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Complications after nonmyeloablative stem cell
transplantation in acute leukemias
G. Massenkeil, I. Genvresse, G. Reich, P.
leCoutre, S. Rackwitz, B. Dörken, and R. Arnold
Dept. of Hematology and Oncology, University
Hospital Charité, Campus Virchow-Klinikum,
Berlin, Germany
Introduction NST has extended the indications
for allogeneic SCT to patients considered
ineligible for standard high-dose conditioning
because of advanced age, poor performance status
or intensive pretreatment including previous stem
cell transplantation. The expectations to NST
were high, hoping that the high morbidity of
standard high-dose radio- and chemotherapy could
be reduced by less intensive conditioning and
lower rates of GvHD and infections. Data on
infections after NST have mainly focussed on
patients with CML, NHL and multiple myeloma
(Bornhäuser 2001, Chakraverty 2002, Mohty 2000,
Mossad 2001). A high rate of bacterial and
CMV-infections was observed in these patients,
which often came apparent late after granulocytic
reconstitution (Junghanss 2002). Only single
patients with ALL and AML have been included in
these studies. We herein report on infectious
and non-infectious complications after NST in a
larger series of patients with high-risk ALL and
AML.
Results Infections during initial
hospitalisation Grampositive sepsis 2 (2 x
staph. epidermidis) Gramnegative
sepsis 4 (ent. faecium, ent. faecalis, 2 x e.
coli) Fever of unknown origin 6 Catheter-relat
ed infections 3 (1 x staph. epidermidis) Progre
ssive fungal pneumonia 2 CMV-infection 7
(antigen pos. 4/7) Infections after
dismissal Pneumonia 2 Pneumonia
meningitis 1 (strep. pneumoniae) Sepsis
1 (fatal) GvHD Acute GvHD 13 / 25
(52) Akute GvHD III-IV 10 / 25
(40) Chronic GvHD 11 / 15 eval.
(73) Chronic extensive GvHD 7 / 15 eval.
(47) Onset of acute GvHD was 83 days after
NST (range 9-97 days). In only 3 patients was the
onset of acute GvHD before day 55, all three had
CSA stopped or changed to oral application
because of suspected early relapse (2/3) or
incompatibility (1/3). Outcome Patients were
dismitted from the hospital 30 days in median
after NST (22-45). 15 patients were readmitted at
a later time point, 8/15 patients because of
relapse and 7/15 because of transplant-associated
complications, namely graft failure (n1),
infection (n4), GvHD (n2). After a median
follow-up of 288 days (95 C.I., 40-536 days)
overall survival at 1 year was 47 (figure 1).
Actuarial disease-free survival in CR is 44
(11/25 patients). 13/25 pts (52) have died from
relapse. TRM is low with 4 (1/25 patients).
Patients and Methods 25 patients with ALL (n9)
and AML (n16) underwent NST from HLA-identical
donors between March 1999 and June 2002. 16/25
pts (64) had uncontrolled leukemia before
NST. Patients characteristics Median age,
years (range) 43 (19-67) Male / Female 16
/ 9 Status of disease at NST 1.CR / 2.CR
/uncontrolled disease 7 / 2 / 16 Donor Related /
Unrelated 17 / 8  Stem cell source peripheral
blood / bone marrow 23 / 2  GvHD-prophylaxis  CSA
/ CSA MMF 22 / 3    Contraindications
against standard conditioning additional
infections Age gt 50 years
7 4/7 Relapse after standard SCT
6 Intensive radiotherapy 2 1/2 Severe
preceding infections 9 Repeated subdural
bleeding 1 ( 7 pneumonia, 2 systemic
candidiasis) Eight patients with residual
infections on CT-scan before NST received
antifungal therapy starting with conditioning
therapy until hematopoietic reconstitution. The
preparative regimen consisted of fludarabine (30
mg/m2, days -10 till -5), busulfan (4 mg/kg, day
-6 and -5) and anti-T-lymphocyte globulin (ATG)
(10 mg/kg, day -4 till -1) (Slavin 1998).
Patients were transplanted with 4.1 x 106 CD34
cells / kg body weight in median (range
2.1-19.8). Prophylactic DLI were given to 15/25
patients 61 days in median after NST (range
21-103 days). Patients underwent standard
prophylactic measures for selective gut
decontamination, against pneumocystis carinii,
and herpes simplex. CMV-negative blood products
were provided for CMV-seronegative
recipient-donor constellation.
Figure 1
Figure XXX
Results 22/25 patients engrafted after NST, 1
had a nonfatal graft failure and 2 reconstituted
with leukemia. Median time to neutrophil recovery
above 0.5/nl was 11 days (9-31). Platelets
exceeded 20/nl without transfusional support on
day 17 in median (0-42). Noninfectious
complications 2/8 patients developed a seizure
after busulfan despite anticonvulsive
prophylaxis serum sickness after ATG was
observed in 1 patient and systemic inflammatory
reponse syndrom (SIRS) after ATG in another. 2/8
patients developed compensated renal
insufficiency after amphotericin B. One patient
developed secondary insulin-dependent diabetes
mellitus while on glucocorticoids because of
chronic GvHD. One patient developed mental
depression after NST. Infections during
hospitalization for NST 8/25 patients (32) had
no infections besides stomatitis after NST and
were afebrile during the entire hospital stay.
Two patients with pneumonia and one with
hepatosplenic candidiasis diagnosed before NST
had clinical and radiologic progression of fungal
infections after NST despite antifungal therapy.
Conclusion NST can cure patients with advanced
ALL and AML. The risk of graft failure is low.
Patients, who were not considered candidates for
standard SCT because of preceding fungal
infections have a high risk of reactivation after
NST despite antifungal prophylaxis. The risk of
acute and chronic GvHD is high. GvHD typically
develops late after NST. However,
transplant-related mortality is low, especially
when considering the unfavourable characteristics
of the patients. NST can be performed in
patients with high-risk acute leukemias.
Infections and GvHD remain major problems after
transplantation, but can be managed by optimal
supportive care and intensive surveillance.