Hematopoietic stem and progenitor cell harvesting: technical advances and clinical utility

Figures & data

Table 1 Recent studies performed to improve amounts of hematopoietic stem and progenitor cell (HSPC) harvested in cord blood (CB)

Type of improvement	Reference	Year	Goal	Results
Technical	Elchalal et al^Citation24	2000	Compare three methods of harvesting process (with or without flushing by a syringe and sodium chloride into an open sterile container or a blood bag). Results on volume, TNC, and bacterial contamination	Flushing increased the volume and total nucleated cell (TNC) numbers Bacterial contamination was lower when harvesting in a blood bag
	Belvedere et al^Citation25	2000	Evaluate a harvesting system (pressure application system) by inducing additional pressure after delivery	Increase in volume and CD34+ cell numbers (40%). The last fraction harvested by the device contained more HSPCs than the first fraction harvested by gravity
	Bornstein et al^Citation26	2005	Evaluate a second fraction harvested after placenta perfusion	This fraction contributed to 32% volume and 15% TNC of the whole CB unit
	Takebe et al^Citation27	2009	Describe a pulsatile machine reperfusion of a placenta to improve harvesting yield	Improved harvest with 1.5-fold increase in CD34+ cells
	Tan et al^Citation28	2012	Describe an auto-perfusing CB harvesting instrument	Generate vibrations during the perfusion phase and a control platform to integrate all systems
Obstetrical	Surbek et al^Citation29	1998	A randomized comparison of harvest while placenta is still in the uterus before vs after placenta delivery	More volume and mononuclear cells harvested before placenta delivery
	Larsky et al^Citation30	2002	Compare the CB harvest while placenta is still in the uterus vs after placental delivery	Both methods produced comparable hematological parameters (volume, TNC, CD34+, CFU-GM)
	Solves et al^Citation18	2003	Compare the CB harvest in the delivery room (while placenta is still in the uterus) vs in an adjacent room after placental delivery	CB harvesting before placental delivery allows the best TNC and HSPC harvest
	Wong et al^Citation31	2001	Compare the CB harvest in the delivery room (while placenta is still in the uterus) vs in an adjacent room after placental delivery	CB harvesting before placental delivery allows the best TNC and HSPC yield
	Omori et al^Citation32	2010	Compare CB collection in cesarean and vaginal delivery	Higher volume when cesarean, but higher CD34+ cells after vaginal delivery
	Cairo et al^Citation33	2005	Analyze the factors associated with better cell yields	Cesarean section is associated to higher total CFU

Abbreviations: GM, granulocyte macrophage; CFU, colony forming unit.

Table 2 Reasons for excluding the CBUs harvested

Exclusion criteria	%
Low volume or low total nucleated cell amounts	52–85
Bacterial cord blood unit (CBU) contaminations	5–17
Storage/transport time >48 h	1–16
Abnormal transport temperature	1–2
Incomplete documentation in hospital	2–3
Parents medical history	2–5
Abnormal maternal infectious disease testing	1–5
Problems during CBU processing	3–5
Clots	2–4

Notes: Data from recent unpublished experience in France and three large cohorts recently published with, respectively, 7,921 CBUs harvested and 2,014 CBUs stored; 31,128 CBUs harvested and 7,056 CBUs stored; and 1170 CBUs harvested and 735 CBUs stored.^17,36,37

Table 3 Main factors that may negatively affect successful HSPC harvest

Factors	Results	Commentary	Reference
Older age	58 years was the cutoff 70 years has been described as another cutoff	Study performed in myeloma patients Factor also described in other diseases	Lacativa et al^Citation61
Diagnosis	NHL, myeloma and AML were alternatively described	More difficult in AML patients	Mendrone et al^Citation59 Koenigsmann et al^Citation60
Prior irradiation	Mainly bone irradiation	Factors described in MM and in most studies	Bensinger et al^Citation56
Bone marrow involvement	Presence and importance of involvement	Factors described in most studies Factors described in most diseases	Bensinger et al^Citation56 Cesaro et al^Citation48
Stage of the disease	Advanced stage	Factors described in NHL and cancers	Weaver et al^Citation57
Number of previous chemotherapy regimens	More than three lines of chemotherapy	Fewer lines are associated to better harvest Factor also described as chemotherapy load	Bensinger et al^Citation56 Ketterer et al^Citation58 Mendrone et al^Citation59
Alkylating agents	Cisplatin is described in most studies Mitoxantrone is described	Factors associated to the number of chemotherapy cycles	Mendrone et al^Citation59
Platelet baseline count	Cutoff: 150,000–161,000 platelets/μL	Factors described in most recent studies	Mendrone et al^Citation59 Lacativa et al^Citation61
Fludarabine exposure	Exposure to several lines	Factor described in NHL Factor confirmed in most studies	Ketterer et al^Citation58 Waterman et al^Citation62
Cancer relapse	More difficult to harvest when relapse	Factors associated to other factors (lines of chemotherapy)	Cesaro et al^Citation48

Abbreviations: AML, acute myeloid leukemia; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; HSPC, hematopoietic stem and progenitor cell.

Table 4 Definition and criteria of poor mobilizers (PMs)

Reference	Year	Definition	Incidence
Predicted PM
Li et al^Citation65	2011	Lower than 15 CD34+ circulating cells/μL while WBC count is >10×10^9/L	Nd
Attolico et al^Citation66	2012	Failed attempt to collect 2×10^6 CD34+ cells/kg BW under three consecutive apheresis Failure to reach a threshold of at least ten CD34+ circulating cells/μL	Nd
Olivieri et al^Citation67	2012	Failed a previous harvest attempt Risk factors for failure in HSPC harvest	Nd
Proven PM
Perseghin et al^Citation68	2009	Failure to reach a threshold of at least 20 CD34+ circulating cells/μL Among them failure to achieve a CD34+ cell dose of 2×10^6/kg BW	335/2,177 (15%)
Wuchter et al^Citation69	2010	Borderline PMs: between 11 and 19 CD34+ circulating cells/μL Relative PMs: between six and ten CD34+ circulating cells/μL Absolute PMs: <5 CD34+ circulating cells/μL	129/840 (15.3%)
Olivieri et al^Citation67	2012	Lower than 20 CD34+ circulating cells/μL after usual mobilizing regimens	15%
Lacativa et al^Citation61	2012	Failure to collect 2×10^6/kg BW in 3 days of apheresis	22/157 (14%)
Cesaro et al^Citation48	2013	Failure to collect 2×10^6/kg BW in 3 days of apheresis	24/145 (17%)

Abbreviations: BW, body weight; HSPC, hematopoietic stem and progenitor cell; Nd, not determined; PMs, poor mobilizers; WBC, white blood cell.

Table 5 Main current apheresis techniques used for hematopoietic stem and progenitor cell (HSPC) harvest

	COBE Spectra	Spectra Optia	Amicus	COM.TEC
Firm	TerumoBCT (Lakewood, Co)	TerumoBCT (Lakewood, Co)	Fenwall (Lake Zurich, IL)	Fresenius Healthcare (Bad Homburg, Germany)
Flow method	Continuous	Continuous	Continuous	Continuous
Blood separation	Continuous separation of blood components	Continuous blood separation monitored by automated interface management (AIM)	Continuous blood separation monitored by two sensors	Blood separation is performed during cycles whose features are individually determined
HSPC harvest	Continuous harvest of the mononuclear cells layer	Harvest in a collection chamber and line during cycles	Harvest in a collection chamber and line	Intermittent harvest at the end of each separation cycle
Operator adjustment	Continuous manual adjustment of the interface and the harvest	Interface and harvest automatically controlled with few adjustments	Interface and harvest automatically controlled	Adjusting the volumes of the separation cycle, buffy coat, and spillover

Note: A modified automatic COBE Spectra technique was also developed and named Auto-PBSC.

Table 6 Recent studies comparing the performances of apheresis devices for HSPC harvesting

Reference (year)	Goal	Number of procedures	Results
Altuntas et al^Citation85 (2007)	Compare Amicus and COM.TEC performances	Amicus: 20 COM.TEC: 20	No difference in numbers of CD34+ cells harvested Higher decrease in PB platelets with COM.TEC
Reinhardt et al^Citation86 (2011)	Evaluate performances of Spectra Optia and comparison with historical performances of COBE Spectra	Spectra Optia: 35 COBE Spectra: 401	Excellent usability of Spectra Optia CE2 superior with Spectra Optia
Wu et al^Citation82 (2012)	Compare HSPC harvest using COBE Spectra, MCS+ Haemonetics, and Baxter Amicus	COBE Spectra: 99 MCS+: 81 Amicus: 38	Similar number of CD34+ cells harvested Better correlation of harvested/circulating HSPCs with COBE Spectra. Amicus collected less platelets
Brauninger et al^Citation87 (2012)	Compare Spectra Optia and COBE Spectra performances	Spectra Optia: 50 COBE Spectra: 89	With Optia – CE1: 7.9% greater – Less platelets but more granulocytes in products
Flommersfeld et al^Citation88 (2013)	Compare COM.TEC, COBE Spectra, and Spectra Optia	COM-TEC: 77 Spectra Optia: 52 COBE Spectra: 58	With Optia: – Higher CE – Longer duration
Ikeda et al^Citation89 (2014)	Compare Spectra-MNC (manual) and Spectra Auto-PBSC performances	Spectra-Auto: 118 Spectra-MNC: 70	Correlation between circulating HSPCs and harvested HSPCs in Spectra – MNC Less reduction in PB platelets in Spectra-Auto
Cherqaoui et al^Citation90 (2014)	Compare Spectra Optia and COBE Spectra performances in low-weight children	Spectra Optia: 8 COBE Spectra: 22	Similar CE Reduced platelet and Hb loss with Spectra Optia but higher duration

Note: Two collection efficiency (CE) indexes are described: CD34 CE1 (%) = absolute number of CD34+ cells harvested (×100%)/([pre-apheresis CD34+ blood levels + post-apheresis CD34+ blood levels]/2) × total processed volume; CD34 CE2 (%) = absolute number of CD34+ cells harvested (×100%)/pre-apheresis CD34+ blood levels × total processed volume.

Abbreviations: Hb, hemoglobin; HSPC, hematopoietic stem and progenitor cell; PB, peripheral blood.

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