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Joint Accreditation Committee of the International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation accreditation for autologous hematopoietic stem cell transplantation in non-leukemic malignancies: burden or benefit?

Huijberts S

Department of Medical Oncology, Antoni van Leeuwenhoek hospital, Plesmanlaan, Amsterdam, the Netherlands

These authors contributed equally to this work

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Baars JW

Department of Medical Oncology, Antoni van Leeuwenhoek hospital, Plesmanlaan, Amsterdam, the Netherlands

These authors contributed equally to this work

Tinteren HV

Department of epidemiology and statistics, Antoni van Leeuwenhoek hospital, Plesmanlaan, Amsterdam, the Netherlands

Holtkamp MJ

Department of Medical Oncology, Antoni van Leeuwenhoek hospital, Plesmanlaan, Amsterdam, the Netherlands

Rodenhuis S

Department of Medical Oncology, Antoni van Leeuwenhoek hospital, Plesmanlaan, Amsterdam, the Netherlands

DOI: 10.15761/IMM.1000265

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Key words

JACIE accreditation, absolute duration neutropenia, autologous HS, non-leukemic malignancies

Autologous hematopoietic stem cell transplantation (HSCT) is considered to be a high-risk procedure and requires the cooperation of many health care professionals. Because of that, a special quality management system ‘Joint Accreditation Committee of the International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation (JACIE)’was implemented in the hope to improve patient care and outcome [1]. In the Netherlands, this system is mandatory for all hospitals performing autologous and allogeneic HSCT. This special quality management system requires among many other things special training for all physicians and nurses involved, special isolation measures, extensive description of standard operating procedures  and  a strict documentation of the bone marrow recovery in every transplanted patient.1 According to our opinion, the complications and complexity of an autologous HSCT in patients with non-acute leukemic malignancies do not differ so much from daily hemato-oncological care that an apart qualification system contributes to the improvement in the outcome of these patients.  Indeed, Gratwohl et al found that the JACIE accreditation had no impact upon the outcome of patients undergoing autologous HSCT [2].

Patients undergoing HSCT are often characterised as high risk patients with an expected duration of neutropenia > 7 days [3].  The underlying diagnosis, the extent of pre-treatment, the amount of reinfused peripheral stem cells and the conditioning regimen before stem cell transplantation have impact upon the duration of neutropenia and other toxicities [3-9] Infections are the most frequent complications in HSCT patients, influenced by the depth and duration of neutropenia and the extent of mucositis [10].

We performed a retrospective study in all patients who underwent an autologous HSCT from 2008-2012 in our institute to investigate the relationship between the absolute duration of neutropenia in relation to the malignancy, the occurrence of neutropenic fever, mucositis and other toxicities. Based on these results, we wish to start a debate if a special time consuming and costly accreditation system and the special measures mandatory to achieve the accreditation are really warranted for the clinical part of autologous HSCT in non-acute leukemic malignancies. Since we do not treat patients with acute leukaemia’s in our hospital, this patient category was not represented in this study.

All patients had given informed consent for high dose treatment and medical record review.  We (SH, JWB) reviewed all records of the patients treated with high dose chemotherapy followed by an autologous stem cell transplantation.  The collected parameters were: age, sex, performance status, comorbidity, diagnosis, treatment before the stem cell transplantation, the amount of CD34+ cells/kg body weight reinfused, type of conditioning regimens before transplantation, duration of absolute neutropenia after the stem cell transplantation, occurrence of fever, culture of causative micro-organisms, mucositis, other side effects of the high dose treatment.

The high dose chemotherapy regimens  administered were:  BCNU 300 mg/m2 during 1 day, etoposide and cytarabine both 200 mg/m2/day during  4 days,  Melphalan 140 mg/m2 during  1 day (BEAM) for patients with malignant lymphoma; high dose Melphalan (HDM) 100 mg/m2/day during  2 days  for patients with multiple myeloma;  cyclophosphamide 1500 mg/m2 /day , carboplatin 5 x area under curve (AUC)/day , thiotepa twice daily 60 mg/m2 all agents for 4 consecutive days (CTC) for patients with testicular cancer and medulloblastoma;  mini CTC for patients with breast cancer: cyclophosphamide 3000 mg/m2 during 1 day, carboplatin 400 mg/m2 ( in case of creatinine clearance < 100 ml/min: 5 x AUC) during 2 days and thiotepa 250 mg/m2 during 1 day. The patients with testicular cancer, medulloblastoma and breast cancer received two transplantations with the same regimen.  All patients received G-CSF (filgastrim) 300 micrograms a day, started one day after the reinfusion until neutrophilic cell count reached 1000 x 106 cells/ml or until the absolute neutrophil count exceeded >500 x 106 cells/ml for 2 consecutive days.

All patients received prophylactic antibiotics according to local guidelines and based on routine cultures taken twice weekly. When fever occurred, broad spectrum antibiotics were started and multiple samples of blood cultures, urine, sputum and specimens from suspected sites were taken to identify the causing micro-organism.  In case of allergy or specific culture results, other antibiotics were administered.

Absolute neutropenia was defined as a neutrophil count of < 500 x 106 cells/ml. Neutrophil engraftment was defined as the first day on which the absolute neutrophil count (ANC) exceeded >500 x 106 cells/ml for 2 consecutive days.

The transfusion threshold for irradiated erythrocytes was hemoglobine < 6g/dl and for irradiated pool platelets a platelet count <10.000/microl.

The patients received standard anti-emetic care.

Mucositis grades were defined according to the common terminology criteria for adverse events (CTCAE) version 4.0 as were the other toxicities.

Fever was defined as a single ear or oral temperature measurement of ≥ 38.5 degrees Celsius or > 38 degrees Celsius over 1 hour period.

The cohort consisted of 86 patients of which 65 patients received a single- and 21 a double transplantation, 107 HSCT in total. Apart from the remission-induction treatment and chemotherapy for stem cell mobilisation, almost half of the patients received their HSCT as part of their salvage therapy for relapse.  25 patients (29%) received one line of pre-treatment and 13 (15%) received two lines. (Table 1)

Seven (8%) patients experienced a prolonged neutropenia (ANC < 500 x 106/ml > 7 days). In eight procedures (7.5%) a prolonged neutropenia occurred.  The patient- and treatment characteristics are shown in table 1.
 

Four patients with duration of neutropenia > 7 days were pre-treated with at least 2 lines of chemotherapy, 2 patients with breast carcinoma had no prior treatment. One patient with multiple myeloma had received the second autologous stem cell transplantation 4 years after the first one. (Table 1)

Table 1. Baseline characteristics

 

Total population

Number (%)

Sex

Men                                                                 

Women                                                           

49 (68)

37 (32)

Age (years)

Median                                                            

Range                                                          

46

21-72

Diagnosis

Medulloblastoma

Breast cancer

Multiple myeloma

Non-Hodgkin lymphoma

Hodgkin lymphoma

Non-seminoma testis

1 (1)

30 (35)

20 (23)

15 (18)

13 (15)

7 (8)

Conditioning regimes

CTC                                                                   

mCTC                                                               

BEAM      

High dose Melphalan                                                                                                            

8 (9)

30 (35)

28 (33)

20 (23)

Transplantations

1 transplantation                                            

2 transplantations                                          

65 (76)

21 (24)

Chemotherapy pre-treatment

No pre-treatment                                           

One line                                                            

Two lines                                                          

48 (56)

25 (29)

13 (15)

Table 2 shows the duration of neutropenia and hospital stay, the number of harvested and reinfused peripheral stem cells, mucositis, occurrence of fever, the median number of transfused unit’s erythrocytes and pools thrombocytes. No grade 3 or 4 transfusion- or stem cell reinfusion related toxicities occurred.  In total 59 episodes of fever were observed. In half of the cases, micro-organisms were cultured, the most frequent coagulase negative staphylococci.  All 4 candida albicans infections were limited to oropharyngeal infections.  6 patients had a grade III/IV mucositis.  4/6 of these patients had a duration of neutropenia > 7 days. All 6 patients developed neutropenic fever. (Table 3)

No grade III, IV organ or lethal toxicities took place during the HSCT.  There was no difference in toxicities between the first or second HSCT. All patients had full bone marrow recovery.

Twelve of the 86 patients were treated with radiotherapy, but in none of these patients a significant part of the bone marrow was located in the radiation field. 

Our study shows that only 8% of our patients undergoing autologous HSCT had an absolute duration of neutropenia (< 0.5 x 109/l) > 7 days and 7% of the patients had a mucositis grade > 3. (Table 2-3) All toxicities, also in the patients with a prolonged duration of neutropenia, were manageable with standard hemato-oncological care. The pattern of bone marrow recovery is stable over years (Table 2).

Table 2. Main toxicities, stem cell harvest and hematologic recovery of 86 patients after HSCT

 

Median

Range

Reinfusion

Harvested CD34+ cells x 106/kg

8.0

 

2.6-88.0

Reinfused CD34+ cells x 106/kg

4.9

 

1.8-11.5

Bone marrow recovery

Duration of ANC < 500 x 106/mL (days)

4.0

2.0-15.0

Leucocytes > 500 x 106/mL after HSCT in days

9.0

8.0-14.0

Thrombocytes > 10.000 /microL after HSCT in days

9.0

6.0-14.0

Thrombocytes > 20.000 /microL after HSCT in days

10.0

6.0-25.0

Thrombocytes > 50.000 /microL  after HSCT in days

16.0

7.0-36.0

Supportive care

Number of transfused filtrated erythrocytes

2.0

0.0-7.0

Number of pooled thrombocytes

2.0

0.0-13.0

Duration of hospital stay (days)

16.0

 

4.0-40.0

Table 3. Toxicities: Fever and mucositis

Fever

Number (%)

Fever

No fever

59 (69)

27 (31)

Mucositis grades (whole population)

No

Grades I and II

Grades III and IV

23 (27)

57 (66)

6 (7)

Mucositis grades and infections

No mucositis

Mucositis gr I and II

Mucositis gr III and IV

12 (26)

29 (62)

6 (12)

The relative short duration of neutropenia in the majority of patients does not warrant strict isolation. Patients can be nursed in a normal ward or stay at home with regular outpatient clinic controls.  Instead of making a file in which the bone marrow recovery is ‘exactly’ documented (results also depending on how frequently blood is taken for laboratory control), one can consider to look which percentage of patients is recovered 14 days after the autologous HSCT in terms of transfusion independency, recovery from non-hematologic  acute toxicities and  the ANC being  > 1000 x 106/ml. This is less time consuming and burdensome for patients and personnel than counting the days before bone marrow recovery takes place.

It is known that centre size and experience of the medical personal with intensive oncological treatments have impact on the outcome of the patients2. The centre has to perform enough procedures per year (>10/year) with a stable senior staff to guarantee good quality of patient care. The authorities have to make demands on the number of patients transplanted each year in a specific hospital. In addition, accreditation systems should be short and comprehensive. The current 473 pages JACIE manual trying to regulate each detail and trying to avoid very rare complications is hardly readable anymore, puts a burden on the medical personnel, quality officers and does not contribute to the improvement of patient care and safety [1,2]. 

References

  1. FACT-JACIE (2016) International standards for hematopoietic cellular therapy, product collection, processing and administration. Accreditation manual. [citied 2016 March 17]. http://www.jacie.org/
  2. Gratwohl A, Brand R, Grath E (2014) Use of the quality management system ‘JACIE’ and outcome after hematopoietic stem cell transplantation. Haematologica 99: 908-915.
  3. Craig M, Cumpston A, Hobbs G, DeVetten M, Sarwari A, Ericson S, et al. (2007) The clinical impact of antibacterial prophylaxis and cycling antibiotics for febrile neutropenia in a haematological malignancy and transplantation unit. Bone Marrow Transplantation 39: 477-482.
  4. Dettenkofer M, Rottele WS, Babikir R, Bertz H, Ebner W, Meyer E, et al. (2005) Surveillance of nosocomial sepsis and pneumonia in patients with a bone marrow or peripheral blood stem cell transplant: a multicenter project. Clinical Infectious Diseases 40: 926-931.
  5. Papaiakovou E, Kostis E, Migkou M, Christoulas D, Terpos E, Graviatopoulou M, et al. (2010) Prophylactic antibiotics for the prevention of neutropenic fever in patients undergoing autologous stem-cell transplantation: results of a single institution, randomized phase 2 trial. American Journal of Hematology 85: 863-867.
  6. Stemmer S, Maor Y, Hardan I (2004) Oral fluconazole for empiric treatment of prolonged fever in neutropenic patients. Prospective study in 250 consecutive patients after stem cell transplantation. American Journal of Clinical Oncology 27: 328-332.
  7. Yeh S, Chiu C, Lo W, Lin C, Hsueh C, Liao M, et al.  (2003) Low infectious morbidity in patients with heavily pretreated haematological malignancies receiving autologous peripheral blood stem cell transplantation without antimicrobial prophylaxis. Ann Hematol 2003: 82: 24-29.
  8. Rosa DL, Anghel G, Pandolfi A, Riccardi M, Amodeo R, Majolino I, et al. (2003) Hemopoietic recovery and infectious complications in breast cancer and multiple myeloma after autologous CD34+ cell-selected peripheral blood progenitor cell transplantation. International journal of hematology 79: 85-91.
  9. Wall E, Richel DJ, Holtkamp MJ, Cortenbach ICS, Schoot CE, Dalesio O et al. (1994) Bone marrow reconstitution after high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation: effect of graft size. Ann Oncol 5: 795-802.
  10. Sohn BS, Yoon DH, Kim S, Lee K, Kang EH, et al. (2012) The role of prophylactic antimicrobials during autologous stem cell transplantation: a single-center experience. Eur J Clin Microbiol Infect Dis 31: 1653-1661. [crossref]

Editorial Information

Editor-in-Chief

Ivan Gout
University College London

Article Type

Commentary

Publication history

Received date: December 02, 2016
Accepted date: December 27, 2016
Published date: December 29, 2016

Copyright

© 2017 Huijberts S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Huijberts S (2017) Joint Accreditation Committee of the International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation accreditation for autologous hematopoietic stem cell transplantation in non-leukemic malignancies: burden or benefit?. Integr Mol Med 4: DOI: 10.15761/IMM.1000265

Corresponding author

J.W. Baars

medical oncologist, Antoni van Leeuwenhoek hospital, Department of Medical Oncology, Plesmanlaan, Amsterdam, the Netherlands

Table 1. Baseline characteristics

 

Total population

Number (%)

Sex

Men                                                                 

Women                                                           

49 (68)

37 (32)

Age (years)

Median                                                            

Range                                                          

46

21-72

Diagnosis

Medulloblastoma

Breast cancer

Multiple myeloma

Non-Hodgkin lymphoma

Hodgkin lymphoma

Non-seminoma testis

1 (1)

30 (35)

20 (23)

15 (18)

13 (15)

7 (8)

Conditioning regimes

CTC                                                                   

mCTC                                                               

BEAM      

High dose Melphalan                                                                                                            

8 (9)

30 (35)

28 (33)

20 (23)

Transplantations

1 transplantation                                            

2 transplantations                                          

65 (76)

21 (24)

Chemotherapy pre-treatment

No pre-treatment                                           

One line                                                            

Two lines                                                          

48 (56)

25 (29)

13 (15)

Table 2. Main toxicities, stem cell harvest and hematologic recovery of 86 patients after HSCT

 

Median

Range

Reinfusion

Harvested CD34+ cells x 106/kg

8.0

 

2.6-88.0

Reinfused CD34+ cells x 106/kg

4.9

 

1.8-11.5

Bone marrow recovery

Duration of ANC < 500 x 106/mL (days)

4.0

2.0-15.0

Leucocytes > 500 x 106/mL after HSCT in days

9.0

8.0-14.0

Thrombocytes > 10.000 /microL after HSCT in days

9.0

6.0-14.0

Thrombocytes > 20.000 /microL after HSCT in days

10.0

6.0-25.0

Thrombocytes > 50.000 /microL  after HSCT in days

16.0

7.0-36.0

Supportive care

Number of transfused filtrated erythrocytes

2.0

0.0-7.0

Number of pooled thrombocytes

2.0

0.0-13.0

Duration of hospital stay (days)

16.0

 

4.0-40.0

Table 3. Toxicities: Fever and mucositis

Fever

Number (%)

Fever

No fever

59 (69)

27 (31)

Mucositis grades (whole population)

No

Grades I and II

Grades III and IV

23 (27)

57 (66)

6 (7)

Mucositis grades and infections

No mucositis

Mucositis gr I and II

Mucositis gr III and IV

12 (26)

29 (62)

6 (12)