Tandem versus single haematopoietic stem cell transplant and BV maintenance in relapsed/refractory Hodgkin lymphoma: A matched cohort analysis from the LYSA.

Autologous hematopoietic stem cell transplant (ASCT) is the standard curative treatment for patients with high-risk relapsed/refractory Hodgkin lymphoma (R/R HL). The AETHERA study showed survival gain with Brentuximab Vedotin (BV) maintenance after ASCT in BV-naive patients, which was recently confirmed in the retrospective AMAHRELIS cohort, including a majority of BV-exposed patients. However, this approach has not been compared to intensive tandem auto/auto or auto/allo transplant strategies, which were used before BV approval. Here, we matched BV maintenance (AMAHRELIS) and tandem SCT (HR2009) cohorts, and observed that BV maintenance was associated with better survival outcome in patients with HR R/R HL.

FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study.

Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4-/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P < .01), but progression-free survival (PFS) and overall survival (OS) were similar in both groups. PET2-/PET4- and PET2+/PET4- patients had similar outcomes. Using ΔSUVmax, 79% of the patients were PET2-/PET4- ΔSUVmaxPET0-4 >70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

New insights into human farnesyl pyrophosphate synthase inhibition by second-generation bisphosphonate drugs.

Pamidronate, alendronate, APHBP and neridronate are a group of drugs, known as second-generation bisphosphonates (2G-BPs), commonly used in the treatment of bone-resorption disorders, and recently their use has been related to some collateral side effects. The therapeutic activity of 2G-BPs is related to the inhibition of the human Farnesyl Pyrophosphate Synthase (hFPPS). Available inhibitory activity values show that 2G-BPs act time-dependently, showing big differences in their initial inhibitory activities but similar final IC50 values. However, there is a lack of information explaining this similar final inhibitory potency. Although different residues have been identified in the stabilization of the R2 side chain of 2G-BPs into the active site, similar free binding energies were obtained that highlighted a similar stability of the ternary complexes, which in turns justified the similar IC50 values reported. Free binding energy calculations also demonstrated that the union of 2G-BPs to the active site were 38 to 54 kcal mol-1 energetically more favourable than the union of the natural substrate, which is the basis of the inhibition potency of the hFPPS activity.

Formation mechanism of glyoxal-DNA adduct, a DNA cross-link precursor.

DNA nucleobases undergo non-enzymatic glycation to nucleobase adducts which can play important roles in vivo. In this work, we conducted a comprehensive experimental and theoretical kinetic study of the mechanisms of formation of glyoxal-guanine adducts over a wide pH range in order to elucidate the molecular basis for the glycation process. Also, we performed molecular dynamics simulations to investigate how open or cyclic glyoxal-guanine adducts can cause structural changes in an oligonucleotide model. A thermodynamic study of other glycating agents including methylglyoxal, acrolein, crotonaldehyde, 4-hydroxynonenal and 3-deoxyglucosone revealed that, at neutral pH, cyclic adducts were more stable than open adducts; at basic pH, however, the open adducts of 3-deoxyglucosone, methylglyoxal and glyoxal were more stable than their cyclic counterparts. This result can be ascribed to the ability of the adducts to cross-link DNA. The new insights may contribute to improve our understanding of the connection between glycation and DNA cross-linking.

Isodesmic reaction for accurate theoretical pKa calculations of amino acids and peptides.

Theoretical and quantitative prediction of pKa values at low computational cost is a current challenge in computational chemistry. We report that the isodesmic reaction scheme provides semi-quantitative predictions (i.e. mean absolute errors of 0.5-1.0 pKa unit) for the pKa1 (α-carboxyl), pKa2 (α-amino) and pKa3 (sidechain groups) of a broad set of amino acids and peptides. This method fills the gaps of thermodynamic cycles for the computational pKa calculation of molecules that are unstable in the gas phase or undergo proton transfer reactions or large conformational changes from solution to the gas phase. We also report the key criteria to choose a reference species to make accurate predictions. This method is computationally inexpensive and makes use of standard density functional theory (DFT) and continuum solvent models. It is also conceptually simple and easy to use for researchers not specialized in theoretical chemistry methods.

High- and low-spin Fe(III) complexes of various AGE inhibitors.

Density functional theory calculations [CPCM/UM06/6-31+G(d,p)] were used to elucidate the structures and relative stability of Fe(III) complexes with various ligands that inhibit the formation of advanced glycation end products (AGEs) or iron overloaded disease (viz. aminoguanidine, pyridoxamine, LR-74, Amadori compounds, and ascorbic acid). EDTA was used as the free energy reference ligand. The distorted neutral octahedral complex containing one iron atom and three molecules of pyridoxamine [Fe(PM)(3)] was found to be the most stable. The stability of the complexes decreases in the following chelate sequence: pyridoxamine, Amadori complex, aminoguanidine, LR inhibitor, and ascorbic acid.

[Treatment of cancer and hematological malignancy in elderly people (Part II)]. / Prise en charge des cancers solides et des hémopathies malignes du sujet âgé: l'oncogériatrie, une discipline en devenir. Seconde partie: traitement des cancers solides (partie 2) et des hémopathies malignes du sujet âgé.

PURPOSE: Fifty percents of cancer arise in people older than 65-year-old. Most clinical trials in cancer treatment are limited in patients younger than 65-year-old. We review literature-describing particularity of cancer treatment in elderly patients. CURRENT KNOWLEDGE AND KEY POINTS: Therapeutic decisions should be based on an estimation of the patient's life expectancy, and risks and benefits should be weighted up accordingly. Geriatric oncology is made of a geriatric evaluation of patient and of knowledge of clinical trial about elderly patients. FUTURE PROSPECTS AND PROJECTS: We present in this issue the principle of geriatric evaluation and the results of recent clinical trial on elderly cancer patients.

Immunological classification of acute myeloblastic leukemias: relevance to patient outcome.

Immunophenotyping is a major tool to assign acute leukemia blast cells to the myeloid lineage. However, because of the large heterogeneity of myeloid-related lineages, no clinically relevant immunological classification of acute myeloblastic leukemia (AML) has been devised so far. To attempt at formulating such a classification, we analyzed the pattern of expression of selected antigens, on blast cells collected at AML diagnosis. Patients were eligible if they had a first diagnosis of de novo AML and a sufficient number of blast cells for proper immunophenotyping. The relative expression of CD7, CD13, CD14, CD15, CD33, CD34, CD35, CD36, CD65, CD117, and HLA-DR were analyzed by cytometry in a test series of 176 consecutive AML cases. Statistical tools of clusterization allowed to remove antigens with overlapping distribution, leading us to propose an AML classification that was validated in a second AML cohort of 733 patients. We identified five AML subsets (MA to ME) based on the expression of seven antigens within four groups (CD13/CD33/CD117, CD7, CD35/CD36, CD15).-MA and MB-AML have exclusively myeloid features with seldom extramedullary disease and rare expression of lymphoid antigens. No cases of acute promyelocytic leukemia (APL) were observed within MB AML. MC AML have either myeloid or erythroblastic features. MD AML have more frequently high WBC counts than other subsets, which were related to the expression of CD35/CD36 and CD14 and to monoblastic differentiation. ME AML lack CD13, CD33, and CD117 but display signs of terminal myeloid differentiation. Specific independent prognostic factors were related to poor overall survival in each immunological subset: CD34+ (P<3 x 10(-4)) in MA AML, CD7+ in MB AML, non-APL cases (P<0.03) in MC AML, CD34+ (P<0.002) and CD14+ (P<0.03) in MD AML, CD14+ in ME AML (P<0.01). The inclusion of seven key markers in the immunophenotyping of AML allows a stratification into clinically relevant subsets with individual prognostic factors, which should be considered to define high-risk AML populations.

Veratridine, but not elevated K+, inhibits excitatory amino acid transporter activity in rat hippocampal slices.

PURPOSE: Excitatory amino acid transporter (EAAT) activity prevents Glu from reaching toxic levels, but their contribution to epileptogenesis remains controversial. We examined how the convulsant veratridine causes inhibition of EAAT activity and how it differs from the effects of another convulsant, high (50 mM) K+, that also increases Na+ conductance. METHODS: Transverse rat hippocampal slices were incubated for 1 h with 100 microM veratridine in oxygenated artificial cerebrospinal fluid (aCSF) with or without extracellular Ca2+. The medium was replaced by 50 microM[(3)H]glutamate in aCSF, and the slices incubated for 10 min at 37 degrees C. The slices were washed 3 times with cold aCSF after removal of the extracellular medium, and the radioactivity was quantified after solubilization of the slices. RESULTS: Veratridine caused a time- and dose-dependent decrease, whereas high K+ had no effect on EAAT activity. The effects of veratridine on EAAT activity were not prevented by tetrodotoxin (TTX; 10 microM). Coincubation of ouabain with veratridine resulted in further decreases of EAAT activity. Removal of extracellular Ca2+ potentiated the inhibitory effects of veratridine (and other convulsants) on EAAT activity. Chelation of intracellular Ca2+ with BAPTA also increased the inhibitory effects of veratridine on EAAT activity. CONCLUSIONS: Veratridine caused changes Ca2+ dynamics that led to inhibition of EAAT activity. Such changes in EAAT activity can contribute to the sustained epileptiform activity caused by veratridine.

Polyvisceral arteritis in chronic graft-versus-host disease: antiphospholipid-negative thrombotic syndrome mimicking polyarteritis nodosa.

A case of polyarteritis is reported in an 18-year old woman, occurring 2 years after an allogeneic bone marrow transplant. The clinical manifestations were similar to those of polyarteritis nodosa (PAN) with a wide range of organs involved including life-threatening cardiac and mesenteric problems requiring plasmapheresis and intravenous immunoglobulin (IgIV).

Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study.

Mantle cell lymphoma (MCL) is a distinct clinico-pathological entity with a poor prognosis. We have conducted a prospective study in patients with MCL to evaluate a therapeutic strategy in which CHOP polychemotherapy was followed by DHAP if CHOP failed to induce complete remission. Responding patients then proceeded to an intensification therapy with autologous peripheral blood stem cell transplantation (APBSCT). Twenty-eight consecutive patients with newly diagnosed aggressive MCL were included. After four cycles of CHOP regimen, two complete responses (CR) were obtained (7%) and 14 (50%), five (18%) and seven (25%) patients achieved partial (PR), minor (MR) and no response, respectively (one patient died from septic complications during CHOP induction). The two patients in CR after CHOP underwent intensification with TBI, high-dose cyclophosphamide-etoposide and APBSCT. The other twenty-five patients received DHAP and in this group a response rate of 92% (21 CR (84%), two PR (8%)) was observed. Two patients had progressive disease. The twenty-three responding patients received high-dose therapy (TAM8 regimen: TBI-cytarabine-melphalan) followed by APBSCT. One of the two partial responding patients achieved CR after TAM8. After a median follow-up of 47.6 months (range, 14-70), seven patients have relapsed. Our data confirm that: (1) CHOP regimen induces a low CR rate in MCL; (2) CHOP plus DHAP appears to be much more efficient and allows a large proportion of patients to proceed to high-dose therapy in CR; (3) consolidation therapy including TBI and high-dose Arac-C followed by APBSCT may improve event-free survival.

Acute myeloid leukaemia M0: haematological, immunophenotypic and cytogenetic characteristics and their prognostic significance: an analysis in 241 patients.

Haematological, immunophenotypic and cytogenetic characteristics were analysed in 241 patients with acute myeloid leukaemia (AML) M0, including 58 children. Children < 3 years and adults between 60 and 70 years of age were most frequently affected. Immunophenotyping showed a heterogeneous phenotype. Anti-myeloperoxidase was positive in about half of the patients. Cytogenetic data were available from 129 (54%) patients. A normal karyotype was found in only 24%. Most of the abnormalities were unbalanced and the chromosomes 5, 7, 8 and 11 were the most frequently affected. Survival data were available from 152 treated patients (63%). The median overall survival for all patients was 10 months, 20 months for children (n = 36), 10 months for the young adult group (n = 50) and 7 months for the elderly patients (n = 66) (P = 0.09). Karyotype was not a prognostic factor influencing survival. AML M0 shows the immunological characteristics of early progenitor cells, but the expression of the different markers and cytogenetic abnormalities is heterogeneous. The prognosis is poor compared with other de novo AML and similar to that of AML with multilineage dysplasia or AML following myelodysplastic syndromes.

Phase II study of 3-hour infusion of high dose paclitaxel in refractory and relapsed aggressive non-Hodgkin's lymphomas. Groupe d'Etude des Lymphomes de l'Adulte.

BACKGROUND AND OBJECTIVE: The first clinical studies of paclitaxel as a single agent for the treatment of relapsed or refractory low or intermediate grade non-Hodgkin's lymphomas (NHL) yielded controversial results regarding the response rates observed, mainly related to the dose and schedule of administration used. To obtain additional data concerning the efficacy and toxicity of paclitaxel in intermediate and high grade NHL we initiated a phase II study using a 3-hour infusion of high doses of paclitaxel. DESIGN AND METHODS: The eligibility criteria included patients with relapsed or refractory aggressive NHL, a performance status < or = 2 (WHO index), a platelet count > or = 100,000/microL, a neutrophil count > or = 2,000/microL, measurable disease, and adequate hepatic function. Patients were excluded if they were infected with HIV, had a left ventricular ejection fraction < 50%, or prior peripheral neuropathy. Paclitaxel was administered as a 3-hour infusion at a dose of 250 mg/m2 every 3 weeks for a maximum of 6 courses. RESULTS: Of 45 eligible patients, 42 received a total 73 courses of paclitaxel. Forty patients were assessable for response (89%), and 42 for toxicity (93%). Six patients (15%) achieved a partial (n = 4) or a complete remission (n = 2). Responses were observed in intermediate grade (n = 4) as well as in high grade lymphoma (n = 2). The main factor influencing the response to paclitaxel was the median duration of response to previous chemotherapy regimens which was 3 times longer in patients who responded to paclitaxel (16.3 months) than in patients who did not respond to paclitaxel (5.2 months) (p<0.05). The most common serious side effects were related to the hematologic toxicity of paclitaxel, and included grade IV granulocytopenia in 20 cases (48%), grade III/IV thrombocytopenia in 14 cases (33%) and grade III-IV anemia in 13 cases (31%). INTERPRETATION AND CONCLUSIONS: Despite frequent manageable hematologic toxicity, paclitaxel is usually well tolerated at a dose of 250 mg/m2 given by a 3-hour infusion. However, the clinical efficiency as a single therapy seems modest in relapsed or refractory aggressive lymphoma.

Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes.

Overexpression of P-glycoprotein (P-gp) in cancer cells reduces intracellular accumulation of various anticancer drugs including anthracyclines and vinca alkaloids. This multidrug resistance (MDR) phenotype can be reversed in vitro by a number of non-cytotoxic drugs. We have identified the quinine's isomer cinchonine as a potent MDR reversing agent, both in vitro and in animal models. Here, we report an open phase I dose escalation trial in patients with refractory or relapsed malignant lymphoid diseases. Cinchonine dihydrochloride was administered by continuous i.v. infusion for 48 h and escalated over five dose levels ranging from 15 to 35 mg/kg/d. Cinchonine infusion started 24 h before i.v. doxorubicin (25 mg/m2), vinblastine (6 mg/m2), cyclophosphamide (600 mg/m2) and methylprednisolone (1 mg/kg/d) (CHVP regimen) and lasted for 24 h after chemotherapy infusion. Thirty-four patients received 87 cycles of CHVP/cinchonine. The MTD of cinchonine administered by continuous i.v. infusion was 30 mg/kg/d. Prolonged cardiac repolarization was the main dose-limiting toxicity. No ventricular arrhythmia including 'torsade de pointes' was observed. An MDR reversing activity was identified in the serum from every patient and correlated with cinchonine serum level. When infused at 30 mg/kg/d, cinchonine demonstrated a limited influence on doxorubicin pharmacokinetic. We conclude that i.v. infusion of cinchonine might be started 12 h before MDR-related chemotherapy infusion and requires continuous cardiac monitoring but no reduction of cytotoxic drug doses.

The reliability and specificity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. The European Group for the Immunological Classification of Leukemias (EGIL).

We document findings on c-kit (CD117) expression in 1,937 pediatric and adult de novo acute leukemia cases, diagnosed in five single European centers. All cases were well characterized as to the morphologic, cytochemical, and immunologic features, according to the European Group for the Immunological Classification of Leukemias (EGIL). The cases included 1,103 acute myeloid leukemia (AML), 819 acute lymphoblastic leukemia (ALL), 11 biphenotypic acute leukemia (BAL), and 4 undifferentiated (AUL). c-kit was expressed in 741 (67%) AML cases, regardless of the French-American-British (FAB) subtype, one third of BAL, all four AUL, but only in 34 (4%) of ALL cases. The minority of c-kit+ ALL cases were classified as: T-cell lineage (two thirds), mainly pro-T-ALL or T-I, and B lineage (one third); cells from 62% of these ALL cases coexpressed other myeloid markers (CD13, CD33, or both). There were no differences in the frequency of c-kit+ AML or ALL cases according to age being similar in the adult and pediatric groups. Our findings demonstrate that c-kit is a reliable and specific marker to detect leukemia cells committed to the myeloid lineage, and therefore should be included in a routine basis for the diagnosis of acute leukemias to demonstrate myeloid commitment of the blasts. c-kit expression should score higher, at least one point, in the system currently applied to the diagnosis of BAL, as its myeloid specificity is greater than CD13 and CD33. Findings in ALL and AUL suggest that c-kit identifies a subgroup of cases, which may correspond to leukemias either arising from early prothymocytes and/or early hematopoietic cells, both able to differentiate to the lymphoid and myeloid pathways.

Immunophenotypic patterns and cytogenetic anomalies in acute non-lymphoblastic leukemia subtypes: a prospective study of 432 patients.

This study prospectively analysed the relationships between immunophenotypic and cytogenetic features of blast cells in 432 acute non-lymphoblastic leukemias (ANLL) at presentation. An abnormal karyotype was detected in 232 cases (54%). These abnormalities were related to immunophenotypic markers as detected using a consensual panel of monoclonal antibodies allowing lineage assignment and investigation of myeloid marker expression on blast cells. In univariate analysis, CD9, CD10, CD15, CD34 and TdT expression appeared significantly associated with chromosomal anomalies. Multivariate analysis identified CD34 and CD9 expression as independently predictive of the presence of at least one cytogenetic abnormality (P < 10(-4) and P < 0.03, respectively). Significant associations between immunophenotypic and karyotypic features were observed both within individual FAB subgroups and independently from morphological criteria. Specific features were seen in five ANLL entities: M0 or M1/B lineage antigen positivity/t(9;22) or del(11)(q23); M2/CD13-/t(8;21); M4/CD13+, CD34+, CD36+/inv(16); M4 or M5/lack of B lineage antigen/del(11)(q23) or t(9;11). More practically, and although the relationships demonstrated only represent a fraction of homogeneous immunophenotypic subgroups, identification of such immunophenotypic features should prompt careful karyotypic examination, eventually using molecular biology analysis on non-growing cells.

Peripheral blood stem cell transplantation in a multiple myeloma patient with end-stage renal failure.

Multiple myeloma with IgG kappa monoclonal gammopathy and oliguric renal failure requiring hemodialysis was diagnosed in a 49-year-old man. Conventional therapy with VAD (vincristin, adriamycin, dexamethasone) failed to induce a complete response (CR) but this was subsequently obtained following two cycles of high-dose intravenous melphalan (70 mg/m2). A relapse occurred 8 months after CR which was treated by intensive myeloablative therapy combining total body irradiation (6 Gy over 2 days) and high-dose intravenous melphalan (140 mg/m2) followed by supportive PBSC transplantation. Hemodialysis was performed every other day during the myeloablative therapy and subsequent aplasia. Fluid subtraction allowed 1500 Cal/day intravenous alimentation and the only adverse event observed was a severe mucositis. A second CR was obtained which lasted 14 months. This observation indicates that multiple myeloma patients with end-stage renal failure can receive intensive myeloablative therapy without major toxicity.