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  • 1
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 21, No. 7 ( 2015-07), p. 1230-1236
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
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  • 2
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 5139-5139
    Abstract: Donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation induce complete remissions in 70 to 80% of patients with relapsed CML in chronic phase, but some patients do not respond sufficiently to DLI. We studied chimerism in subsets of immune cells in relation to the induction of alloreactivity. T cells and two subsets of DC (blood precursor myeloid dendritic cells [MDC] and blood precursor plasmacytoid dendritic cells [PDC] ) were isolated from 15 relapsed CML-patients shortly before DLI for chimerism analysis. Furthermore, the absolute blood counts of DC-subsets were determined. Based on chimerism we identified three groups. Group 1 (4 patients) was complete donor chimeric in T cells and DC-subsets. These patients had an early stage of relapse and 3 of 4 patients attained a complete molecular remission (mCR) without significant GVHD. Group 2 (6 patients) was complete donor in T cells and mixed chimeric in DC-subsets. Median percentage of recipient MDC in 4 patients with mixed chimerism was 67% (range, 36%–72%). One patient was complete donor and one patient complete recipient chimeric in MDC. Median percentage of recipient PDC was 37% (range, 18%–58%) in 5 patients with mixed chimerism and in 1 patient PDC were complete recipient derived. All patients entered mCR, however in combination with GVHD in 4 and bone marrow hypoplasia in 3 patients. Group 3 (5 patients) had mixed chimerism in T cells and complete recipient chimerism in MDC in 4 of 5 patients. Only 2 patients entered mCR. Absolute DC numbers at the time of DLI did not predict the induction of an allo-immune response, however very low numbers of MDC and PDC were associated with progressive disease and a poor outcome. The combination of donor chimerism in T cells and mixed chimerism in DC-subsets in advanced relapse is associated with the most potent GVL effect following DLI. GVL and GVHD are separated in patients with an early relapse and donor chimerism in both T cells and DC-subsets. Finally, absolute DC numbers do not predict the strength of the alloresponse.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 3
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 263-263
    Abstract: Donor lymphocyte infusions (DLI) have radically changed the prognosis of patients relapsing after allogeneic hematopoietic stem cell transplant (SCT) for chronic myeloid leukemia (CML). Major obstacles to success with DLI are represented by leukemia resistance and by secondary GvHD (GvHD2). The best result of is when a patient treated with DLI achieve a durable molecular remission without experiencing GvHD2. It is unclear which factors may predict for such a favourable outcome when CML patients are treated with DLI. We retrospectively identified 500 patients (59% males, median age 39 years, range 4–64), treated with DLI for CML relapse (81 molecular [16%], 150 cytogenetic [30%] , 211 hematological chronic [42%], and 58 hematological accelerated [12%] ) at 68 EBMT centers before 2004 with adequate information collected on disease response, GvHD2 and survival after DLI. Donor was an HLA-identical sibling in 73%, unrelated in 27%. DLI started with a cell dose 〈 2×107 CD3+ cells/Kg in 62% of the cases; 208 patients (42%) received 2 or more additional infusions of donor cells. Cumulative cell dose ranged from 1×105 CD3+ cells/Kg to 1.4×109 (median 7×107). Molecular remission and/or cytogenetic complete remission was achieved in 340 patients (68%) in a median of 7.5 months (95% within 41 months). GvHD2 occurred in 60% of patients at a median of 3 months from 1st transfusion of donor lymphocytes (95% within 24 months). Sixteen recurred at a median of 19 months (range 3–48). Actuarial probability of being alive and responsive to DLI without experiencing any GvHD2 was 29% (95% confidence interval [95CI] : 27–31%) and 27% (95CI: 24–30%) at 5 and 10 years after DLI, respectively. We studied the prognostic effect of following factors: patient age at DLI, donor type, donor sex, sex mismatch with the donor, phase at SCT, stem cell source, T-depletion, total body irradiation in the conditioning regimen, GvHD prior to DLI, interval from SCT to DLI, type of relapse. Multivariate analysis with a Cox model adjusted for the period of DLI (≤1997 vs 〉 1997), showed that chronic GvHD after transplant and prior to relapse (hazard ratio [HR]: 1.5, 95CI: 1.2–1.9, p 〈 0.001), an interval from SCT to DLI 〈 1 year (HR: 1.7, 95CI: 1.3–2.2, p 〈 0.001), and hematological relapse (HR: 1.6, 95CI: 1.2–2.0, p 〈 0.001), were adverse features. 94 patients (20%), 222 (48%), 133 (28%), and 17 (4%) had 0, 1, 2, and 3 adverse features, respectively. Survival in remission without experiencing GvHD2 at 5 years improved from 14%, 30%, to 56% in patients with 2–3, 1, and 0 adverse features, respectively. We conclude that:“pure” GvL effect (ie. durable remission without GvHD2) was observed in more than 25% of patients treated with DLI for CML relapsing after allogeneic SCT;occurrence of chronic GvHD prior to relapse, the interval from SCT to DLI, and the type of relapse are the main factors associated with the chance of a “pure” GvL effect;patients treated with DLI beyond 1 year from SCT for a molecular/cytogenetic relapse that was not preceded by chronic GvHD have more than 50% chance of exploiting the “pure” GvL effect.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 4
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3501-3501
    Abstract: Abstract 3501 Acute myeloid leukemia (AML) with translocation t(6;9)(p23;q34)/DEK-NUP214(CAN) rearrangement (t(6;9) AML) is a rare but well-characterized entity, associated to a poor prognosis. In this regard, a possible benefit of allogeneic hematopoietic stem-cell transplantation (alloHSCT) has been suggested, based on small series of patients. To investigate the potential role of alloHSCT for the management of t(6;9) AML we analyzed the outcome of patients with this AML subtype submitted to alloHSCT and reported to the ALWP, and compared it to other well-defined cytogenetic categories. Overall, we identified 74 patients (median age: 38, 18–65; 51% male) diagnosed with t(6;9) AML allografted since 1988 (median year of transplant: 2004). Most transplants were performed in complete response (CR1=56, 76%; CR2=8, 11%), whereas only a minority were performed in advanced phase (primary refractory, n=5; relapse, n=5). Donor was an HLA-identical sibling in 43 transplants (58%), and a matched unrelated donor in 24 (32%). Conditioning regimen consisted of a myeloablative regimen in most patients (n=61, 82%), and source of stem-cells was peripheral blood in 41 (55%) and bone marrow in 32 (43%). After a median follow-up of 51 months, 3-year leukemia-free survival (LFS), relapse incidence (RI), and non-relapse mortality (NRM) for patients allografted in CR1 was 51±7%, 19±6%, and 30±7%, respectively, whereas LFS for patients transplanted in other disease status was only 16±10% (p 〈 0.0001). A multivariate analysis performed among patients who received alloHSCT in CR1 identified a short interval CR-alloHSCT ( 〈 90 days) as the only favorable outcome for LFS (3-yr LFS: 57±10% vs. 51±7%; hazard ratio, HR=0.36, 95% CI:0.15-0.89; p=0.03) and NRM (47±11% vs. 17±8%; HR:3.84, 1.18–12.5; p=0.03), whereas reduced-intensity conditioning was followed by a higher RI (3-yr RI: 32±20% vs.17±6%; HR:4.86, 1.06–22.36; p=0.04). Moreover, the outcome of t(6;9) AML patients submitted to alloHSCT in CR1 was compared to that of patients with normal cytogenetics AML (NC-AML, n=2767) and poor cytogenetics AML (PR-AML, n=714) also allografted in CR1 in a multivariate analysis which included main prognostic variables. Interestingly, LFS and RI after alloHSCT of t(6;9) AML patients was similar to that observed in patients with NC-AML (51±7% and 58±1% for LFS, 19±7% and 23±1% for RI, respectively). On the contrary, the outcome of PR-AML was significantly poorer to NC-AML, with a 3-yr LFS and RI of 38±2% (p 〈 0.0001; HR=1.58, 1.39–1.82) and 41±2%, respectively (p 〈 0.0001; HR=2.09, 1.76–2.49; figure). In conclusion, alloHSCT in early phase resulted in a favourable outcome in patients with AML associated to translocation t(6;9), comparable to that of patients with NC-AML, suggesting that this procedure might overcome the adverse prognosis associated to this entity. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 5
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 19-19
    Abstract: Imatinib mesylate (IM) induces a high rate of cytogenetic remissions in first chronic phase CML, but molecular remissions are rare. A recent phase II study suggested a higher rate of molecular remissions upon treatment with 800 mg IM (Cortes et al. Blood 2004). Cytarabin (Ara-C) is an active drug in myeloid leukemias, especially when intensified dosages are applied. In-vitro studies of IM and Ara-C have been shown synergistic anti-proliferative effects. With the aim to prevent resistance and to induce an early, high rate of molecular remissions, we set out to evaluate the combination of IM and Ara-C in a dose-escalation study of consecutive cohorts treated with daily IM at dosages of 200 mg, 400 mg, 600 mg or 800 mg combined with intravenous Ara-C, added as 2 consecutive cycles of i.v. therapy at days 1–7 at a dose of 200 mg/m2/24 hrs or 1,000 mg/m2/24 hrs. Primary endpoints are dose-limiting-toxicity (DLT) and quantitative molecular response as assessed by standardized real-time Taqman PCR of bcr/abl transcripts. Patients without a major molecular response after 12 months are evaluated for mutations by direct sequencing. From the start in August 2001, thusfar 127 pts are included in cohorts I through V. The median age is 48 (20–66) years. Sofar, 2 DLTs were observed following evaluation of 112 pts, including reversible grade IV CZS toxicity (cohort IIIb, Ara-C 1,000/IM 400) and one pneumonia, complicated by lethal respiratory failure in cohort IIIa (Ara-C 200/IM 600). The median number of neutropenic ( 〈 500/m l) days following 200 and 1,000 mg/m2 Ara-C was 14 and 16, respectively. Hematological recovery appeared not significantly affected by an increased dose of IM. Opportunistic infections were predominantly central venous catheter related and 7 pneumonias, CTC grade II-III, were observed. Cohorts I-IV were demonstrated feasible, accrual is continued (cohorts IV and V) for evaluation of efficacy. Overall probabilities of developing a major (≥ 3 log reduction of bcr/abl copies) or complete ( 〉 4.5 log) molecular response were, respectively, 51% (±7) and 28% (±7) at 18 months from the start of treatment. Probabilities for major and complete cytogenetic response rates were 83% and 67%, respectively, at 18 months. Overall survival was 99 (±1) at 18 months and progression-free survival was 94% (±3). Two patients developed accelerated disease, 1 patients lost a complete hematological response. Among 30 pts without a major molecular response at 12 months, 2 pts acquired a point mutation of the Abl kinase domain resulting in amino-acid substitutions Phe359→ Val and Glu459→ Lys, respectively. These results suggest that the combination of escalated Imatinib combined with standard or intensified Ara-C may prevent resistance and mirrors the synergy of both drugs that was found in-vitro.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 6
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2055-2055
    Abstract: Donor lymphocyte infusions (DLI) are an well established treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation. In a previous analysis including mainly patients receiving DLI from HLA-identical siblings (Guglielmi et al., Blood 2002), it could be shown, that it was of major prognostic significance to start with a low cell dose (≤ 0.2 x 108 mononuclear cells/kg body weight). In the present analysis we retrospectively analyzed patients receiving DLI from unrelated donors. In the data base of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation 130 patients from 28 centers were identified, who received DLI from unrelated donors between 1987 and 2003 for treatment of relapse of Philadelphia chromosome positive CML and in whom data on the cell doses of DLI were available. According to the cell dose of the initial DLI patients were divided in 3 groups: 59 patients received DLI in a starting cell dose of ≤1x106 CD3 cells/kg body weight (group A), 39 patients received between 1 and 10x106 CD3 cells/kg (group B) and 32 patients received an initial cell dose of ≥10x106 CD3 cells/kg (group C). The three groups did not differ regarding age (median age 34 ys. in all groups), sex, sex mismatch and were comparable regarding the time interval from transplant to relapse (190d, 231d and 241d) and that from transplant to first DLI (453 d, 581d and 417d). In group C more patients were transplanted for CML beyond first chronic phase (41%), compared to 20% (group A) and 21% (group B), respectively. At first DLI relapse was molecular/cytogenetic in 60%, 64% and 38% of the patients, respectively. Relapse in accelerated phase/blast crisis at DLI was present in 3%, 13% and 22% of the patients. Multiple infusions were given in 80% of the patients in group A, 46% in group B and 6% in group C. In group A 61% of the patients received 2–3 DLI and 19% 4 or more DLI. The numbers were 33% and 13% in group B and in group C no patient received more than 2 DLI. The median total number of CD3 cells/kg given was 11 x 106 (0.5–311), 10 x 106 (3–860) and 75 x 106 (11–712) in the three groups. A cytogenetic or molecular response was achieved in 68% of the patients in group A, in 65% in group B and in 63% in group C. Acute GvHD occurred in 27% of the patients in group A (I/IIo 17%, IIIo 9%), in 28% in group B (I/IIo 20%, IIIo 8%) and in 66% in group C (I/IIo 31%, IIIo 25%, IVo 10%). Myelosuppression occurred in 20%, 23% and 22% of the patients, respectively. Survival at 6 ys. was 68± 6% in group A, 67±12% in group B and 30±9% in group C. If patients treated for acc. phase or blast crisis were excluded, survival was 71±6% in group A, 72±13% in group B and 39±11% in group C.We conclude that treatment with DLI from unrelated donors with a starting dose of 〈 10 x 106 CD3 cells/kg is efficient and results in a GvHD incidence of 27–28% with 8–9% GvHD 〉 IIo. Starting with a lower cell dose (group A) did not compromise overall efficacy but did not reduce the incidence of GvHD or myelosuppression, probably due to the fact that total number of cells given was comparable to group B. An initial cell dose of 〉 10 x 106 CD3 cells/kg resulted in more GvHD and a poorer survival.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 7
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1817-1817
    Abstract: Using data submitted to the EBMT registry, we analyzed outcome on 344 patients (pts) who had received donor lymphocyte infusions (DLI) for relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) in 31 centers. 113/344 pts (33%) developed acute graft-versus-host disease (aGVHD) a median of 50 days post DLI (max grade: I=42, II=30, III=31, IV=6)(60% grade II–IV). Organs involved (%): skin (88), liver (42), gut (30). Median age was 38 (4–59), 58% pts were male, 62 transplants were HLA-identical sibling and 51 unrelated. 74 were T-cell depleted, 92 transplanted in CP1, 21 beyond CP1. Relapse was molecular in 19 pts, cytogenetic in 31, hematological in 49, accelerated or blastic in 12. Median initial cell dose was 107CD3+ cells/kg (0.01–32), median number of DLI was 1 (1–10). aGvHD was treated with prednisone in 92% of pts, CSA in 52 %, ATG and monoclonal antibodies in 2% and other in 19%. aGVHD resolved in 53% of the pts within a median of 63 d (7–546). 82/344 pts (24%) had chronic GVHD (cGVHD)(30 limited, 50 extensive, 2 not specified), of those 46 (56%) following aGVHD post DLI. Organs involved (%): skin (75), liver (35), lungs (13), mouth (43), eyes (22) and gut (5). Median age was 35 (6–58), 51% were male, stem cell source was PB in 15% and marrow in 85%, 43 underwent HLA-identical sibling HSCT and 39 unrelated donor HSCT. Forty-three were T-cell depleted, 66 transplanted in CP1, 16 beyond CP1. Relapse was molecular in 21 pts, cytogenetic in 29, hematological in 22, accelerated or blastic in 7. Median initial cell dose was 107 CD3+ cells/kg (0.05–40), median number of DLI was 1 (1–7). 61 pts are alive with a median follow-up of 50 mth. Treatment was with steroids in 83% of pts, CSA in 58 %, MMF in 20%, thalidomide in 15%, photopheresis in 15%, PUVA in 10% and other in 17%. cGVHD resolved in 39% of the pts within a median of 354 d (44–1588). The estimated 5-y OS post-DLI was significantly lower in pts who developed aGVHD post-DLI, 61 ± 10% vs 74 ± 7% in the one that did not, p=0.007 and also a tendency to have a lower 5-y EFS, 58 ± 10% vs 65 ± 7%, p=0.19. Median duration of response to DLI in aGVHD pts was 4 y. aGVHD post-DLI did not influence the relapse rate (5 ± 5% vs 6 ± 5% in the absence of aGVHD). 5-y DLI related mortality was significantly higher in aGVHD pts, 31 ± 8% vs 4 ± 4%, p 〈 0.00001. On the other hand, pts that developed cGVHD post-DLI had a tendency to have a better 5-y OS and EFS, 74 ± 11% and 71 ± 11% respectively vs 69 ± 6% and 62 ± 7% in those that did not, p=0.32 and 0.09. This was related to a tendency to lower incidence of relapse, 2 ± 3% in pts with cGVHD vs 9 ± 6% without, p=0.2. DLI related mortality was not different, 11 ± 8% vs 10 ± 5%, p=0.77. aGVHD post-DLI for CML relapse is mainly of advanced stage and negatively influence OS and EFS with a higher DLI related mortality. cGVHD post-DLI is mainly extensive, but pts with cGHVD tend to have better outcome with better 5-y OS, EFS and less relapse than those without, although this was not statistically significant.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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