Advanced Indolent non-Hodgkin Lymphoma Research Articles

Impact of bone marrow biopsy on response assessment in immunochemotherapy-treated lymphoma patients in GALLIUM and GOYA

AbstractThe utility of posttreatment bone marrow biopsy (BMB) histology to confirm complete response (CR) in lymphoma clinical trials is in question. We retrospectively evaluated the impact of BMB on response assessment in immunochemotherapy-treated patients with previously untreated follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the phase 3 Study of Obinutuzumab (RO5072759) Plus Chemotherapy in Comparison With Rituximab Plus Chemotherapy Followed by Obinutuzumab or Rituximab Maintenance in Patients With Untreated Advanced Indolent Non-Hodgkin's Lymphoma (GALLIUM; NCT01332968) and A Study of Obinutuzumab in Combination With CHOP Chemotherapy Versus Rituximab With CHOP in Participants With CD20-Positive Diffuse Large B-Cell Lymphoma (GOYA; NCT01287741) trials, respectively. Baseline BMB was performed in all patients, with repeat BMBs in patients with a CR by computed tomography (CT) at end of induction (EOI) and a positive BMB at baseline, to confirm response. Positron emission tomography imaging was also used in some patients to assess EOI response (Lugano 2014 criteria). Among patients with an EOI CR by CT in GALLIUM and GOYA, 2.8% and 4.1%, respectively, had a BMB-altered response. These results suggest that postinduction BMB histology has minimal impact on radiographically (CT)-defined responses in both FL and DLBCL patients. In GALLIUM and GOYA, respectively, 4.7% of FL patients and 7.1% of DLBCL patients had a repeat BMB result that altered response assessment when applying Lugano 2014 criteria, indicating that bone marrow evaluation appears to add little value to response assessment in FL; however, its evaluation may still have merit in DLBCL.

A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

Does Radiation Have a Role in Advanced Stage Hodgkin's or Non-Hodgkin Lymphoma?

Radiation therapy (RT) is one of the most effective agents available in the treatment of lymphomas. However, it is a local treatment, and today, with systemic treatments assuming a primary role for induction of response, RT is primarily used for consolidation. For advanced stage lymphomas, the indications for the use of RT have been questioned and debated, and proper randomized evidence is sparse. RT has significant long-term side effects, and the very extended RT fields of the past yielded unacceptable toxicity in many patients. Modern advanced imaging and conformal RT techniques now enable treatment of larger and anatomically more challenging target volumes with much less radiation to normal tissues and consequently much lower risks of long-term complications. The modern concept of involved site radiation therapy (ISRT) has now been accepted as standard in lymphomas. In advanced Hodgkin lymphoma (HL), RT to residual disease and/or initial bulk benefits some patients, depending on the chemotherapy regimen used. The more intensive the chemotherapy regimen, the fewer patients benefit from RT. In advanced aggressive non-Hodgkin lymphoma (NHL), most of the evidence comes from the most common type, the diffuse large B cell lymphoma (DLBCL). In patients treated with modern immunochemotherapy, RT to initial bulky disease or extralymphatic involvement is beneficial. For both HL and aggressive NHL, RT to residual masses after systemic treatment is of benefit. The role of PET in the evaluation and indication for RT to residual masses has not been tested in randomized trials. In advanced indolent NHL, very low dose RT offers excellent palliation with very few side effects. Modern RT in advanced lymphomas warrants further evaluation in randomized trials.

A Phase I Study of Lenalidomide Plus a Next Generation Anti-CD20 Antibody, Obinutuzumab, in Relapsed Indolent Lymphoma

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. In preclinical studies, we have shown the synergistic anti-tumor effect of combining lenalidomide with anti-CD20 molecules. (Wang 2007) The combination of rituximab and lenalidomide (R2) in relapsed and untreated iNHL is highly active. (Fowler 2014) We hypothesize these responses are related to augmentation of immune response and ADCC through alteration of immune cell subsets in tumor and peripheral blood. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this study was to determine the safety and maximum tolerated dose of lenalidomide and obinutuzumab in patients with relapsed/refractory iNHL.Methods: Patients with relapsed SLL, marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles. All patients received prophylactic steroids prior to obinutuzumab. In the absence of toxicity or progression, the combination was continued for up to 12 cycles. The standard '3+3' design was used with dose limiting toxicities (DLT) assessed during cycle 1. Patients attaining ≥partial response continued obinutuzumab every 2 months for up to 24 months. Prophylactic growth factors were not used. Adverse events were graded using CTCAE version 4.03.Results: 15 patients ( 9 during dose escalation, 6 during dose expansion at target dose) were enrolled; all were evaluated for safety and efficacy (all having had at least 1 post-baseline response assessment). The median age was 60 (36-82) years, and 7 (47%) were male. 21% of patients with follicular lymphoma had low, 29% intermediate, and 50% high FLIPI scores at study entry, 1 patient had SLL. No DLTs were observed during dose escalation. The most common grade 1-2 non-hematologic toxicities were fatigue 12/15 (80%), constipation 9/15 (60%), diarrhea 7/15 (47%), dyspnea 7/15 (47%), and myalgia 7/15 (47%). Grade ≥ 3 events included neutropenia (n=3, 20%), infection (n=2, 13%),thrombocytopenia (n=1, 6%), and two infusion related reactions (13%), both occurring during the first infusion of obinutuzumab. With a median follow up of 8.2 (4.1-14 mo), the overall response rate was 93% with 27% (4/15) achieving a complete response and 67% (10/15) with a partial response, all responding patients remain on active therapy. One patient progressed after 8 months and was withdrawn from study.Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinatuzumab is safe and effective in patients with relapsed iNHL. Adverse events appeared similar to our prior experience with lenalidomide and rituximab. Overall response rates were high, with complete responses increasing with prolonged duration of therapy. Correlative efforts are ongoing to study the immunomodulatory potential of the combination and to identify biomarkers of response. The phase II portion of this study is currently enrolling with dose expansions in relapsed iNHL. DisclosuresOff Label Use: Lenalidomide off label in low grade lymphoma Obinutuzumab off label in low grade lymphoma. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Nastoupil:Celgene: Honoraria; Janssen: Research Funding; AbbVie: Research Funding; TG Therapeutics: Research Funding; Genentech: Honoraria.

Secondary efficacy subanalysis by histology from the phase III BRIGHT study: First-line bendamustine-rituximab (BR) compared with standard R-CHOP/R-CVP for patients with advanced indolent non-Hodgkin lymphoma (NHL) or mantle cell lymphoma (MCL).

8537 Background: BR was previously reported to be statistically noninferior to R-CVP/R-CHOP for complete response rate in the treatment of patients with indolent NHL or MCL. Evaluation of time-to-event outcomes is immature. This subanalysis reports response by histology. Methods: Indolent NHL or MCL was histologically confirmed <6 months before study enrollment in patients who were therapy-naïve. Patients were stratified according to predetermined standard treatment (R-CHOP or RECVP) and lymphoma type, then assigned to receive BR (28-day cycles: bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2on day 1) or standard treatment (21-day cycles at standard doses) for 6-8 cycles. Responses were assessed by a blinded independent review committee. The primary efficacy measure was noninferiority of BR complete response (CR) rate for evaluable patients with ≥1 postbaseline efficacy assessment. If the noninferiority threshold was met, superiority was assessed. Secondary measures included tolerability. Results: Of 447 patients enrolled in the study, 213 receiving BR and 206 receiving R-CHOP/R-CVP were evaluable with postbaseline data (Table). BR achieved a statistically noninferior CR rate compared with R-CHOP/R-CVP in patients with indolent NHL and MCL. Conclusions: In patients with treatment-naïve indolent NHL and MCL, BR achieved the primary endpoint of noninferior CR rate. Most CR rates were numerically, but not significantly, higher with BR. Small subgroup results should be interpreted with caution. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00877006. [Table: see text]

Differences in Quality of Life Between Bendamustine Plus Rituximab Compared with Standard First-Line Treatments in Patients with Previously Untreated Advanced Indolent Non-Hodgkin's Lymphoma or Mantle Cell Lymphoma

AbstractAbstract 155 BackgroundBendamustine is a unique alkylating agent, active as monotherapy and in combination with rituximab for relapsed and refractory indolent non-Hodgkin's lymphoma (NHL). This study compared efficacy and safety of bendamustine-rituximab (BR) with standard treatment regimens of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in first-line treatment of patients with indolent NHL or mantle cell lymphoma (MCL). The primary objective was to determine whether the complete response rate for BR was noninferior to R-CHOP/R-CVP (presented separately). The present analysis reports results for quality of life (QOL) as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). MethodsPreviously untreated patients with indolent NHL or MCL were randomized to receive BR (bendamustine 90 mg/m2/day on days 1 and 2; rituximab 375 mg/m2 on day 1 of each 28-day cycle) or R-CHOP/R-CVP (rituximab 375 mg/m2 and vincristine 1.4 mg/m2 (up to maximum 2 mg) on day 1 and prednisone at 100 mg on days 1–5 (of a 21-day cycle), plus either [1] cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 or [2] cyclophosphamide 750 mg/m2 or 1000 mg/m2(investigator choice) on day 1. QLQ-C30 was administered at screening (baseline); after cycles 1, 3, 6, 8; and at the end-of-treatment visit. Linear transformation to standardize raw scores was performed.The QLQ-C30 is composed of 5 multi-item functional scales, 1 global health status (GHS)/QOL scale, 3 symptom scales, and 6 single-item measures; all scores could range from 0 to 100. Rising scores for functional scales and GHS/QOL indicate improvement. Rising scores for symptom scales/single items indicate worsening. GHS/QOL score change at last QLQ-C30 administration postbaseline was interpreted using analysis of covariance. Data from the last observation (end-of-treatment visit) were analyzed. ResultsThe 447 enrolled patients were randomly assigned to 1 of the 2 treatments; 224 to BR (NHL n=187, MCL n=36, missing n=1) and 223 to R-CHOP/R-CVP (NHL n=184, MCL n=38, missing n=1). Treatment groups were well matched for demographic and clinical characteristics.Among all randomized patients, mean change in GHS/QOL score from baseline to final visit was significantly higher (indicating relative improvement) for patients treated with BR than those treated with R-CHOP/R-CVP (3.6 vs −5.1 respectively, P=0.0005). For patients with indolent NHL, mean change in GHS/QOL score by final visit was significantly higher in patients treated with BR than those receiving R-CHOP/R-CVP (2.1 vs −6.3, respectively, P=0.0021); in patients with MCL, mean change in GHS/QOL score was numerically higher in the BR group, but the difference was not statistically significant (10.9 vs 1.6, P=0.0654).All randomized patients receiving BR showed greater improvement in QLQ-C30 Emotional Functioning (from baseline to final visit), compared with patients receiving R-CHOP/R-CVP. Mean change from baseline scores (± SEM) for QLQ-C30 for Cognitive, Physical, Role, and Social Functioning scales of the QLQ-C30 decreased (signifying deteriorating effect) in both treatment groups, with patients treated with BR deteriorating less than patients treated with R-CHOP/R-CVP (Figure). For symptom scales/item measures, patients treated with BR showed larger reductions in mean scores from elevated baseline levels (signifying greater improvement), compared with R-CHOP/R-CVP for Appetite Loss (−2.9 for BR vs −1.1 for R-CHOP/R-CVP), Pain (−5.6 vs −1.7), and Constipation (−0.7 vs 1.8). For symptom scales/item measures of Dyspnea, Fatigue, and Financial Difficulties, both treatments showed deteriorating effects, with BR showing less than R-CHOP/R-CVP: Dyspnea (0.8 vs 4.8), Fatigue (0.5 vs 7.2), and Financial Difficulties (0.9 vs 1.3). Patients receiving R-CHOP/R-CVP had larger reductions in mean scores for Insomnia (−2.1 for BR vs −6.7 for R-CHOP/R-CVP), Diarrhea (0.5 vs −1.3), and Nausea and Vomiting (1.8 vs 0.9). ConclusionsIn this study, BR significantly improved GHS/QOL, compared with R-CHOP/R-CVP treatment, in previously untreated patients with indolent NHL or MCL. In addition, BR provided improved patient QOL scores for most aspects of functioning and symptoms, as measured by the QLQ-C30.Support: Teva Pharmaceutical Industries Ltd. [Display omitted] Disclosures:Burke:Spectrum Pharmaceuticals: Consultancy. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Van der Jagt:Celgene: Consultancy, Research Funding, Sponsorship Other; Novartis: Consultancy, Research Funding, Sponsorship, Sponsorship Other; Roche: Consultancy, Sponsorship, Sponsorship Other; Teva: Consultancy, Research Funding; Incyte: Research Funding; Xanthus: Research Funding; Bristol-Myers Squibb: Consultancy. Kahl:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. MacDonald:Lundbeck: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Teva Pharmaceutical Industries Ltd.: Employment. Munteanu:Teva Pharmaceutical Industries Ltd.: Employment. Clementi:Teva Pharmaceutical Industries Ltd.: Employment. Chen:Teva Pharmaceutical Industries Ltd.: Employment. Flinn:Teva: Research Funding.

Pharmacokinetic Exploration of Potential for Bendamustine to Affect Rituximab Concentrations and of Cytochrome P450 1A2 Inhibitors to Affect Bendamustine Concentrations in Patients with Non-Hodgkin and Mantle Cell Lymphoma

AbstractAbstract 4919 BackgroundBendamustine, a unique alkylating agent that leads to cancer cell death via several pathways, and rituximab, an anti-CD20 monoclonal antibody, are effective as combination therapy for non-Hodgkin's lymphoma (NHL) and mantle cell lymphoma (MCL). Because bendamustine and rituximab are molecularly unique, drug-drug interactions may be unlikely. Bendamustine is primarily metabolized via hydrolysis, also reducing the likelihood of drug-drug interactions. A recently reported analysis confirmed that rituximab does not affect systemic exposure to bendamustine, but the potential impact of bendamustine on rituximab has not been reported. Moreover, because bendamustine is a CYP1A2 substrate, the potential may exist for drug-drug interactions with CYP1A2 inhibitors and inducers. This analysis graphically explored the potential for drug-drug interactions by examining (1) the effect of bendamustine on rituximab pharmacokinetics (PK) and (2) bendamustine metabolism in the presence of cytochrome P450 (CYP) 1A2 inhibitors. MethodsData from a phase 3 study of combination bendamustine-rituximab in patients with advanced indolent NHL or MCL were assessed to evaluate the potential of bendamustine to affect systemic rituximab exposure. Rituximab 375 mg/m2 was administered on day 1 followed by bendamustine 90 mg/m2 30-min infusion on days 1 and 2 of 6 to 8 consecutive 28-day cycles. Serum rituximab concentrations at end of rituximab infusion (ie, rituximab monotherapy), 24 hours and 7 days postinfusion (ie, after bendamustine exposure) were measured. Data were compared with published literature on PK of rituximab administered without bendamustine (data on methods used in the published reports were limited). To evaluate effect of CYP1A2 inhibitors on bendamustine PK, graphical displays of observed bendamustine concentrations versus time since previous dose stratified by presence or absence of CYP1A2 inhibitors were generated. ResultsThe full analysis population included 49 patients (median age, 63. 1 years; range 37–84). To analyze the effect of bendamustine on rituximab PK, 77 rituximab PK sample records from a subset of 19 patients were available. Minimum, median, and maximum observed serum rituximab concentrations in the absence (at end of rituximab infusion) and presence (at 24 hours and 7 days after rituximab infusion) of bendamustine are shown in Figure 1. The slope of rituximab concentrations from end of infusion to 24 hours and 7 days was similar to that seen in rituximab studies without bendamustine. In this study, rituximab concentrations with and without bendamustine were consistently lower than those in the literature (24% at end of infusion, 30% at 24 hours, and 53% at 7 days).To analyze the effect of CYP1A2 inhibitors on bendamustine PK, 141 samples from 29/49 (59%) patients were taken in the presence of CYP1A2 inhibitors, and 102 samples from the remaining 20/49 patients were CYP1A2 inhibitor-free. Bendamustine concentrations were similar in observed time plots stratified by presence or absence of CYP1A2 inhibitors (Figure 2).Serious adverse events considered related to bendamustine plus rituximab were neutropenia, transient acantholytic dermatosis, bacteremia, pyrexia, and febrile neutropenia, which is consistent with the serious adverse event profile for this combination in larger studies. ConclusionsThis graphical exploration suggests that no drug-drug interactions were demonstrated between bendamustine and rituximab or CYP1A2 inhibitors. Just as rituximab does not affect bendamustine PK, bendamustine did not appear to affect rituximab PK over time. Differences in observed rituximab concentration could be due to potential differences in assay methods/sensitivity or the length of rituximab infusion. Analysis of graphical displays of bendamustine concentrations in the presence and absence of CYP1A2 inhibitors suggests that CYP1A2 inhibitors do not increase systemic exposure to bendamustine, a result that is consistent with the near instantaneous hydrolytic metabolism of bendamustine. These results suggest that CYP1A2 is not a substantial metabolic pathway for bendamustine; however, whether CYP1A2 inducers have clinically relevant drug-drug interactions was not analyzed in this study. Based on results from this study, the likelihood of drug-drug interactions with bendamustine appears to be low.Support: Teva Pharmaceutical Industries Ltd. [Display omitted] [Display omitted] Disclosures:Darwish:Teva Pharmaceuticals: Employment. Bond:Teva Pharmaceuticals: Employment. Burke:Spectrum Pharmaceuticals: Consultancy. Hellriegel:Teva Pharmaceutical Industries Ltd: Employment. Robertson:Teva Pharmaceutical Industries Ltd: Employment. Phillips:Cognigen Corporation, which received research funding from Teva Pharmaceuticals: Employment, Research Funding. Grasela:Cognigen Corporation, which received research funding from Teva Pharmaceuticals: Employment, Research Funding.

Low-dose Involved-field Radiation in the Palliation Of Non-Hodgkin Lymphoma: Predictors of Response and Treatment Failure

Purpose/Objective(s)Low-dose involved-field radiation therapy (LD-IFRT) is successful in palliating local sites in patients with advanced indolent non-Hodgkin lymphoma (NHL). We investigated clinical and pathologic factors significant in predicting local response and freedom from further treatment (FFFT) following LD-IFRT for NHL.Materials/MethodsThis was an IRB-approved retrospective review of records. The study cohort consisted of advanced-stage NHL patients treated at a single institution between April, 2004 and September, 2011. LD-IFRT was given as 4 Gy in 2 fractions over two consecutive days. Treatment response and disease control were determined by radiographic studies and/or physical examination.ResultsA total of 187 sites in 127 patients received LD-IFRT. The median age at diagnosis was 54 years. Fifty-four percent of patients were male. Histology of NHL included 66% follicular, 9% CLL, 10%, MALT/marginal zone (MZ), 6% mantle cell, and 8% other. Sites treated included head and neck (HandN) (36%), cutaneous (19%), supradiaphragmatic (non-HandN) (15%), infradiaphragmatic (12%) and pelvic (19%). The median tumor size was 4.0 cm (range, 0.6-35.0 cm). Median follow-up time was 19.1 months (range, 0.03-77.8 months). The complete response (CR), partial response (PR) and overall response rates were 50%, 32%, and 82%, respectively. Median time to CR or PR was 2.3 months. Histology was the only significant predictor of response (CR or PR), with all histologies having a response rate ≥84% except CLL, which had a 52% response rate (p = 0.01). Tumor size, site, age at diagnosis and the use of prior systemic therapy were not associated with response. The median time to local failure leading to re-irradiation or initiation of systemic therapy was not reached. The median time to distant failure requiring irradiation or systemic therapy was 39.1 months. Significantly higher 2-year rates of FFFT (local and/or systemic therapy) were associated with histologies other than CLL/MCL (p = 0.01), no prior systemic therapy (p = 0.01), cutaneous sites (p = 0.03) and having achieved an initial CR or PR (p = 0.03).ConclusionsHigh local response rates were achieved with LD-IFRT across most histologies. Histologies other than CLL/MCL, cutaneous sites, initial response to LD-IFRT and lack of prior systemic therapy were associated with significantly longer freedom from further therapy after LD-IFRT. Purpose/Objective(s)Low-dose involved-field radiation therapy (LD-IFRT) is successful in palliating local sites in patients with advanced indolent non-Hodgkin lymphoma (NHL). We investigated clinical and pathologic factors significant in predicting local response and freedom from further treatment (FFFT) following LD-IFRT for NHL. Low-dose involved-field radiation therapy (LD-IFRT) is successful in palliating local sites in patients with advanced indolent non-Hodgkin lymphoma (NHL). We investigated clinical and pathologic factors significant in predicting local response and freedom from further treatment (FFFT) following LD-IFRT for NHL. Materials/MethodsThis was an IRB-approved retrospective review of records. The study cohort consisted of advanced-stage NHL patients treated at a single institution between April, 2004 and September, 2011. LD-IFRT was given as 4 Gy in 2 fractions over two consecutive days. Treatment response and disease control were determined by radiographic studies and/or physical examination. This was an IRB-approved retrospective review of records. The study cohort consisted of advanced-stage NHL patients treated at a single institution between April, 2004 and September, 2011. LD-IFRT was given as 4 Gy in 2 fractions over two consecutive days. Treatment response and disease control were determined by radiographic studies and/or physical examination. ResultsA total of 187 sites in 127 patients received LD-IFRT. The median age at diagnosis was 54 years. Fifty-four percent of patients were male. Histology of NHL included 66% follicular, 9% CLL, 10%, MALT/marginal zone (MZ), 6% mantle cell, and 8% other. Sites treated included head and neck (HandN) (36%), cutaneous (19%), supradiaphragmatic (non-HandN) (15%), infradiaphragmatic (12%) and pelvic (19%). The median tumor size was 4.0 cm (range, 0.6-35.0 cm). Median follow-up time was 19.1 months (range, 0.03-77.8 months). The complete response (CR), partial response (PR) and overall response rates were 50%, 32%, and 82%, respectively. Median time to CR or PR was 2.3 months. Histology was the only significant predictor of response (CR or PR), with all histologies having a response rate ≥84% except CLL, which had a 52% response rate (p = 0.01). Tumor size, site, age at diagnosis and the use of prior systemic therapy were not associated with response. The median time to local failure leading to re-irradiation or initiation of systemic therapy was not reached. The median time to distant failure requiring irradiation or systemic therapy was 39.1 months. Significantly higher 2-year rates of FFFT (local and/or systemic therapy) were associated with histologies other than CLL/MCL (p = 0.01), no prior systemic therapy (p = 0.01), cutaneous sites (p = 0.03) and having achieved an initial CR or PR (p = 0.03). A total of 187 sites in 127 patients received LD-IFRT. The median age at diagnosis was 54 years. Fifty-four percent of patients were male. Histology of NHL included 66% follicular, 9% CLL, 10%, MALT/marginal zone (MZ), 6% mantle cell, and 8% other. Sites treated included head and neck (HandN) (36%), cutaneous (19%), supradiaphragmatic (non-HandN) (15%), infradiaphragmatic (12%) and pelvic (19%). The median tumor size was 4.0 cm (range, 0.6-35.0 cm). Median follow-up time was 19.1 months (range, 0.03-77.8 months). The complete response (CR), partial response (PR) and overall response rates were 50%, 32%, and 82%, respectively. Median time to CR or PR was 2.3 months. Histology was the only significant predictor of response (CR or PR), with all histologies having a response rate ≥84% except CLL, which had a 52% response rate (p = 0.01). Tumor size, site, age at diagnosis and the use of prior systemic therapy were not associated with response. The median time to local failure leading to re-irradiation or initiation of systemic therapy was not reached. The median time to distant failure requiring irradiation or systemic therapy was 39.1 months. Significantly higher 2-year rates of FFFT (local and/or systemic therapy) were associated with histologies other than CLL/MCL (p = 0.01), no prior systemic therapy (p = 0.01), cutaneous sites (p = 0.03) and having achieved an initial CR or PR (p = 0.03). ConclusionsHigh local response rates were achieved with LD-IFRT across most histologies. Histologies other than CLL/MCL, cutaneous sites, initial response to LD-IFRT and lack of prior systemic therapy were associated with significantly longer freedom from further therapy after LD-IFRT. High local response rates were achieved with LD-IFRT across most histologies. Histologies other than CLL/MCL, cutaneous sites, initial response to LD-IFRT and lack of prior systemic therapy were associated with significantly longer freedom from further therapy after LD-IFRT.

Radioimmunotherapy with Yttrium-90-Ibritumomab Tiuxetan as Part of a Reduced Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation in Patients with Advanced Indolent Non-Hodgkin Lymphoma: Interim Analysis of a Phase II Study.

Allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) regimens offers a potential curative therapy to patients with advanced indolent NHL. RIC HCT induces potent graft-versus-lymphoma effects, with best results in patients with low tumor burden at time of HCT. Combined use of radioimmunotherapy (RIT) with RIC may increase anti-lymphoma activity of RIC. A multicenter phase II study of allogeneic HCT combining RIT using yttrium-90-ibritumomab tiuxetan (Y90-CD20, Zevalin®) with 0.4 mCi (15 MBq)/kg on day -14 combined with RIC using fludarabine (30 mg/m2 day -4 to -2) and 2 Gy TBI (day 0) followed by allogeneic HCT from matched related or unrelated donors was initiated. Postgrafting immunosuppression consists of cyclosporine and mycophenolate mofetil. Targeted enrolment is 40 patients with dosimetry on day -21 in the first five patients. Primary objective of this study was the evaluation of treatment related mortality and engraftment after RIT-RIC HCT. Secondary objectives were disease response, relapse rate, disease free and overall survival, GVHD and immune reconstitution.To date, 36 patients are evaluable. Diagnoses were follicular lymphoma (n=15), mantle cell lymphoma (n=8), chronic lymphocytic leukemia (n=11), marginal zone lymphoma (n=1) and immunocytoma (n=1). Median age was 56 (range, 34–68) years. PBSC grafts were either from matched related (n=11) or matched unrelated donors (n=25). All patients were “high risk” with refractory disease or relapse after preceding autologous HCT. Disease stage at time of HCT was CR=7, PR=24, SD=5. No additional toxicity due to RIT in comparison to our previous experience with the same RIC was observed. Engraftment was rapid and sustained with no graft rejections. Median time to >500 granulocytes/μL was 14 (range, 0–69) days, and to >20000 platelets/μL 8 (range, 0–69) days. In 14 patients platelets never dropped below 20000/μL and in 8 patients granulocytes never below 500/μL, illustrating the non-myeloablative intensity of the conditioning regimen. TRM in the first 100 days was 8% (n=3) and overall 25% (n=9). Incidence of grade II-IV GVHD was 44% (II=4, III=10, IV=2). To date, extensive chronic GVHD occurred in 6 patients. Deaths occurred due to infections=5, GVHD=2, relapse=2 and multi organ failure=2. 25/36 (69%) of all patients are alive with a median follow up of 453 (range, 39–713) days, resulting in a Kaplan-Meier estimate 1 year survival of 67%. Disease status of patients alive is CR=18 and PR=7.In conclusion, a combination of RIT with RIC is feasible with no additional toxicity due to RIT and with stable engraftment in all patients. Disease response and treatment related mortality seems promising even in this elderly and heavily pretreated cohort but requires further follow-up.