Olivier Casasnovas

Early Positron Emission Tomography Response-Adapted Treatment in Stage I and II Hodgkin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial.

Purpose Patients who receive combined modality treatment for stage I and II Hodgkin lymphoma (HL) have an excellent outcome. Early response evaluation with positron emission tomography (PET) scan may improve selection of patients who need reduced or more intensive treatments. Methods We performed a randomized trial to evaluate treatment adaptation on the basis of early PET (ePET) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in previously untreated-according to European Organisation for Research and Treatment of Cancer criteria favorable (F) and unfavorable (U)-stage I and II HL. The standard arm consisted of ABVD followed by involved-node radiotherapy (INRT), regardless of ePET result. In the experimental arm, ePET-negative patients received ABVD only (noninferiority design), whereas ePET-positive patients switched to two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) and INRT (superiority design). Primary end point was progression-free survival (PFS). Results Of 1,950 randomly assigned patients, 1,925 received an ePET-361 patients (18.8%) were positive. In ePET-positive patients, 5-year PFS improved from 77.4% for standard ABVD + INRT to 90.6% for intensification to BEACOPPesc + INRT (hazard ratio [HR], 0.42; 95% CI, 0.23 to 0.74; P = .002). In ePET-negative patients, 5-year PFS rates in the F group were 99.0% versus 87.1% (HR, 15.8; 95% CI, 3.8 to 66.1) in favor of ABVD + INRT; the U group, 92.1% versus 89.6% (HR, 1.45; 95% CI, 0.8 to 2.5) in favor of ABVD + INRT. For both F and U groups, noninferiority of ABVD only compared with combined modality treatment could not be demonstrated. Conclusion In stage I and II HL, PET response after two cycles of ABVD allows for early treatment adaptation. When ePET is positive after two cycles of ABVD, switching to BEACOPPesc + INRT significantly improved 5-year PFS. In ePET-negative patients, noninferiority of ABVD only could not be demonstrated: risk of relapse is increased when INRT is omitted, especially in patients in the F group.

Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial

BACKGROUNDnBruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity.nnnMETHODSnIn this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926.nnnFINDINGSnFrom March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1-2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62-80), 67% (58-75), and 87% (79-92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 [38%]), diarrhoea (38 [31%]), fatigue (34 [27%]), and myalgia (26 [21%]). The most common grade 3 or worse adverse events were neutropenia (13 [10%]), anaemia (11 [9%]), and pneumonia (six [5%]). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13·8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]).nnnINTERPRETATIONnAcalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population.nnnFUNDINGnAcerta Pharma, a member of the AstraZeneca Group.

Cryopreservation, semen use and the likelihood of fatherhood in male Hodgkin lymphoma survivors: An EORTC-GELA lymphoma group cohort study

STUDY QUESTIONnHow does the successful cryopreservation of semen affect the odds of post-treatment fatherhood among Hodgkin lymphoma (HL) survivors?nnnSUMMARY ANSWERnAmong 334 survivors who wanted to have children, the availability of cryopreserved semen doubled the odds of post-treatment fatherhood.nnnWHAT IS KNOWN ALREADYnCryopreservation of semen is the easiest, safest and most accessible way to safeguard fertility in male patients facing cancer treatment. Little is known about what proportion of patients achieve successful semen cryopreservation. To our knowledge, neither the factors which influence the occurrence of semen cryopreservation nor the rates of fatherhood after semen has been cryopreserved have been analysed before.nnnSTUDY DESIGN, SIZE, DURATIONnThis is a cohort study with nested case-control analyses of consecutive Hodgkin survivors treated between 1974 and 2004 in multi-centre randomized controlled trials. A written questionnaire was developed and sent to 1849 male survivors.nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnNine hundred and two survivors provided analysable answers. The median age at treatment was 31 years. The median follow-up after cryopreservation was 13 years (range 5-36).nnnMAIN RESULTS AND THE ROLE OF CHANCEnThree hundred and sixty-three out of 902 men (40%) cryopreserved semen before the start of potentially gonadotoxic treatment. The likelihood of semen cryopreservation was influenced by age, treatment period, disease stage, treatment modality and education level. Seventy eight of 363 men (21%) used their cryopreserved semen. Men treated between 1994 and 2004 had significantly lower odds of cryopreserved semen use compared with those treated earlier, whereas alkylating or second-line (chemo)therapy significantly increased the odds of use; no other influencing factors were identified. We found an adjusted odds ratio of 2.03 (95% confidence interval 1.11-3.73, P = 0.02) for post-treatment fatherhood if semen cryopreservation was performed. Forty-eight out of 258 men (19%) who had children after HL treatment became a father using cryopreserved semen.nnnLIMITATIONS, REASONS FOR CAUTIONnData came from questionnaires and so this study potentially suffers from response bias. We could not perform an analysis with correction for duration of follow-up or provide an actuarial use rate due to lack of dates of semen utilization. We do not have detailed information on either the techniques used in cryopreserved semen utilization or the number of cycles needed.nnnSTUDY FUNDING/COMPETING INTERESTSnLance Armstrong Foundation, Dutch Cancer Foundation, René Vogels Stichting, no competing interests.

Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study.

High variability in patient outcome after rituximab-based treatment is partly explained by rituximab concentrations, and pharmacokinetic (PK) variability could be influenced by tumor burden. We aimed at quantifying the influence of baseline total metabolic tumor volume (TMTV0) on rituximab PK and of TMTV0 and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV0 was measured by 18F-fluorodeoxyglucose-positron emission tomography-computed tomography in 108 previously untreated DLBCL patients who received four 375 mg/m2 rituximab infusions every 2 weeks in combination with chemotherapy in 2 prospective trials. A 2-compartment population model allowed describing rituximab PK and calculating rituximab exposure (area under the concentration-time curve; AUC). The association of TMTV0 and AUC with metabolic response after 4 cycles, as well as progression-free survival (PFS) and overall survival (OS), was assessed using logistic regression and Cox models, respectively. Cutoff values for patient outcome were determined using receiver operating characteristic curve analysis. Exposure to rituximab decreased as TMTV0 increased (R2 = 0.41, P < .0001). A high AUC in cycle 1 (≥9400 mg × h per liter) was associated with better response (odds ratio, 5.56; P = .0006) and longer PFS (hazard ratio [HR], 0.38; P = .011) and OS (HR, 0.17; P = .001). A nomogram for rituximab dose needed to obtain optimal AUC according to TMTV0 was constructed, and the 375 mg/m2 classical dose would be suitable for patients with TMTV0 <281 cm3 In summary, rituximab exposure is influenced by TMTV0 and correlates with response and outcome of DLBCL patients. Dose individualization according to TMTV0 should be evaluated in prospective studies. These studies were registered at www.clinicaltrials.gov as #NCT00498043 and #NCT00841945.

Is there an optimal method for measuring baseline metabolic tumor volume in diffuse large B cell lymphoma

Dear Sir, Given the absence of a recognized gold standard for assessing the metabolic tumor volume (MTV) in FDG PET, it is important to discuss the strengths and weaknesses of the different methods used in DLBCL. Intheir retrospectiveseriesof147patients,Ylyasetal. [1] tested three different fixed thresholding methods: SUV ≥ 2.5, ≥ 41% of the SUVmax and a liver uptake dependent threshold as suggested inPERCIST.Theyconfirmed the strongprognostic valueofbaselineMTV, regardless of themethodused, consistentwithprevious findings [2, 3]. These results deserve further comments. The median MTV reported in this study with the 41% SUVmax method is surprisingly low (165 cm) with a large difference with the 2.5 method (~590 cm). Although the population included 70% of advanced stage patients, their median is much lower than values reported in previous studies employing 41% SUVmax method in DLBCL, with medians of 258 cm [4], 315 cm [5], 320 cm [6], and 373 cm [7]. Using a threshold based on liver SUV, Kostakoglu et al. [8] reported a median of 336 cm in 1,334 DLBCL patients. Ilyas et al. used either house-made or commercial software. VOI were obtained automatically for 2.5 and 41% thresholding after the operator-selected tumor sites using a single click for each region. Although the algorithms used are not described, it is likely that the volume was determined by region growing techniques dependent on a threshold and on the choice of the click position [9, 10]. Figure 6 of [1] clearly shows that a single VOI or click for all mediastinal nodes excludes a large part of the tumor. The authors wrote that they have edited additional volumes manually, but did not mention how many VOIs per patient, which makes the results difficult to interpret. The manual VOIs selection process, before applying any segmentation, has a major impact on the delineated metabolic volumes and must be determined carefully when applying the 41% method which is a weakness of this thresholding method. Furthermore, the Ilyas et al. results have been obtained using scans acquired 90 min post-injection and may not hold for recommended 60 min post-injection scans. The 2.5 method, supported by the authors, also includes a number of severe limitations. First, due to the limited spatial resolution of PET systems causing partial volume effect, the apparent activity of a tumor region depends on its volume, and there is no single absolute threshold that can accurately estimate the volume of a tumor regardless off the tumor volume and uptake [11]. In Figure 6 of [1] and in the figure of a recent editorial [12], it is clear that tumor peripheral background, i.e. non tumor regions, is included in the tumor volume when the 2.5 threshold method is used. The necrotic part of a bulky mass with high uptake could also be included in the volume as a result of partial volume. In addition, the authors report a 95% confidence interval of 313.2 cm when the same observers used two different software applications, which is about 30% of the reported mean MTV value (~990 cm), demonstrating the high impact of the practical implementation of the 2.5 threshold. The * Anne-Ségolène Cottereau annesegolene.cottereau@aphp.fr

Prognostic value of baseline metabolic tumor volume in early stage Hodgkin's lymphoma in the standard arm of H10 trial

We tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early-stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS (P < .0001) and OS (P = .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (>147 cm3) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (≤147 cm3). In multivariable analysis including iPET2, TMTV was the only baseline prognosticator compared with the current staging systems proposed by the European Organization for Research and Treatment of Cancer/Groupe dEtude des Lymphomes de lAdulte, German Hodgkin Study Group, or National Comprehensive Cancer Network. TMTV and iPET2 were independently prognostic and, combined, identified 4 risk groups: low (TMTV≤147+DS1-3; 5-year PFS, 95%), low-intermediate (TMTV>147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV≤147+DS4-5; 5-year PFS, 50%), and high (TMTV>147+DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well.

Lenalidomide in combination with R-CHOP (R2-CHOP) as first-line treatment of patients with high tumour burden follicular lymphoma: a single-arm, open-label, phase 2 study

BACKGROUNDnImmunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard front-line treatment for follicular lymphoma. The combination of lenalidomide and rituximab has shown high efficacy in relapsed or refractory and untreated follicular lymphoma. We aimed to evaluate the safety and activity of the combination of lenalidomide and R-CHOP (R2-CHOP) in previously untreated patients with high burden follicular lymphoma.nnnMETHODSnThis single-arm, open-label, multicentre, phase 2 trial was done in 16 hospitals in France, all of which were Lymphoma Study Association (LYSA) sites. Eligible patients were aged 18-70 years and had previously untreated CD20-positive follicular lymphoma of grade 1, 2, or 3a; at least one high tumour burden criterion according to Groupe dEtude des Lymphomes Folliculaires criteria; an Eastern Cooperative Oncology Group performance status score of 2 or less; and a minimum life expectancy of more than 3 months. Patients received induction therapy with six cycles of R2-CHOP every 3 weeks (one cycle involved standard R-CHOP on days 1-5, and 25 mg oral lenalidomide per day on days 1-14), followed by two rituximab infusions at 3-week intervals. The total treatment schedule was 24 weeks. Patients who achieved a complete or partial response to induction therapy received maintenance therapy consisting of one rituximab infusion every 8 weeks for 2 years. The primary outcome was the proportion of patients who achieved a complete response (complete response and complete response unconfirmed), according to International Workshop to Standardize Response Criteria, at the end of induction treatment. Safety was assessed in all patients who completed treatment. This trial is registered with ClinicalTrials.gov, number NCT01393756, and is closed to accrual.nnnFINDINGSnBetween Dec 21, 2010, and Jan 25, 2012, 80 patients were enrolled, and 68 (85%) completed six cycles of R2-CHOP. At the end of the induction phase, 59 patients achieved a complete response (74%, 95% CI 63-83). 55 patients achieved a complete response at 30 months from enrolment (69%, 57-78). The most frequent adverse event was grade 4 neutropenia in 52 (65%) patients. The most frequent non-haematological side-effects included grade 1-2 sensory neuropathy in 28 (35%) patients and grade 1-2 transient rash in 27 (34%) patients. Four patients died during the study period; none of these deaths were judged to be related to treatment.nnnINTERPRETATIONSnLenalidomide in combination with R-CHOP had an acceptable safety profile and showed anti-cancer activity in patients with previously untreated high burden follicular lymphoma. A future comparative study showing evidence of a survival advantage would be necessary for this combination to be proposed as a treatment for follicular lymphoma.nnnFUNDINGnFrench Ministry of Health, Celgene Corporation, and Amgen France.

Role of FDG PET-CT in the treatment management of Hodgkin lymphoma

Fluorodeoxyglucose (FDG) positons emission tomography (PET)-computed tomography (CT) is used in many ways at baseline and during the treatment of patients with Hodgkin lymphoma. Many properties of the technique are used in the different steps of patients management. Initial staging with PET-CT is more accurate than conventional imaging and PET-CT also became the gold standard imaging at the end of treatment with a negative PET-CT mandatory for reaching a complete remission. Early assessment of response by PET-CT is one of the most powerful prognostic factors for progression-free survival of patients with localized and advanced stages and allows guiding treatment. Conversely, previous studies showed that there is no role of FDG PET-CT for the patients follow-up.

OBINUTUZUMAB PLUS IBRUTINIB IN RELAPSE/REFRACTORY MANTLE CELL LYMPHOMA PATIENTS: FIRST RESULTS OF THE OASIS PHASE I TRIAL

Introduction: We report interim results of a CpG‐activated whole tumor cell vaccine for patients with newly diagnosed Mantle Cell Lymphoma (MCL). This phase I/II trial (NCT00490529) had the primary end points of safety and freedom from minimal residual disease (MRD) at 1 year post autologous stem‐cell transplant (ASCT). Secondary end points include time to treatment failure (TTF) from initial chemotherapy, overall survival (OS), and T cell immune response. Methods: Prior to treatment, patient‐specific vaccines were made by activating freshly collected tumor cells with PF‐3512676 (CpG) followed by radiation (200 Gy). Patients with a partial or complete response after standard immunochemotherapy received three subcutaneous injections with the vaccine product together with additional CpG (18 mg). T‐cells were collected by leukapheresis after the last vaccine and cryopreserved. The day after an ASCT, theT‐cell product was infused and a 4th vaccination was given. A 5th booster vaccination was given ~3 months post ASCT. Blood samples were collected at various time points for measurement of anti‐tumor immune responses and for detection of MRD by VDJ high throughput sequencing of blood mononuclear cells (ClonoSeqTM). Results: Between April 2008 and August 2016, 65 patients were enrolled and 43 patients have completed ASCT and are included in the safety analysis. The CpG MCL vaccine was well tolerated. The most common toxicity was grade I/II erythematous rash at the injection site (98%), and no unexpected toxicities were seen before or after ASCT. 34 patients are at least 1 year post ASCT and included in the primary analysis. 31 (91%) patients were MRD negative at the previously validated threshold (1 MCL clone per 10,000 input genome equivalents of DNA). MRD negativity at 1‐year post ASCT predicted longer subsequent remission duration (p < 0.0001) and survival (p = 0.0021). Lower levels of MRD down to 1 per million were occasionally detected but were not associated with relapse or survival. Median TTF and OS have not been reached (NR) with an average follow‐up of 4.91 years. By comparison a contemporaneous cohort of similar patients with MCL who received the same ASCT at our institution, but with no vaccine, have a median TTF of 4.03 years (p = 0.164). Analysis of the vaccine characteristics revealed that patients whose tumor cells demonstrated CpG‐induced elevation of PD‐L1 had significantly worse TTF (2.4 years vs NR, p = 0.0037) and OS (3.2 years vs NR, p = 0.0042). We also detected tumor‐specific CD4+ and CD8+ T cell immune responses following vaccination. Conclusion: The addition of a CpG‐activated, autologous tumor cell vaccination and adoptive immune T‐cell product to standard therapy for MCL is feasible and safe. At this interim analysis, vaccinated patients had freedom from MRD at 1 year post transplant that surpasses previously reported rates.

CHARACTERISTICS AND OUTCOMES OF RELAPSED FOLLICULAR LYMPHOMA AFTER AUTOLOGOUS STEM CELL TRANSPLANTATION IN THE RITUXIMAB ERA

(RTX), approved for all indications by the EMA. CT‐P10 has demonstrated pharmacokinetics (PK) and efficacy equivalence in patients with rheumatoid arthritis (Yoo, ACR 2016) and PK equivalence in patients with advanced follicular lymphoma (AFL) (Coiffier, ASH 2016). This study aimed to demonstrate non‐inferiority (NI) of efficacy and PK equivalence between CT‐P10 and RTX in patients with newly diagnosed AFL (NCT02162771). Methods: A total of 140 patients were randomized in a 1:1 ratio to receive CT‐P10 or RTX (375 mg/m i.v.) plus CVP (cyclophosphamide, vincristine and prednisone) every 3 weeks over 8 cycles. Overall response rate (ORR) according to the 1999 IWG criteria based on best overall response over 24 weeks was assessed by the independent review committee. Results: An ORR of 97.0% and 92.6% and a CR/CRu of 39.4% and 33.8% for CT‐P10 and RTX, respectively, was observed after 8 cycles of therapy (Table 1). Based on this, the therapeutic NI of CT‐P10 to RTX with regard to ORR over 8 cycles was demonstrated as the difference in ORR between the two groups was 4.3%, and the lower bound of the two‐sided 95% CI was −4.25%. The lower bound (−4.25%) was greater than the pre‐defined NI margin (−7%), by this fulfilling the criteria for NI of CT‐P10 to RTX. At a median follow‐up of 17 months, 10 patients in the CT‐P10 group and 13 patients in the RTX group experienced disease progression or death. There was no statistically significant difference between the two groups for PFS (P‐value: 0.4802, Log‐rank test) although the median PFS survival has not been reached in either arm as a longer follow‐up is required (Figure 1). Median number of B‐cells decreased to the lower limit of quantification (LLoQ) after the 1st infusion and remained at the LLoQ over 8 cycles in both groups. Overall safety profile of CT‐P10 was consistent with that of RTX (Table ). and the proportion of patients with positive anti‐drug antibody was similar between the two groups (4.3% and 2.9%) over 24 weeks. No progressive multifocal leukoencephalopathy or Hepatitis B virus reactivation was reported in both groups. Conclusions: This study demonstrates therapeutic NI of CT‐P10 to RTX plus CVP in previously untreated AFL. CT‐P10 was well tolerated, and the safety profile including immunogenicity of CT‐P10 was comparable to that of RTX over 8 cycles.