the standard of care, and it is integrated into the management of many diseases. Hematopoietic stem cell transplant was established at Shiraz University of Medical Sciences in 1993. Here, we describe 15 years’ experience with stem cell transplant at our center in southern Iran. We provide information on indication, donor type, conditioning chemotherapy regimen, outcome, survival, and long-term follow-up in our stem cell activity.
Patients and Methods: From May 1993 to October 2008, 423 patients underwent allogeneic (n=311) and autologous (n=112) stem cell transplants at our center. For allogeneic stem cell transplant, the conditioning chemotherapy regimen comprised busulfan, cyclophosphamide, and antithymocyte globulin for thalassemic patients; busulfan and cyclophosphamide for leukemia patients; and cyclophosphamide and antithymocyte globulin for patients with aplastic anemia.
Results: During this period, 155 B-thalassemia major patients (mean age, 9.5 years; range, 2-20 years) underwent allogeneic marrow transplant. Of 155 patients with a diagnosis of thalassemia major, 112 are alive (72%) with full engraftment after a median follow-up of about 8.1 years (range, 12-184 months). During this time, 127 leukemia patients including acute myelogenous leukemia (n=68), acute lymphoblastic leukemia (n=30) and chronic myelogenous leukemia (n=29), received allogeneic stem cell transplant. In this group, long-term, disease-free survival (cure rate) was 67%, 60%, and 62%.
Conclusions: These data reflect the important role of hematopoietic stem cell transplant in improving survival for a variety of hematopoietic system disorders at our center in southern Iran. In patients with B-thalassemia major hematopoietic stem cell transplant seems to be the treatment of choice, because it leads to a cure in all classes (Lucarelli risk group, I-III). Based on high success rates in patients with class II and III thalassemia with the addition of the antithymocyte globulin to conditioning regimen of stem cell transplant, we also recommend using this new method of conditioning in transplant of thalassemia patients.
Key words : Bone marrow, B-thalassemia, Leukemia
Transplanting of hematopoietic stem cells is an established therapy for many congenital or acquired severe disorders of the hematopoietic system, as well as for chemosensitive or radiosensitive malignancies. Over the past 2 decades, hematopoietic stem cell transplant has evolved from an experimental procedure to the standard of care and is integrated into the treatment algorithm for many disease categories. Better management of the patients, improved supportive care, increased donor pools, and novel conditioning regimens have extended its use to new patient categories and new disease indications. Based on current data, more than 25 000 patients are now treated annually in Europe with hematopoietic stem cell transplant, and an estimated near 100 000 patients worldwide (1, 2).
Hematopoietic stem cell transplant was established in Shiraz University of Medical Sciences in 1993 for adult and pediatric patients (3, 4). Here, we describe our 15-year experience with stem cell transplant at our center in southern Iran. This report provides information on indication, donor type, conditioning chemotherapy regimen, outcome, survival, and long-term follow-up of our stem cell activity in Shiraz University of Medical Sciences.
Patients and Methods
From May 1993 to October 2008, 423 patients including 155 thalassemia major, 85 acute myelogenous leukemia, 30 acute lymphoblastic leukemia, 29 chronic myelogenous leukemia, 20 severe aplastic anemia, 74 lymphoma (NHL and HD), 24 multiple myeloma, 4 germ cell tumors, 1 Ewing sarcoma, 1 myelodysplastic syndrome, and 1 osteopetrosis underwent allogeneic or autologous hematopoietic stem cell transplant.
The source of hematopoietic stem cell transplant was bone marrow (n=198) and peripheral blood (n=225) in these cases. We have done 311 allogeneic and 112 autologous stem cell transplant; all of the 311 donors for allogeneic transplant were from HLA compatible relatives of patients including siblings (n=291) and other family members (n=20).
In allogeneic transplant, conditioning chemotherapy regimen was busulfan 14-15mg/kg po), cyclophosphamide (120-200 mg/kg), and antithymocyte globulin (40 mg/kg) for thalassemic patients, busulfan (16 mg/kg) or busulfan IV (80% of po dosages), and cyclophosphamide (120-200 mg/kg) for leukemia (acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia patients), and cyclophosphamide (60-120 mg/kg) and antithymocyte globulin (90 mg/kg) for severe aplastic anemia and Fanconi anemia.
In autologous transplant, conditioning chemotherapy regimen was CCNU (200 mg/m2), etoposide (1000 mg/m2), Ara-C 1000 mg/m2) and melphalan (140 mg/m2) for lymphoma (HD and NHL), busulfan (12 mg/kg) and etoposide (30 mg/kg) for acute myelogenous leukemia and melphalan (140-200/m2) for multiple myeloma patients.
Graft-versus-host disease prophylaxis consisted of cyclosporine and methylprednisolone, or methotrexate. Prophylactic antibiotics, antifungal and antiviral drugs were prescribed for all the patients. All the blood products were irradiated with gamma rays to prevent posttransfusion graft-versus-host disease.
During this period, 155 B-thalassemia major patients (mean age, 9.5 years; range, 2-20 years) underwent allogeneic marrow transplant. Distribution of cases according to Lucarelli classification was 43 cases with class I, 53 cases with class II, and 59 cases with class III. One hundred twelve of 155 patients (72%) with diagnosis of thalassemia major are living with full engraftment, with median follow-up of approximately 8.1 years (range, 12-184 months). In thalassemic patients, we had 23 cases (14.8%) of transplant-related mortality and 20 graft rejections (12.9%) after the first transplant. In 5 patients, the second stem cell transplant was done, and in 3 cases, it was successful. Overall survival rate in this group was 85.1%. Table 1 shows the result of stem cell transplant in thalassemia major according to the Lucarelli classification.
During this period, 127 leukemia patients—including acute myelogenous leukemia (n=68), acute lymphoblastic leukemia (n=30), and chronic myelogenous leukemia (n=29), with a mean age of 29 years and range of 5-57 years—were transplanted as allogeneic stem cell transplant. In this group, long-term disease-free survival (cure rate) was 67%, 60%, and 62%. There were 45 mortality cases (35%) in this group after stem cell transplant, mainly due to the relapse of malignancy.
In our 20 patients with diagnosis of severe aplastic anemia (mean age, 10.1 years), 16 patients (80%) were cured with full engraftment, and 3 of them (15%) died directly due to transplant-related mortality. In this group, the cure rate for patients with Fanconi anemia who received allogeneic stem cell transplant was 75% (3 of 4).
In patients with NHL (n=39) who underwent autologous stem cell transplant, 22 out of 31 (70%) are disease-free with a median follow-up of 20 months (range, 6-41 months). Disease-free survival for HD (n=35) after autologous transplant was (21 of 29), 72% with a median follow-up of 21 months (range, 6-60 months). The results of autologous stem cell transplant in multiple myeloma patients (n=24) at our center show that 70% (17 of 24) are disease-free, with a median follow-up of 23 months (range, 6-50). In 17 patients with diagnosis of acute myelogenous leukemia who underwent autologous stem cell transplant, 11 of 17 (58%) are in complete remission with a median follow-up 20 months (range, 6-48)
Despite the high cost and complexity of procedure, hematopoietic stem cell transplant has developed in developing countries. Iran is located in Middle East and its total population is about 70 million. Our center is located in south of Iran and is the referral center for at least 10 million persons for treatment of hematology-oncology diseases. Based on 15 years’ experience and more than 423 transplants, this article presents special issues and results of hematopoietic stem cell transplant practices, and activity in a developing country and in our region. Differences in the number of hematopoietic stem cell transplants, in transplant rates, in indications, and in techniques between counties have been reported (5). They were attributed mainly to differences in the economic situation of countries or to differences in prevalence of the disease (5).
The hematopoietic stem cell transplant as a therapeutic approach for B thalassemia major pioneered by the Pesaro group (6-12) and is now applied worldwide. Hematopoietic stem cell transplant was established as a curative method for treatment of thalassemia major in our center in 1993 (4). In patients with thalassemia major (the most common indication for allogeneic hematopoietic stem cell transplant in our center), the data indicated successful engraftment in 72%, with a median follow-up of about 8.1 years, which is in good agreement with the best previously reported results (13). Giardini and Lucarelli have reported survival-free and event-free survival 93% and 91% for class I, 87% and 83% for class II, and 79% and 58% for class III (14). Our results for stem cell transplant for thalassemia patients according to the Lucarelli risk classification were comparable to those reported by Giardini and Lucarelli from Italy (Table 1) (4, 14). In our study—using low-dose antithymocyte globulin as a part of the conditioning regimen in the majority of cases of class II and III thalassemia—resulted in a lower risk of rejection severe graft-versus-host disease, and a high chance of full engraftment and survival in classes II and III (4).
In patients with acute myelogenous leukemia (n= 85) (the second-most common group for hematopoietic stem cell transplant at our center), we achieved long-term, disease-free survival of 67% of the patients, with a median follow-up of 5.5 years. We used allogeneic stem cell transplant as one of the postremission strategies, attempting to eradicate subclinical disease in patients with acute myelogenous leukemia. Acute myelogenous leukemia was the most-frequent indication for an allogeneic hematopoietic stem cell transplant in 2007 in European group for blood and marrow transplant (15). The current results for acute myelogenous leukemia patients transplanted in first complete remission (CR1) from HLA compatible siblings gives a probability of disease-free survival ranging from 45% to 70%, and European group for blood and marrow transplant registry data of the last 5-7 years indicating approximately 55% to 60% disease-free survival.
There is a variation among centers, depending on the type of patient transplanted and on the experience and skill of the center (16). In our center, 2 factors might have resulted in a better outcome for the leukemia group: 100% of donors for allogeneic hematopoietic stem cell transplant in acute myelogenous leukemia and acute lymphoblastic leukemia were done with HLA-compatible siblings. And 2, we have done transplants for younger patients (mean age, 29 years) in allogeneic setting.
In a European group for blood and marrow transplant survey 2007, HLA-identical siblings were used as donors for 47% of the recipients (15). In the acute lymphoblastic leukemia group, the results show a cure rate of 60%. According to the results of acute leukemia (acute myelogenous leukemia, acute lymphoblastic leukemia) patients that are better than those of other methods of treatments at our center, we highly suggest hematopoietic stem cell transplant for these indications.
At our center, the most common indications for hematopoietic stem cell transplant are different from data reported by the European group for blood and marrow transplant. In a European group for blood and marrow transplant survey of 1990-2000, the main indications for allogeneic hematopoietic stem cell transplant were leukemia (75.9%), lymphoproliferative disorders (8.9%), and nonmalignant disease including thalassemia (12.9%) (17). At our center, the main indications for allogeneic hematopoietic stem cell transplant were thalassemia major (155 out of 311) 49.8%, and leukemia (127 out of 311), 40.8% of which reflect a high prevalence of thalassemia in our area, in southern of Iran.
Gratwohl and associates reported that there were clear differences in transplant rates for certain disease indications in European group for blood and marrow transplant survey 2006, which might be related to a different prevalence of the disease, for example, hemoglobinopathies (5). During the past 10 years, screening and prevention of the marriage of thalassemia minor patients with each other in our country resulted in a decrease of the rate of thalassemia major in our area. Thus, today, in our center, leukemia and lymphoproliferative disorders have become the most-common indications for allogeneic and autologous transplant that is similar to data of European group for blood and marrow transplant (18-19).
The result of aplastic anemia group (cure rate, 75%) in our center also indicates that hematopoietic stem cell transplant is an effective, curative method of therapy for severe aplastic anemia, especially in young patients. Treatment strategies for patients with severe aplastic anemia depend on the severity of disease, the age of the patient, and the availability of a family donor (20). Currently, the actuarial 10-year survival in 2479 patients registered within the European group for blood and marrow transplant, is 73% and 68% for patients receiving first-line bone marrow transplant or immunosuppressive therapy, and survival is significantly better in children (< 16 years) as compared with adults (21).
Hematopoietic stem cell transplant activity expanded rapidly in Shiraz, especially during the last 5 years; however, if we compare the total transplant to total population in our region, the rate is low. A European group for blood and marrow transplant group analyzed the evolution transplant rate (numbers of transplant per 10 million inhabitants) from 1990 to 2004 for all major disease categories and used Gross National Income (GNI) per capital, team density (numbers of team per 10 million inhabitants), and team distribution (numbers of team per 10 000 Km2 ) to measure of impact of economic factors in countries (22). Results have revealed that GNI per capital, team density, team distribution, team size, and team experience all have impact on transplant activity (5). Moreover, other factors might have been involved in the decisions to perform or not to perform hematopoietic stem cell transplant. In this report, there were also clear differences in transplant rates for certain disease indications, which might relate to a different prevalence of the disease (5, 22).
These data reflect the important role of hematopoietic stem cell transplant in improvement of survival for a variety of hematopoietic system disorders in our center in Southern Iran. In patients with B-thalassemia major, hematopoietic stem cell transplant seems to be the treatment of choice, and curative method in all classes (Lucarelli risk group I-III). Based on higher successful engraftment in class II and III in our center, with addition of antithymocyte globulin, we also recommend using this new method of conditioning chemotherapy, as a regimen with high success rate of class II and III thalassemic patients. In hematologic malignancies (which are now main indication for transplant in our center similar to European center) results are better than other methods of treatment, and we suggest hematopoietic stem cell transplant for these indications in our region.
It is clear that the need for hematopoietic stem cell transplant will continue to increase in the near future. The policy of the government should be encouraging and supportive of such a difficult, comprehensive, and complicated, but powerful and curative therapeutic approach in our country.
Volume : 8
Issue : 1
Pages : 61 - 65
From the Department of Hematology-Oncology and Stem Cell Transplantation, Shiraz
University of Medical Sciences, Shiraz, Iran
Acknowledgement: The author would like to thank Dr H. Haghighi nejhad for editing.
Address reprint requests to: Mani Ramzi, MD, Department of Hematology-Oncology & Stem Cell Transplantation, Shiraz University of Medical Sciences, Shiraz, Iran.
Phone: +98 711 6474301
Fax: +98 711 6474301
Table 1. Results of European group for blood and marrow transplant in B-thalassemiamajor patients in Shiraz according to Lucarelli classification and comparison of the results with Giardini and Lucarelli report from Italy.