12th Congress of the European Hematology ... - Haematologica

12 th Congress of the European Hematology Association
ly cured by allogeneic hematopoietic stem cell transplantation. Since
CLL affects predominantly older people, there is a need for some lowtoxicity
conditioning with, on the other hand, strong anti-leukemia
activity. Since there are very encouraging results with busulfan + F conditionings
in myeloid malignancies, and since the clinical study with
the combination treatment with CHL + F was stopped prematurely for
myelotoxicity, we hypothesized, that this CHL + F combination might
have the potential as a good conditioning for high-risk lymphoid malignancies.
Aims. To test the CHL + F combination in vitro and in vivo (rats)
for anti-leukemia effects and for toxicity. Methods. In vitro cell viability
testing: DHL-4 (mut-p53), DOHH2 cell lines (wt-p53), and three B-CLL
primary cultures (two wt-p53 and one mut-p53) were used for WST-1
viability assay. Animal experiments: Male Wistar rats were used for all
experiments. First, the maximal tolerated dose (MTD) of either drug
was tested. For F, doses of 0.75 - 60 mg/kg/d were used, and for CHL,
doses of 0.15 - 50 mg/kg/ were used, all administered for 5 days. Then,
the combination treatment was tested: 1) F+CHL, 2) F followed by CHL,
3) CHL followed by F; all drugs were administered for 5 days. Results. In
vitro testing: Cell lines testing did not reveal significant differences
between simultaneous vs. sequential drug applications. The combination
treatment of CLB and FLU caused a prominent decrease of viability
in p53-mut cells compared to individual drugs alone both for cell lines
and for B-CLL cells, which can have significant clinical importance. Animal
experiments. For F alone, the MTD has not been reached. Clinically,
the rats tolerated well even the highest doses. Moreover, no myelotoxicity
was seen. However, histological examination found pneumotoxicity,
hepatotoxicity, nephrotoxicity, and gastrointestinal toxicity. For
CHLB alone, the MTD is about 40-50 mg/kg/d. Pneumotoxicity, nephrotoxicity,
gastrointestinal toxicity, and mild myelotoxicity was seen.
Combination treatment tested fixed dose of F (3 mg/kg/d) and three
doses of CHL (1, 2, and 4 mg/kg/d). Clinically, the combination tolerated
at best was F followed by CHL. Myelotoxicity was mild, usually
affecting predominantly lymphocytes, and interestingly, was most pronounced
in the clinically best tolerated regimen. Conclusions. Rats can tolerate
extremely high doses of F and CHL. Based on these experiments,
for further development, hopefully into the clinical usage, we could recommend
administration of fludarabine, followed by chlorambucil. This
combination will be further tested together with monoclonal antibodies
and total lymphoid irradiation.
Supported by Research Grant MSM 0021622430 and IGA MHCR n.
8445-3/2005.
0452
HAEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) FOR HIGH RISK REFRACTORY
MULTI SYSTEM LANGERHANS CELL HISTIOCYTOSIS (MS-LCH) IN CHILDREN
M. Caniglia, 1 R.M. Pinto, 1 I. Rana, 1 A. Lombardi, 1 M. El Hachem, 1
F. Zinno, 1 G. Isacchi, 1 W. Arcese, 2 G. De Rossi1 1 2 Bambino Gesù Children's Hospital, ROME; Hematology Tor Vergata University,
ROMA, Italy
Background/Aims. LCH is a heterogeneus proliferative disease varying
between a reactive or a neoplastic process. The Histiocyte Society Working
Group identified a single system LCH as usually associated with a
favourable prognosis, while multisystem LCH as an extremely variable but
aggressive clinical course. The LCH-II Study showed that response to initial
therapy is a powerful prognostic predictor; MS-LCH patients nonresponders
after 6 weeks of initial therapy, have extremely poor prognosis
with only 17% of survival at 3 years. The high rate of mortality in this
latter subgroup justifies an early switch to salvage approaches; HSCT has
been indicated as an alternative salvage therapy. Myeloablative conditioning
regimens were associated with a high treatment-related morbidity
and mortality while Reduced Intensity Conditioning regimen, recently
reported by an Histiocyte Society Study, has an increased risk of nonengraftment
and graft rejection. Methods. Here we describe four consecutive
refractory MS-LCH paediatric patients diagnosed and treated at the
Haematology Department of Bambino Gesù Children's Hospital. All
patients were males with a median age at diagnosis of 9 months (4-25
months). All received first-line LCH therapy according to the study protocol
LCH-II or LCH-III and all experienced severe disease progression,
unresponsive to chemotherapy. All patients recived allogeneic HSCT at
median of 38 months after diagnosis (10-72 months). Stem cell source was
HLA-matched sibling donor in two cases and unrelated cord blood (CB)
donor (1 and 2 HLA mismatched antigens) in the remaining two. Conditioning
regimen included oral Busulfan (16 mg/kg) + Fludarabine (120
mg/m 2 ) in 4 days + Thyotepa (10 mg/kg) for 1 day. GvHD prophylaxis
consisted of Cyclosporine, horse Antilymphocyte Globulin and Methylprednisolone.
Results. Median time to neutrophil engraftment was 43 days
168 | haematologica/the hematology journal | 2007; 92(s1)
(14-99 days), while platelets engraftment was 136 days (19-437 days). All
patients reached full donor chimerism at day 25, 24, 25, 41 respectively,
which persisted until the last follow-up. Three patients presented acute
GvHD (two patients grade II, with skin involvement and one grade III,
with skin and gut involvement). Long term follow-up showed a peculiar
recovery from the underlying disease. In the post transplant period no
additional therapy specific for LCH was administered to any patient. Conclusions.
The literature reports enlist only 38 LCH patients who underwent
HSCT. Therefore, even if limited to 4 patients, our prospective unicentric
contribute could be significant to consider: HSCT is a good salvage
approach for resistant LCH patients with MS organ involvement unrelated
CB is a reliable alternative option in high-risk patients lacking sibling
donor. By using an immune-myeloablative conditioning regimen, all
patients obtained a full stable engraftment with no TRM even if a diffuse
disease was present at moment of HSCT and regardless of the stem cell
source . Acute GvHD did not exceed grade III. At the time of last followup
(median 1470 days; range 990-1920), all patients are still alive in
absence of active LCH disease (Lansky scale> 90%).
Table 1. HSCT characteristics and results.
Pts HSCT/HLA Number of Stem Engrafment a/c F-up LCH
mathc donor Cell transplanted GVHD
1 MSD NC/kg 3.578×10 8 PMN⇒g+33 II grade 58 m NAD
HLA Hydentical CD34+/kg 14.4×10 6 PLTS⇒g+50 (Skin) 1740 days
VNTR⇒Full Alive
donor+25
2 MSD NC/kg 7.6×10 8 PMN⇒g+14 0 33 m NAD
HLA Hydentical CD34+/kg 9.6×10 6 PLTS⇒g+19 990 days
VNTR⇒Full Alive
donor+24
3 U-CBT NC/kg 5.5×10 7 PMN⇒g+29 II grade 33 m NAD
HLA 5/6 CD34+/kg 7.5×10 6 PLTS⇒g+19 (Skin Gut) 990 days
1-1 class Ag VNTR⇒Full Chronic Alive
m.matched donor+25 (Skin Lungs)
4 U-CBT NC/kg 11.0×10 7 PMN⇒g+99 II grade 64 m NAD
HLA 4/6 CD34+/kg 2.5×10 6 PLTS⇒g+437 (Skin) 1920 days
1-1 class Ag VNTR⇒Full Alive
m.matched donor+70
UCBT: Umbelical Cord Blood transplantation; MSD: Matched Sibling Donor; NAD: Non Active Disease
0453
CHRONIC KIDNEY DISEASE AFTER MYELOABLATIVE ALLOGENEIC HEMATOPOIETIC STEM
CELL TRANSPLANTATION
S. Kersting, R.J. Hené, H.A. Koomans, L.F. Verdonck
UMC Utrecht, UTRECHT, Netherlands
Background. Because many recipients of hematopoietic stem cell transplantation
now have long term survival, late complications become more
important. Chronic kidney disease is a complication that is not wellestablished
after stem cell transplantation. Aims. The aim of this study
was to determine incidence of chronic kidney disease in recipients of
allogeneic stem cell transplantation with a long follow up, and to determine
baseline factors, complications and mortality associated with
chronic kidney disease. Methods. We performed a single centre retrospective
cohort analysis on 271 adult patients that received a hematopoietic
stem cell transplantation between 1993 and 2004 and survived for
more than 6 months. All patients had a myeloablative conditoning regimen
that consisted of cyclophosphamide (60 mg/kg/day for two days),
followed by total-body irradiation (600 cGy/day for two days) with partial
shielding of the lungs (total lung dose 850cGy) and partial shielding
of the kidneys (500 cGy/day for 2 days). Follow up was through February
2006. Primary outcome was the incidence of chronic kidney disease
defined as a glomerular filtration rate (GFR) of < 60 mL/min/1.73 m2 , calculated
using the Modification of Diet in Renal Disease (MDRD) study
equation. Results. Chronic kidney disease developed in 62 (23%) of 271
patients. Severe kidney disease (GFR of < 30 mL/min/1.73 m2) developed
in 8 (3%) of 271 patients, of which 2 patients needed dialysis. Factors
associated with chronic kidney disease were lower GFR (p