ISSN 1866-8836
Клеточная терапия и трансплантация

Astana experience: Department of Oncohematology and Bone Marrow Transplantation, National Research Center of Oncology and Transplantation

Vadim M. Kemaikin, Anastasiya A. Olifirovich, Alexandr V. Kolesnev, Anatoliy V. Nemerovchenko, Ruzal F. Vildanova, Olga V. Gainutdinova, Adiya A. Tusipova, Ayauzhan E. Esimbekova, Aliya K. Baimursina, Ayzat S. Suleimenova, Olga O. Lesechko, Gulnaz D. Ansatbaeva, Mariya S. Alimbetova
Bone Marrow Transplantation Department, National Research Center for Oncology and Transplantation, Astana, Republic of Kazakhstan
Dr. Vadim M. Kemaikin, Chief, BMT Department, National Research Centre for Oncology and Transplantation, Kerey, Zhanibek Khanov st., 3, Astana, 010000, Republic of Kazakhstan
Phone: +7 7172 70 29 41 E-mail: hematology.astana@gmail.com
doi 10.18620/ctt-1866-8836-2017-6-1-30-36
Submitted 02 February 2017
Accepted 02 February 2017
Published 24 February 2017

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Cellular Therapy and Transplantation (CTT)
Volume 6, Number 1
Contents 

Summary

The Unit of Oncohematology and Bone Marrow Transplantation (BMT) was arranged on basis of the Republican Research Center of Hospital Emergencies SC (Astana, Republic of Kazakhstan) in August 2010. Since July 2014, a Clinical Department with 69 beds was arranged, and National Research Center for Oncology and Transplantation SC was arranged. From 2010 to 2016, the modalities of hematopoietic stem cell transplantation have been advanced, from autologous BMT to allogeneic hematopoietic stem cell transplants (HSCT) from matched donors (33%), and haploidentical HSCTs (43% in 2016), a total of 186 transpants. Bone marrow was used as a source of stem cells in 71 cases (71 donors for allo-HSCT in 69 recipients), whereas peripheral stem cells were harvested in 73 cases (15 donors for 15 recipients of allo-BMT, and 58 marrow harvests for autologous BMT). In particular, our BMT clinic and Bone Marrow Donor Registry developed with invaluable support and contribution by the leading specialists from R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the St. Petersburg. This system of education and training allowed to arrange an effective HSCT structure within 3 years. This assistance was performed in order to consult severe patients, arrange optimal transplantation regimens, analyze difficult clinical cases, perform master classes and conferences.

Keywords

Hematopoietic stem cell transplantation, clinical advancements, Astana, Republic of Kazakhstan.

Introduction

The Unit of Oncohematology and Bone Marrow Transplantation  (BMT)  was  arranged  on  basis  of  the  Republican  Research Center of Hospital Emergencies SC (Astana, Republic of Kazakhstan) in August 2010, using previous clinical experience  of  the  regional  hematologists.  At  the  beginning,  our  unit consisted of ten hospital beds for chemotherapy of leukemia  and  lymphomas.  First  bone  marrow  transplantation  in  Kazakhstan  was  performed  just  on  the  basis  of  our  specialized unit. Time sequence of our main advances is shown in Table 1.

Table 1. Main steps in development of Oncohematology Unit

table-1-main-steps-in-development-of-oncohematology-unit.jpg

Invaluable  support  and  contribution  to  the  development  of  the  BMT  Unit  should  be  mentioned.  Our  activities  were  supported  by  Professor  Boris  Afanasyev,  Director,  R.  Gorbacheva  Memorial  Research  Institute  of  Children  Oncology, Hematology and Transplantation at the St. Petersburg I. Pavlov  State  Medical  University.  Several  leading  specialists  from the Gorbacheva Institute, e.g., Professor Alexander D. Kulagin, Dr. Sergey N. Bondarenko, Dr. Vladimir N. Vavilov worked hardly at Astana, in order to consult severe patients, arrange  optimal  transplantation  regimens,  analyze  difficult  clinical cases, perform master classes and conferences. This collaboration  has  been  sufficiently  promoted  by  Dr.  Irina  Pivovarova whose contribution to these advances should be highly evaluated.

Since  01.03.2013,  the  Department  was  rearranged  to  the  Unit  of  Hemoblastoses,  Hematopoietic  Aplasias  and  BMT,  followed by extension to 25 beds, with appropriately trained staff.  The  unit  is  a  part  of  Hematology  and  Transfusiology  Department.

Deep renovation of the hospital building (April to September 2013) resulted into opening of aseptic wards with laminar air flow, including BMT unit with six beds and an intensive care unit of four hospital beds.

In September 2013, the Institute of Children Oncology, Hematology  and  Transplantation  (St.  Petersburg,  Russia),  together with our Department, performed the VII Memorial R. Gorbacheva International Symposium with a main topic: Hematopoietic Stem Cell Transplantation in Children and Adults. This event has promoted further development of BMT in Republic of Kazakhstan, and broadening of international cooperation  in  the  field.  Due  to  these  advances,  Kazakhstan  first  appeared at the EBMT map, with a total of 46 transplants in 2013 (Fig. 1). The Memorial Symposium attracted prominent specialists from Europe and USA (Fig. 2, 3).

Figure 1. Allogeneic stem cell transplants per 10,000,000 inhabitants: an EBMT map for 2013 (EBMT Report, 2013).

Figure 1. Allogeneic stem cell transplants per 10,000,000 inhabitants: an EBMT map for 2013 (EBMT Report, 2013).

figure-2-participants-at-the-vii-r-gorbacheva-memori-.jpg

Figure 2. Participants at the VII R. Gorbacheva Memorial International Symposium in Hematology and transplantation in Astana (September 2013).

figure-3-international-team-of-hematologists-visiting-the-new-bmt-department-in-astana.jpg

Figure 3. International team of hematologists visiting the new BMT Department in Astana (September 2013).

Since July 4, 2014, a Clinical Department with 69 beds was arranged,  and  the  Centre  was  renamed  to  the  National  Research Centre for Oncology and Transplantation SC. An oncohematological and BMT Department consisted of a Transfusion Unit and Oncohematology Unit with an intensive care ward  (4  beds).  20.09.2016,  the  Department  was  rearranged  once again, with a Unit of Oncohematological Resuscitation and Intensive Care for 6 beds established.

Clinical activities

Composition  of  hematological  disorders  treated  at  the  Department changed over years, however, with acute leukemias (AL)  taking  a  leading  place  (54.8%).  Meanwhile,  this  ratio  is increased by 10% in 2015, as compared to 2013, with increased admittance of the patients with acute lymphoblastic leukemias  (increase  by  16.6%  against  2013),  mainly,  due  to  introduction  of  continuous  treatment  protocols,  including  high-dose consolidation phase.

Since 2016, we noted higher admission for the patients with acute promyelocytic leukemia, due to improved diagnostics of  this  leukemia  type,  e.g.,  molecular  genetic  studies  performed  by  FISH  assays  at  the  laboratory  in  St.  Petersburg  (Russia).  The  most  significant  admittance  growth  was  for  bone marrow harvesting, i.e., from 9 cases in 2013 to 55 in 2016,  due  to  establishment  and  development  of  bone  marrow transplantation in the country.

Along with leukemias, we observed a significant increase in hospitalized  patients  with  lymphoproliferative  disorders  is,  i.e.,  with  non-Hodgkin’s  lymphomas  (from  18  to  85  cases),  Hodgkin’s  disease  (from  8  to  60  cases),  and  with  multiple  myeloma (from 23 to 100 subjects).

Bone marrow transplantation

The first bone marrow transplantation at our clinic was performed in 2010. In further time, a weak growth in HSCT was noted,  i.e.,  only  six  in  2011  (including  1  allogeneic  related,  and  1  haploidentical;  nine,  in  2012  (5  allogeneic  and  4,  autologous).  Since  2013,  after  opening  a  clean  block  (6  beds),  we have sufficiently increased the BMT number, i.e., 18 BMT (5 auto, 9 allogeneic compatible, and 4 haploidentical transplants); in 2014, 46 (5 auto-, 9 allogeneic and 4 haploidentical). During next years, a stabilization in HSCT amounts is observed: 2015, 54 BMT, 2016, 52 BMT (Fig.4).

Bone  marrow  was  used  as  a  source  of  stem  cells  in  71  cases  (71 donors for allo-HSCT in 69 recipients), whereas peripheral stem cells were harvested in 73 cases (15 donors for 15 recipients of allo-BMT, and 58 marrow harvests for autologous BMT). Poor stem cell mobilizing ability was revealed in multiple  myeloma  (1  case  after  Cyclophosphamide  injections)  and  2  lymphoma  patients  (DHAP-treatment).  Better  HSC  mobilization  was  performed  with  Etoposide  (in  myeloma  case), and in 1 patient, G-CSF was applied as hemostimulant. In 40 cases, both primed BM and PBSCs were infused to the patients.  Peripheral  stem  cell  harvesting  was  performed  at  the Center of Blood Transfusion in Astana by means of obsolete collection devices (Haemonetics MCS+). At initial steps of  our  transplantation  activities,  we  obtained  inferior  stem  cell harvests, therefore infusing additional amounts of native bone marrow cells. However, the situation has changed since 2016,  after  installation  of  new  equipment  (Terumo  Spectra  Optia), we are able to yield sufficient amounts of peripheral stem cells for transplantation.

figure-4-total-bmt-figures-by-years-at-the-center-of-oncohematology-and-bone-marrow-transplantation.jpg

Figure  4.  Total  BMT  figures  by  years  at  the  Center  of  Oncohematology  and  Bone  Marrow  Transplantation  (Astana,  Kazakhstan).  A  total  of  186  transplants  were  performed. Abscissa, number of transplants; ordinate, year of observation.

The  total  amounts  of  HSCT  do  not  meet  appropriate  Kazakhstan requirements. As seen from EBMT Reports, most European countries perform over 100 transplants per 10 Mio persons. To reach this level, we should make about 200 transplants annually (Table 2).

Table 2. Estimated BMT requirements for Republic of Kazakhstan

table-2-estimated-bmt-requirements-for-republic-of-kazakhstan.jpg

Donor availability

The  ratio  of  haploidentical  transplants  performed  in  our  clinic is increased from 4 BMTs (2013) to 23 transplants in 2015. (Fig. 5). A significant growth in haplo-HSCT is noted in 2015 (23 BMTs, 43%) as compared to 2014 (9 BMTs, 19% of total). However, a lack for HLA-identical donors was evident. According to ASBMT, about 70% of the patients with malignant blood disorder do not have available HLA-identical related donor [1]. A median tine for searching an unrelated donor is ca. 4 months in 50-60% of cases. This term is too long, due to risk of the disease relapse.

There  is  an  imbalance  for  different  BMT  types  (Fig.  6).  The  number of auto-BMT, according to EBMT data, twice exceeds allo-BMT  numbers.  Relative  number  of  auto-BMT  (24%  in  2015)  is  minimal  at  the  Oncohematology  and  Bone  Marrow  Transplantation Department, compared to other types. Haplo-BMT  (43%)  and  allogeneic  BMT  (33)  are  prevailing  here.  Such an imbalance occurs due to deficiency of transplantation beds, low activities of regions by the patient stratification and their selection for bone marrow transplantation.

Therefore,  we  considered  arrangement  of  a  local  hematopoietic stem cell donor registry as a possible solution of this problem. This Registry was established in 2013. Consolidated registry of Russian Federation and Kazakh Republic have been created year later, and, currently, 5500 potential donors from Kazakhstan are introduced to this database. In 2014, a first HLA-identical donor from Kazakhstan was activated in this Registry, and the first unrelated allogeneic transplantation  from  this  donor  was  performed  02.09.2016  at  out  Department.  Arrangement  and  advances  of  the  Bone  Marrow  Donor  Registry  in  our  Republic  are  closely  associated  with  collaboration  and  advices  from  Dr.  Alexander  L.  Alyansky,  Chief of a big Donor Registry at the R. Gorbacheva Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg).

figure-5-ratios-of-different-transplant-types.jpg

Figure 5. Ratios of different transplant types.

figure-6-time-dynamics-of-bmts-by-several-years-with-respect-to-the-bmt-types.jpg

Figure 6. Time dynamics of BMTs by several years, with respect to the BMT types.

Clinical results of BMT procedures

In 2015, we have performed analysis of total survival among the BMT patients (Fig. 7). This analysis shows a significantly higher  total  survival  in  a  group  of  patients  after  allo-BMT  performed  in  the  1st  remission,  as  compared  to  survival  in  the  group  after  allogeneic  BMT  carried  out  in  the  absence  of remission, i.e., 59% vs 20%. Overall survival after haploidentical BMT is also higher in the patients transplanted in 1st remission, as compared to the patients, undergoing BMT out of remission (41% vs 23%).

Clinical results of BMT proceduresIn 2015, we have performed analysis of total survival among the BMT patients (Fig. 7). This analysis shows a significantly higher  total  survival  in  a  group  of  patients  after  allo-BMT  performed  in  the  1st  remission,  as  compared  to  survival  in  the  group  after  allogeneic  BMT  carried  out  in  the  absence  of remission, i.e., 59% vs 20%. Overall survival after haploidentical BMT is also higher in the patients transplanted in 1st remission, as compared to the patients, undergoing BMT out of remission (41% vs 23%).

figure-7-total-survival-after-allogeneic-bmt-and-haplo-bm.jpg

Figure 7. Total survival after allogeneic BMT and haplo-BMT in the patients with acute leukemias dependent on the state of disease by the time of transplant.

Overall survival (OS) was also determined in a group of patients with acute myeloblastic leukemia. We compared 3 patient groups, Group1, patients receiving chemotherapy only; Group 2 obtained BMT in remission, and Group3, patients receiving  an  off-remission  BMT  (Fig.7).  Overall  survival  among  patients  from  the  2nd  group  was  sufficiently  higher  than  for  groups  1  and  3,  i.e.,  10%  vs  60%.  However,  OS  among  the  patients  after  BMT  beyond  remission  was  twofold higher than among subjects getting chemotherapy only (20% vs 10%).

Preliminary  analysis  of  overall  survival  among  acute  leukemia patients (observed for 30 months in haplo-HSCT, or 40 months in allo-HSCT) has shown an important role of the disease status by the time of BMT, thus being in full accordance with available international data. Our results should be further  analysed  for  5-year  survival  in  a  group  of  ≥30  patients [2, 3, 4].

figure-8-overall-survival-among-patients-with-acute-leukemias-aml-and-all.jpg

Figure 8. Overall survival among patients with acute leukemias (AML and ALL), when performing standard chemotherapy (left) and allo-HSCT at our BMT Department (right).

Despite the arrangement of ‘clean unit’, and BMT numbers increased to 54 in 2015, high requirements for transplantation remain in the country. E.g., according to statistical data (Table 2), 152 patients in Kazakhstan need BMT yearly, either allogeneic  or  autologous  procedure.  Acute  leukemias  (77  BMTs  per year) are most common at our Department, including 29 ALL cases and 48 AML patients. Multiple myeloma takes next position (31 BMT annually), followed by aplastic anemia (14 BMTs),  myelodysplastic  syndromes  (n=12)  and  non-Hodgkin’s  lymphomas  (n=12),  as  well  as  Hodgkin’s  lymphoma  (6  BMTs yearly). To cover these requirements, we are planning increase in patient places (beds), with subsequent expansion of the ‘clean’ space from 6 to 15 beds.

Cooperation with clinics abroad

A  big  contribution  to  development  of  the  Oncohematology  Department  and  BMT  activity  was  made  by  the  staff  of  the R. Gorbacheva Research Institute of Children Oncology, Hematology and Transplantation at the First I. Pavlov State Medical  University  (St.  Petersburg,  Russia),  having  been  provided over last years. Over 2014-2015, we have trained in St.  Petersburg  four  clinicians  in  Hematology  at  a  postgraduate  course  Current  Hematology  and  Bone  Marrow  Transplantation;  two  clinical  laboratory  doctors  for  diagnostics  of  malignant  blood  disorders,  trained  a  laboratory  doctor  in  clinical  cytogenetics.  Our  collaborators  from  Gorbacheva Institute have teached a specialist in hematopoietic stem cells harvesting, treatment and cryoconservation; performed educational courses for 5 clinical hematolologists at the VIII and  IX  R.  Gorbacheva  Memorial  Symposia  (2014,  2015,  St. Petersburg).

Moreover,  some  specialists  from  St.  Petersburg  R.  Gorbacheva  Memorial  Institute  performed  in  Kazakhstan  several seminars and master classes over 2014, e.g., in flow cytometry for detection of minimal residual disease (Babenko Elena  V.,  2014);  arrangement  of  hematological  services  in  Kazakhstan  (Morozova  Elena  V.,  Bondarenko  Sergey  N.,  Darskaya  Elena  I.);  a  4-week  tutorial  concerning  Basics  of  Modern Diagnostics and Treatment in Oncohematology which took place in Almaty (Kazakhstan).

A  special  longitudinal  cooperation  is  performed  in  the  field  of  arrangement  of  a  Bone  Marrow  Donor  Registry  in  Kazakhstan  Republic.  A  common  Russian-Kazakh  donor  search platform is arranged in order to recruit bone marrow donors from Russian Registry for Kazakh patients.

Some   other   tutorials   were   performed   in   2015,   including   a   school   for   paroxysmal   nocturnal   hemoglobinuria   (Babenko E. V., Kulagin A. D., held in St. Petersburg), a master class by E. V. Babenko concerning immune phenotyping of PNH markers (April 2015, Astana, Kazakhstan); an expert council on invasive fungal invasions in hematology (13 May, 2015, Research Institute of Pediatrics and Children Surgery, Prof.  K.  O.  Omarova,  N.  N.  Klimko,  PhD  M.  O.  Popova). A  tutorial  “Hematopoietic  stem  cell  transplantation  in  the  children  with  oncohematological  diseases  and  orphan  diseases” was performed on May 25-30, 2015, in Astana, led by Dr. S. N. Bondarenko), followed by a master class: Arrangement  of  a  Bone  Marrow  Donor  Registry  (May  26-28,  2015,  Astanа, led by Dr. A. L. Alyansky).Further prospectivesFuture cooperation between the 1st St. Petersburg State Medical  I.  Pavlov  University  and  hematological  institutions  in  St. Petersburg and Kazakhstan in the field of hematopoietic transplantation should be developed in the abovementioned directions:

  1. Hematopoietic  transplantation  in  pediatric  practice  and  adult patients.

    1. Further development of diagnostic base in oncohematology  (morphology,  immunohistochemistry,  immune  phenotyping, cytogenetics, molecular diagnostics).

    2. Unified and improved diagnostic and therapeutic protocols, in order to assess and treat tumor and non-tumor blood diseases.

    3. Orphan dieases (diagnostics, registries, bone marrow transplantation, target therapy).

  2. Functioning of a common Bone Marrow Donor Registry.

Our plans for the nearest future are connected with meeting the requirements of Kazakh patients in transplantation assistance, e.g., an increase of clinical facilities by 5 hospital beds, and  opening  a  special  block  for  therapy  of  lymphoproliferative disorders with 15 beds, as well as expansion of critical care unit to 9 beds. Increasing number of patients needs arrangement of outpatient service and polyclinics.

Conflicts of interest

The authors have no conflict of interest to declare.

References

  1. Bayraktar  UD,  Champlin  RE,  Ciurea  SO.  Progress  in  haploidentical stem cell transplantation. Biol Blood Marrow Transplant 2012; 18:372-380.

  2. Olifirovich A, Pivovarova I, Kemaykin V, Klodzinskiy A, Nemerovchenko  A,  Tussipova  A,  Vildanova  R,  Sataeva  M,  Kolesnev A, Iskakova A. Remission at secondary acute myeloid leukemia after haploidentical stem cells microtransplantation (a clinical case); Abstract XXXV World Congress International Society of Hematology, Sept. 4-7, Beijing, China, 2014: 133, ЕР-05-001.

  3. Pivovarova  IA,  Klodzinsky  AA,  Kemaikin  VM,  Olifirovich  AA,  Kolesnev  AV,  Iskakova  AM,  Sataeva  MS.  Lethality  trends  after  haploidentical  hematopoietic  stem  cell  transplantation.  Kazakhstanskaya  Transplantologiya,  2014;  No1:46-53.

  4. Vildanova   R,   Pivovarova   I,   Klodzinskiy   A,   Kemaikin  V,  Kolesnev  A,  Sataeva  M,  Iskakova  A,  Olifirovich  A,  Tussipova  A,  Nemerovchenko  A.  BeEAM  as  conditioning  regimen for haploidentical bone marrow transplantation in patients  with  Ph-positive  ALL  (two  case  reports);  Abstract  XXXV  World  Congress  International  Society  of  Hematology, Sept. 4-7, Beijing, China, 2014: 124, ЕР-04-001.

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