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

12 th Congress of the European Hematology Association
1444
PROGNOSTIC FACTORS IN SECOND-LINE THERAPY FOR AGGRESSIVE NON-HODGKIN'S
LYMPHOMA
M. Stein, Z. Chameisi
Rambam Health Care Campus, HAIFA, Israel
Background. Seventy percent of patients with advanced, aggressive
non-Hodgkin’s lymphoma [NHL] can achieve complete remission following
1st line treatment, although about half of these patients will
relapse and will be treated with a 2nd line regimen. There are various
studies concerning the importance of initial prognostic factors for the
outcome of treatment and for the creation of an International Prognostic
Index. Aims. The purpose of this study was to define prognostic factors
for various outcome parameters (complete remission, time to tumor
progression, survival) in patients with persistent/recurrent aggressive
NHL undergoing 2nd line chemotherapy and their implementation in the
therapeutic decision planning. Methods. This was a retrospective study
of 70 patients (30 males, 40 females) ranging in age from 18-86 years
(mean: 54 years) with recurrent (following complete remission) or persistent
(primary refractory) aggressive NHL who were treated with
CHOP (cyclophosphamide, adriamycin, vincristine, dexamethasone -
conventional or high dose) as 1st line treatment. Second-line treatment
included DVIP (cisplatin, VP-16 (etoposide), ifosfamide, dexamethasone),
DAIP (cisplatin, VP-16, cytosine-arabinosid, dexamethasone) or
DVIP-high dose methotrexate regimen. All patients had a follow-up of
at least 1 year from the start of their salvage regimen. Results. The following
parameters were analyzed for their influence on complete remission
(CR) rate, time to tumor progression (TTP) and survival: performance
status (PS),B symptoms, bulky disease, lactate dehydrogenase
(LDH), hemoglobin and albumin levels, location/number of nodal and
extranodal sites, and splenic involvement. CR was achieved in 46% and
partial remission in 28% of patients. Median TTP and survival were 6
months and 10 months, respectively. The following parameters were
associated with better TTP: high-dose chemotherapy (HD-CT), higher
hemoglobin level at the onset of 2nd line treatment, and splenic involvement
at initial diagnosis. Improved survival was associated with HD-CT,
good PS before introduction of 2nd line chemotherapy and splenic
involvement at initial diagnosis. Longer duration of CR following 1st line
chemotherapy and higher initial hemoglobin level at initial diagnosis
predicted higher CR rate with 2nd line chemotherapy. Conclusion.
Assignment (or classification) of various risk factors in aggressive, recurrent
or therapy-refractory NHL might have paramount importance in
treatment decision making. Patients with poor predictive factors should
be treated with a more intensive treatment schedule, such as HD-CT
with bone marrow or peripheral blood stem cell support.
1445
PNEUMONITIS AND RENAL TOXICITY WITH SIROLIMUS BASED GVHD PROPHYLAXIS
FOR RIC ALLOGENEIC HSCT
A. Bryant, J. Moore, A. Dodds, S. Milliken, K. Fay, D. Ma
St Vincent’s Hospital, SYDNEY, Australia
Background and Aims. A challenge with reduced intensity conditioning
(RIC) allografting is to adequately manage acute graft versus host disease
(aGVHD) without negating a graft versus leukaemia/lymphoma
(GVL) effect. Previous studies (Antin et al.) suggest reduced rates of
aGVHD with sirolimus based GVHD regimens. The aim was to assess
sirolimus based GVHD prophylaxis in RIC HSCT in a single transplant
centre. Methods. The RIC included fludarabine 30 mg/m2 x5 and melphalan
140 mg/m2 x1. Intravenous Tacrolimus was administered at 0.02
mg/kg daily, oral sirolimus 1mg daily (for 28 days) and methotrexate 5
mg/m2 (days 1,3,6 and 11). Sirolimus dose was reduced to account for
our use of azole antifungal prophylaxis. After the first 15 patients,
tacrolimus was substituted with intravenous cyclosporin (1 mg/kg daily)
because of renal toxicity and difficulties with drug monitoring and
dosing. Results. Twenty-five consecutive patients with median age of 54
(37-67) and high risk features were enrolled. 13 had matched unrelated
donors and 12 sibling donors. 72% of the patients survived at a median
follow up of 351 days (70-1056). Median relapse free survival was 351
days (49-1055) and overall survival 356 days (70-1057). Seven died (4 sepsis,
3 relapsed disease). 15/25 is alive in complete remission and 3/25 is
alive with relapsed disease. Transplant related mortality at 100 days was
8%. Grade 2-4 GVHD was seen in 11 of 13 (85%) unrelated donor RIC
HSCT and 2 of 12 (17%) sibling HSCT. Toxicity from this regimen
included renal impairment (13), thrombotic thrombocytopaenic purpura
(3) and pneumonitis (2). Renal impairment was a major management
516 | haematologica/the hematology journal | 2007; 92(s1)
problem in 13 patients with two requiring temporary renal dialysis. The
two patients who developed sirolimus related pneumonitis required a
temporary period of mechanical ventilation. Conclusions. This pilot study
found that sirolimus based GVHD prophylaxis in RIC HSCT led to low
transplant related mortality at 100 days with acceptable relapse free and
overall survival for this poor risk group of patients. Secondly, the introduction
of sirolimus did not significantly reduce rates of aGVHD in unrelated
RIC HSCT. Thirdly, the combination of sirolimus and a calcineurin
inhibitor resulted in significant toxicity. Finally, to our knowledge, this
is the first report of sirolimus associated pneumonitis in bone marrow
transplant patients, which has only been reported in solid organ transplant
literature.
Reference
1. Antin, J. etal. Sirolimus, tacrolimus, and low dose methotrexate for graftversus-host
disease prophylaxis in mismatched related donor or unrelated
donor transplantation. Blood. 2003;102:1601-1605.
1446
SEVERE HYPOXIA ENHANCES EX VIVO HAEMATOPOIETIC EXPANSION UNDER CLINICAL
GRADE CONDITIONS
M.P. Mariani, 1 A. Taddei, 1 F. Bambi, 1 M.G. Gelli, 1 S. Giuntoli, 2
M.G. Cipolleschi, 2 P. Dello Sbarba2 1 Azienda Ospedaliera Universitaria Meyer, FIRENZE; 2 Department of Experimental
Pathology and, FIRENZE, Italy
Background. Haematopoietic cells isolated from bone marrow or mobilized
peripheral blood, to become suitable for therapeutical haematopoietic
reconstitution, often require to be expanded ex vivo. Enhancement
of stem cell self-renewal is the natural issue of such a procedure, as an
increased number of stem cells is a key factor in the overall numerical
expansion of the explanted cell population. In a number of studies carried
out over the last 15 years, we demonstrated that very low oxygen
tensions in vitro (severe hypoxia) help to preserve the stem cell potential
within haematopoietic cell populations obtained ex vivo (Blood 82:2031-
2037, 1993; Leukemia 14:735-739, 2000). Severe hypoxia was shown to
influence the balance between stem cell differentiation commitment
and self-renewal in favour of the latter and to restrain the effects of
cytokines boosting commitment and clonal expansion (Exp. Hematol.
30:67-73, 2002). Aims. The target of this study was the development of
protocols for the in vitro expansion of haematopoietic potential under
good medical practice (GMP) conditions, suitable for clinical use. Serumfree
incubation media were therefore used, supplemented with a combination
of stem cell-active cytokines, to incubate explanted
haematopoietic populations in order to compare their in vitro expansion
under severe hypoxia with that in normoxia. Methods. Cells were
obtained from mobilized peripheral blood of 3 donors. CD34 + cells were
isolated from buffy-coat by the Miltenyi Biotec indirect immunomagnetic
technique, using for the first passage the midi column and for the
second the mini column. Cells were then analysed by flow cytometry
using anti-CD34,-CD133, -CD61, -CD3, -CD19 antibodies. The purity
of the isolated CD34 + cells was 35-75%. Cells were cultured in the HP01
medium (MacoPharma), in the presence of the FKT6 cytokine combination,
including Flt3-ligand, Stem Cell Factor/Kit-ligand, ThromboPoietin
and Interleukin-6. Incubation under severe hypoxia (0.1% O2) was carried
out in a water-saturated Ruskinn Concept 400 anaerobic incubator,
flushed with a preformed gas mixture (0.1% O2, 5% CO2, 95% N2);
incubation in normoxia (21% O2) was carried out in a 5% CO2, 95%
air, water-saturated atmosphere. Culture expansion was measured after
14 days of incubation, with respect to either the overall number of viable
cells or the number of colony-forming cells (CFC), as determined following
cell transfer to secondary FKT6-supplemented MethoCult (StemCell
Technologies Inc.) semisolid cultures and a further 7-day incubation
therein, in any case in normoxia. Results. Haematopoietic expansion in
hypoxia was 2.8-fold higher than in normoxia as determined by counting
the overall number of viable cells, and 3.5-fold higher as determined
by counting the number of CFC. Conclusions. In the presence of the FKT6
cytokine combination, incubation in severe hypoxia resulted an efficient
method to markedly improve the expansion of haematopoietic
cell populations under clinical grade conditions.