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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 40  |  Issue : 1  |  Page : 37-43

Cryopreservative against noncryopreservative therapy in autologous hematopoietic stem cell transplantation (the Egyptian experience)


Hematology and Bone Marrow Transplantation Unit, Department of Internal Medicine, Ain Shams University, Cairo, Egypt

Date of Submission23-Jan-2015
Date of Acceptance25-Jan-2015
Date of Web Publication24-Apr-2015

Correspondence Address:
Dr. Mohamed M Moussa
Hematology and Bone Marrow Transplantation Unit, Department of Internal Medicine, Ain Shams University, Lotfi El-Sayed Street, 11566, Abassia, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.155796

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  Abstract 

Introduction Autologous peripheral blood stem cell transplantation is a 'rescue' of patients' self hematopoietic stem cells from the myeloablative effects of chemotherapy or irradiation. Cryopreservation of hematopoietic stem cells using 10% dimethyl sulfoxide as a cryoprotectant under liquid nitrogen storage conditions (−196°C) for long-term usage is a well-established procedure, whereas liquid preservation of stem cells is usually performed for storage at 4°C for 36-96 h. The aim of the study was to compare the outcome of autologous stem cell transplantation using cryopreserved or noncryopreserved stem cells.
Patients and methods Twenty adult patients younger than 60 years of age were enrolled in this study. They had undergone autologous peripheral stem cell transplantation. They had been stratified into two groups: 10 patients received cryopreserved autologous peripheral stem cell transplantation (PBSCT) and the remaining 10 patients received noncryopreserved autologous PBSCT.
Results When we compared the cryopreserved and the noncryopreserved groups for the clinical outcome, there had been a longer overall survival and disease-free survival in favor of the cryopreserved group, but this had not been translated into statistically significant values. In addition, there was no significant difference with regard to the recurrence of disease. However, the noncryopreserved group had a shorter hospital stay and entailed less cost than the cryopreserved group (8149$ against 8900$, respectively). This could be attributed to the fact that liquid nitrogen was not used, and the shorter hospital stay (P = 0.000) lowered the cost for medications, laboratory tests, and procedures. Cryopreserved therapy was found to be cost-effective with regard to keeping the patient alive in those who cannot tolerate proceeding to autologous stem cell transplant immediately after mobilization.
Conclusion
Noncryopreserved therapy required a lesser number of aphaeresis sessions, was associated with a shorter hospital stay, was less costly than cryopreserved therapy, and it yielded the possibility of transplantation in patients with hepatitis without the need for buying a special liquid-nitrogen tank.

Keywords: autologous hematopoietic stem cell transplantation, cryopreservative, noncryopreservative


How to cite this article:
Elzemity MT, Elwahed EA, Elafifi AM, Moussa MM, Attia MH, Hegab HM, Elsaid HM. Cryopreservative against noncryopreservative therapy in autologous hematopoietic stem cell transplantation (the Egyptian experience). Egypt J Haematol 2015;40:37-43

How to cite this URL:
Elzemity MT, Elwahed EA, Elafifi AM, Moussa MM, Attia MH, Hegab HM, Elsaid HM. Cryopreservative against noncryopreservative therapy in autologous hematopoietic stem cell transplantation (the Egyptian experience). Egypt J Haematol [serial online] 2015 [cited 2020 Jan 18];40:37-43. Available from: http://www.ehj.eg.net/text.asp?2015/40/1/37/155796


  Introduction Top


Bone marrow transplantation refers to the intravenous infusion of hematopoietic progenitor cells to re-establish hematopoiesis in a patient with a defective or a damaged bone marrow [1] .

Autologous transplantation is a moderate-morbidity, low-mortality procedure that can be performed with relative safety even in individuals in the seventh and the eighth decades of life. It is used with curative intent in individuals who have non-Hodgkin's lymphoma (NHL) or Hodgkin's disease in second remission and as remission consolidation for patients who have multiple myeloma in a minimal residual disease state, where the procedure is expected to prolong disease-free survival (DFS), but not cure the disorder. Occasionally, individuals who have acute leukemia in second or greater remission undergo autologous transplantation, but generally only when a suitable allogeneic donor is not available for acute myeloid leukemia (AML) in first remission; the value of autologous stem cell transplantation as consolidation is less clear [2] .

The rationale for autologous transplantation is that cryopreservation of the patient's own stem cells allows the delivery of high-dose chemotherapy and radiotherapy that would otherwise produce lethal bone marrow suppression. The donor and the recipient are the same person and the patient's immune recovery is more rapid and there is no potential risk of graft versus host disease [3] .

Before the collection of autologous stem cells, the patient is usually given chemotherapy to debulk the malignant disease. Thereafter, further chemotherapy and stem cell growth factor (granulocyte colony-stimulating factor) is given to stimulate the stem cells to leave the bone marrow and enter the peripheral blood. The patient then undergoes one or two (sometimes three) leukapheresis procedures during which the blood are processed; the component containing the stem cells is cryopreserved until it is needed for reinfusion on day 0 [3] .

Peripheral blood progenitor cells (PBPCs) are usually harvested and stored in liquid N 2 until reinfusion. Storage at this low temperature will block all enzymatic pathways and metabolism in the cell. Cryopreservative(s) must be added to the PBPC before freezing to protect the cells. The concentration of the cryoprotectant and the rate at which the cells are frozen are the main factors governing the survival of the cells. Current protocols for the human PBPC are based on freezing to −100°C in 10% dimethyl sulfoxide (DMSO) in a freezer programmed for temperature rate control. Thereafter, the cells are stored in liquid N 2 . DMSO has been the most favored additive for long-term storage of stem cells obtained from the bone marrow or by leukopheresis since the beginning of the 1960s [4] .

The objective of noncryopreserved autologous stem-cell transplant is to examine the feasibility and the safety of this technique. This technique avoids the cost of establishing and maintaining a cryopreservation facility and may be of value for transplant centers in regions with limited economic resources [5] .


  Patients and methods Top


The current study included 20 patients (14 men and six women) who received autologous PBSC transplantation at the Bone Marrow Transplantation Unit of the Faculty of Medicine, Ain Shams University Hospital, Cairo, Egypt, between July 2007 and August 2012. This study was approved by the Ain Shams University, Faculty of Medicine Ethical committee. The patients' mean age was 43 years (range from 20 to 60 years); diagnoses were high-risk or relapsed NHL (n = 3, 0.15%), multiple myeloma (n = 10, 50%), relapsed Hodgkin disease (n = 5, 25%), first complete remission (CR) acute lymphoblastic leukemia (ALL) (n = 1, 0.05%), and second CR AML (n = 1, 0.05%). These patients had been previously treated with high-dose chemotherapy, and three patients received chemoradiotherapy.

Patients were randomly divided into two groups. Group I included 10 patients who received cryopreserved autologous PBSCT and group II included 10 patients who received noncryopreserved autologous PBSCT.

Written consents were obtained from all patients participating in the study.

Patients with impaired liver function or those who had active viral infection as diagnosed using quantitative PCR, patients with impaired renal function, and patients older than 60 years were excluded from the study.

Patients were subjected to the following pretransplant analyses.

Detailed medical history taking, thorough medical examination, and screening for risk factors before the commencement of granulocyte-colony stimulating factor (G-CSF) injections; the pretransplant evaluation included the following:

The complete blood picture, the ABO blood group and RH, the complete liver profile, the complete renal profile, random blood sugar, the complete lipid profile, the coagulation profile, the lactate dehydrogenase enzyme level, viral markers including hepatitis C virus PCR, hepatitis B virus surface antigen, hepatitis B virus surface antibody, hepatitis B virus e antigen, hepatitis B virus e antibody, hepatitis B virus core antibody (HBcIgM, HBcIgG), cytomegalovirus antibody (CMV IgM, CMV IgG), CMV PCR if indicated, Epstein-Barr virus antibody (EBVIgM, EBVIgG), toxoplasma Ab, and herpes simplex virus type I antibody (HSVIgM, HSVIgG), bone marrow aspirate, trephine biopsy, flow cytometry, immunohistochemistry if indicated, dental examination, and cardiopulmonary assessment including ECG, echocardiography, chest radiography, and a pulmonary function test.

Mobilization and cryopreservation procedures

  1. Seven patients were mobilized using a single dose of cyclophosphamide (3 g/m 2 ), followed after 5 days by 10 μg/kg/day recombinant human granulocyte colony-stimulating factor (rhG-CSF); rhG-CSF was continued until the end of leukapheresis with daily follow-up for the CD34 count in the peripheral blood [6] .
  2. Eleven patients (seven patients with multiple myeloma, three patients with lymphomas, and one patient with ALL) were mobilized with G-CSF administered subcutaneou sly at a dose of 10-16 μg/kg daily [7] .
  3. One AML patient was mobilized with cytosine arabinoside (Ara-C) 2000 mg/m 2 twice a day for 4 days concurrent with etoposide 40 mg/kg by continuous infusion over 4 days, and G-CSF 10 μg/kg/day until the end of leukapheresis [8] .
  4. One Hodgkin disease (HD) patient with central nervous system infiltration was mobilized with methotrexate (3.5 g/m 2 ), cytosine arabinoside (Ara-C) (3 g/m 2 ) daily for 2 days, and G-CSF 10 μg/kg/day recombinant human granulocyte colony-stimulating factor (rhG-CSF); rhG-CSF was continued until the end of leukapheresis [9] .


The minimum target of CD34 cells was defined as 4 × 10 6 /kg of the recipient.

Cryopreservation of PBSC was based on freezing to −100°C in 10% DMSO in a freezer programmed for temperature rate control. Thereafter, the cells were stored in liquid N 2 . DMSO has been the most favored additive for long-term storage of stem cells obtained from the bone marrow or by leukopheresis since the beginning of the 1960s [9] .

Post-transplantation treatment

  1. All patients were treated with G-CSF (5 μg/kg) beginning on day +1 and continuing until the engraftment of neutrophils was recorded as the first day in 3 consecutive days with polymorph count greater than 500/μl [10] .
  2. All patients received prophylactic antiviral therapy for herpes zoster and herpes simplex infection after transplantation for the initial 6 months in the form of acyclovir 200 mg twice daily and received a prophylactic antibiotic and an antifungal against bacterial and fungal infections in the form of ciprofloxacin and fluconazole orally, respectively, in addition to trimethoprim-sulfamethoxazole, which was administered twice weekly as prophylactic treatment against pneumocystis carinii infection [11] .


Patients from the two groups were followed up after transplantation, ranging from 6 to 55 months, and have been monitored for the following.

Early detection of complications, complete blood count daily, complete chemistry, including liver and kidney functions, serum lactate dehydrogenase enzyme, prothrombin time, international normalized ratio, and partial thromboplastin time three times weekly, CMV PCR weekly, multiple bone marrow aspirate, trephine biopsy, flow cytometry, and immunohistochemistry according to each disease state day (D 28, D 90, D 180) after transplant.

The engraftment date of neutrophils and platelets (engraftment of neutrophils was recorded as the first day in 3 consecutive days with a polymorph count >500/μl and for platelets as the first day in 7 consecutive days with a count >20 000/μl without platelet transfusion), recurrence of disease, the nonrelapse mortality (NRM), the overall survival (OS), and bacterial, viral, and fungal infections were monitored.

Cost

The cost analysis was based on a detailed review of patient and hospital records. The cost figures used were direct inpatient costs (room costs, pharmacy, and blood bank including stem cell infusion, laboratory tests, and imaging procedures) and did not include physician fees and outpatient costs. All costs were estimated in Egyptian pounds. Effectiveness end points were survival [12] .

Statistical methods

  1. The statistical presentation and analysis of our study was conducted using the mean, the standard error, the Student t-test, the χ2 -test, and the analysis of variance test by SPSS (Chicago, IL, USA) V17.
  2. All numeric variables were expressed as mean ± SD.
  3. Survival analysis was performed using the Kaplan-Meier test and comparison of survival between groups was performed by the log rank test.
  4. The unpaired Student t-test was used to compare two groups of quantitative data.



  Results Top


The study included 20 patients eligible for autologous PBSCT. The median age of the patient cohort was 43 years (range 20-60 years). They were divided into two groups.

Other characteristics are summarized in [Table 1].
Table 1 General characteristics of the patients

Click here to view


We found a statistically significant difference between the two studied groups with regard to apheresis sessions (P = 0.035).

The median number of CD34+ cells infused was slightly higher in group I compared with group II (4.758 ± 2.932 vs. 3.745 ± 1.474 CD34+ cells/kg, respectively; P = 0.342).

White blood cells were engrafted at a mean of 12 days (range 10-14 in group I and 11-14 days in group II), whereas platelets were engrafted at a mean of 15 days (range 11-20 in group I and 9-26 days in group II).

Concerning the relapse rate, four patients (40%) relapsed in group I compared with one patient (10%) in group II; however, the difference was statistically nonsignificant (P = 0.112).

We found no statistically significant difference between the two studied groups with regard to the NRM [1 (10%) in group I vs. 2 (20%) in group II respectively; P = 0.528].

Patients in group I had a longer mean DFS (22 ± 17.477 months; range 4-50 months) compared with the mean DFS in group II (18 ± 10.612 months; range 0-32 months), and this difference was statistically nonsignificant (P = 0.477).

In addition, patients in group I had a statistically nonsignificantly longer mean OS of 39.760 ± 8.40 months as compared with a mean OS of 30.000 ± 1.870 months in group II (P = 0.253) ([Figure 1]).
Figure 1 The overall survival curve of bone marrow transplant patients.

Click here to view


On correlation analysis, no correlation was found between the CD34+ cell count/kg and OS and DFS in both groups, whereas platelet engraftment correlated positively with OS in group II.

The mean total cost was 54.295 Egyptian pounds (range 44 070-75 000) in group I [8900 $US (1 $US = 6.1 Egyptian pounds during the period 2005-2012)], whereas it was 49.713 Egyptian pounds (range 26.220-79.667) in group II (8149 $US). It can be noted that there was no dominance in the two groups (group II was less costly and less effective and group I was more costly and more effective). The cost-effectiveness of each treatment modality has been calculated by dividing the mean total cost of each treatment group by its mean survival [12] .

Regarding overall survival

Group I: 54 295/3.3 = 16 453 Egyptian pounds/life-year saved.

Group II: 49 713/2.5 = 19 885 Egyptian pounds/life-year saved.

It should be noted that group I was more cost-effective than group II at the end of the follow-up period with regard to OS.


  Discussion Top


When we compared both groups with regard to the age, there was a statistically significant difference. The age was significant in group I between 20 and 30 years, whereas it was significant in group II between 41 and 50 years. This could be attributed to the variable diagnoses of patients, indication of transplantation, and the performance status of the patients included in the study; most patients in group I were diagnosed to have lymphomas, whereas most of the patients in group II were diagnosed to have multiple myeloma, which had been presented in this age.

The sex was an independent factor affecting the clinical outcome in patients of both groups. There was no statistically significant difference between the two studied groups with regard to the sex, and this concurs with the studies conducted by Wannesson et al. [5] and Mabed and Shamaa [13] .

There was no statistically significant difference between the two studied groups regarding the diagnosis: in group I, two patients had NHL, three patients had HD, three patients had MM, one patient had ALL, and one patient had AML, whereas in group II, one patient had NHL, two patients had HD, and seven patients had MM. Similar results were found in the study conducted by Wannesson et al. [5].

After transplantation, four patients (40%) relapsed in group I and only one patient (10%) relapsed in group II. Yet, there was no statistically significant difference between the two studied groups with regard to the recurrence of disease. This concurs with the studies conducted by Wannesson et al. [5] ; Mabed and Shamaa [13] ; Ahmed et al. [14] and Beaujean et al. [15] .

Transplant-related mortality in the patients in group I was 40%, which was classified into two NRMs (20%): one patient died from fever, chest infection, and disseminated intravascular coagulopathy, whereas the other died during stem cell infusion of allogenic PBSCT after he had relapsed subsequent to autologous cryopreserved PBSCT. Two cases of relapse-related mortality (20%) occurred due to recurrence of disease.

However, transplant-related mortality in patients in group II was 20%, which included one NRM (10%); the patient died from aspergillosis in the lung, septic shock, and graft failure, which is similar to the result obtained by Wannesson et al. [5] , who record only one transplant-related (septic) death, which occurred in a patient not achieving neutrophil engraftment beyond day +28. One case of relapse-related mortality (10%) occurred due to the recurrence of disease.

This high percentage of transplant-related mortality in our study could be attributed to the small number of patients enrolled in our study.

Our results were consistent with the study performed by Sierra et al. [16] , who reported transplant-related mortalities of 22 and 13% for the cryopreserved and the noncryopreserved groups, respectively, caused by each of the following for each case: infection, liver veno-occlusive disease, heart toxicity, interstitial pneumonitis, and one unspecified case [17],[18] .

Despite having given prophylactic antibiotic in the form of ciprofloxacin 500 mg tablets twice daily before and after transplantation, bacterial infection was noted in all transplanted patients of both groups. The most common organisms infecting the patients in our study during the hospital stay, which were obtained from cultures, included nonhemolytic streptococci, staphylococcus coagulase negative, actinobacter,  Escherichia More Details coli, Klebsiella, Pseudomonas aeruginosa, and Staphylococcus aureus. Our results were similar to that of Mayo Clinic BMT Center [19] .

Herpes simplex virus infection was recorded in two patients (20%) in group I and in one patient (10%) in group II. Yet, there was no statistically significant difference between the two studied groups. This could be attributed to the use of prophylactic antiviral therapy given to all transplanted patients in the form of acyclovir 200 mg tablet twice daily [20] .

Results of CMV screening by CMV PCR were negative in all patients of both groups before and after transplantation during the period of follow-up.

Fungal infection was observed in three patients (30%) of group I and four patients (40%) of group II, but no statistically significant difference was registered despite the prophylactic antifungal therapy given to all transplanted patients of both groups in the form of fluconazole 100 mg tablet twice daily [20] .

Our results show that despite early engraftment and nonhematological toxicities, infectious complications remain the main determinants of the duration of hospitalization in the patients after PBSCT, but we were not able to identify any statistically significant correlation between viral infection and the hospital stay and also between fungal infection and the hospital stay, which is consistent with the results found in the study performed by Cetkovsk et al. [21] .

Regarding infusion-related toxicity among the patients in the two studied groups, no toxicity was documented. Similar results were found in the study of Wannesson et al. [5] .

Meanwhile, in our study, apheresis sessions showed a statistically significant difference between the two studied groups: the highest value was 40% in patients in group I having undergone three apheresis sessions and the highest value was 60% in patients in group II having undergone two apheresis sessions. This was because most patients in group I received large doses of aggressive chemotherapy before transplantation, and so they needed more number of apheresis sessions to collect the adequate amount of stem cells required for transplantation.

Regarding the CD34 count, most transplant centers make plans to obtain a target of 3.0 to 4.0 × 10 6 CD34+ cells/kg in case of auto-HSCT [22] .

In our study, the mean dose of CD34 was 4.7 × 10 6 /kg (range 2.1 × 10 6 /kg−12.4 × 10 6 /kg) in group I and 3.7 × 10 6 /kg (range 2.1 × 10 6 /kg-6.1 × 10 6 /kg) in group II. The lowest value observed was in patients in group II, but there was no statistically significant difference between the two studied groups with regard to the CD34 count.

The time to neutrophil and platelet engraftment correlated negatively with the CD34 cell number infused in the study conducted by Beaujean et al. [15] .

Engraftment of neutrophils was recorded as the first day in 3 consecutive days with a polymorph count greater than 500/μl [5] .

The mean days of neutrophil engraftment were 12 days in both groups. Hence, no statistically significant difference was recorded in our study between both groups.

Platelet engraftment was presented as the first day in 7 consecutive days with the number of platelets greater than 20 × 10 9 /l without transfusion [5] .

The mean days of platelet engraftment were 15 days in both groups. Hence, no statistically significant difference was recorded in our study between both groups.

Studies comparing the overnight storage of autologous stem cell apheresis products at 4°C with immediately cryopreserved products showed no statistically significant difference between both groups regarding the neutrophil and the platelet engraftment days, the safety, and even the long-term outcome of the primary disease. Additional benefits of overnight storage of the harvested products were reduction in costs and processing time [23],[24],[25],[26] , which were in agreement with our study results.

Our results with regard to the engraftment of neutrophils and platelets were also consistent with the study performed by Sierra et al. [16] , who analyzed a cohort of 94 NHL patients rescued with cryopreserved and 38 with noncryopreserved PBSC autografts. No statistically significant differences were found in both groups.

Moreover, Ahmed et al. [14] published a similar study. Fifteen patients had cryopreserved marrow stored for an average of 56 days and 38 patients had bone marrow stored at 4°C for a mean of 3 days (range 2-5 days), and the median nucleated cell count was 2.5 × 10 8 /kg for the cryopreserved group and 3.0 × 10 8 /kg for the noncryopreserved group.

In our study, despite the OS being higher in group I (the mean was 23 months, with a range of 5-55 months) in comparison with group II (the mean was 19 months, with a range of 1-32 months), yet there was no statistically significant difference between the two studied groups.

The DFS was defined as the time from PBSC reinfusion to the time of disease progression or the last follow-up [6] .

It should also be noted from our results that despite a better DFS in patients in group I, with a mean of 22 months (range 4-50 months), compared with patients in group II, with a mean of 18 months, this had not been translated into a significantly better OS among the studied groups, which is similar to the results of the study performed by Pivkova et al. [27] , where the survival analysis of the group of patients who received cryopreserved autologous PBSCT showed a better OS and DFS with a median period of follow-up of 43 months (range 3-84 months) compared with the group of patients who received noncryopreserved autologous PBSCT.

Survival: Fourteen of the enrolled patients in our study are alive and diseases free with a median follow-up of 20 months (range 6-55 months). The survival curve by Kaplan-Meier is presented in [Figure 1].

The mean treatment cost for group II in our study was low (49713.600 LE; 8149 $US) in comparison with that for group I (54295.100 LE; 8900 $US). Despite the fact that noncryopreserved autologous PBSCT (group II) was less costly than cryopreserved autologous PBSCT (group I), yet there was no statistically significant difference between both groups with regard to the cost; this may be explained by the lower number of patients enrolled in the study.

The lower cost of noncryopreserved autologous PBSCT could be attributed to the lower number of days spent in the hospital in laminar airflow units, lesser liability to complications, and hence the lower cost for medications, laboratory tests, and procedures, and also because there is no special equipment (liquid nitrogen tank) in group II.

Our results were consistent with the study performed by Mabed and Shamaa [13] , who found that the approximate cost of the noncryopreserved autologous PBSCT procedure was 10.8% for in-hospital procedures, and for outpatient autografts, substantially lower than the figures reported from the USA for autotransplants.

The use of such noncryopreserved stem cells may yield cost savings; when performing autologous stem cell transplantation, the cost of the entire transplantation was ~12% less when using noncryopreserved cells than when using a comparable treatment regimen with cryopreserved cells. The difference is mostly attributed to the lower cost of storing and infusing the noncryopreserved cells [23] .

On calculation of the cost-effectiveness, by dividing the mean total cost of each treatment group by its mean survival/life-year saved [12] , we found that the treatment of patients who received cryopreserved autologous PBSCT (group I) was more cost-effective with regard to keeping the patients alive because the OS was higher in patients in group I than in patients in group II. This may be attributed to the patients' characteristics in group I; 50% of the patients in group I were in the age group between 20 and 30 years, whereas 70% of the patients in group II were in the age group between 41 and 50 years; 70% of the patients in group I had no associated comorbidities before transplant in comparison with only 40% of the patients in group II.


  Conclusion Top


Noncryopreserved therapy required a lesser number of apheresis sessions, had a shorter hospital stay, and was less costly than cryopreserved therapy, and it yielded the possibility of transplantation in patients who had hepatitis C virus and hepatitis B virus infection without the need for buying a special liquid nitrogen tank; meanwhile, cryopreserved therapy was more cost effective in keeping the patients alive.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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Abstract
Introduction
Patients and methods
Results
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