Intensification treatment based on early FDG‐PET in patients with high‐risk diffuse large B‐cell lymphoma: a phase II GELTAMO trial

We conducted a multicentre, phase II study of interim positron emission tomography (PET) as a guide to risk‐adapted therapy in high‐risk patients with newly diagnosed diffuse large B‐cell lymphoma (DLBCL). Patients achieving negative fluorodeoxyglucose (FDG)‐PET after three courses of R‐MegaCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) received three additional courses, whereas PET‐positive patients received two courses of R‐IFE (rituximab, ifosfamide, etoposide) followed by BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem‐cell transplantation. The primary endpoint was progression‐free survival (PFS). 71 patients (median age 55 years, range 25–69) were enrolled. With a median follow‐up of 42·8 months (range 7·2–58·4), the estimated 4‐year PFS and overall survival (OS) were 67% and 78%, respectively, for the global series. Patients in complete remission after interim PET (N = 36) had significantly better 3‐year PFS than those with partial response (N = 30) [81% vs. 57%, Hazard ratio (HR) = 2·6, 95% confidence interval (CI) = 1·02–6·65] but not a statistically significant longer OS. A retrospective PET central review was done for 51 patients. According to semiquantitative analysis, 3‐year PFS (81% vs. 33%; HR = 6·9, 95% CI = 2·35–20·6) and OS (95% vs. 33%, HR = 19·4, 95% CI = 3·89–97·0) were significantly better for negative than for positive interim PET patients. Early PET assessment is valuable for risk stratification in DLBCL; for this purpose semiquantitative evaluation is a better predictor than visual criteria.     

Primary gastric diffuse large B‐cell Lymphoma (DLBCL): analyses of prognostic factors and value of pretreatment FDG‐PET scan

Objectives: We report a single institution experience with gastric diffuse large B‐cell lymphoma (DLBCL) in an attempt to evaluate the roles of different treatment modalities, to assess the value of pretreatment positron emission tomography (PET) scan, and to identify potential prognostic factors. Methods: Among 384 patients diagnosed with DLBCL between 1995 and 2008, 75 patients had primary gastric DLBCL and were reviewed and analyzed. Results: The median age was 66. International prognostic index (IPI) risk was low in 52%, low‐intermediate in 23%, high‐intermediate in 9%, and high in 16%. Pretreatment PET scan was highly sensitive in detecting gastric lesions except stage I gastric DLBCL without detectable mass by CT or gastroscopy. As a general rule, patients with limited‐stage disease were treated with three times of CHOP (with or without rituximab) and radiotherapy, and those with advanced‐stage disease were treated with eight cycles of CHOP (with or without rituximab), and radiotherapy was given to residual diseases after chemotherapy. Three‐year overall survival (OS) rate was 78%. Multivariate analysis revealed that low albumin, hemoglobin <12.0 g/dL, and treatment without rituximab were independently associated with shorter OS. Low albumin, hemoglobin <12.0 g/dL,and advanced stage were independently associated with shorter progression‐free survival. Conclusion: We showed the survival benefit of rituximab and potential prognostic value of pretreatment hemoglobin and serum albumin levels in gastric DLBCL.     

Pretransplant FDG‐PET in aggressive non‐Hodgkin lymphoma: systematic review and meta‐analysis

This study aimed to systematically review and meta‐analyze the value of pretransplant FDG‐PET in predicting outcome after autologous stem cell transplantation in aggressive non‐Hodgkin lymphoma. MEDLINE was systematically searched; included studies were methodologically assessed and meta‐analyzed, when possible. Overall methodological quality of included studies (n = 11) was poor, with moderate risk of bias in the domains of study participation (n = 7) and prognostic factor measurement (n = 7), and high risk of bias in the domains of outcome measurement (n = 10), and study confounding (n = 11). In all aggressive non‐Hodgkin lymphomas, pooled sensitivity and specificity were 54.0% and 73.1% in predicting treatment failure, and 54.5% and 68.7% in predicting death. Because of interstudy heterogeneity, additional subgroup analyses were performed. In newly diagnosed aggressive non‐Hodgkin lymphoma, pooled sensitivity and specificity were 20.0% and 70.0% in predicting treatment failure, and 8.3% % and 30.5% in predicting death. In refractory/relapsed aggressive non‐Hodgkin lymphoma, pooled sensitivity and specificity were 68.1% and 72.1% in predicting treatment failure, and 77.3% and 69.6% in predicting death. At present, pretransplant FDG‐PET cannot be recommended in aggressive non‐Hodgkin lymphoma, because available studies suffer from major methodological flaws, and reported prognostic estimates are low (i.e., poor in newly diagnosed and moderate in refractory/relapsed aggressive non‐Hodgkin lymphoma).     

Hodgkin lymphoma: a negative interim‐PET cannot circumvent the need for end‐of‐treatment‐PET evaluation

We examined the outcome of a cohort of patients with Hodgkin lymphoma (HL) in order to assess if fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) at the end of treatment (end‐PET) can be omitted when the interim PET (int‐PET) is negative. Seventy‐six ABVD(adriamycin, bleomycin, vinblastine, dacarbazine)‐treated patients were retrospectively included. No change in treatment was made on the basis of int‐PET results. Suspicious foci on end‐PET received biopsy confirmation whenever possible. Median follow‐up was 58·9 months. Uptake on int‐PET higher than liver (scores 4–5) was rated positive according to the Lugano classification, while a positive end‐PET corresponded to scores 3, 4 and 5. Fifteen patients had treatment failure. Sensitivity, specificity, positive predictive value (PPV), negative predictive value and accuracy of int‐PET were 46·7%, 85·2%, 43·8%, 86·7% and 77·6%, respectively. For end‐PET the figures were: 80%, 93·4%, 75%, 95% and 90·8%. Eight patients with negative int‐PET had treatment failure; six of them were identified as non‐responders with end‐PET. The 5‐year progression‐free survival (PFS) was 87% for patients with negative int‐PET versus 56% with positive int‐PET. The 5‐year PFS was 96% with negative end‐PET versus 23% with positive end‐PET. The prognostic information from int‐PET as regards PFS (log‐rank test P = 0·0048) was lower than that provided by end‐PET (P < 0·0001). Int‐PET predicted only half of the failures. When used in clinical routine, a negative int‐PET study cannot obviate the need for end‐PET examination.     

Prognostic utility of pre-transplantation [18F] fluorodeoxyglucose positron emission tomography/computed tomography in patients with diffuse large B-cell lymphoma who underwent rituximab,dexamethasone, high-dose cytarabine,carboplatin salvage chemotherapy

We analysed the outcomes of 62 patients with refractory/relapsed diffuse large B-cell lymphoma (rrDLBCL) who had pre-transplantation fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) after R-DHAC (rituximab, dexamethasone, high-dose cytarabine, carboplatin) salvage chemotherapy, and were evaluated using Deauville criteria and total lesion glycolysis (TLG). A positive pre-transplantation PET/CT with Deauville score of 5 was associated with shorter progression-free survival (PFS) (P = 0·01), while a Deauville score of 4 was not predictive of outcome. Only pre-transplant TLG was significantly associated with both PFS (P = 0·005) and overall survival (P = 0·03). TLG deserves to be further investigated in prospective studies.     

F‐18 FDG‐PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem‐cell transplantation for relapsed and refractory Hodgkin lymphoma

Total lymphoid irradiation (TLI) followed by high‐dose chemotherapy and autologous haematopoietic stem cell transplant (aHSCT) is an effective strategy for patients with relapsed/refractory classical Hodgkin lymphoma (HL). We report outcomes for patients with relapsed/refractory HL who received TLI followed by high‐dose chemotherapy and aHSCT. Pre‐transplant fludeoxyglucose positron emission tomography (FDG‐PET) studies were scored on the 5‐point Deauville scale. Of 51 patients treated with TLI and aHSCT, 59% had primary refractory disease and 63% had active disease at aHSCT. The 10‐year progression‐free survival (PFS) and overall survival (OS) for all patients was 56% and 54%, respectively. Patients with complete response (CR) by PET prior to aHSCT had a 5‐year PFS and OS of 85% and 100% compared to 52% and 48% for those without CR (P = 0·09 and P = 0·007, respectively). TLI and aHSCT yields excellent disease control and long‐term survival rates for patients with relapsed/refractory HL, including those with high‐risk disease features. Achievement of CR with salvage therapy is a powerful predictor of outcome.     

Uterine,but not ovarian,female reproductive organ involvement at presentation by diffuse large B‐cell lymphoma is associated with poor outcomes and a high frequency of secondary CNS involvement

Involvement of the internal female reproductive organs by diffuse large B‐cell lymphoma (DLBCL) is uncommon, and there are sparse data describing the outcomes of such cases. In total, 678 female patients with DLBCL staged with positron emission tomography/computed tomography and treated with rituximab‐containing chemotherapy were identified from databases in Denmark, Great Britain, Australia, and Canada. Overall, 27/678 (4%) had internal reproductive organ involvement: uterus (n = 14), ovaries (n = 10) or both (n = 3). In multivariate analysis, women with uterine DLBCL experienced inferior progression‐free survival and overall survival compared to those without reproductive organ involvement, whereas ovarian DLBCL was not predictive of outcome. Secondary central nervous system (CNS) involvement (SCNS) occurred in 7/17 (41%) women with uterine DLBCL (two patients with concomitant ovarian DLBCL) and 0/10 women with ovarian DLBCL without concomitant uterine involvement. In multivariate analysis adjusted for other risk factors for SCNS, uterine involvement by DLBCL remained strongly associated with SCNS (Hazard ratio 14·13, 95% confidence interval 5·09–39·25, P < 0·001). Because involvement of the uterus by DLBCL appears to be associated with a high risk of SCNS, those patients should be considered for CNS staging and prophylaxis. However, more studies are needed to determine whether the increased risk of secondary CNS involvement also applies to women with localized reproductive organ DLBCL.     

Controversies on the prognostic value of interim FDG‐PET in advanced‐stage Hodgkin lymphoma

Hodgkin lymphoma, even in advanced‐stage, is a highly curable malignancy, but treatment is associated with short‐term toxicity and long‐term side effects. Early predictive markers are required to identify those patients who do not require the full‐length standard therapy (and thus qualify for therapy de‐escalation) and those patients who will not be cured by standard therapy (and thus qualify for therapy escalation). Multiple trials have assessed the value of ¹⁸F‐fluoro‐2‐deoxy‐d ‐glucose positron emission tomography (FDG‐PET) after a few cycles of chemotherapy (also known as ‘interim FDG‐PET’) in predicting outcome in advanced‐stage Hodgkin lymphoma. Furthermore, multiple interim FDG‐PET‐adapted trials, in which patients with positive interim FDG‐PET scans are assigned to escalated therapies, and patients with negative interim FDG‐PET scans are assigned to de‐escalated therapies, have recently been published or are currently ongoing, with generally heterogeneous results. The present article reports the currently available evidence (and controversies) on the prognostic value of interim FDG‐PET in advanced‐stage Hodgkin lymphoma in patients with positive and negative interim FDG‐PET findings following continuation of standard chemotherapy or escalated/de‐escalated therapy.     

Impact of prior rituximab on outcomes of autologous stem‐cell transplantation in patients with relapsed or refractory aggressive B‐cell lymphoma: a multicentre retrospective Spanish group of lymphoma/autologous bone marrow transplant study

The use of highly effective rituximab‐containing therapy for treating diffuse large B‐cell lymphoma (DLBCL) makes it more difficult to salvage relapsed or refractory patients. Autologous stem‐cell transplantation (ASCT) is the reference treatment for these patients, but the impact of previous exposure to rituximab on the subsequent results of ASCT remains unknown. We analysed 248 patients with relapsed or refractory DLBCL or grade 3B follicular lymphoma pre‐treated with rituximab as part of first‐line therapy (R+ group) who received ASCT, in comparison with a control group of 127 patients without previous exposure to rituximab (R? group). The complete remission (CR) rates were similar in both groups. Multivariate analysis identified age‐adjusted International Prognostic Index at diagnosis, extranodal involvement and disease status at transplant, and the number of previous chemotherapy lines as independent factors with a negative influence on CR rate. Compared with R? patients, those in the R+ group had a significantly better progression‐free survival (63% vs. 48% at 5 years) and overall survival (72% vs. 61% at 5 years). This observation was independent of other prognostic factors that affected these outcomes. In conclusion, ASCT is no less effective in patients with relapsed or refractory aggressive B‐cell lymphoma pre‐treated with first‐line rituximab‐containing therapy than in rituximab‐naive patients.     

Guidelines for the management of diffuse large B‐cell lymphoma

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8–10 months. We conducted a phase II trial of standard CHOP‐21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2–6: 1000 mg day 1) (CHOP‐O) followed by 12 months ofatumumab maintenance (1000 mg given 8‐weekly for up to six cycles). Forty‐three patients were recruited of whom 37 were evaluable. Seventy‐three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide‐based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression‐free survival was 6·2 months (95% confidence interval [CI] 4·9–14·0 months) and median OS was 11·4 months (95% CI 6·4–25·6 months). Treatment‐naïve and TP53‐intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non‐neutropenic infections were observed. There were no treatment‐related deaths. Seven patients received platinum‐containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP‐O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.     

The role of FDG‐PET/CT in the evaluation of residual disease in paediatric non‐Hodgkin lymphoma

¹⁸F‐labelled–fluorodeoxyglucose positron emission tomography (FDG‐PET) findings are challenging to interpret for residual disease versus complete response in paediatric patients with non‐Hodgkin lymphoma (NHL). A biopsy is often warranted to confirm the presence or absence of viable tumour if there is clinical or radiographic evidence of residual disease. In this study, we compared conventional imaging and FDG‐PET/computerized tomography (CT) findings with biopsy results in 18 children with NHL. Our goal was to provide additional data to establish more reliable criteria for response evaluation. Residual disease was suspected after conventional imaging alone in eight patients, after FDG‐PET/CT alone in three and after both modalities in seven patients. Biopsy confirmed the presence of viable tumour in two patients. Two additional patients experienced progressive disease or relapse. The sensitivity and negative predictive value of FDG‐PET/CT using the London criteria to indicate residual tumour detectable by biopsy were 100%, but specificity was low (60%), as was the positive predictive value (25%). Thus, in this study, a negative FDG‐PET/CT finding was a good indicator of complete remission. However, because false‐positive FDG‐PET/CT findings are common, biopsy and close monitoring are required for accurate determination of residual disease in individual patients.     

Weekly rituximab consolidation following four cycles of R‐CHOP induction chemotherapy in very elderly patients with diffuse large B‐cell lymphoma: Consortium for improving survival of lymphoma study (CISL)

This study aimed to determine the objective response, toxicity, and clinical outcome of weekly rituximab consolidation after four cycles of R‐CHOP21 in very elderly patients with DLBCL. A prospective, multi‐institutional phase II trial was conducted on patients with previously untreated CD20⁺ DLBCL who were older than 70 yr. Patients were treated with four cycles of R‐CHOP21 followed by weekly consolidation with rituximab (375mg/m², four times infusion) (NCT01181999). We also compared the clinical outcomes with an historical case‐matched control group treated conventionally with six cycles of R‐CHOP21. A total of 51 patients with newly diagnosed DLBCL were enrolled at 15 institutes between June 2010 and September 2013 . The median age was 76 yr (range: 70–89). Forty‐one of the 51 patients completed the planned rituximab consolidation (R‐consolidation). The overall response rate was 78.4%, comprising 74.5% with a complete response and 3.9% with a partial response. After a median follow‐up of 20.3 months, 2‐yr progression‐free survival and overall survival were 63.9% and 68.7%, respectively. No serious toxicities were reported during rituximab consolidation. Weekly rituximab consolidation following four cycles of R‐CHOP21 resulted in an acceptable response with high tolerability and could be a good compromise between efficacy and safety for elderly patients with DLBCL.