Advani, Ranjana H.

Summary A persistently positive positron emission tomography ( PET ) scan during therapy for diffuse large B‐cell lymphoma ( DLBCL ) is predictive of treatment failure. A response‐adapted strategy consisting of an early treatment change to four cycles of R‐ ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R‐ CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET ‐positive patients received four cycles of R‐ ICE , PET ‐negative patients received two more cycles of R‐ CHOP . A ≥45% 2‐year progression‐free survival ( PFS ) for mid‐treatment PET ‐positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two‐year PFS was 70%; 42% [90% confidence interval (CI), 19–63%] for PET ‐positives and 76% (90% CI 65–84%) for PET ‐negatives. Three‐year overall survival ( OS ) was 69% (90% CI 43–85%) and 93% (90% CI 86–97%) for PET ‐positive and ‐negative cases, respectively. The 2‐year PFS for mid‐treatment PET ‐positive patients intensified to R‐ ICE was 42%, with a wide confidence interval due to the low proportion of positive mid‐treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials.

Abstract Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

SummaryPrimary breast diffuse large B‐cell lymphoma (DLBCL) is a rare subtype of non‐Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow‐up of 4·5 years (range 0·6–20·6 years), the Kaplan–Meier estimated median progression‐free survival was 10·4 years (95% confidence interval [CI] 5·8–14·9 years), and the median overall survival was 14·6 years (95% CI 10·2–19 years). Twelve patients (16%) had CNS relapse. A low stage‐modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage‐modified IPI score is associated with survival.

A 15-gene expression signature predicts whether a patient with diffuse large B cell lymphoma will respond to dacetuzumab, a therapeutic antibody.

Abstract Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET+ interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: κ statistic = 0.445 using ECOG criteria, and κ statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924.

Purpose To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Patients and Methods A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n = 66) versus MEC (n = 63) to treat patients with relapsed or refractory AML and high-risk MDS. Results For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P = not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased—35% versus 15% for the remaining patients (P = .018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients’ overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR− patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P = .09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents. Conclusion CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.