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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 44  |  Issue : 2  |  Page : 111-117

Outcome of reduced-intensity allogeneic stem cell transplantation in Egyptian patients with myelodysplastic syndromes


1 Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
2 Department of Clinical Pathology, Clinical Hematology Unit, Faculty of Medicine, Assiut University, Assiut, Egypt
3 Department of Internal Medicine, Clinical Hematology Unit, Faculty of Medicine, Assiut University, Assiut, Egypt
4 Department of Oncological Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
5 Department of Medical Oncology, South Cancer Institute, Assiut University, Assiut, Egypt

Date of Submission13-Jan-2019
Date of Acceptance10-Feb-2019
Date of Web Publication15-Nov-2019

Correspondence Address:
Safinaz Hussein
Clinical Hematology, Department of Internal Medicine, Assiut University, Assiut, 71516
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_2_19

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  Abstract 


Background Reduced-intensity conditioning for allogeneic stem cell transplantation (allo-SCT) is possible for patients with myelodysplasia syndrome (MDS) who are ineligible for high-dose myeloablative conditioning allo-SCT.
Objective To determine the outcome of reduced-intensity allo-SCT in Egyptian patients with MDS.
Patients and methods A total of 18 patients with MDS were included, and the median age was 39 years. The conditioning regimen consisted of fludarabine (150 mg/m2) and busulfan (8 mg/kg). All patients received mobilized peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate.
Results The Kaplan–Meier-estimated 2-year overall survival and disease-free survival were 49 and 33%, respectively. The Kaplan–Meier-estimated probability of relapse at 2 years was 43.5%. The Kaplan–Meier-estimated probability of nonrelapse mortality at 2 years was 43%, and severe acute GVHD and sepsis were the main causes of death. The Kaplan–Meier-estimated probabilities of acute and chronic GVHD were 31 and 20%, respectively.
Conclusion Although reduced-intensity conditioning regimens allowed for decreased transplant-related toxicities and increased durable engraftments, their use was associated with a high incidence of relapse in patients with MDS.

Keywords: myelodysplasia syndrome, reduced intensity, stem cell transplantation


How to cite this article:
Samra MA, Ahmed SM, Hafez R, Hussein S, Mansor SG, Eltyb HA. Outcome of reduced-intensity allogeneic stem cell transplantation in Egyptian patients with myelodysplastic syndromes. Egypt J Haematol 2019;44:111-7

How to cite this URL:
Samra MA, Ahmed SM, Hafez R, Hussein S, Mansor SG, Eltyb HA. Outcome of reduced-intensity allogeneic stem cell transplantation in Egyptian patients with myelodysplastic syndromes. Egypt J Haematol [serial online] 2019 [cited 2019 Dec 14];44:111-7. Available from: http://www.ehj.eg.net/text.asp?2019/44/2/111/271080




  Introduction Top


Myelodysplasia syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis resulting in peripheral cytopenias, and an increased risk of progression to acute myeloid leukemia [1].

Hematopoietic cell transplantation (HCT) is the only curative therapeutic option for patients with MDS, associated with long-term survival (25–75%) [2],[3],[4].

However, the success of HCT has multiple challenges such as the complications of the conditioning regimen, adverse effects related to transplant such as infections and graft-versus-host disease (GVHD), and the inability to eradicate the underlying disease. In patients with high-risk karyotype or advanced disease, relapse is considered the major cause of HCT failure [4],[5].

The classic conditioning regimens, total body irradiation-based high-dose conditioning regimens, have been effective but are associated with acute and delayed complications [6].

The reduced-intensity conditioning (RIC) regimen is a thriving option allowing the application of allogeneic hematopoietic stem cell transplantation (HSCT) while reducing regimen-related toxicity and morbidity for ineligible patients [7].

All RIC protocols depend upon intensive immunosuppression to allow donor engraftment and donor–recipient chimerism, which rapidly develops into full donor chimerism with withdrawal of immunosuppression. The graft-versus-leukemic (GVL) effect and the chemotherapy administered during conditioning are mandatory for the control of the disease [8].

The aim of this study is to evaluate the outcome of RIC transplant using fludarabine/busulfan conditioning regimen in Egyptian patients with MDS.

Primary end point

Overall survival (OS) in transplanted patients is the primary end point.

Secondary end points

The secondary end points included the following:
  1. Disease-free survival (DFS) rates after transplantation.
  2. Rates of nonrelapse mortality (NRM).
  3. Incidence of relapse.
  4. Incidence of neutrophil and platelet engraftment.
  5. Incidence of acute and chronic GVHD.



  Patients and methods Top


Patient characteristics

This prospective study was conducted at the Stem Cell Transplantation Unit at Nasser Institute, Cairo, Clinical Hematology Unit, Internal Medicine Department, Assiut University and Medical Oncology Department,South Egypt Cancer Institute, during the period between January 2016 and December 2017. Written informed consent was taken from all participants,this study was approved by the ethical committee of Assiut University. This study included 18 patients with MDS who underwent RIC transplant with a median age of 39 years (range, 16–53 years), and a male to female ratio of 0.6. They underwent transplantation according to the WHO classification system, including 10 (55.5%) patients with refractory anemia (RA), three (16.7%) patients with refractory cytopenia with multilineage dysplasia, one (5.5%) patient with RA with excess blasts-1 (RAEB-1), and four (22.2%) patients with RAEB-2. According to International Prognostic Scoring System (IPSS), seven (38.9%) patients had low IPSS risk score, six (33.3%) patients had INT-1 IPSS risk score, four (22.2%) patients had INT-2 IPSS risk score, and one (5.5%) patient had a high IPSS risk score. Patient and disease characteristics are listed in [Table 1].
Table 1 Patient and disease characteristics

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Donors and stem cell source

High-resolution PCR with sequence-specific primers for HLA classes I and II was performed. All were 6/6 matches, with the exception of one donor who had one antigen mismatch. All patients received a granulocyte colony-stimulating factor-mobilized peripheral blood stem cells graft with a median CD34+ cell dose of 8.7×106/kg (range, 4.1–15).

Preparative regimen

All patients received fludarabine 30 mg/m2/day in 100-ml normal saline through intravenous infusion over an hour for 4 days from day 6 to day 2 (total dose of 150 mg/m2), followed by administration of busulfan 3.2 mg/kg/day (total dose of 8 mg/kg) given by intravenous infusion over 3 h once daily on day 5 to day 4, and phenytoin in a loading dose 20 mg/kg given before starting dose of busulfan followed by a maintenance dose of 5 mg/kg/day continued until 24 h after the last dose of busulfan.

Patients with one antigen mismatched-related donors received antithymocyte globulin 20 mg/kg daily from day 3 to day 1.

Graft-versus-host disease prophylaxis

It consisted of cyclosporine A (CSA) given at 3 mg/kg/day in 500-ml normal saline by continuous intravenous route, starting on the day before marrow infusion. Oral CSA was substituted for intravenous administration when tolerated in a dose of 6 mg/kg/12 h. Doses of CSA were adjusted downward if necessary (usually because of renal or hepatic dysfunction) or occasionally upward (if evidence of GVHD developed). CSA was followed by methotrexate (MTX) given at 15 mg/m2 given intravenously on day 1 and 10 mg/m2 on day 3, day 6, and day 11. MTX administration was adjusted downward for severe mucositis, extravascular fluid accumulation, or impaired renal function. Folinic acid as rescue agent at 15 mg/m2 intravenous tds may be given 24 h after each MTX injection for 24 h (rescue protocol designed to reduce mucositis).

Supportive care

Supportive care, including prophylactic antibiotics, antifungal therapy, total parenteral nutrition, hematopoietic growth factors and treatment of mucositis and neutropenic fever, was provided in accordance with the institutional standard practice guidelines.

Statistical analysis

All patients were enrolled prospectively in the study. The duration of OS was calculated from the date of diagnosis until death from whatever the cause. The duration of DFS was calculated from the time of transplant until the date of first relapse or death. The survival curves were computed using the Kaplan–Meier technique. The significance of difference between the curves was estimated by the log-rank test. The estimates of acute and chronic GVHD and relapse were obtained by one-survival curve technique. Data were analyzed using the Statistical Package for the Social Science, version 21 (IBM corp., Armonk, NY).


  Results Top


Engraftment

Sixteen patients had a sustained engraftment as defined by an absolute neutrophil count above 0.5×109/l and a nontransfused platelet count above 25×109/l for at least 3 days in a row. The median time to recover an absolute neutrophilic count above 0.5×109/l was 13.5 days (range, 7–29 days), and the median time to achieve platelets above 25×109/l was 12.5 days (range, 7–39 days). Two patients had primary graft failure; one of them died shortly after transplant.

Posttransplant transfusions

Platelet transfusions were indicated in 16 (88%) patients, whereas two (11%) cases never received platelet transfusions. Packed red blood cells (RBCs) were also indicated in 16 (88%) patients, whereas two (11%) patients never needed RBCs.

The median number of platelet transfusions was five transfusions (range, 0–19), and the median number of packed RBC transfusions was eight transfusions (range, 0–29).

Acute and chronic graft-versus-host disease

Of 18 patients, 5 (28%) experienced grades II–IV acute GVHD and three of them had died because of it. The Kaplan–Meier-estimated probability of acute GVHD was 31% ([Figure 1]).
Figure 1 Kaplan–Meier-estimated probability of acute GVHD in RIC. GVHD, graft-versus-host disease; RIC, reduced-intensity conditioning.

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Only one (6.6%) patient in this group experienced extensive chronic GVHD 9 months after transplant. The Kaplan–Meier-estimated probability of extensive chronic GVHD was 20% ([Figure 2]).
Figure 2 Kaplan–Meier-estimated probability of chronic GVHD in RIC. GVHD, graft-versus-host disease; RIC, reduced-intensity conditioning.

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Nonrelapse mortality

Seven (38.8%) patients died because of transplant. Three patients died owing to severe acute GVHD 2 months after transplant. Two patients died owing to infection 2 and 6 months after transplant. One patient died owing to transfusion-related acute lung injury 2 months after transplant and one patient died owing to primary graft rejection. The Kaplan–Meier-estimated probability of NRM at 2 years was 43% ([Figure 3]).
Figure 3 Kaplan–Meier-estimated probability of 2-year NRM in RIC. NRM, nonrelapse mortality; RIC, reduced-intensity conditioning.

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Disease status and relapse

Ten patients had achieved complete response (CR); of which five patients had not relapsed so far, and the other five had relapsed: one of them had relapsed 2 ms after transplant and died shortly after, and the other four patients relapsed 1, 2, 4, and 6 months after transplant and are living with disease progression. The Kaplan–Meier-estimated probability of relapse at 2 years was 43.5% ([Figure 4]).
Figure 4 Kaplan–Meier-estimated probability of relapse in RIC group. RIC, reduced-intensity conditioning.

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Overall survival and disease-free survival

Ten (55%) patients are still living: five patients in CR, four patients relapsed and are living with disease progression, and one patient had primary graft rejection and is still living with the disease. The Kaplan–Meier-estimated 2-year OS was 49%, and the Kaplan–Meier-estimated 2-year DFS was 33% ([Figure 5] and [Figure 6]).
Figure 5 The Kaplan–Meier-estimated 2-year DFS in RIC transplant was 49%. DFS, disease-free survival; RIC, reduced-intensity conditioning.

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Figure 6 Kaplan–Meier-estimated 2-year overall survival of RIC. RIC, reduced-intensity conditioning.

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  Discussion Top


Allogeneic HSCT establishes a successful therapy for MDS. Several studies of RIC in MDS evaluated high rates of engraftment and low transplant-related mortality [9].

The reduced-intensity regimen of fludarabine/busulfan used in our study resulted in engraftment in all patients receiving allogeneic peripheral blood HSCT, as defined by achieving an absolute neutrophil count above 0.5×109/l and a nontransfused platelet count above 20×109/l for at least 3 days in a row, except two patients. The median time to neutrophil recovery was 13.5 days (range, 7–29 days) and median time to platelet recovery was 12.5 days (range, 7–39 days). Other studies using RIC reported the same results, such as Bokhari et al. [10], who reported a median time to neutrophil recovery of 15 days (range, 12–23 days) and a median time to platelet recovery of approximately 12 days (range, 5–20 days).

In the cohort of RIC transplant, seven patients died owing to transplant-related causes, where three patients died owing to severe acute GVHD 2 months after transplant, two patients died owing to sepsis 2 and 6 months after transplant, one patient died owing to primary graft rejection, and another one died owing to transfusion-related acute lung injury 2 months after transplant. The Kaplan–Meier-estimated probability of NRM at 2 years was 43%.

Our results of NRM matched with other studies, which reported NRM rates of 41% [11], with a median follow up of 614 days, and NRM rates of 38% at 2 years [12].

However, some studies reported higher NRM rates than ours, such as Wong et al. [13], who reported NRM rates of 49% at 1 year, and Wong et al, who reported NRM rates of 55% at 1 year [14]. This can be explained by the high median age of patients and the high number of relapsed and refractory cases in both studies.

Other studies reported lower rates of NRM than ours, such as Bokhari et al. [10], who reported NRM rates of 30% at 2 years; Lee et al. [15], who reported NRM rates of 20.5% at 2 years, and Davies et al. [16], who reported NRM rates of 9% at 5 years.

Bokhari et al. [10] suggested three patient-specific adverse factors, which are age more than 60 years, disease status at transplant of CR2/PR/high-risk MDS, and HCT-comorbidity index comorbidity scores more than or equal to 3; these had become more significant in predicting both NRM and survival when taken together. The study suggested that the presence of two or more of these factors predicts poor outcome.

Using CSA plus MTX for GVHD prophylaxis, five (28%) patients experienced grades II–IV acute GVHD and three of them died because of it 2 months after transplantation. The Kaplan–Meier-estimated probability of acute GVHD at 100 days was 31%.

Our results for acute GVHD were comparable to results of other studies, which reported acute GVHD probabilities of 38% [9], 34% [17], and 39% [15]. However, our results compared favorably to other studies, which reported higher rates of acute GVHD at 72% [18].

Only one patient in the RIC group in our study experienced extensive chronic GVHD, and the Kaplan–Meier-estimated probability of extensive chronic GVHD in the RIC group was 20%, which confirmed the results of other studies such as Chan et al. [19] who reported a chronic GVHD rate of 18%, and Lim et al. [20], who reported chronic GVHD incidence of 28%. Some studies reported lower rates than us, such as Flynn and colleagues [21], who reported chronic GVHD rate of 6%, whereas many other studies reported higher chronic GVHD rates than ours, such as Lee et al. [15] who reported a chronic GVHD rate of 44.6, and Khabori et al. [18], who reported a chronic GVHD rate of 61%.

The incidences of chronic GVHD vary widely after RIC transplant, which could be owing to the variable lengths of follow-up and different sample sizes [22].

In our study, five patients relapsed after transplant. One of them relapsed 2 months after transplant and died shortly after, and the other four are still living with disease progression. The five patients who relapsed included three low-risk patients with RA and two high-risk patients with RAEB-2. The Kaplan–Meier-estimated probability of relapse at 2 years was 43.5% in our study.

Some studies reported comparable relapse rates to our study, such as Luger et al. [23] who reported a relapse rate of 39%; Martino et al. [24], who reported 45% relapse probability rates; and Shimoni et al. [25], who reported relapse probability rate of 49% and postulated that patients with active disease at stem cell transplantation had very poor outcome owing to very high risk of relapse and that the median time to relapse in patients with active disease was 2.1 months (range, 1–12 months) compared with 5.3 months (range, 1.5–22 months) for patients transplanted in remission. RIC requires induction of GVL as the curative therapeutic tool, and this may require several months after transplant to evolve. Patients with active disease may progress early after transplant, outpacing the development of effective GVL. However, some studies reported lower relapse probability rates than us, such as Lee et al. [15] who reported a relapse rate of 20%; Khabori et al. [18], who reported a relapse rate of 25%; and Nelson et al. [9], who reported a relapse rate of 30% but reported a cumulative incidence of relapse of 61%, which was higher than our results, but their study did not identify any specific factor (including donor–recipient sex mismatch, development of acute GVHD, or number of CD34+ cells infused) that influenced chimerism after transplant.

The Kaplan–Meier-estimated probability of 2-year OS in RIC transplant patients was 49%. Our results of OS were comparable to other studies which reported OS rates of 55% [16], 56% [10], and 49% [17]. Valcarcel et al. [17] suggested that chemotherapy-refractory disease, presence of more than 5% blast in bone marrow at stem cell transplantation, high-risk cytogenetics, advanced stage disease, and absence of chronic GVHD were related to poorer OS.One study reported higher OS of 67% [15] and another one reported lower OS of 33% [19].

In our study, ten (55.5%) patients achieved CR, where five of them had not relapsed so far. The Kaplan–Meier-estimated probability of 2-year DFS was 33%.

Our results of DFS confirmed the results of previous studies of RIC transplant such as Flynn and colleagues, who reported DFS rate of 31%; Martino et al. [24], who reported DFS rate of 33%; Tauro and colleagues, who reported DFS rate of 34%; and Solomon et al. [26], who reported DFS rate of 37%. However, some other studies reported higher DFS rates than ours, such as Valcarcel et al. [17], who reported DFS rate of 49%; Nelson et al. [9], who reported DFS rate of 40%; Khabori et al. [18], who reported a DFS rate of 47%; Davies et al. [16], who reported DFS rate of 45%; Lee et al. [15], who reported DFS rate of 63%; and Bokhari et al. [10] who reported DFS rate of 79%.

Many RIC trials have short patient follow-up and small sample sizes. In general, a high relapse rate, surprisingly low engraftment failure, and low NRM were seen in these trials. RIC is a feasible treatment modality for older patients with MDS. There is a large overlap in the rate of OS and DFS published for MA and RIC. It is, therefore, fair to speculate that RIC may be appropriate for younger patients with MDS who could otherwise tolerate myeloablation. Receiving MA transplant for young patients (<40–45 years) with MDS and offering RIC to all others, especially if they had a response to initial therapy, appears a sensible approach, as prospective data accumulate [27].

Financial support and sponsorship

Nil.

Conflicts of interest

None declared.



 
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