Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma.

BACKGROUND: Five-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody-drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available. METHODS: We randomly assigned patients in a 1:1 ratio to receive up to six cycles of A+AVD or ABVD. The primary end point, modified progression-free survival, has been reported previously. The key secondary end point was overall survival in the intention-to-treat population. Safety was also assessed. RESULTS: A total of 664 patients were assigned to receive A+AVD and 670 to receive ABVD. At a median follow-up of 73.0 months, 39 patients in the A+AVD group and 64 in the ABVD group had died (hazard ratio, 0.59; 95% confidence interval [CI], 0.40 to 0.88; P = 0.009). The 6-year overall survival estimates were 93.9% (95% CI, 91.6 to 95.5) in the A+AVD group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Progression-free survival was longer with A+AVD than with ABVD (hazard ratio for disease progression or death, 0.68; 95% CI, 0.53 to 0.86). Fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation, and fewer second cancers were reported with A+AVD (in 23 vs. 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with A+AVD. More patients had peripheral neuropathy with A+AVD than with ABVD, but most patients in the two groups had resolution or amelioration of the event by the last follow-up. CONCLUSIONS: Patients who received A+AVD for the treatment of stage III or IV Hodgkin's lymphoma had a survival advantage over those who received ABVD. (Funded by Takeda Development Center Americas and Seagen; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.).

Revisiting the predictive role of 18F-fluorodeoxyglucose positron emission tomography/computerized tomography on treatment outcome in early-stage favorable Hodgkin lymphoma.

In the present manuscript Gallamini et al. comment the results of three large, phase III, randomized clinical trials in early-stage favorable Hodgkin Lymphoma (HL), aimed at exploring the non-inferiority of ABVD chemotherapy alone compared to combined-modality treatment with ABVD and Involved Field/Node Radiotherapy (INRT). The authors also report the preliminary results of risk-stratification in the first 60 enrolled patients in the phase 2, prospective, international study RAFTING: RAdiotherapy Free Treatment IN Good-prognosis early-stage HL (National Trial Identifier 04866654). In this trial patients are stratified, before treatment onset, according to the risk of therapy failure in a single patient basis, taking into account non only the results of interim and End-of-Therapy PET, but also the value of new metrics extracted from the baseline PET/CT such as the Large Nodal Mass (LNM) and Total Metabolic Tumor Volume (TMTV). Treatment intensity, consisting in ABVD chemotherapy, INRT and Nivolumab maintenance, is modulated on the presence/absence of the above factors, in a personalized-medicine approach. The most frequently detected factors driving treatment intensity were LNM and TMTV, while the results of interim and end-of-treatment PET were also determinant, albeit in a lower percentage of cases.

Predictive value on advance hodgkin lymphoma treatment outcome of end-of treatment FDG PET/CT in the HD0607 clinical trial.

The Lugano classification for response assessment in lymphoma recommends the use of the 5-point-scale Deauville Score (DS) to assess response evaluation of end-of-treatment FDG-PET/CT (eotPET) in Hodgkin Lymphoma (HL); nevertheless, there is a paucity of data on its accuracy and reproducibility. We focus here on the cohort of advanced stage IIb-IV HL patients enrolled in the HD0607 clinical trial (NCT identifier 00795613) that having had a negative interim PET performed 6 cycles of ABVD (Doxorubicin, Vinblastine, Vincristine and Dacarbazine) and then performed an eotPET. Negative patients were randomized to radiotherapy and no further treatment while positive patients were treated based on local policies. eotPET was re-evaluated independently by two readers evaluated and progression free survival was analysed (PFS). eotPET of 254 patients were analysed. The median follow-up was 43 months. The best receiver operator characteristics cut-off values to distinguish positive and negative patients was 4. The area-under-the-curve was 0.81 (95%CI, 0.70-0.91). Three-years PFS was 0.95 (95% CI 0.90-0.97) in eotPET negative and 0.22 (95% CI 0.11-0.43) in eotPET positive. DS demonstrated a good reproducibility of positivity/negativity between the readers consensus and local site evaluation where the agreement occurred on 95.0% of patients. The present study demonstrates that eotPET is an accurate tool to predict treatment outcome in HL and confirms the appropriateness of the Lugano classification for eotPET evaluation.

Incorporating Monoclonal Antibodies into the First-Line Treatment of Classical Hodgkin Lymphoma.

The long-term survival of Hodgkin lymphoma (HL) patients treated according to the current standard of care is excellent. Combined-modality schedules (ABVD plus radiotherapy) in early-stage disease, along with treatment intensity adaptation to early metabolic response assessed by PET/CT in advanced stage HL, have been the cornerstones of risk stratification and treatment decision-making, minimizing treatment-related complications while keeping efficacy. Nevertheless, a non-negligible number of patients are primary refractory or relapse after front-line treatment. Novel immunotherapeutic agents, namely Brentuximab Vedotin (BV) and immune checkpoint inhibitors (CPI), have already shown outstanding efficacy in a relapsed/refractory setting in recent landmark studies. Several phase 2 single-arm studies suggest that the addition of these agents in the frontline setting could further improve long-term disease control permitting one to reduce the exposure to cytotoxic drugs. However, a longer follow-up is needed. At the time of this writing, the only randomized phase 3 trial so far published is the ECHELON-1, which compares 1 to 1 BV-AVD (Bleomycin is replaced by BV) with standard ABVD in untreated advanced-stage III and IV HL. The ECHELON-1 trial has proven that BV-AVD is safe and more effective both in terms of long-term disease control and overall survival. Just recently, the results of the S1826 SWOG trial demonstrated that the combination nivolumab-AVD (N-AVD) is better than BV-AVD, while preliminary results of other randomized ongoing phase 3 trials incorporating anti-PD-1 in this setting will be soon available. The aim of this review is to present the recent data regarding these novel agents in first-line treatment of HL and to highlight current and future trends which will hopefully reshape the overall management of this disease.

Brentuximab vedotin with chemotherapy for stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study.

The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with doxorubicin, vinblastine, and dacarbazine (AVD; A+AVD) exhibited superior modified progression-free survival (PFS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL). Maturing positron emission tomography (PET)-adapted trial data highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET scan after cycle 2 (PET2)-negative (PET2-) patients. We present an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. A total of 1334 patients with stage III or IV cHL were randomized 1:1 to receive 6 cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was required. At median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2- patients aged <60 years were 87.2% vs 81.0%, respectively. A beneficial trend in PET2+ patients aged <60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% vs 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL, consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or bleomycin exposure. This trial was registered at www.clinicaltrials.gov as #NCT01712490 (EudraCT no. 2011-005450-60).

Older patients (aged ≥60 years) with previously untreated advanced-stage classical Hodgkin lymphoma: a detailed analysis from the phase III ECHELON-1 study.

Effective and tolerable treatments are needed for older patients with classical Hodgkin lymphoma. We report results for older patients with classical Hodgkin lymphoma treated in the large phase III ECHELON-1 study of frontline brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Modified progression-free survival per independent review facility for older versus younger patients (aged ≥60 vs. <60 years) was a pre-specified subgroup analysis; as the ECHELON- 1 study was not powered for these analyses, reported P-values are descriptive. Of 1,334 enrolled patients, 186 (14%) were aged ≥60 years (A+AVD: n=84, ABVD: n=102); results below refer to this age group. Modified progression-free survival per independent review facility was similar in the two arms at 24 months (A+AVD: 70.3% [95% confidence interval (CI): 58.4-79.4], ABVD: 71.4% [95% CI: 60.5-79.8], hazard ratio (HR)=1.00 [95% CI: 0.58-1.72], P=0.993). After a median follow-up of 60.9 months, 5-year progression-free survival per investigator was 67.1% with A+AVD versus 61.6% with ABVD (HR=0.820 [95% CI: 0.494-1.362], P=0.443). Comparing A+AVD versus ABVD, grade 3/4 peripheral neuropathy occurred in 18% versus 3%; any-grade febrile neutropenia in 37% versus 17%; and any-grade pulmonary toxicity in 2% versus 13%, respectively, with three (3%) pulmonary toxicity-related deaths in patients receiving ABVD (none in those receiving A+AVD). Altogether, A+AVD showed overall similar efficacy to ABVD with survival rates in both arms comparing favorably to those of prior series in older patients with advanced-stage classical Hodgkin lymphoma. Compared to ABVD, A+AVD was associated with higher rates of neuropathy and neutropenia, but lower rates of pulmonary-related toxicity. Trials registered at ClinicalTrials.gov identifiers: NCT01712490; EudraCT number: 2011-005450-60.

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma.

BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin's lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).

Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.

Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.

Dose-dense ABVD as first-line therapy in early-stage unfavorable Hodgkin lymphoma: results of a prospective, multicenter double-step phase II study by Fondazione Italiana Linfomi.

We investigated the feasibility and activity of an intensified dose-dense ABVD (dd-ABVD) regimen in patients with early-stage unfavorable Hodgkin lymphoma (HL). This prospective, multicenter, phase II study enrolled 96 patients with newly diagnosed, unfavorable stage I or II classical HL. The patients received four cycles of dd-ABVD followed by radiotherapy. Interim PET (PET-2) was mandatory after two courses. Primary endpoints were the evaluation of dd-ABVD feasibility and activity (incidence of PET-2 negativity). The feasibility endpoint was achieved with 48/52 (92.3%) patients receiving > 85% of the programmed dose. The mean dose intensity in the overall patient population (n = 96) was 93.7%, and the median duration of dd-ABVD was 85 days (range, 14-115) versus an expected duration of 84 days. PET-2 was available for 92/96 (95.8%) patients, of whom 79 were PET-2 negative (85.9%). In total, 90 (93.8%) patients showed complete response at the end of treatment. With a follow-up of 80.9 months (3.3-103.2), the median progression-free survival (PFS) and overall survival (OS) were not reached. At 84 months, PFS and OS rates were 88.4% and 95.7%, respectively. No evidence for a difference in PFS or OS was observed for PET-2-negative and PET-2-positive patients. Infections were documented in 8.3% and febrile neutropenia in 6.2% of cases. Four patients died: one had alveolitis at cycle 3, one death was unrelated to treatment, and two died from a secondary cancer. dd-ABVD is feasible and demonstrates activity in early-stage unfavorable HL. The predictive role of PET-2 positivity in early-stage unfavorable HL remains controversial. The study was registered in the EudraCT (reference number, 2011-003,191-36) and the ClinicalTrials.gov (reference number, NCT02247869) databases.

Concomitant semi-quantitative and visual analysis improves the predictive value on treatment outcome of interim 18F-fluorodeoxyglucose/positron-emission tomography in advanced Hodgkin lymphoma.

BACKGROUND: Qualitative assessment using the Deauville five-point Scale (DS) is the gold standard for interim and end-of treatment positron-emission tomography (PET) interpretation in lymphoma. In the present study we assessed the reliability and the prognostic value of different semi- quantitative parameters in comparison with DS for interim PET (iPET) interpretation in Hodgkin lymphoma (HL). METHODS: A cohort of 82 out of 260 patients with advanced stage HL enrolled in the International Validation Study (IVS), scored as 3 to 5 by the expert panel was included in the present report. Two nuclear medicine physicians blinded to patient history, clinical data and treatment outcome reviewed independently the iPET using the following parameters: DS, SUVmax, SUVpeak of the most active lesion, Qmax (ratio of SUVmax of the lesion to liver SUVmax) and Qres (ratio of SUVpeak of the lesion to liver SUVmean). The optimal sensitivity, specificity, positive and negative predictive value to predict treatment outcome was calculated for all the above parameters with the receiver operator characteristics analysis. RESULTS: The prognostic value of all parameters were similar, the best cut-off value being 4 for DS (area under the curve [AUC], 0.81 95% CI: 0.72-0.90), 3.81 for SUVmax (AUC 0.82 95% CI: 0.73-0.91), 3.20 for SUVpeak (AUC 0.86 95% CI: 0.77-0.94), 1.07 for Qmax (AUC 0.84 95% CI: 0.75-0.93) and 1.38 for Qres (AUC 0.84 95% CI: 0.75-0.93). The reproducibility of different parameters was similar as the inter-observer variability measured with Cohen's kappa were 0.93 (95% CI: 0.84-1.01) for the DS, 0.88 (0.77-0.98) for SUVmax, 0.82 (0.70-0.95) for SUVpeak, 0.85 (0.74-0.97) for Qres and 0.78 (0.65-0.92) for Qmax. Due to the high specificity of SUVpeak (0.87) and to the good sensitivity of DS (0.86), upon the use of both parameters the positive predictive value increased from 0.65 of the DS alone to 0.79. When both parameters were positive in iPET, 3-years Failure-Free Survival (FFS) was significantly lower compared to patients whose iPET was interpreted with qualitative parameters only (DS 4 or 5): 21% vs. 35%. On the other hand, the FFS of patients with negative results was not significantly different (88% vs. 86%). CONCLUSIONS: In this study we demonstrated that, combining semi-quantitative parameters with SUVpeak to a pure qualitative interpretation key with DS, it is possible to increase the positive predictive value of iPET and to identify with higher precision the patients subset with a very dismal prognosis. However, these retrospective findings should be confirmed prospectively in a larger patient cohort.

Early serum TARC reduction predicts prognosis in advanced-stage Hodgkin lymphoma patients treated with a PET-adapted strategy.

Among patients with advanced-stage classical Hodgkin lymphoma (cHL) receiving ABVD chemotherapy, PET performed after the first two treatment cycles (PET-2) has prognostic value. However, 15% of patients with a negative PET-2 will experience treatment failure. Here we prospectively evaluated serum thymus and activation-regulated chemokine (TARC) levels, to improve risk assessment in patients treated according to HD0607 PET-driven trial (#NCT00795613). In 266 patients with available serum samples, who have agreed to participate in a sub-study for assessment of the role of TARC monitoring, serum TARC levels were measured at baseline and at time of PET-2 by commercially available ELISA test kits. The primary end-point was to evaluate the association between TARC after 2 ABVD cycles and PFS. Median TARC-2 values were significantly higher in PET-2-positive patients compared to PET-2-negative patients (P = .001), and in patients with treatment failure compared to those in continuous CR (P = .01). The 4-year PFS significantly differed between patients with TARC-2 >800 pg/mL vs ≤800 pg/mL (64% vs 86%, P = .0001). Moreover, among PET-2-negative patients, elevated TARC-2 identified those with a worse prognosis (74% vs 89%; P = .01). In multivariable analysis, TARC-2 >800 pg/mL was a significant independent predictor of PFS in the whole study population (HR 2.39, P = .004) and among the PET-2-negative patients (HR 2.49, P = .02). In conclusion, our results indicate that TARC-2 serum levels above 800 pg/mL suggest the need for a stringent follow-up in PET-2-negative patients, and the evaluation of new drugs in PET-2-positive, who will likely fail to respond to intensification with escalated BEACOPP.

Interpretation criteria for FDG PET/CT in multiple myeloma (IMPeTUs): final results. IMPeTUs (Italian myeloma criteria for PET USe).

ᅟ: FDG PET/CT (18F-fluoro-deoxy-glucose positron emission tomography/computed tomography) is a useful tool to image multiple myeloma (MM). However, simple and reproducible reporting criteria are still lacking and there is the need for harmonization. Recently, a group of Italian nuclear medicine experts defined new visual descriptive criteria (Italian Myeloma criteria for Pet Use: IMPeTUs) to standardize FDG PET/CT evaluation in MM patients. The aim of this study was to assess IMPeTUs reproducibility on a large prospective cohort of MM patients. MATERIALS AND METHODS: Patients affected by symptomatic MM who had performed an FDG PET/CT at baseline (PET0), after induction (PET-AI), and the end of treatment (PET-EoT) were prospectively enrolled in a multicenter trial (EMN02)(NCT01910987; MMY3033). After anonymization, PET images were uploaded in the web platform WIDEN® and hence distributed to five expert nuclear medicine reviewers for a blinded independent central review according to the IMPeTUs criteria. Consensus among reviewers was measured by the percentage of agreement and the Krippendorff's alpha. Furthermore, on a patient-based analysis, the concordance among all the reviewers in terms of positivity or negativity of the FDG PET/CT scan was tested for different thresholds of positivity (Deauville score (DS 2, 3, 4, 5) for the main parameters (bone marrow, focal score, extra-medullary disease). RESULTS: Eighty-six patients (211 FDG PET/CT scans) were included in this analysis. Median patient age was 58 years (range, 35-66 years), 45% were male, 15% of them were in stage ISS (International Staging System) III, and 42% had high-risk cytogenetics. The percentage agreement was superior to 75% for all the time points, reaching 100% of agreement in assessing the presence skull lesions after therapy. Comparable results were obtained when the agreement analysis was performed using the Krippendorff's alpha coefficient, either in every single time point of scanning (PET0, PET-AI or PET-EoT) or overall for all the scans together. DS proved highly reproducible with the highest reproducibility for score 4. CONCLUSIONS: IMPeTUs criteria proved highly reproducible and could therefore be considered as a base for harmonizing PET interpretation in multiple myeloma. A prospective clinical validation of IMPeTUs criteria is underway.

Autoimmune hemolytic anemia after nivolumab treatment in Hodgkin lymphoma responsive to immunosuppressive treatment. A case report.

The patients with refractory Hodgkin lymphoma have a poor prognosis. The nivolumab, an IgG4 monoclonal antibody inhibiting the program death 1 pathway has recently demonstrated its efficacy and its safety in patients with heavily pretreated refractory Hodgkin lymphoma. The side effects of this immunotherapy include autoimmune-like syndromes. A 75-year-old woman with no significant comorbidities was treated by nivolumab (3 mg/kg every 2 wk) as a third-line treatment for refractory Hodgkin lymphoma. A clinical response was observed with the first injection of nivolumab, with a reduction in superficial lymph nodes. After the second injection, the patient presented an authentic autoimmune hemolytic anemia with a profound anemia at 64 g/L and biologic characteristics of hemolysis (elevated unconjugated bilirubin, lactate dehydrogenase, and reticulocytes). The direct antiglobulin test was strongly positive for IgG antibodies, and the indirect antiglobulin test became positive with a very high level of autoantibodies. After 2 injections of nivolumab, the patient underwent a fluodeoxyglucose F 18 positron emission tomography-computed tomography, showing a partial response according to modified Cheson criteria. A treatment with prednisone (2 mg/kg), initiated after transfusion of 2 units of red blood cells, permitted the complete resolution of this autoimmune reaction after 3 months of corticotherapy. The fluodeoxyglucose F 18 positron emission tomography-computed tomography performed at the end of the corticotherapy showed a clear disease progression. Considering the very good response achieved after only 2 injections of nivolumab, the limited therapeutic resources for this old woman, and the complete resolution of the autoimmune hemolytic anemia, nivolumab was reintroduced at the same dose, with close clinical and biological monitoring. She received 6 more injections of nivolumab without recurrence of hemolysis.

Image interpretation criteria for FDG PET/CT in multiple myeloma: a new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma criteria for PET USe).

PURPOSE: FDG PET/CT is able to detect active disease in patients with multiple myeloma (MM) and can be helpful for staging and assessing therapy response, but no standard interpretation criteria have been proposed for the evaluation of FDG PET/CT in MM. METHODS: A group of Italian nuclear medicine physicians and haematologists met to propose new visual interpretation criteria to standardize FDG PET/CT evaluation in MM patients (Italian Myeloma criteria for PET USe; IMPeTUs) and the reproducibility of these criteria was tested. This Italian multicentre protocol was set up as a subprotocol of EMN02, an international prospective multicentre trial of the European Myeloma Network. The criteria were agreed at multidisciplinary consensus meetings. They include a description of the metabolic state of the bone marrow (BM), number and site of focal PET-positive lesions, the number of osteolytic lesions, and the presence and site of extramedullary disease, paramedullary disease and fractures. A visual degree of uptake was defined for the target lesion and extramedullary lesions according to modified Deauville criteria. MM patients who had undergone FDG PET/CT at baseline (PET-0), after induction (PET-AI) and at the end of treatment (PET-EoT) were enrolled. The patients had been prospectively enrolled in EMN02 and their PET scans were a posteriori reinterpreted in a blinded independent central review process managed by WIDEN®. Five expert nuclear medicine physicians scored the scans according to the new criteria. A case was considered read when four out of the five reviewers completed the report. Concordance among reviewers on different metrics was calculated using Krippendorff's alpha coefficient. RESULTS: A total of 17 consecutive patients were enrolled. On PET-0, the alpha coefficients for the BM score, the score for the hottest focal lesion, the number of focal lesions and the number of lytic lesions were 0.33 and 0.47, 0.40 and 0.32, respectively. On PET-AI, the alpha coefficients were 0.09 and 0.43, 0.22 and 0.21, respectively, and on PET-EoT, the alpha coefficients were 0.07, 0.28, 0.25 and 0.21, respectively. BM was generally difficult to score since grades 2 and 3 are difficult to discriminate. However, since neither of the two grades is related to BM myelomatous involvement, the difference was not clinically relevant. Agreement on focal lesion scores and on the number of focal lesions was good. CONCLUSION: The new visual criteria for interpreting FDG PET/CT imaging in MM patients, IMPeTUs, were found to be feasible in clinical practice.

Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program.

We assessed the prognostic value of minimal residual disease (MRD) within the ML17638 phase 3 trial from the Fondazione Italiana Linfomi, investigating the role of rituximab maintenance in elderly follicular lymphoma (FL) patients after a brief first-line chemoimmunotherapy. MRD for the bcl-2/IgH translocation was determined on bone marrow cells in a centralized laboratory belonging to the Euro-MRD consortium, using qualitative and quantitative polymerase chain reactions (PCRs). Of 234 enrolled patients, 227 (97%) were screened at diagnosis. A molecular marker (MM) was found in 51%. Patients with an MM were monitored at 8 subsequent times. Of the 675 expected follow-up samples, 83% were analyzed. Conversion to PCR negativity predicted better progression-free survival (PFS) at all post-treatment times (eg, end of therapy: 3-year PFS, 72% vs 39%; P < .007). MRD was predictive in both maintenance (83% vs 60%; P < .007) and observation (71% vs 50%; P < .001) groups. PCR positivity at the end of induction was an independent adverse predictor (hazard ratio, 3.1; 95% confidence interval, 1.36-7.07). MRD is a powerful independent outcome predictor in FL patients who receive rituximab-intensive programs, suggesting a need to investigate its value for decision-making. This trial was registered at www.clinicaltrial.gov as #NCT01144364.

Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia.

Developing optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized, phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m(2) in Philadelphia-negative B- and T-cell disease, respectively. The primary study objective was the comparative assessment of the risk/benefit ratio, combining the analysis of feasibility, toxicity and efficacy. In the liposomal cytarabine arm 17/71 patients (24%) developed grade 3-4 neurotoxicity compared to 2/74 (3%) in the triple therapy arm (P=0.0002), the median number of episodes of neurotoxicity of any grade was one per patient compared to zero, respectively (P=0.0001), and even though no permanent disabilities or deaths were registered, four patients (6%) discontinued intrathecal prophylaxis on account of these toxic side effects (P=0.06). Neurotoxicity worsened with liposomal cytarabine every 14 days (T-cell disease), and was improved by the adjunct of intrathecal dexamethasone. Two patients in the liposomal cytarabine arm suffered from a meningeal relapse (none with T-cell disease, only one after high-dose chemotherapy) compared to four in the triple therapy arm (1 with T-cell disease). While intrathecal liposomal cytarabine could contribute to improved, radiation-free central nervous system prophylaxis, the toxicity reported in this trial does not support its use at 50 mg and prompts the investigation of a lower dosage. (clinicaltrials.gov identifier: NCT-00795756).

FDG PET/CT imaging as a biomarker in lymphoma.

FDG PET/CT has changed the management of FDG-avid lymphoma and is now recommended as the imaging technique of choice for staging and restaging. The need for tailoring therapy to reduce toxicity in patients with a favourable outcome and for improving treatment in those with high-risk factors requires accurate diagnostic methods and a new prognostic algorithm to identify different risk categories. New drugs are used in relapsed/refractory patients. The role of FDG PET/CT as a biomarker in this context is summarized in this review. New trends in FDG metabolic imaging in lymphoma are addressed including metabolic tumour volume measurement at staging and integrative PET which combines PET data with clinical and molecular markers or other imaging techniques. The quantitative approach for response assessment which is under investigation and is used in large ongoing trials is compared with visual criteria. The place of FDG in the era of targeted therapy is discussed.

The prognostic value of positron emission tomography performed after two courses (INTERIM-PET) of standard therapy on treatment outcome in early stage Hodgkin lymphoma: A multicentric study by the fondazione italiana linfomi (FIL).

This retrospective study included 246 patients with a new diagnosis of Hodgkin Lymphoma (HL) with a localized-stage (IA-IIA), consecutively admitted from January 2002 to December 2008, by twelve Italian hematological centers on behalf of Fondazione Italiana Linfomi (FIL). Patients were staged at baseline and after two cycles of chemotherapy with PET. All patients were treated with four cycles of ABVD followed by involved-field radiotherapy. No treatment change, based on PET-2 results was allowed. Endpoint of the study was the predictive role of PET-2 on 2-y failure-free survival (FFS). PET-2 was positive in 36 patients (15%) and negative in 210. After a mean follow-up of 46 (3-105) months 19/36 PET-2 positive patients progressed or relapsed and 17 achieved and maintained a CCR. The positive and negative predictive value of a PET2 was 53% and 95%, respectively. The sensibility, specificity and accuracy of PET2 were 65.5%, 92% and 89%, respectively. PET-2 positive scans were centrally reviewed according to the recently defined Deauville Criteria. Upon review the PPV and NPV was 73% and 96% overall. Factors with prognostic significance for progression in univariate analysis were a positive PET-2 (P = 0.000) and the presence of bulky disease (P < 0.01). In a multivariate analysis the only factor that affected negatively FFS was a positive PET-2 (P = 0.000). This study confirms that interim-PET could be considered a prognostic test also in early stage HL, but is unlikely to be a factor that will justify the change of therapeutical approach.

Peripheral blood CD34+ percentage at hematological recovery after chemotherapy is a good early predictor of harvest: a single-center experience.

Several algorithms for early prediction of poor-mobilizing patients after chemotherapy and granulocyte colony-stimulating factor administration have been proposed. They generally define peripheral blood cut-off levels of CD34+ cells at a fixed day after starting chemotherapy, mostly with cyclophosphamide. To define an algorithm for early addition of plerixafor regardless of the chemotherapy regimen used, we retrospectively analyzed 280 chemomobilization attempts in 236 patients treated at our institution between 2002 and 2012. In multivariate analysis, CD34+ absolute count and CD34+ percentage upon total leukocyte count at day 1 (defined as the first day in which leukocytes reached a value > 1 × 10(9)/L) were the only factors able to predict a total harvest ≥ 2 × 10(6) CD34+/kg. In patients with day 1 CD34+ lower than 20/µL, the CD34+ percentage was a more reliable predictor of stem cell harvest in the following days than CD34+ absolute count. Upon definition of the best CD34+ cut-off value for identification of poor-mobilizing patients, an algorithm was set up to guide plerixafor administration. It was prospectively validated in 20 patients in 2013 with encouraging results in terms of low incidences of both mobilization failure and plerixafor use. Large prospective trials that define the most cost-effective strategy for just-in-time rescue plerixafor are warranted.