Reduced-intensity conditioning allogeneic stem cell transplantation for patients with chemoresistant or relapsed follicular lymphoma.
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Adult↗
Biomedical subjects
Norbert Vey
Publications and source records attributed to Norbert Vey.
Arsenic trioxide in patients with myelodysplastic syndromes: a phase II multicenter study.
PURPOSE: Evaluation of the safety and efficacy of arsenic trioxide in patients with myelodysplastic syndromes (MDS). PATIENTS AND METHODS: MDS patients diagnosed according to standard French-American-British criteria received a loading dose of 0.3 mg/kg per day of arsenic trioxide for 5 days followed by a maintenance dose of 0.25 mg/kg arsenic trioxide twice weekly for 15 weeks. Patients were divided into two cohorts: lower-risk MDS (International Prognostic Scoring System risk category low or intermediate 1) and higher-risk MDS (International Prognostic Scoring System risk category intermediate 2 or high). Modified International Working Group criteria were used for response evaluation. RESULTS: Of 115 patients enrolled and treated in the study, 67% of patients were transfusion dependent at baseline; median age was 68 years. Most treatment-related adverse events were mild to moderate. The overall rate of hematologic improvement (intent-to-treat) was 24 (19%) of 115, including one complete and one partial response in the higher-risk cohort. The hematologic response rates were 13 (26%) of 50 and 11 (17%) of 64 in patients with lower-risk and higher-risk MDS, respectively. Major responses were observed in all three hematologic lineages; 16% of RBC transfusion-dependent patients and 29% of platelet transfusion-dependent patients became transfusion independent. At data cut off, the median response duration was 3.4 months, with responses ongoing in nine patients. CONCLUSION: Arsenic trioxide treatment consisting of an initial loading dose followed by maintenance therapy has moderate activity in MDS, inducing hematologic responses in both lower- and higher-risk patients. This activity combined with a manageable adverse effect profile warrants the additional study of arsenic trioxide, particularly in combination therapy, for the treatment of patients with MDS.
Adult↗
A phase II study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients with very high risk relapsed acute myeloid leukemia.
Cloretazine (VNP40101M) is a sulfonylhydrazine alkylating agent with significant anti-leukemia activity. A multicenter phase II study of cloretazine was conducted in patients with first relapse of acute myeloid leukemia (AML) following an initial complete remission (CR) of less than 12 months. Cloretazine was given as a single intravenous infusion at a dose of 600 mg/m(2). Fifty-three patients (median age 62 years (18-84), 41 of 44 (93%) evaluable with intermediate or high risk cytogenetics, 32 (60%) with initial CR durations < or =6 months) were treated on study. Two patients (4%) achieved a second CR. Five (9%) patients died within 30 days of receiving cloretazine therapy. Median overall survival (2.3 months) in the study cohort was directly comparable to that of 233 matched patients treated with other single agents. The study cloretazine regimen had minimal activity in a very high risk subset of patients with relapsed AML.
Acute Disease↗
Cloretazine for the treatment of acute myeloid leukemia.
Cloretazine is a new sulfonylhydrazine alkylating agent with antileukemic activity. Phase I studies have shown myelosuppression to be the dose limiting toxicity in both solid tumors and leukemias. A large Phase II study of single agent cloretazine (600 mg/m2) confirmed its activity in patients with relapsed acute myeloid leukemia, and in elderly patients with previously untreated acute myeloid leukemia or myelodysplastic syndrome. It also confirmed the limited nonhematological toxicity, even in elderly patients. Cloretazine can be safely combined with cytarabine, and this combination regimen is currently being tested in a large Phase III study in patients with relapsed acute myeloid leukemia. Cloretazine is a promising new antileukemic agent that may be incorporated into an intensive combination regimen.
Acute Disease↗
Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment.
BACKGROUND: Thirty-three patients (median age 52; range 26-60) with acute myeloblastic leukemia (AML) were included in a pilot study of allogeneic stem cell transplantation (Allo-SCT) following a reduced-intensity conditioning (RIC). METHODS: Patients achieving first complete remission (CR1) were selected for their high-risk clinical and/or leukemic features. All patients received two courses of consolidation chemotherapy including one high-dose cytarabine course. Among them, 13 patients in addition received a high-dose melphalan course followed by autologous SCT. Then, all patients received an RIC Allo-SCT combining fludarabine, busulfan, and antithymocyte globulin. RESULTS: All patients engrafted had cumulative incidences of Gluksberg System Grade 2 acute and chronic graft-versus-host-disease (GVHD) of 24 (9-39%) and 64 (48-80%), respectively. Three patients died from nonrelapse causes (NRD) (cumulative incidence: 9%, 95% confidence interval (CI): 0-19) and 6 relapsed (cumulative incidence: 18%, 95% CI: 5-31). With a median follow-up of 18 months (range 7-52) after Allo-SCT, 26 patients are alive, of whom 24 remained in CR1 for a 2-year overall survival and leukemia-free survival (LFS) probabilities of 79 (range 61-90%) and 76 (range 59-87%), respectively. In a 'landmark' analysis starting on Day 100, the occurrence of chronic GVHD was associated with a lower relapse rate (0% vs. 44%: P = 0.007) and improved outcome (LFS; 95% vs. 53%, P = 0.007; overall survival, 95% vs. 61%, P = 0.05). CONCLUSIONS: We conclude that the sequential combination of intensive chemotherapy and allogeneic immunotherapy might offer relatively low NRD and leukemia relapse rates even in high-risk patients.
Adult↗
Early allogeneic stem-cell transplantation for young adults with acute myeloblastic leukemia in first complete remission: an intent-to-treat long-term analysis of the BGMT experience.
PURPOSE: We analyzed the impact of allogeneic stem-cell transplantation (alloSCT) as an early consolidation for young patients with acute myeloblastic leukemia in first complete remission (CR1) through four successive protocols. PATIENTS AND METHODS: Of the 472 patients who achieved CR1, 182 (38%) had an HLA-identical sibling (donor group), and alloSCT was performed in 171 patients (94%). Of the 290 patients without donor (no-donor group), 62% received an autologous SCT. RESULTS: In an intent-to-treat analysis based on donor availability, the overall 10-year survival probability was 51% v 43% (P = .11) for the donor and no-donor groups, respectively. A Cox analysis determined that four factors had independent prognostic significance for survival (initial WBC count, French-American-British subtypes, cytogenetic risk, and number of induction courses). This permitted constitution of a simple index that reclassified 21% of the patients compared with usual cytogenetic classification and identified three subpopulations with different outcome and different impact of alloSCT. CONCLUSION: AlloSCT was associated with a survival advantage for an intermediate-risk group. In other groups, numbers are limited for definitive conclusion. However, early performed alloSCT does not seem to be the optimal treatment of high-risk patients or offer any advantage over intensive chemotherapy in low-risk patients.
Acute Disease↗
Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation.
This study investigated the role of inflammatory cytokines in acute graft-versus-host disease (aGVHD) incidence and severity in 113 patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Among all tested cytokines in the first 3 months after allo-SCT, only interleukin-12 p70 (IL-12p70) levels in the first month were significantly associated with grades II to IV aGVHD development (P < .001). IL-12p70 levels were directly correlated with aGVHD severity grade (P < .001). Before aGVHD onset, blood monocytes, the main precursor pool of IL12p70-secreting dendritic cells, recovered more rapidly in patients with grades II to IV aGVHD (P = .005). Similarly, at the effector level, there was a more robust reconstitution of naive CD3+CD4+CD45RA+CD27+ T cells in patients developing grades II to IV aGVHD (P = .006). In multivariate analysis, IL-12p70 level measured in the first month was the strongest predictive factor for aGVHD development (P < .001). These findings, reconstituting a T(H)1 loop, support a model in which aGVHD reflects a type 1 alloreaction after RIC allo-SCT.
Acute Disease↗
Acute leukemia during pregnancy: a report on 37 patients and a review of the literature.
BACKGROUND: Acute leukemia (AL) requiring cytotoxic treatment occurring during pregnancy poses a very difficult therapeutic dilemma. METHODS: By means of a mail questionnaire, information on a series of 37 patients with a diagnosis of AL during pregnancy was collected from 13 French centers between December, 1988 and November, 2003. RESULTS: Thirty-one patients had acute myeloid leukemia (AML), and 6 patients had acute lymphoblastic leukemia (ALL). Nine patients were diagnosed during the first trimester, 10 patients were diagnosed during the second trimester, and 18 patients were diagnosed during the third trimester. Fifteen pregnancies ended with therapeutic or spontaneous abortion. There were 13 normal deliveries, including 1 gemellary pregnancy, and 9 Cesarean sections. Twenty-three healthy babies survived from the 37 pregnancies, of whom 15 babies had been exposed to chemotherapeutic agents. A complete remission was achieved in 34 patients. Eleven women had severe extrahematologic complications during the induction remission course. The median disease-free survival (DFS) was not reached, with a 5-year DFS of 54%. Ten patients developed recurrent disease. Overall, 12 of 37 pregnant women died from leukemia. CONCLUSIONS: Pregnancy does not affect the course of AL. In the first trimester, termination of pregnancy should be discussed because of the potential fetal consequences of chemotherapy. Chemotherapy treatment during the second or third trimester may not require termination of pregnancy, because as remission of AL and delivery of a normal infant are likely to be obtained.
Acute Disease↗
Impact of TCR status and genotype on outcome in adult T-cell acute lymphoblastic leukemia: a LALA-94 study.
Patients with T-cell acute lymphoblastic leukemias (T-ALLs) within the Leucemies Aigues Lymphoblastiques de l'Adulte-94 (LALA-94) prospective trial were treated with a 4-drug per 4-week induction, with intermediate-dose cytarabine and mitoxantrone salvage treatment for patients not achieving complete remission (CR) in 1 course. Only the latter received allografts, if possible, thus providing an informative setting for assessing early response. Representative patients with T-ALL (91 patients) were classified into surface T-cell receptor (TCR)-expressing T-ALL patients (TCRalphabeta+ or TCRgammadelta+), pre-alphabeta T-ALL patients (cTCRbeta+, TCR-), and immature (IM) cTCRbeta-, TCR- T-ALL patients; 81 patients underwent genotyping for SIL-TAL1, CALM-AF10, HOX11, and HOX11L2. Overall, CR was obtained in 81 (89%) patients; relapse rate was 62% at 4 years and overall survival (OS) rate was 38%. CR rate was significantly lower in IM T-ALL patients after 1 course (45% vs 87%; P < .001) and after salvage (74% vs 97%; P = .002), with the latter inducing a higher rate of CR (9 [64%] of 14) than initial induction. Once CR was obtained, cumulative relapse rates were similar for IM, pre-alphabeta, and TCR+ T-ALL patients (P = .51), but were higher in HOX11L2 (83%) and SIL-TAL1 (82%) T-ALL patients compared with other genetic subgroups (48%; P = .05). This was associated with an inferior OS for HOX11L2 T-ALLs (13% vs 47% in HOX11L2-T-ALLs; P = .009). The majority of patients with HOX11 T-ALL underwent allografting, predominantly in second CR, but were not associated with a superior OS. Both TCR and genotypic stratification can therefore contribute to risk-adapted management of adult T-ALLs.
Adolescent↗
One versus two high-dose cytarabine-based consolidation before autologous stem cell transplantation for young acute myeloblastic leukaemia patients in first complete remission.
We report on a randomized trial aimed to determine the impact of a second consolidative high-dose cytarabine-based chemotherapy (HiDAC) in patients with acute myeloid leukaemia prior to an autologous stem cell transplantation (ASCT). Patients aged 18-60 years, in complete remission (CR) received a first consolidation with daunorubicin and cytarabine at reduced dose. Patients not allocated to allogeneic transplantation received one course of HiDAC and then were randomized to receive an ASCT immediately (HiDAC 1 group) or after one more course of HiDAC (HiDAC 2 group). Out of the 437 initial patients, 351 achieved CR (80%), of those 277 (79%) were eligible for first HiDAC, and 128 (36%) were randomized (HiDAC 1:65, HiDAC 2:63). Overall survival, leukaemia-free survival and cumulative incidence of relapse and non-relapse deaths were 41% and 53% (P = 0.14), 39% and 48% (P = 0.12), 57% and 47% (P = 0.11), 8% and 8% (P = 0.95) for HiDAC 1 and HiDAC 2 groups, respectively. Further studies are warranted with a larger number of patients to test the place of a second course of HiDAC in this setting.
Adolescent↗
Dual lympho-myeloproliferative disorder in a patient with t(8;22) with BCR-FGFR1 gene fusion.
The case of a patient presenting with a myeloproliferative disorder (MPD) characterized by a t(8;22) (p12;q11) translocation was investigated. The rearrangement resulted in the production of BCR-FGFR1 and FGFR1-BCR chimeric transcripts after in-frame fusions of BCR exon 4 with FGFR1 exon 9 and FGFR1 exon 8 with BCR exon 5, respectively. The four previously reported patients with such translocation presented with an atypical chronic myeloid leukemia (CML) without Philadelphia chromosome. In addition to a myeloproliferation, the patient had a B cell proliferation. The phenotypic characterization of the lymphoid cells in the bone marrow showed a continuum of maturation from blast B cells to polyclonal lymphocytes. In the blood, B cells showed a complete polyclonal maturation. The BCR-FGFR1 gene fusion was detected by dual-color fluorescence in situ hybridization in both CD19- and CD19+ populations. In contrast to the other FGFR1-MPDs that show myeloid and T cell proliferation, we propose that this t(8;22) MPD is a myeloid and B cell disease, and potentially a novel type of hematological disease. Although the FGFR1-MPD is rare, its study provides interesting clues to the understanding of hematopoietic stem cell biology and oncogene activation.
Aged↗
Identification of new classes among acute myelogenous leukaemias with normal karyotype using gene expression profiling.
Conventional cytogenetic analysis currently stratifies acute myelogenous leukaemia (AML) into prognostically relevant groups. However, approximately 50% of adult AMLs have normal cytogenetics (NC-AMLs), and represent a heterogeneous and poorly understood group. We analysed gene expression in 55 AML samples including 53 cases from adult patients with NC-AML (n = 36), trisomy 8, t(15;17), t(8;21), t(11;19), 7q deletion, and two cell lines using 9000-gene DNA microarrays. Global hierarchical clustering showed that NC-AMLs are a heterogeneous group. Supervised analysis distinguished two subgroups of NC-AML: one subgroup constituted a homogeneous NC cluster ('pure NC-AML'), and the other NC-AMLs were close to the AML cases with translocations ('translocation like'). Gene expression signatures were also derived for patients with trisomy 8, as well as FLT3 and MLL gene duplications. Importantly, samples from 24 NC-AML patients who could be evaluated for clinical outcome were analysed. In all, 43 genes that discriminated two classes of patients with significantly different prognosis were identified. The poor prognosis class contained a majority of 'pure NC-AMLs', whereas the 'translocation-like' AMLs were in the good prognosis class. Discriminator genes included genes involved in drug resistance (TOP2B), protein transport (MTX2, SLC35A2), and cell signalling (MAPK1, PRKAB2). Our results demonstrate the transcriptional heterogeneity of NC-AMLs, and suggest the existence of 'translocation-like' NC-AMLs and of a gene expression signature that may predict response to chemotherapy.
DNA-Binding Proteins↗
Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.
PURPOSE: We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. PATIENTS AND METHODS: A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. RESULTS: Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. CONCLUSION: Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.
Adolescent↗
The benefit of induction chemotherapy in patients age > or = 75 years.
BACKGROUND: Patients age > or = 75 years with acute myeloid leukemia (AML) generally are offered palliative treatments instead of induction chemotherapy. The authors conducted a retrospective study comparing the outcomes among these elderly patients with the outcomes among younger patients to assess the impact of intensive treatment approaches in this age group. METHODS: One hundred ten consecutive patients age > or = 75 years with newly diagnosed AML (excluding patients with acute promyelocytic leukemia) were treated in the authors' center over 10 years. Initial treatment was comprised of anthracycline-based induction chemotherapy (i.e., intravenous idarubicin or daunorubicin for 3 days plus cytarabine [ARAC] for 7 days [3 + 7 regimen] or oral idarubicin) for 62 patients (56%), antimetabolite-based chemotherapy (including low-dose ARAC, oral 6-mercaptopurine plus methotrexate, or hydroxyurea) for 40 patients (36%), and supportive care only for 8 patients (7%). Results were compared with the results from 200 patients ages 65-74 years who were treated during the same period. RESULTS: A complete response (CR) to anthracycline-based induction therapy was achieved by 23 of 62 patients (37%), and the 2-year overall survival rate was 22% (which was not statistically different from the group of patients ages 65-74 years). In a multivariate analysis of the entire study group (310 patients), treatment (anthracycline-based vs. other) and age as continuous variable were found to affect survival significantly. In a Landmark analysis, the achievement of a CR translated into improved survival in patients age > or = 75 years. CONCLUSIONS: Patients age > or = 75 years should not be excluded systematically from intensive chemotherapy regimens. Decisions should be based on stratification systems that include functional status and comorbidity assessments as well as prognostic factors, such as cytogenetics.
Aged↗
Imatinib and plasmacytoid dendritic cell function in patients with chronic myeloid leukemia.
Plasmacytoid dendritic cells (PDCs) are crucial effectors in innate immunity. In this study, we show that imatinib, a potent inhibitor of BCR/ABL tyrosine kinase activity, in the presence of Flt3-Ligand, could induce CD34+ progenitors from chronic myeloid leukemia (CML) to give rise in vitro to typical BDCA-2+ type I interferon-producing PDCs. The effect of imatinib on PDC generation was related to up-regulation of Flt3 on leukemic CD34+ progenitors. Moreover, patients with chronic myeloid leukemia (CML) who were in complete cytogenetic or molecular response after imatinib treatment restored their blood PDCs both quantitatively and functionally comparable to healthy donors, in contrast to patients not responding to imatinib, further confirming that disease response to imatinib is accompanied by restoration of PDC function in vivo. These findings provide evidence that response to imatinib is capable to restore some DC-related immune functions in CML that might be beneficial for long-term disease control.
Antineoplastic Agents↗
Sometimes appendicitis can wait.
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Adult↗
CD8+ T cell dose affects development of acute graft-vs-host disease following reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation.
OBJECTIVE: Acute graft-vs-host disease (aGVHD) remains an important cause of morbidity after reduced-intensity conditioning (RIC) allogeneic transplantation (allo-SCT). It has been shown that antithymocyte globulin (ATG) dose infused during RIC is a major determinant for the likelihood of developing aGVHD. The ATG modulation on aGVHD is likely related to in vivo T-cell depletion. PATIENTS AND METHODS: We therefore investigated the relationship between the cellular composition of the allograft and clinical outcome in 57 patients who received allogeneic peripheral blood stem cells from HLA-identical siblings following an ATG-based RIC. RESULTS: In a multivariate analysis, the CD8+ T cell dose infused was the only parameter associated with the risk of aGVHD (p=0.031; RR=1.96; 95% CI, 1.1-3.6). When looking at the extremes, patients experiencing grade III-IV aGVHD received a median of 143 x 10(6)/kg CD8+ T cells, while patients without aGVHD received a median of 96 x 10(6)/kg CD8+ T cells (p=0.021). None of the different cell subtypes contained in the allograft was associated with a significant probability of developing chronic GVHD. Patients with grade II aGVHD who received an intermediate dose of CD8+ T cells (median, 111 x 10(6)/kg) had a significantly better overall survival in comparison to patients with grade 0-I or grade III-IV aGVHD (p=0.009). CONCLUSION: In comparison to myeloablative allo-SCT, these results demonstrate that a cautious monitoring of the number of cells infused, at least in the context of ATG-based RIC, may represent an important predictive indicator of early transplant-related events and outcome after RIC allo-SCT.
Acute Disease↗
Arsenic trioxide for the treatment of myelodysplastic syndromes.
The impressive activity of arsenic trioxide in acute promyelocytic leukaemia (APL) has renewed the interest in this old compound. Arsenic trioxide targets the sulfhydryl groups present in many proteins involved in oncogenesis and has a broad spectrum of biological activities. This article will review the mechanisms of action of the drug and their relevance to the treatment of myelodysplastic syndrome (MDS), a disease for which no standard treatment currently exists. The early clinical experience has confirmed the activity of arsenic trioxide in MDS. The preliminary results of ongoing Phase II studies conducted in patients with MDS suggest that arsenic trioxide produces haematological improvement including durable transfusion independence in approximately 30% of patients. The current data are presented and discussed in this review.
Antineoplastic Agents↗