Journal of Hematology - Supplements - Haematologica
Journal of Hematology - Supplements - Haematologica
Journal of Hematology - Supplements - Haematologica
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14<br />
fact the common feature <strong>of</strong> these protocols is<br />
that intensive short-term immunosuppression is<br />
performed in order to induce host tolerance<br />
against donor cells which in turn enable a potent<br />
GVL effect by large numbers <strong>of</strong> donor-derived<br />
immunocompetent T-cells. GVL is then enhanced<br />
by subsequent DLI, if needed.<br />
Here below we report the conditioning regimens<br />
adopted by most Institutions.<br />
Condition regimens<br />
Hadassah University Hospital (Jerusalem). The basic<br />
protocol is fludarabine (30 mg/m 2 /d for 6 consecutive<br />
days), oral busulfan 4 mg/kg/d for 2<br />
consecutive days and anti-T-lymphocyte globulin<br />
ATG (5-10 mg/kg/d Fresenius for 4 consecutive<br />
days). This schedule has been subsequently modified<br />
in selected patients with genetic disease or<br />
aplastic anemia in that busulfan was substituted<br />
by cyclophosphamide, or low dose TBI in single<br />
dose (200 cGy).<br />
MD Anderson (Houston). Fludarabine 30 mg/<br />
m 2 /d and Ara-C 2 g/m 2 /d for 4 days, idarubicin<br />
12 mg/m 2 /d for 3 days. Patients previously<br />
exposed to fludarabine received Ara-C 1 g/m 2 /d<br />
and 2-CDA at a dose <strong>of</strong> 12 mg/m 2 /d for 5 days.<br />
Fred Hutchinson (Seattle). Low-dose TBI (200<br />
cGy) in a single dose.<br />
Ospedale San Martino (Genoa). Thiothepa 10<br />
mg/kg 1 dose, then cyclophosphamide 50<br />
mg/kg/d for 2 days.<br />
Another approach based on autografting followed<br />
by non-myeloablative allograft was proposed<br />
in alternative to this protocol. In this case<br />
conditioning includes fludarabine 30 mg/kg/d<br />
and cyclophosphamide 300 mg/m 2 /d for 3 days.<br />
San Raffaele Hospital (Milan). Thiothepa 5 to 15<br />
mg/kg according to the age <strong>of</strong> the patient, fludarabine<br />
60 mg/m 2 and cyclophosphamide 60<br />
mg/kg. Infusion <strong>of</strong> engineered lymphocytes<br />
(thymidine kinase gene) in subsequent weeks was<br />
planned.<br />
Harvard Medical School (Boston). Cyclophosphamide<br />
50 mg/kg/d for 4 days and thymic irradiation.<br />
University Hospital Carl Gustav (Dresden). Busulfan<br />
3.3 mg/kg/d i.v. or 4 mg/kg/d p.o. for 2 days<br />
and fludarabine 30 mg/m 2 /d for 5 days.<br />
In order to infuse a higher number <strong>of</strong> CD34 +<br />
cells and T-lymphocytes, peripheral blood stem<br />
cells were used in most cases. In some cases bone<br />
harvest and in a few patients cord blood were<br />
used as the stem cell source. GVHD prophylaxis<br />
consisted <strong>of</strong> cyclosporinA (CSA), CSA and a<br />
short course <strong>of</strong> methotrexate (MTX), CSA and<br />
methylprednisolone, CSA and m<strong>of</strong>etil mycophenolate<br />
(MMF). CSA administration was planned<br />
for a shorter period <strong>of</strong> time compared to standard<br />
protocols and then modulated according<br />
to GVHD severity.<br />
In most cases the donors were matched siblings,<br />
but cases <strong>of</strong> unrelated donors have been<br />
described. Some cases <strong>of</strong> 1-3 locus mis-matched<br />
transplants are reported.<br />
These heterogeneous conditioning regimens<br />
were employed in different settings <strong>of</strong> patients. In<br />
the first experiences these protocols were suggested<br />
for patients aged more than 50-55 years<br />
and therefore not eligible for conventional transplant,<br />
or for heavily pre-treated younger patients<br />
with reduced performance status or who had<br />
relapsed after a first autologous or allogeneic<br />
transplant. 10,19-20,21,27-29 Conversely the Hadassah<br />
team explored these transplants also in patients<br />
eligible for standard treatment and in non-malignant<br />
diseases. 10,32-34,37,40,41 These wide differences<br />
make the comparison <strong>of</strong> data and results from<br />
various reports difficult; furthermore it must be<br />
remembered that these results emerge from pilot<br />
and ongoing studies with a short follow-up.<br />
Results and Conclusions<br />
Based on cumulative experience reported in the<br />
literature it may be argued that allogeneic nonmyeloablative<br />
regimens are much better tolerated<br />
than standard protocols, leading to a similar<br />
or even lower toxicity than conventional<br />
chemotherapy, improving quality <strong>of</strong> life and cost<br />
effectiveness. 25,27,28<br />
Limited non-hematologic and hematologic toxicity<br />
and faster recovery compared to those produced<br />
by standard protocols were observed in<br />
almost all cases. Similarly, transfusional support<br />
and antibiotic administration as well as time<br />
spent in hospital were reduced in the majority <strong>of</strong><br />
recipients <strong>of</strong> non-myeloablative regimens compared<br />
to in recipients <strong>of</strong> standard transplants.<br />
Engraftment and stable full or mixed chimerism<br />
were observed in about 90% <strong>of</strong> patients receiving<br />
either HLA-identical or mis-matched transplants,<br />
but this percentage reached 100% in some studies.<br />
Interestingly it has been well documented that<br />
host-derived cells may slowly disappear leading to<br />
complete chimerism development. This confirms<br />
that once a state <strong>of</strong> tolerance is achieved, donor<br />
cells engraftment is progressively able to replace<br />
normal and malignant cells through a non-clinical<br />
GVH reaction. Lasting mixed chimerism was<br />
observed also in haplo-identical settings. 10,12,13,27,28<br />
Concerning the control <strong>of</strong> underlying disease,<br />
results should be carefully reviewed in consideration<br />
<strong>of</strong> the advanced stage <strong>of</strong> disease in most<br />
patients, the heterogeneity <strong>of</strong> the cases and the<br />
relatively short follow-up. Preliminary results<br />
confirm that non-ablative regimens may control<br />
the neoplastic disease also in advanced stage,<br />
but, albeit encouraging results, recurrence <strong>of</strong> disease<br />
remains the most important cause <strong>of</strong> trans-<br />
haematologica vol. 85(supplement to n. 11):November 2000