FACTORES ALREDEDOR DE LA POBREZA EN EL ECUADOR

I n t r o d u c t i o n

The success o f haematopoietic cell transplantation is determined by many parameters. These include the type o f haematological disorder (Burnett and Eden, 1997; Clift et al., 1993), stage o f disease at the time o f transplant (Horowitz, 1992), HLA-m atching o f donor and patient and whether the donor and patient are related or unrelated (Davies et a i , 1997; Gustafsson et al., 2000; Hows et al., 1986; Marks et al., 1993), pre-transplant conditioning (Feinstein et al., 2001; M ichallet et a i , 2001; Morecki et al., 2001; Nagler et al., 2001), T-cell depletion (Ash et a i , 1991; Gilmore et al., 1986; Prentice et al., 1984), GVHD prophylaxis (M cGlave et a i , 1993), incidence and severity o f G VH D (Hansen et al., 1998; Marks et al., 1993; M cGlave et al., 1993), post-transplant infections (Davies et a i , 1995; Hansen et al., 1998; Hongeng et al., 1997; Keman et al., 1993; Marks et al., 1993; Oakhill et al., 1996; Ochs et al., 1995; Small et al., 1997; Snyder et al., 1993), patient age (Madrigal et al., 1997) and stem cell source (reviewed in (Korbling et al., 2001)). While each o f these parameters may have mutually exclusive effects on the outcom e o f the transplant, it is the com bination o f all o f these parameters that will determine the ultimate success of the transplant.

The immediate post-transplant period is follow ed by a severe and often p rolonged immune deficiency that results in prolonged susceptibility to infection (Hansen et a i , 1998; Hongeng et al., 1997; Keman et al., 1993; Marks et al., 1993; Oakhill et al., 1996; Ochs et al., 1995). Although infections that occur in the first month after engraftm ent probably result from deficiencies in both granulocytes and other m ononuclear cell subsets, the more prolonged immune deficiency arises from deficiencies in effective CD4^ T -cell and B -cell reconstitution (Small et al., 1997; Small et al., 1999; Storek et al., 2 0 0 0 ; Storek et al., 1997). Later studies showed that restoration o f T -cell immunity was dependent on recovery o f the CD4"^CD45RA'’ T -cell (Dumont-Girard et al., 1998; Roux et al., 2000).

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ C H A P T Ü R 4

The previous observations led to the suggestion that the reconstitution and maintenance o f effective T-cell immunity after HCT was dependent on education o f T -cell precursors in the thymus (Dumont-Girard et al., 1998; Mackall et at., 1995; Roux et a l , 2 0 0 0 ). Furthermore, these observations generated considerable interest in the factors affecting the reconstitution o f T-cell immunity through thym ic-dependent pathways (Niehues et at., 2001; W einberg et al., 2001). Using phenotypic markers o f T-cell naivety (primarily the C D 45R A antigen), initial studies demonstrated that increasing patient age had an adverse effect on the regeneration o f naïve CD4"^ T-cells, presumably due to age-related thym ic involution (Mackall et al., 1995). Som e o f the problems in using phenotypic markers such as C D 45R A in monitoring T-cell reconstitution were highlighted in Chapter 3.

Recent studies confirmed that increasing patient age had an adverse effect on thym ic output (Douek et al., 1998; Douek et al., 2000). In addition, the thymus has been demonstrated to be a target o f GVHD and the presence o f GVHD after HCT is associated with decreased TREC levels (Weinberg et al., 2001). There is also som e evidence that thymic output can be influenced by donor lym phocyte infusions (H ochberg et al., 2 0 0 1 ) and pre-BM T radiotherapy (Chung et al., 2001).

The results from Chapter 3 demonstrated that the contribution o f thym ic-dependent and thym ic-independent pathways to T-cell reconstitution was highly variable between different individuals and that the recovery of T-cell populations often fell out-with Gaussian distributions. Therefore, the aim o f this chapter is to carry out an analysis o f the factors affecting total T -cell reconstitution, thymic output and memory and effector T -cell reconstitution. The final analysis was based on 32 patients from the Royal Free Hospital and the Institute Português de Oncologia, Portugal.

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Table 4.1: Clinical characteristics o f patients enrolled in the study

UPN Age Diagnosis* Stem Cell

Source

Donorot Conditioning** Infections# C urrent sta tu s

37 6 ALL BM Sibling Cy/TBI Alive a n d well 25 6 FA PB sib lin g Cam/Cy/TAI - Alive a n d well 26 7 FA PB sib lin g Cam/Cy/TAI - Alive a n d well 12 11 ALL BM sib lin g Cy/TBI VZV Alive a n d well 35 14 ALL BM Mis-UD Cam /Cy/Flu/TBI Candida^, Streptococcus

spp.

Alive a n d well 2 0 15 SAA BM sib lin g C am /Cy/Flu - Alive a n d well 9 17 FA BM sib lin g Cam/Cy/TAI CMV Alive a n d well 39 21 MDS PB sib lin g Cy/Flu/TBI HHV6, T o x o p lasm o sis

CMV

Alive, cGvHD 4 6 22 AA/PNH PB sib lin g C am /Cy/Flu VZV, s e p tic a e m ia Alive a n d well 63 24 CML BM MUD Cam /Cy/Flu/TBI P. aeruginosa, CMV Alive, re la p s e d

7 27 CML BM MUD Cam /Cy/Flu/TBI MRSA, C N S, HHV6 Alivet]) 183 29 CML BM MUD Cam /Cy/Flu/TBI S e p tic a em ia, CMV Died (se p tic ae m ia )

44 30 SAA PB sib lin g C am /Cy/Flu T u b e rc u lo s is Alive a n d well 2 8 32 CALL PB sib lin g Cy/TBI C N S Died (relap se) 21 32 AML Ml BM Mis-UD Cam /Cy/Flu/TBI CMV, C N S, Candida^, P.

aeruginosa, Citrobacter, PC P Died (relap se) 152 37 CML PB MUD Cam /Cy/Flu/TBI S. aureus, H. infiuenzae,

CMV, MRSA

Alive, re so lv e d cGVHD 2 9 37 AML PB sib lin g Bu/Cy - Alive a n d well 59 37 AML PB MUD C am /C y/Flu/B u C N S, HHV6 Alive, cGVHD 151 38 AML-M2 BM sib lin g Cy/Flu/TBI CMV Alive, re so lv ed

cGHVD Alive a n d well 23 38 AML M2 PB sib lin g Cam /Flu/B u -

24 38 AML M4 PB sib lin g Cy/TBI CMV, a d e n o v iru s Died, (h ae m o rrh a g e ) 3 39 ALL PB sib lin g Mel/TBI B eta-h ae m o ly tic

Streptococcus

Alive, cGVHD 31 4 0 CML PB c o u s in Bu/Cy - Alive a n d well 34 4 0 CML PB c o u s in Bu/Cy - Alive a n d well 178 4 5 AML-M5 PB sib lin g Cam /Cy/Flu/TBI CMV, VZV Alive a n d well 4 7 4 5 MM PB sib lin g Cy/TBI - Alive a n d well 112 4 7 MDS PB sib lin g Bu/Cy CMV Alive a n d well 171 50 AML BM sib lin g Bu/Cy CMV Alive a n d well 33 50 ALL PB c o u s in Cy/TBI VZV, e n ce p h a litis Alive a n d well 104 50 NHL PB sib lin g Cy/TBI S. aureus (eye) Alive, cGVHD 122 50 MM PB sib lin g Cy/TBI CMV, s e p tic a e m ia Died, cGVHD 22 53 AML P B sib lin g Cy/TBI CMV Alive a n d well

* FA = Fanconi anaem ia, A LL = acute lym p hocytic leukaem ia, A M L = acute m yeloid leukaem ia, S A A = sev ere aplastic an aem ia, CM L = chronic m yeloid leukaem ia, cA L L = com m on acute lym p hocytic leukaem ia, M D S = m yelod ysp lastic syndrom e, N H L = non -H odgk ins lym p hom a, PNH = paroxysm al nocturnal haem oglobinuria, M M = m u ltiple m yelom a.

oc D onors w ere either H L A -m atch ed related (siblings or cou sin s), H L A -m atch ed unrelated (M U D ) or H L A -m ism atch ed unrelated (M is-U D ).

** Conditioning: Cy = cyclop h osp h am id e, TBI = total body irradiation, T A I = th oraco-ab dom in al irradiation. Flu = fludarabine, Bu = busulphan, M el = m elphalan. Cam = Campath.

# In fection s, i.e. bacteraem ia and pn eu m onia, virus reactivation s/in fection s occu rin g within the first year after stem c e ll transplant. V Z V = va ricella zoster virus; C M V = cytom egalovirus; M RSA = m ethicillin/m ulti resistant S ta p h y lo c o c c u s a u r e u s \ C N S = cosigu\ase n e g a t\\e S ta p h y lo c o c c u s s p p .\ H H V 6 = Human Herpes V irus-6, P se u d o m o n a s a eruginosa', PCF =

P n e u m o c y s tis p n e u m o n ia , § Oral C andidiasis.

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Table 4.2: T-cell related clinical data

UPN T-Cell Depletion* Donor leukocyte Infusion** T-cell dose# Acute GVHD?t Chronic

GVHD prophylaxiscj) Additional Post-Tx Immune suppression 37 N N 0 .4 3 1 N CsA j/M tx N 25 N N 1.48 N N C sA „ N 26 N N 1.48 N N C sA, 2 N 12 N N 0 .1 9 1 N CsA^/Mtx N 35 Y N TCD N N TCD /CsA j N 20 N N 0.0 9 N N CsA,2/Mtx N 9 N N 0.3 9 N N C sA, 2 N 39 N N 2 .8 7 1 E C sA /M tx FK506=c, s te r o id s ^ 46 Y N TCD N N M yco°c/Mtx N 63 Y 8M, 12M TCD N N TCD N 7 Y 19M, 22M TCD N N TCD N 183 Y N TCD N N TCD s te r o id s 44 Y N TCD N N CsA,2/Mtx N 21 Y N TCD 1 L TCD/CsA,2 stero id s 28 N 7 M 1.40 N N C sA /M tx N 152 Y N TCD 1 E TCD s te r o id s 29 N N 1.37 N N C sA N 59 Y N TCD II L TCD s te r o id s 24 Y N TCD 1 E TCD ste ro id s, PUVAvy 151 N N 1.45 II E CsA^/Mtx s te r o id s 23 N 8M 1.72 N N CsA^/Mtx N 3 N N 1.75 N L C sA /M tx s te r o id s 31 N N 1.80 N N C sA N 34 N N 2 .6 0 N N C sA N 4 7 Y N TCD N N TCD N 178 Y N TCD N N C sA , N 112 N N N/A II N C sA /M yco N 171 N N 1.07 N N C sA /M y co N 3 3 N N 3 .5 6 N N C sA /M yco N 122 Y N TCD N E TCD s te r o id s 104 N N 3 .4 5 1 E C sA /M tx stero id s 22 N 6M 2 .6 2 N N C sA /M tx N * T -cell d ep letio n (T C D ) w as ca rried ou t ac co rd in g to C am p ath U sers P ro to co l N o .4 (C a m p a th -IH "In th e b ag ", w ith in -v iv o p r e ­ tra n sp la n t C a m p a th -IH ).

** 5 p atients receiv ed D LI w ithin the tim e fram e o f this study.

# T -cell dose is show n as CD3* ce lls infusedxlO V kg. T -cell dose in recip ien ts o f a T -cell d ep leted (T C D ) d o n o r p ro d u c t was d e f i n e d as “ u n k n o w n ” .

G V H D ; A cute G V H D w as defined as g rad e I-IV ; C h ro n ic G V H D w as defined as L = L im ited o r E = E xtensive; N = no clinical G V H D . $ G V H D p ro p h y lax is: C y clo sp o rin A (C sA ) w as ad m in iste red on D ay -1 and p atien ts rem ain ed on C sA fo r a p e rio d o f 3 ( C s A ,) o r 12 (C s A ,,) m onths; M eth o trex ate (M tx) w as ad m in iste red on day s +1, +3, and +6.

oc P atien t su ffe re d allerg ic reactio n to C sA and w ere p laced on e ith e r F K 5 0 6 o r M y co p h e n o la te (M y co ) as a lte rn a tiv e im m u n o s u p p r e s s iv e th e ra p y .

= P atien ts u n d erg o in g e p iso d e s o f e ith e r acu te o r ch ro n ic G V H D w ere tre ated with one o r m ore o f the follow ing: P r e d n i s o l o n e , M eth y lp re d n is o lo n e , M y co p h en o late, w ith a d d itio n a l im m u n o su p p ressio n u sin g C sA as d ee m ed a p p ro p ria te by th e clin ic ian \|/ A d d itio n al G V H D th e rap y in c lu d e d P so ra le n A ctiv ated U ltra v io le t A p h o to th e ra p y ( P U V A ) .

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