Background— A significant number of patients treated with anthracyclines develop cardiotoxicity (anthracycline-induced cardiotoxicity [ACT]), mainly presenting as arrhythmias (acute ACT) or congestive heart failure (chronic ACT). There are no data on pharmacogenomic predictors of ACT. Methods and Results— We genotyped participants of the German non-Hodgkin lymphoma study (NHL-B) who were followed up for the development of heart failure for a median of >3 years. Single-nucleotide polymorphisms (SNPs) were selected from 82 genes with conceivable relevance to ACT. Of 1697 patients, 55 developed acute and 54 developed chronic ACT (cumulative incidence of either form, 3.2%). We detected 5 significant associations with polymorphisms of the NAD(P)H oxidase and doxorubicin efflux transporters. Chronic ACT was associated with a variant of the NAD(P)H oxidase subunit NCF4 (rs1883112, −212A→G; symbols with right-pointing arrows, as edited?‘ odds ratio [OR], 2.5; 95% CI, 1.3 to 5.0). Acute ACT was associated with the His72Tyr polymorphism in the p22phox subunit (rs4673; OR, 2.0; 95% CI, 1.0 to 3.9) and with the variant 7508T→A (rs13058338; OR, 2.6; 95% CI, 1.3 to 5.1) of the RAC2 subunit of the same enzyme. In agreement with these results, mice deficient in NAD(P)H oxidase activity, unlike wild-type mice, were resistant to chronic doxorubicin treatment. In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95% CI, 1.0 to 5.4). Polymorphisms in adrenergic receptors previously demonstrated to be predictive of heart failure were not associated with ACT. Conclusions— Genetic variants in doxorubicin transport and free radical metabolism may modulate the individual risk to develop ACT.

The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone, given every 3 weeks (CHOP-21) is standard chemotherapy for aggressive lymphomas. To determine whether CHOP given every 2 weeks (CHOP-14) or the addition of etoposide (CHOEP-21, CHOEP-14) can improve results in patients ages 18 to 60 years with good prognosis (normal lactic dehydrogenase [LDH] level), 710 patients were randomized to 6 cycles of CHOP-21, CHOP-14, CHOEP-21 (CHOP plus etoposide 100 mg/m 2 days 1-3), or CHOEP-14 in a 2 ؋ 2 factorial study design. Patients in the biweekly regimens received granulocyte colony-stimulating factor (G-CSF) starting from day 4. Patients received radiotherapy (36 Gy) to sites of initial bulky disease and extranodal disease. CHOEP achieved better complete remission (87.6% versus 79.4%; P ‫؍‬ .003) and 5-year event-free survival rates (69.2% versus 57.6%; P ‫؍‬ .004, primary end point) than CHOP, whereas interval reduction improved overall survival (P ‫؍‬ .05; P ‫؍‬ .044 in the multivariate analysis). Although the CHOEP regimens induced more myelosuppression, all regimens were well tolerated. CHOEP should be the preferred chemotherapy regimen for young patients with good-prognosis (normal LDH level) aggressive lymphoma.

The incidence of CNS relapse in 1693 patients treated for aggressive lymphomas on DSHNHL protocols from 1990 to 2000 was low (2.2%), although CNS prophylaxis was administered to <5% of patients. Thus, a general prophylaxis for all patients is not warranted, the less so since the effectiveness of i.th. prophylaxis itself is judged controversially. Increased LDH and involvement of more than one extranodal site were confirmed as independent risk factors. A cumulative 20% incidence of CNS disease in certain prognostic subgroups of elderly patients may render these candidates for i.th. prophylaxis; however, this approach would imply a potential overtreatment of approximately 80% of these patients deemed at high risk.

CHOP-14 with the addition of rhG-CSF is safe and practicable in a large multicentre setting in patients aged 18-75 years. Despite shorter treatment intervals it can be delivered at the same dose as the classical 3-weekly CHOP with a comparable toxicity profile. The addition of etoposide is feasible and safe for patients 60 years of age the addition of etoposide is associated with marked dose erosion due to increased toxicity. In this age group CHOEP should be used with caution.

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BACKGROUNDPatients with aggressive lymphoma and high‐risk features at the time of diagnosis are reported to have a poor prognosis with standard therapy. Attempts to improve the results achieved with the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) using second‐generation or third‐generation chemotherapy have failed. In the current study, the authors increased the doses and dose intensity of drugs used for the conventional first‐line therapy of aggressive lymphoma and designed a Phase II randomized trial that compared four and six courses of dose‐escalated CHOP plus etoposide (megaCHOEP) supported by the transplantation of peripheral blood stem cells.METHODSEighty‐four patients age < 60 years with aggressive lymphoma and elevated lactate dehydrogenase (LDH) levels were randomized to receive either 4 (Arm A) or 6 (Arm B) courses of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (megaCHOEP). The last three treatment courses were supported by autologous peripheral blood stem cell transplantation. Although the total doses of cyclophosphamide and etoposide were comparable, the dose intensity during the first 3 treatment courses was planned to be 2.8‐fold and 2.0‐fold higher, respectively, for patients in Arm A.RESULTSThirty‐seven patients in Arm A (90.2%) but only 18 patients in Arm B (69.2%) were able to complete therapy (P = 0.048). The complete response rate was 65.8% in Arm A and 50.0% in Arm B; the disease recurrence rates were 18.5% versus 61.5% (P = 0.011). Freedom from treatment failure at 2 years was 52.5% (95% confidence interval [95% CI], 36.9–68.2%) in Arm A and 23.1% (95% CI, 6.9–39.3%) in Arm B (P = 0.02). The overall survival rate was 70% (95% CI, 54.9–85.0%) in Arm A and 46.2% (95% CI, 27.0–65.3%) in Arm B (P = 0.037).CONCLUSIONSThe results of the current study demonstrate that dose intensity, in particular early dose intensity, significantly influences disease control with high‐dose therapy (HDT) and autologous stem cell transplantation. These results also may explain the failure of HDT with low early dose intensity to improve the results obtained with conventional chemotherapy. Cancer 2006. © 2005 American Cancer Society.

Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. The role of an autologous tumor-specific immune control contributing to the variable length of survival in CLL is poorly understood. We investigated whether humoral immunity specific for the CLL-associated Ag oncofetal Ag/immature laminin receptor (OFA/iLR) has a prognostic value in CLL. Among sera of 67 untreated patients with CLL, 23 (34.3%) had detectable OFA/iLR Abs that were reactive for at least one specific OFA/iLR epitope. Patients with humoral responses compared with patients with nonreactive sera had a longer progression-free survival (p = 0.029). IgG subclass analyses showed a predominant IgG1 and IgG3 response. OFA/iLR Abs were capable of recognizing and selectively killing OFA/iLR-expressing CLL cells in complement-mediated and Ab-dependent cellular cytotoxi cityassays. In the analysis of 11 CLL patients after allogeneic hematopoetic stem cell transplantation, 8 showed high values for OFA/iLR Abs that specifically recognized the extracellular domain of the protein, suggesting a potential role of anti-OFA/iLR-directed immune responses to the graft-vs-leukemia effect in CLL. Our data suggest that spontaneous tumor-specific humoral immune responses against OFA/iLR exist in a significant proportion of CLL patients and that superior progression-free survival in those patients could reflect autologous immune control.

Interval reduction from 3 (CHOP-21) to 2 weeks (CHOP-14; Pfreundschuh et al., Blood, 2004) and the addition of rituximab to CHOP-21 (R-CHOP-21; Coiffier et al., NEJM, 2002) improved outcome in elderly patients with DLBCL to a similar extent without increasing toxicity compared to CHOP-21. In the RICOVER-60 trial, elderly patients (61–80 years, stages I–IV) were randomized to receive 6 or 8 cycles of CHOP-14 with or without 8 applications of rituximab given on days 1, 15, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. The primary endpoint was freedom from treatment failure (FFTF) with events defined as additional therapy, failure to achieve complete remission, progressive disease, relapse, or death. The trial was powered to show a 9% difference in FFTF rate after 3 years. Between 07/2000 and 06/2005, 1330 patients were recruited. A planned interim analysis was performed on 828 evaluable patients with CD20+ DLBCL (median age 68 years; IPI=1: 32%, IPI=2: 29%; IPI=3: 23%; IPI=4,5: 16%). As by intention to treat, there was no difference in FFTF between 6 (n=414) and 8 (n=413) cycles (p=0.23), but FFTF after R-CHOP-14 (n=414) was significantly better than after CHOP-14 (n=413) alone (p=0.000025). As the empirical p-value of the log rank test statistics for FFTF was considerably lower than the critical value for the interim analysis (pcrit=0.031), the formal criterion for stopping the trial according to the alpha spending function (O’ Brien and Fleming boundary) was met and the trial was stopped on June 17, 2005 with 50/1330 patients still under therapy. After a median observation time of 26 months, there was a trend for a better FFTF after 8 cycles of CHOP-14 (n=210) compared to 6 cycles (n=203; 58% vs. 53%; p=0.13), but this trend was neutralized after the addition of rituximab: 70% FFTF for both 6 (n=211) and 8 cycles R-CHOP-14 (n=203). The advantage of R-CHOP-14 over CHOP-14 with respect to overall survival after 26 months is not yet significant (74% vs. 78%; p=0.13). Excluding patients with stage I, the RICOVER-60 population is very similar to the one included in the GELA 98.5 trial; however, the projected 2.5-year survival rate for elderly stage II–IV patients after 6 x R-CHOP-14 (74%) compares favorably with 8 x R-CHOP-21 in the GELA trial (64%; Feugier et al. JCO 2005). The superiority of 6 x R-CHOP-14 over 8 x R-CHOP-21 is mostly due to the better 2.5-year survival of poor-prognosis patients (IPI=3,4,5: 64% in the RICOVER trial vs. 54% in the GELA trial). In conclusion, the results observed with 6 cycles of R-CHOP-14 in this largest randomized trial of DLBLC performed to date are the best ever reported for elderly patients with DLBCL. 6 x R-CHOP-14 should be considered as reference standard in future trials for elderly patients with DLBCL.