25 research outputs found
PCR real time assays for the early detection of BKV-DNA in immunocompromised patients
Testing for viral BKV-DNA in urine is a non-invasive early detection and monitoring tool in the diagnostic of BKVrelated pathologies: quantitative analysis by Real-Time PCR can provide useful information in addition to cytologic analysis, although our study suggests that high BKV viruria is not necessarily associated with kidney or bladder damage
INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia
Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL 6560 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and \u3b3-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade 653, 18.2%) and 27.3% (grade 653, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107
Stimulatory autoantibodies to PDGF receptor in patients with extensivechronic graft-versus-host disease
Extensive chronic graft-versus-host disease
(ecGVHD) is characterized by fibrosis
similar to that of patients with systemic
sclerosis (scleroderma). Since
stimulatory autoantibodies against the
platelet-derived growth factor (PDGF) receptor
(PDGFR) have been found in patients
with scleroderma and are responsible
for the activation of skin fibroblasts,
we tested the hypothesis that these autoantibodies
are also present in patients
affected by ecGVHD. Serum from 39 patients
subjected to allogeneic stem cell
transplantation for hematologic malignancies
(22 with ecGVHD and 17 without
cGVHD) and 20 healthy controls was assayed
for the presence of stimulatory
autoantibodies to the PDGFR by incubating
purified IgG with mouse-embryo fibroblasts
lacking PDGFR or chains or
with the same cells expressing PDGFR .
Stimulatory antibodies to the PDGFR were
found selectively in all patients with
ecGVHD but in none of the patients without
cGVHD. Higher levels were detected
in patients with generalized skin involvement
and/or lung fibrosis. Antibodies recognized
native PDGFR, induced tyrosine
phosphorylation, accumulation of reactive
oxygen species (ROS), and stimulated
type 1 collagen gene expression
through the Ha-Ras-ERK1/2-ROS signaling
pathway. The biologic activity of these
autoantibodies suggests a role in the
development of fibrosis and argues for a
common pathogenetic trait in ecGVDH
and scleroderma phenotypes
Low-dose Gemtuzumab-Ozogamicin as post-consolidation therapy in elderly patients with acute myeloid leukaemia: a pilot study.
The incidence of acute myeloid leukemia (AML) increases with
advancing age, and in older patients the chance of cure has not
substantially improved recently. In the elderly the incidence of
secondary AML is high, and is often associated with both high-
risk cytogenetic abnormalities and expression of the multidrug
resistance protein (MDR1) and p-glycoprotein (p-gp), both of
which are associated with poor outcomes (Appelbaum et al,
2006).
Gemtuzumab-Ozogamicin (GO) is a humanized anti-CD33
monoclonal antibody conjugated to Calicheamicin that is
rapidly internalized after binding to CD33. GO seems to be
more selective than conventional chemotherapy, as CD33 is
expressed on AML cells but not in normal haematopoietic
stem cells (SCs) or in non-haematopoietic tissues (Sievers et al,
2001). In a series of phase II studies including 142 patients
with AML in first relapse, GO monotherapy was associated
with a 30% overall complete remission (CR) rate, including a
26% rate in patients over 60 years of age (Sievers et al, 2001;
Larson et al, 2002). These results led to US Food and Drug
Administration approval of GO for the treatment of patients
over 60 years with relapsed AML (Bross et al, 2001). As a
consequence of these results, there is interest in extending the
use of GO to a frontline treatment for AML in combination
with conventional chemotherapy.
Little is known about the usefulness of GO as consolidation
and/or maintenance therapy, and no data on the topic have
been published to date. In particular, there are no data
concerning the safety and efficacy of GO in the setting of
post-consolidation therapy in AML patients except for a short
report concerning the effects after autologous stem cell
transplantation (ASCT) (Cascavilla et al, 2008). GO mono-
therapy has typically been administered as a 2-h infusion at a
dose of 9 mg/m2 on days 1 and 15 of treatment, but the
administration of fractionated doses has recently been reported
to have a better safety profile (Taksin et al, 2007).
We evaluated the efficacy of low-dose GO as late
consolidation therapy after CR in a subset of fit elderly
patients who were enrolled in a prospective study. From June
1999 to December 2007, 125 patients of 60 years of age or
older with morphologically-confirmed AML and non-acute
promyelocytic leukaemia were observed in our institution. The
preliminary results from 42 patients were reported in 2007
(Olivieri et al, 2007). Fit patients, selected according to
previously published inclusion criteria (Olivieri et al, 2007),
were treated with intensive chemotherapy, followed by SC
mobilization and ASCT (Olivieri et al, 2007). Patients who
successfully mobilized SCs underwent ASCT, while poor
mobilisers received a further consolidation including standard
chemotherapy or investigational immunotherapy with GO.
Among the initial 125 patients, 79 fulfilled the inclusion
criteria; of those, 56 (72Æ1%) achieved CR, and 52 received the
first intensive consolidation course followed by G-CSF to
collect SC for ASCT. In cases of mobilisation failure, patients
were allowed to chose between an experimental approach
B J H 8 1 6 8 B Dispatch: 8.3.10 Journal: BJH CE: Varun Kumar
Journal Name Manuscript No. Author Received: No. of pages: 3 PE: Subhashree
Table I. Clinical and biological characteristics of the three groups of
patients receiving consolidation with GO (A), ASCT (B), Chemo-
therapy (CHT) (C) and Allogeneic Transplantation (D).
A (%) B (%) C (%) D (%) P
Gender
Male 8 (62) 8 (42Æ1) 3 (50) 3 (60) N.S.
Female 5 (38) 11 (57Æ9) 3 (50) 2 (40)
Age (years)
Median = 70 (range, 61–76)
£70 7 (54) 10 (52Æ6) 5 (83Æ3) 4 (80) N.S.
>70 6 (46) 9 (47Æ4) 1 (16Æ7) 1 (20)
FAB subtype
M0 0 5 (26Æ5) 0 0 N.S.
M1 3 (23) 4 (21) 2 (33Æ3) 2 (40)
M2 3 (23) 8 (42) 4 (66Æ7) 2 (40)
M4 3 (23) 2 (10Æ5) 0 1 (20)
M5 3 (23) 0 0 0
M6 1 (8) 0 0 0
M7 0 0 0 0
Leucocytosis (·109/l)
WBC <10 8 (61Æ5) 9 (47Æ4) 4 (66Æ7) 4 (80) N.S.
WBC 10–50 5 (38Æ5) 6 (31Æ6) 1 (16Æ7) 1 (20)
WBC >50 0 4 (21) 1 (16Æ7) 0
Karyotype
Poor 2 (15Æ4) 7(36Æ8) 1 (16Æ7) 4 (80) N.S.
Intermediate 6 (46Æ2) 8 (42Æ1) 4 (66Æ7) 0
Favourable 2 (15Æ4) 0 1 (16Æ7) 1 (20)
NE 3 (15Æ4) 4 (21Æ1) 0 0
Secondary disease*
Yes 3 (23) 8 (42) 2 (33Æ3) 1 (20) N.S.
No 10 (77) 11 (58) 4 (66Æ7) 4 (80)
FAB, French-American-British classification; NE, not evaluated; WBC,
white blood cell.
*To chemotherapy or Myelodysplastic Syndrome.
correspondence
ª 2010 Blackwell Publishing Ltd, British Journal of Haematology doi:10.1111/j.1365-2141.2010.08168.x
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including low-dose GO or a further conventional consolidation
course. GO was administered on a compassionate basis, and the
costs were charged to our department. Among the 52 patients
who received intensive consolidation, two died and seven
relapsed; thus, 43 patients were evaluable for post-remission
treatment after the SC mobilization attempt. Of those, 19
patients (44%) successfully mobilized SC and received ASCT.
Of the 24 that did not mobilise SC, 13 received GO, six patients
refused GO and received a second consolidation with chemo-
therapy, and five patients received reduced intensity
conditioning allogeneic transplant from sibling donors.
The current analysis did not include all patients receiving
allogeneic transplant because of the poor prognosis of the
disease. The disease characteristics of the remaining patients
were equally distributed in the three groups, and the data are
shown in Table I.
All the patients received GO at a dose of 3 mg/m2 three
times monthly on an outpatient basis and received common
antimicrobial prophylaxis. No patients needed hospitalisation
for infections or other major toxicities; the median duration of
neutropenia (PMN <0Æ5 · 109/l) after GO was 12 d (range
0–33 d). The main toxicities (World Health Organization
grade III–IV) were myelosuppression (n = 9), hypertransam-
inasaemia (n = 1) and anaphylaxis (n = 3); no major unex-
pected adverse events were observed. With a median follow up
of 58 months (range 19–89), a total of 15 patients were alive
and in CR: five received ASCT (median follow-up 77 months,
range 45-89), nine received GO (median follow-up 38 months,
range: 19–75 months), and one, who received chemotherapy,
has been followed for 72 months. Two patients receiving GO
relapsed and eventually died after 13 and 19 months from CR
after the first consolidation. Two more patients relapsed after
15 and 32 months after a second CR after salvage chemother-
apy, followed by three doses of GO 3 mg/m2 administered as
consolidation therapy.
In conclusion, nine of the 13 patients who received GO as
late consolidation therapy were alive and in continuous CR
(including two patients with secondary AML and two with a
complex karyotype). The Landmark survival analysis showed
better overall survival (OS) and disease-free survival (DFS)
(P = 0Æ017 and 0Æ01 respectively) in the 13 patients that
received GO (5-year OS, 60%; 5-year DFS, 67%) compared
with patients that received either ASCT (5-year OS and DFS:
26%) or chemotherapy (5-year OS and DFS: 17%) (Fig 1).
Our preliminary data support a potential role for low-dose
GO in consolidation therapy in elderly patients with AML
who are able to achieve CR after intensive induction. Late
consolidation with low-dose GO seems to be safe and easily
manageable; the myelosuppression was relevant, but generally
short. All patients received the 3 GO infusions on an
outpatient basis without further readmissions and without
fatal events.
These preliminary data encourage the use of low-dose GO as
late consolidation therapy to eliminate the minimal residual
disease (MRD) in older patients with AML. Larger studies are
needed for confirmation, possibly including monitoring of
MRD during treatment. It also remains to be established if SC
collection failure after CR represents an independent favour-
able prognostic factor in AML patients, as suggested by some
retrospective data (Keating et al, 2003).
Antonella Poloni1
Debora Capelli1
Silvia Trappolini1
Benedetta Costantini1
Mauro Montanari1
Guido Gini1
Ilaria Scortechini1
Giorgia Mancini1
Giancarlo Discepoli2
Pietro Leoni1
Attilio Olivieri3
1Dipartimento di Scienze Mediche e Chirurgiche, Sezione di Ematologia,
Universita` Politecnica delle Marche and Azienda Ospedaliera Ospedali
Riuniti, 2Laboratorio di Citogenetica e Genetica Molecolare, Clinica di
Pediatria, Ospedali Riuniti, Ancona, and 3Azienda Ospedaliera San
Carlo, Potenza, Italy.
E-mail: [email protected]
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20
40
60
80
100
0 12 24 36 48 60 72 84 96
Cumulative probability (%)
Months
OS
GO
ASCT
CHT
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96
Cumulative probability (%)
Months
DFS
Fig 1. Comparison of the outcome (OS and DFS) of patients receiving late consolidation with Gemtuzumab-Ozogamicin (GO), autologous stem cell
transplantation (ASCT) or chemotherapy (CHT) (log rank test).
Correspondence
2 ª 2010 Blackwell Publishing Ltd, British Journal of Haematology
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References
Appelbaum, F.R., Gundacker, H., Head, D.R., Slovak, M.L., Willman,
C.L., Godwin, J.E., Anderson, J.E. & Petersdorf, S.H. (2006) Age and
acute myeloid leukaemia. Blood, 107, 3481–3485.
Bross, P.F., Beitz, J., Chen, G., Chen, X.H., Duffy, E., Kieffer, L., Roy,
S., Sridhara, R., Rahman, A., Williams, G. & Pazdur, R. (2001)
Approval summary: gemtuzumab ozogamicin in relapsed acute
myeloid leukemia. Clinical Cancer Research, 7, 1490–1496.
Cascavilla, N., D’Arena, G., Greco, M.M., Melillo, L., Merla, E. &
Carella, A.M. (2008) Gemtuzumab-Ozogamicin as maintenance
therapy after Autologous Stem Cell Transplantation in elderly
patients with Acute Myeloid Leukaemia. British Journal of Haematology
, 142, 852–853.
Keating, S., Suciu, S., de Witte, T., Zittoun, R., Mandelli, F., Belhabri,
A., Amadori, S., Fibbe, W., Gallo, E., Fillet, G., Varet, B., Meloni, G.,
Hagemeijer, A., Fazi, P., Solbu, G., Willemze, R., EORTC Leukemia
Group & GIMEMA Leukemia Group. (2003) The stem cell
mobilizing capacity of patients with acute myeloid leukemia in
complete remission correlates with relapse risk: results of EORTC-
GIMEMA AML 10 trial. Leukemia, 17, 60–67.
Larson, R.A., Boogaerts, M., Estey, E., Karanes, C., Stadtmauer, E.A.,
Sievers, E.L., Mineur, P., Bennett, J.M., Berger, M.S., Eten, C.B.,
Munteanu, M., Loken, M.R., Van Dongen, J.J., Bernstein, I.D.,
Appelbaum, F.R. & Mylotarg Study Group. (2002) Antibody-
targeted chemotherapy of older patients with acute myeloid
leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin).
Leukemia, 16, 1627–1636.
Olivieri, A., Capelli, D., Troiani, D., Poloni, A., Montanari, M.,
Offidani, M., Discepoli, G. & Leoni, P. (2007) A new intensive
induction schedule, including high-dose Idarubicin, high-dose
Aracytin and Amifostine, in older AML patients: feasibility and
long-term results in 42 patients. Experimental Hematology, 35,
1074–1082.
Sievers, E.L., Larson, R.A., Stadtmauer, E.A., Estey, E., Lo¨wenberg, B.,
Dombret, H., Karanes, C., Theobald, M., Bennett, J.M., Sherman,
M.L., Berger, M.S., Eten, C.B., Loken, M.R., Van Dongen, J.J.,
Bernstein, I.D., Appelbaum, F.R. & Mylotarg Study Group. (2001)
Efficacy and safety of gemtuzumab ozogamicin in patients with
CD33-positive acute myeloid leukemia in first relapse. Journal of
Clinical Oncology, 19, 3244–3254.
Taksin, A.L., Legand, O., Raffoux, E., de Revel, T., Thomas, X., Con-
tenin, N., Bouabdallah, R., Pautas, C., Turlure, P., Reman, O.,
Gardin, C., Varet, B., de Botton, S., Pousset, F., Farhat, H., Chevret,
S., Dombret, H. & Castaigne, S. (2007) High efficacy and safety
profile of fractionated doses of Mylotarg as induction therapy in
patients with relapsed acute myeloblastic leukemia: a prospective
study of the alfa group. Leukemia, 21, 66–71.
Keywords: AML, chemotherapy,
Gemtuzumab-Ozogamicin as Post-Consolidation Therapy In Elderly Patients with Acute Myeloid Leukemia: a Pilot Study
none12Debora, Capelli; Mancini, Giorgia; Chiarucci, Martina; Saraceni, Francesco; Poloni, Antonella; Trappolini, Silvia; Costantini, Benedetta; Montanari, Mauro; Gini, Guido; Scortechini, Ilaria; Leoni, Pietro; Olivieri, AttilioDebora, Capelli; Mancini, Giorgia; Chiarucci, Martina; Saraceni, Francesco; Poloni, Antonella; Trappolini, Silvia; Costantini, Benedetta; Montanari, Mauro; Gini, Guido; Scortechini, Ilaria; Leoni, Pietro; Olivieri, Attili
Cytokine expression profile of selected cell populations from patients with chronic graft-versus-host disease after allogeneic bone marrow transplantation wih reduced conditioning.
Telomere length, c-myc and mad-1 expression could represent prognosis markers of myelodysplastic syndrome
tTelomere dysfunction might generate genomic instability leading to the progression of myelodysplasticsyndromes (MDS) into acute myeloid leukemia (AML). We investigated telomere length (TL), telome-rase activity (TA) and hTERT, c-myc, mad1, and p53 expression in the bone marrow of patients withMDS (n = 109), AML (n = 47) and in controls (n = 24). TL was lower in MDS patients than in controls(p < 0.001) and higher in L-MDS (low, intermediate-1 IPSS, p < 0.01) respect H-MDS (high, intermediate-2IPSS, p < 0.01) patients. Mad-1 expression was higher in MDS patients than in controls (p < 0.01), c-mycexpression was highest in AML and in H-MDS patients. Our results show that the telomere dynamicsmight be useful for stratifying patients according to a risk scoring system