Impact of BMI on patient outcome in acute myeloid leukaemia patients receiving intensive induction therapy: a real-world registry experience.

BACKGROUND: Acute myeloid leukaemia (AML) is treated with intensive induction chemotherapy (IT) in medically fit patients. In general, obesity was identified as a risk factor for all-cause mortality, and there is an ongoing debate on its impact on outcome and optimal dosing strategy in obese AML patients. METHODS: We conducted a registry study screening 7632 patients and assessed the impact of obesity in 1677 equally IT treated, newly diagnosed AML patients on the outcome (OS, EFS, CR1), comorbidities, toxicities and used dosing strategies. RESULTS: Obese patients (BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, P = 0.015) and CR1 rate (78.7% vs. 84.3%, P = 0.015) without differences in median EFS (7.8 vs. 9.89 months, P = 0.3) compared to non-obese patients (BMI < 30). The effect was predominantly observed in older (≥60 years) patients. Obesity was identified as an independent risk factor for death, and obese patients demonstrated higher rates of cardiovascular or metabolic comorbidities. No differences for OS, EFS, CR1 or treatment-related toxicities were observed by stratification according to used dosing strategy or dose reduction. CONCLUSIONS: In conclusion, this study identifies obesity as an independent risk factor for worse OS in older AML patients undergoing curative IT most likely due to obesity-related comorbidities and not to dosing strategy.

The new German evidence-based guideline on diffuse large B-cell lymphoma-key aspects for radiation oncologists.

PURPOSE: Diffuse large B­cell lymphoma (DLBCL) is an aggressive lymphoma subtype treated successfully with immunochemotherapy. However, there are conflicting data on the role and impact of consolidative radiation therapy (RT). The publication of the national evidence-based guideline on DLBCL prompted us to review relevant passages on radiation oncology. METHODS: The following article reviews the evidence and recommendations given in the current German evidence-based guideline on DLBCL regarding RT and summarizes pivotal aspects. Additional literature is presented to provide a comprehensive background for the published recommendations. RESULTS: RT shall be administered to all patients with localized positron emission tomography(PET)-positive residues after completion of immunochemotherapy and should use a dose of 30-40 Gray in normofractionation. For RT planning, PET information before and after immunochemotherapy shall be used, with either a PET-CT in the RT treatment position or an image fusion to the planning CT. Conformal techniques shall be used for target volume coverage, with a risk-benefit evaluation for the individual patient. Additionally, RT may be used in the treatment context of various subtypes of DLBCL as well as in the recurrent or refractory treatment situation. CONCLUSION: RT remains an integral part of the treatment repertoire of DLBCL. With the use of PET-guided treatment, RT is indicated for patients with metabolically active tumors. In the context of the ongoing development of targeted therapies, new RT indications may evolve.

B-cell receptor reactivity against Rothia mucilaginosa in nodular lymphocyte-predominant Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a Hodgkin lymphoma expressing functional B-cell receptors (BCR). Recently, we described a dual stimulation model of IgD+ lymphocyte-predominant cells by Moraxella catarrhalis antigen RpoC and its superantigen MID/hag, associated with extralong CDR3 and HLA-DRB1*04 or HLADRB1* 07 haplotype. The aim of the present study was to extend the antigen screening to further bacteria and viruses. The fragment antibody-binding (Fab) regions of seven new and 15 previously reported cases were analyzed. The reactivity of non-Moraxella spp.-reactive Fab regions against lysates of Rothia mucilaginosa was observed in 5/22 (22.7%) cases. Galactofuranosyl transferase (Gltf) and 2,3-butanediol dehydrogenase (Bdh) of R. mucilaginosa were identified by comparative silver- and immuno-staining in two-dimensional gels, with subsequent mass spectrometry and validation by western blots and enzyme-linked immunosorbent assay. Both R. mucilaginosa Gltf and Bdh induced BCR pathway activation and proliferation in vitro. Apoptosis was induced by recombinant Gltf/ETA'-immunotoxin conjugates in DEV cells expressing recombinant R. mucilaginosa-reactive BCR. Reactivity against M. catarrhalis RpoC was confirmed in 3/7 newly expressed BCR (total 10/22 reactive to Moraxella spp.), resulting in 15/22 (68.2%) cases with BCR reactivity against defined bacterial antigens. These findings strengthen the hypothesis of bacterial trigger contributing to subsets of NLPHL.

Impact of trisomy 19 on outcome according to genetic makeup in patients with acute myeloid leukemia.

We retrospectively studied 97 acute myeloid leukemia patients with trisomy 19 (median age at diagnosis 57 years; range, 17- 83 years) treated between 2001 and 2019 within two multicenter study groups. Trisomy 19 occurred alone in ten (10.5%) patients, with additional abnormalities being present in non-complex karyotypes in eight (8%) patients and in complex karyotypes in 79 (82%) patients. Altogether, karyotypes characterized by trisomies only were present in 27 (28%) patients. Data on response and outcome of intensively treated patients were available for 92 cases. The median follow-up was 6.4 years (95% confidence interval [95% CI]: 2.9-9.0 years). The complete remission (CR) rate after induction therapy was 52% (48 patients); the early death rate was 10% (n=9). Notably, patients with trisomy 19 as the sole abnormality had a CR rate of 89%. Allogeneic hematopoietic stem cell transplantation (allo-HCT) was performed in 34 (35%) patients (CR, n=19; active disease, n=15). Five-year relapse-free and overall survival rates were 26% (95% CI: 16-43%) and 20% (95% CI: 13-31%), respectively. Overall survival rates were significantly higher in patients with trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only (P=0.05). An Andersen-Gill model including allo-HCT as a time-dependent covariable on overall survival revealed that trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only was a favorable factor (hazard ratio [HR]=0.47; P=0.021); higher age at diagnosis had an adverse impact (10 years difference; HR=1.29; P=0.002), whereas allo-HCT did not have a beneficial impact (odds ratio=1.45; P=0.21). In our cohort, patients with trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only had a high CR rate and better clinical outcome.

Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD.

Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI], 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.

Identification of the atypically modified autoantigen Ars2 as the target of B-cell receptors from activated B-cell-type diffuse large B-cell lymphoma.

It has been suggested that B-cell receptor (BCRs) stimulation by specific antigens plays a pathogenic role in diffuse large B-cell lymphoma (DLBCL). Here, it was the aim to screen for specific reactivities of DLBCL-BCRs in the spectrum of autoantigens and antigens of infectious origin. Arsenite resistance protein 2 (Ars2) was identified as the BCR target of 3/5 ABC-type DLBCL cell lines and 2/11 primary DLBCL cases. Compared to controls, Ars2 was hypo-phosphorylated exclusively in cases and cell lines with Ars2-specific BCRs. In a validation cohort, hypo-phosphorylated Ars2 was found in 8/31 ABC-type, but only 1/20 germinal center B cell (GBC)-like type DLBCL. Incubation with Ars2 induced BCR-pathway activation and increased proliferation, while an Ars2/ETA-toxin conjugate induced killing of cell lines with Ars2-reactive BCRs. Ars2 appears to play a role in a subgroup of ABC-type DLBCLs. Moreover, transformed DLBCL lines with Ars2-reactive BCRs still show growth advantage after incubation with Ars2. These results provide knowledge about the pathogenic role of a specific antigen stimulating the BCR pathway in DLCBL.

FDG PET/CT to detect bone marrow involvement in the initial staging of patients with aggressive non-Hodgkin lymphoma: results from the prospective, multicenter PETAL and OPTIMAL>60 trials.

PURPOSE: Fluorine-18 fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET/CT) is the standard for staging aggressive non-Hodgkin lymphoma (NHL). Limited data from prospective studies is available to determine whether initial staging by FDG PET/CT provides treatment-relevant information of bone marrow (BM) involvement (BMI) and thus could spare BM biopsy (BMB). METHODS: Patients from PETAL (NCT00554164) and OPTIMAL>60 (NCT01478542) with aggressive B-cell NHL initially staged by FDG PET/CT and BMB were included in this pooled analysis. The reference standard to confirm BMI included a positive BMB and/or FDG PET/CT confirmed by targeted biopsy, complementary imaging (CT or magnetic resonance imaging), or concurrent disappearance of focal FDG-avid BM lesions with other lymphoma manifestations during immunochemotherapy. RESULTS: Among 930 patients, BMI was detected by BMB in 85 (prevalence 9%) and by FDG PET/CT in 185 (20%) cases, for a total of 221 cases (24%). All 185 PET-positive cases were true positive, and 709 of 745 PET-negative cases were true negative. For BMB and FDG PET/CT, sensitivity was 38% (95% confidence interval [CI]: 32-45%) and 84% (CI: 78-88%), specificity 100% (CI: 99-100%) and 100% (CI: 99-100%), positive predictive value 100% (CI: 96-100%) and 100% (CI: 98-100%), and negative predictive value 84% (CI: 81-86%) and 95% (CI: 93-97%), respectively. In all of the 36 PET-negative cases with confirmed BMI patients had other adverse factors according to IPI that precluded a change of standard treatment. Thus, the BMB would not have influenced the patient management. CONCLUSION: In patients with aggressive B-cell NHL, routine BMB provides no critical staging information compared to FDG PET/CT and could therefore be omitted. TRIAL REGISTRATION: NCT00554164 and NCT01478542.

Age-dependent increase of treatment-related mortality in older patients with aggressive B cell lymphoma: analysis of outcome, treatment feasibility, and toxicity in 1171 elderly patients with aggressive B cell lymphoma-data from phase II and III trials of the DSHNHL (German High-Grade Non-Hodgkin's Lymphoma Study Group).

In elderly patients (pts) with aggressive B cell lymphoma (aNHL), curative treatment often cannot be administered because of comorbidities and tolerability. We analyzed the influence of age in pts > 60 years receiving the R-CHOP-14 regimen within different prospective DSHNHL trials. Of the RICOVER-60 trial and CHOP-R-ESC trials, 1171 aNHL pts were included in this retrospective analysis of age-dependent event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All patients received prophylactic G-CSF, and anti-infective prophylaxis with amphotericin B mouth wash and oral fluorchinolone was optional. In the CHOP-R-ESC trials, prophylaxis was augmented to include mandatory continuous orally administered aciclovir and a pneumocystis prophylaxis with cotrimoxazole as well as oral fluorchinolones during neutropenia. The patient population was separated into 4 age groups (61-65 years, 66-70 years, 71-75 years, and 76-80 years). The results from the RICOVER-60 trial were subsequently confirmed in the following CHOP-R-ESC trials by a multivariate analysis adjusted for IPI factors and gender. Significant differences (p < 0.001) in EFS, PFS, and OS were seen between age groups (RICOVER-60). Hematotoxicity, infections, and TRM increased with age. TRM was significantly elevated in the age group 76-80 years. Therefore, this analysis shows that an age above 75 years defines an especially vulnerable patient population when being treated with chemoimmunotherapy for aNHL. Prophylactic anti-infective drugs are essential and clinically effective in reducing morbidity when treating elderly aNHL pts.

VEGFR2 and VEGFA polymorphisms are not associated with an inferior prognosis in Caucasian patients with aggressive B-cell lymphoma.

PURPOSE: Previous published data showed an impact of single-nucleotide polymorphisms in the VEGF A and VEGFR2 genes on the survival of patients with various malignancies, among others diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: We investigated the role of four VEGF-A and two VEGFR-2 gene polymorphisms on the outcome of 273 patients with diffuse large B-cell lymphoma who were treated with R-CHOP within a prospective, randomized trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). The genomic DNA samples were analyzed using commercial DNA Probes (Applied Biosystems, USA) to detect single-nucleotide polymorphisms in the VEGF A rs699947, rs1570360, rs2010963, rs3025039 and rs1870377, and rs2305948 in the VEGFR2 receptor. Hundred healthy blood donors served as a control. RESULTS: There was no difference between the SNP allele frequencies in lymphoma patients compared to the control group for all investigated SNPs. None of the investigated SNPs was significantly associated with EFS or OS. After adjusting for the International Prognostic Index risk factors in a multivariate analysis, these results could be confirmed. CONCLUSION: Single-nucleotide polymorphisms of the VEGF and VEGFR2 were not associated with a worse outcome in Caucasian patients with DLBCL.

Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.

BACKGROUND: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis. METHODS: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1·4 mg/m2, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421. FINDINGS: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy. INTERPRETATION: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population. FUNDING: Deutsche Krebshilfe.

Characterization of an HLA-restricted and human cytomegalovirus-specific antibody repertoire with therapeutic potential.

With an infection rate of 60-90%, the human cytomegalovirus (HCMV) is very common among adults but normally causes no symptoms. When T cell-mediated immunity is compromised, HCMV reactivation can lead to increased morbidity and mortality. HCMV antigens are processed and presented as peptides on the cell surface via HLA I complexes to the T cell receptor (TCR) of T cells. The generation of antibodies against HCMV peptides presented on HLA complexes (TCR-like antibodies) has been described, but is without therapeutic applications to date due to the polygenic and polymorphic nature of HLA genes. We set out to obtain antibodies specific for HLA/HCMV-peptides, covering the majority of HLA alleles present in European populations. Using phage display technology, we selected 10 Fabs, able to bind to HCMV-peptides presented in the 6 different HLA class I alleles A*0101, A*0201, A*2402, B*0702, B*0801 and B*3501. We demonstrate specific binding of all selected Fabs to HLA-typed lymphoblastoid cell lines (EBV-transformed B cells) and lymphocytes loaded with HCMV-peptides. After infection with HCMV, 4/10 tetramerized Fabs restricted to the alleles HLA-A*0101, HLA-A*0201 and HLA-B*0702 showed binding to infected primary fibroblasts. When linked to the pseudomonas exotoxin A, these Fab antibodies induce highly specific cytotoxicity in HLA matched cell lines loaded with HCMV peptides. TCR-like antibody repertoires therefore represent a promising new treatment modality for viral infections and may also have applications in the treatment of cancers.

High-dose therapy and autologous stem cell transplantation in marginal zone lymphomas: a retrospective study by the EBMT Lymphoma Working Party and FIL-GITMO.

The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphoma (MZL) is debatable. This study investigated the outcome and prognostic factors affecting the outcome of patients undergoing ASCT for MZL. Eligible patients had non-transformed nodal, extra-nodal (MALT) or splenic MZL (SMZL), aged ≥18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, [111 MALT lymphoma, 55 nodal MZL (NMZL) and 33 SMZL]. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1-8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy-based high-dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub-group and more transplants performed in recent years in the other sub-groups. After a median follow-up of 5 years, 5-year cumulative incidence of relapse/progression and non-relapse mortality were 38% and 9%, respectively. Five-year event-free survival (EFS) and overall survival (OS) were 53% and 73%, respectively. Five-year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age ≥65 years was associated with a shorter EFS and OS. In addition, patients with SMZL had a shorter OS than those with MALT. ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy.

Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients.

Male sex is associated with unfavourable pharmacokinetics and prognosis in elderly patients with diffuse large B-cell lymphoma (DLBCL). We investigated higher rituximab doses for elderly male DLBCL patients. Elderly patients (61-80 years) received 6 cycles CHOP-14 (cyclophosphamide, doxorubicin, vincristine and prednisone at 14-day intervals) and were randomized to 8 cycles rituximab (males 500 mg/m2 , females 375 mg/m2 ) every 2 weeks or according to an upfront dose-dense schedule. In 268 (120 females, 148 males) no difference between the standard and the upfront dose-dense rituximab schedule was found (3-year PFS 72% vs. 74%; OS 74% vs. 77%; P = 0.651). The 500 mg/m2 dose of rituximab for male patients was associated with serum levels and exposure times slightly better than in females and a male/female hazard ratio of 0.9 for progression-free survival (PFS) and 0.8 for overall survival. For elderly males, 500 mg/m2 was not more toxic than 375 mg/m2 rituximab, but improved PFS by 32.5% (P = 0.039), with a trend for a (30%) better overall survival (P = 0.076) in a planned subgroup analysis adjusting for International Prognostic Index risk factors. We conclude that the higher rituximab dose for elderly male patients abrogated the adverse prognosis of male sex without increasing toxicity. In the era of personalized medicine, sex-specific pharmacokinetics and toxicities should be investigated for all drugs where these parameters impact on outcome.

MHC/Peptide-Specific Interaction of the Humoral Immune System: A New Category of Antibodies.

Abs bind to unprocessed Ags, whereas cytotoxic CD8(+) T cells recognize peptides derived from endogenously processed Ags presented in the context of class I MHC complexes. We screened, by ELISA, human sera for Abs reacting specifically with the influenza matrix protein (IMP)-derived peptide(58-66) displayed by HLA-A*0201 complexes. Among 653 healthy volunteers, blood donors, and women on delivery, high-titered HLA-A*0201/IMP(58-66) complex-specific IgG Abs were detected in 11 females with a history of pregnancies and in 1 male, all HLA-A*0201(-). These Abs had the same specificity as HLA-A*0201/IMP(58-66)-specific cytotoxic T cells and bound neither to HLA-A*0201 nor the peptide alone. No such Abs were detected in HLA-A*0201(+) volunteers. These Abs were not cross-reactive to other self-MHC class I alleles displaying IMP(58-66), but bound to MHC class I complexes of an HLA nonidentical offspring. HLA-A*0201/IMP(58-66) Abs were also detected in the cord blood of newborns, indicating that HLA-A*0201/IMP(58-66) Abs are produced in HLA-A*0201(-) mothers and enter the fetal blood system. That Abs can bind to peptides derived from endogenous Ags presented by MHC complexes opens new perspectives on interactions between the cellular and humoral immune system.

Suboptimal dosing of rituximab in male and female patients with DLBCL.

To determine the effect of gender on outcome, the male hazard ratio for progression-free survival (HRPFS-male) was determined in patients with diffuse large B-cell lymphoma (DLBCL). In young patients (MapThera International Trial study), HRPFS-male was 1.3 (P = .092) without and 1.1 (P = .660) with rituximab. In elderly patients (RICOVER-60 study), HRPFS-male was 1.1 (P = .348) with CHOP but increased to 1.6 (P = .004) with R-CHOP. The similar improvements of outcome in young patients were associated with similar rituximab clearances in young males and females (9.89 vs 10.38 mL/h; P = .238), whereas the greater benefit for elderly females was associated with a slower rituximab clearance (8.47 vs 10.59 mL/h; P = .005) and hence higher serum levels and longer exposure times, attributable to an age-dependent (P = .004) decrease of rituximab clearance in females but not males. Compared with elderly females, all other subgroups had significantly faster rituximab clearances and hence appear to be suboptimally dosed when rituximab is given at 375 mg/m(2). Although early results of pharmacokinetic-based prospective trials designed to exploit the full therapeutic potential of rituximab suggest that increased doses and/or prolonged exposure times can improve the outcome of elderly males with DLBCL, further studies are warranted that address the optimization of rituximab dose and schedule in all subgroups of DLBCL patients.

The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial aggressive B-cell lymphomas.

To define the role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement (ECFI) of aggressive B-cell lymphoma, we analyzed 11 consecutive German High-Grade Non-Hodgkin Lymphoma Study Group trials. ECFI occurred in 290/4155 (7.0%) patients (orbita, 31; paranasal sinuses, 93; main nasal cavity, 38; tongue, 27; remaining oral cavity, 99; salivary glands, 54). In a multivariable analysis adjusted for International Prognostic Index rituximab improved event-free and overall survival both in patients with and without ECFI. Three-year event-free (79% vs 79%; P = .842) and overall survival (86% vs 88%; P = .351) rates were similar in 145 patients receiving and 57 not receiving radiotherapy. Without rituximab, the 2-year cumulative rate of central nervous system (CNS) disease was increased in 205 ECFI patients compared with 2586 non-ECFI patients (4.2% vs 2.8%; P = .038), whereas this was not observed with rituximab (1.6% in 83 ECFI vs 3.4% in 1252 non-ECFI patients; P = .682). In 88 ECFI patients who received intrathecal prophylaxis with methotrexate, the 2-year rate of CNS disease was 4.2% compared with 2.3% in 191 patients who did not (P = .981). In conclusion, rituximab eliminates the increased risk for CNS disease in patients with ECFI. This retrospective analysis does not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission. These findings should be confirmed in a prospective study.

Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation.

The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITDs), as well as concurrent gene mutations, with regard to postremission therapy in 323 patients with FLT3-ITD-positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (P = .004) and IS in the tyrosine kinase domain 1 (TKD1, P = .06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (n = 121) or autologous hematopoietic stem cell transplantation (HSCT, n = 17), an allelic ratio ≥ 0.51 was associated with an unfavorable relapse-free (RFS, P = .0008) and overall survival (OS, P = .004); after allogeneic HSCT (n = 93), outcome was significantly improved in patients with a high allelic ratio (RFS, P = .02; OS, P = .03), whereas no benefit was seen in patients with a low allelic ratio (RFS, P = .38; OS, P = .64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AMLHD93 and AMLHD98A, previously published; AML SG 07-04, ClinicalTrials.gov identifier #NCT00151242.

Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients.

The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255.

All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07-04 study.

The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m2, days 6-8; 15 mg/m2, days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95).