ALBERT

Description: Most patients with follicular lymphoma (FL) achieve a complete response (CR) after treatment, but eventually most of them, particularly those with stage IV, relapse due to minimal residual disease (MRD). The t(14;18) gives rise to a rearrangement of the bcl-2 oncogene that constitutes an excellent target for detection of MRD by polymerase chain reaction (PCR). One hundred ninety-four previously untreated patients with indolent FL and detectable bcl-2 rearrangement were studied. The PCR assay was used to detect bcl-2–rearranged cells in blood and marrow before and after treatment. Molecular response rate was 37%, 53%, 56%, and 66% at 3 to 5, 6 to 8, 9 to 14, and 15 to 18 months from the start of therapy, respectively. Although molecular response was higher among clinical CRs, one third of partial responders at 3 to 5 months also achieved a molecular response. Patients who achieved a molecular response during the first year of treatment had a significantly longer failure-free survival (FFS) than those who did not (4-year FFS: 76% v 38%, respectively; P 〈 .001). Similar results were also observed in the subset of patients in clinical CR 1 year after treatment. By multivariate analysis, β2-microglobulin (β2-M; P 〈 .01), and molecular response (P 〈 .001) were the most important variables associated with outcome. When we combined β2-M and molecular response, three prognostic groups emerged: (1) low β2-M and molecular responders, (2) low β2-M and nonresponders or high β2-M and responders, and (3) high β2-M and nonresponders. The 4-year FFS of these 3 groups were 86%, 65%, and 23%, respectively. Finally, patients who achieved molecular response and sustained it had better FFS than those who either reverted back to PCR-positive or who never achieved molecular response. Serial PCR analysis to determine the molecular response in FL correlates well with outcome especially when combined with pretreatment β2-M.

Description: Introduction: High standardized uptake value (SUV) on FDG PET scan in follicular lymphoma (FL) suggests aggressive disease and possible transformation to diffuse large B-cell lymphoma. Schoder et al, J Clin Oncol, 2005, reported that SUV 〉10 predicted aggressive lymphoma with 〉80% certainty and SUV 〉13 with 〉90% certainty. However, it is unknown whether the maximum SUV (SUVmax) on FDG PET scan at baseline, suggesting the possibility of focal aggressive or transformed disease, has prognostic value in FL. Here, we determined the prognostic value of SUVmax on baseline FDG PET scan in patients with advanced stage FL treated uniformly with R-CHOP chemoimmunotherapy at initial diagnosis. Methods: We reviewed medical records of all patients with stage III or IV FL who had FDG PET scan at initial diagnosis and were treated with R-CHOP chemoimmunotherapy at MD Anderson Cancer Center between January 2001 and December 2012. Patients with histological diagnosis of concurrent diffuse large B-cell lymphoma were excluded. Results: For the 225 patients studied, the median age was 57 years (range, 20-82). 83 (37%) patients were 〉= age 60, 137 (61%) had grade 1 or 2 FL, and 88 (39%) had grade 3A (n=57, 25%) or 3B (n=31, 14%). The Ki-67 score was 40% for 56 (40%) patients. FLIPI risk groups were 54 patients (24%) low, 74 (33%) intermediate, and 97 (43%) high. GELF criteria were met in 133 (59%) patients. Tumor bulk of 〉= 6 cm was seen in 97 (43%) patients. The absolute lymphocyte count (ALC) was normal or high in 155 (69%) patients and low in 70 (31%). Sixty-nine (31%) patients received rituximab maintenance. There was no correlation between baseline SUVmax on FDG PET scan and Ki-67 score (Pearson correlation co-efficient of 0.168). The overall and complete response rates were 96% and 87%, respectively. The median follow-up time was 66 months. At 5 years, progression-free survival (PFS) was 85% and overall survival (OS) was 90%. Male gender, stage IV, high risk FLIPI, presence of GELF criteria, high beta-2 microglobulin, and low ALC were associated with significantly inferior PFS and OS (p= 60 was associated with inferior OS but not PFS. Rituximab maintenance was associated with improved PFS but not OS. On baseline FDG PET scan, median SUVmax was 13.7 and the SUVmax range was 1.5-42.1. 105 (47%) patients had SUVmax 13. Patient characteristics including age, gender, histological grade, Ki-67 score, and FLIPI risk groups were not significantly different between the two SUVmax populations (p〉0.05). The overall response rates were 94% and 96% for the SUVmax 13 groups, respectively. The complete response rate was 87% in both groups. At 5 years, the PFS and OS were not significantly different between the low and high SUVmax groups (61% vs 63% for PFS, p=0.98 and 90% vs 89% for OS, p=0.63). PFS and OS were not significantly different even when the patients were grouped into SUVmax 10 (p=0.9 and 0.61, respectively) or when other cut-offs were used. SUVmax was also not predictive of PFS and OS when only the patients meeting GELF criteria were analyzed. Conclusions: In this large cohort of advanced stage FL patients treated uniformly with R-CHOP chemoimmunotherapy, SUVmax on baseline FDG PET scan was not predictive of clinical outcome or correlated with other features. It is possible that the doxorubicin-based chemotherapy regimen may have benefited patients with high SUVmax who may have underlying aggressive or undiagnosed transformed disease. It remains to be determined whether SUVmax is predictive of clinical outcome in FL patients treated with other commonly used therapies such as rituximab monotherapy, rituximab and bendamustine, or R-CVP. Figure 1 Figure 1. Disclosures Wang: Pharmacyclics, Janssen: Honoraria, Research Funding. Westin:Novartis: Research Funding.

Description: Purpose: We assessed the survival outcome of patients with anaplastic large cell lymphoma (ALCL) who experienced disease progression or relapse after first line and subsequent therapy. We sought to evaluate the impact of brentuximab vedotin (BV), and survival outcome of patients with ALCL who experienced progression after BV. Patients and Methods: A total of 176 patients (74 ALK+, 102 ALK-) initially diagnosed between 1999 and 2014 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) after the progression/relapse following first-line chemotherapy (PFS1 and OS1), after first salvage therapy (PFS2 and OS2) and after second salvage therapy (PFS3 and OS3) were calculated. Outcome was separately analyzed according to the ALK status focusing on the use of BV. Results: The median age of the patients was 50 (range: 18-89). With a median follow up of 64 months, 111 patients (38 ALK+, 73 ALK-) experienced progression/relapse after the first-line therapy, of which 4 ALK- patients were post upfront stem cell transplant (SCT). Thirty and 15 patients eventually underwent autologous and allogeneic SCT after salvage chemotherapy, respectively. The median PFS1 and OS1 in patients with ALK+ALCL and ALK-ALCL were 8.4 and 28.5 months, and 13.1 and 47.7 months, respectively. In patients with ALK+ALCL, the median PFS1, PFS2 and PFS3 were 53.6, 5.2 and 2.3 months, respectively. The median OS1, OS2 and OS3 were not reached, 47.3 and 6.1 months, respectively. In patients with ALK-ALCL, the median PFS1, PFS2 and PFS3 were 12.9, 3.0 and 2.0 months, respectively. The median OS1, OS2 and OS3 were 54.3, 10.8 and 5.8 months, respectively. Interestingly, there were no significant difference in PFS2 between ALK+ALCL and ALK-ALCL. However, OS2 was significantly longer in patients with ALK+ALCL, suggesting possibly continued chemosensitivity of recurrent ALK+ALCL. A total of 30 patients received BV in 1st salvage (15 patients) and after 2nd salvage (15 patients).The use of BV at 1st salvage was associated with significantly longer PFS2 and OS2 both in patients with ALK-ALCL but not with ALK+ALCL likely due to small number of cases. Mutivariate analysis adjusting baseline PIT risk factors and the duration of the response to first line therapy revealed that use of BV (at any point in the salvage setting) is significantly associated with longer OS2 (HR: 0.43, 95%CI: 0.23-0.80). Overall, 12 patients experienced relapse/progression after BV treatment. The median OS after BV failure was 1.4 months (95%CI: 0.5-9.5 months) (Figure). Summary: Survival outcome for relapsed/refractory patients with ALK+ and ALK- patients is improved with BV. However, survival outcome after BV failure is very poor. A new treatment strategies to consolidate or maintain the response after BV and to develop more safe and better therapeutic options are needed. Figure 1. Figure 1. Disclosures 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. Westin:Spectrum: Research Funding. Nastoupil:Celgene: Honoraria; Genentech: Honoraria; AbbVie: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Wang:Celgene: Research Funding.

Description: INTRODUCTION More active high-dose regimens are needed for non-Hodgkin’s (NHL) and Hodgkin’s lymphomas (HL), where standard BEAM offers poor results in refractory or poor-risk relapsed tumors. We previously developed a regimen of infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel), exploiting the synergy between gemcitabine and alkylators based on inhibition of DNA damage repair. Gem/Bu/Mel was safe and highly active against refractory lymphomas (Nieto, BBMT 2012). To further increase its activity we combined it in preclinical experiments with SAHA, which induces relaxation of the chromatin and renders DNA more accessible to DNA-targeting agents. Concurrent exposure to SAHA and Gem/Bu/Mel resulted in markedly increased apoptosis and cytotoxicity in refractory B- and T-NHL lines, with increased PARP1 cleavage and γ-H2AX reflecting increased DNA damage (Valdez, Exp Hematol 2012). SAHA has a dose-response effect in refractory lymphoma lines up to clinically achievable levels with doses of 1,000 mg, higher than its usual dose. We wished to clinically study the concurrent combination of SAHA and Gem/Bu/Mel in refractory NHL and HL. Methods Patients ages 12-65 with refractory lymphomas and adequate end-organ function were eligible for this dose-finding study of SAHA combined with Gem/Bu/Mel. SAHA was given on days -8 to -3 at 200-1,000 mg PO daily (levels 1-11), preceding all chemotherapy. Gemcitabine was given as a loading dose of 75 mg/m2 followed by infusion at a fixed dose rate of 10 mg/m2/min over 3.5 (levels 1-5), 4 (level 6) or 4.5 hours (levels 7-11) on days -8 and -3. Each gemcitabine dose was immediately followed by the corresponding dose of busulfan or melphalan. After a test dose on day -10, busulfan was given from days-8 to -5 targeting a daily AUC of 4,000. Melphalan was infused at 60 mg/m2/day on days -3 and -2. ASCT was on day 0. Patients with CD20+ tumors received rituximab (375 mg/m2) on days +1 and +8. Dose limiting toxicities (DLT) were defined as any G4-5 nonhematological organ toxicity, or as G3 skin or G3 mucositis lasting 〉3 days at peak severity. Dose escalation followed a Bayesian design targeting a maximal DLT probability of 20%. Results Between 10/11 and 6/13, 66 patients were enrolled with DLCL, HL and T-NHL (Table 1). SAHA was escalated up to 1,000 mg PO daily, combined with full doses of Gem/Bu/Mel without encountering DLTs. There were no treatment-related deaths. The toxicity profile was manageable, including mucositis (48% G2, 31% G3), skin (11% G2, 3% G3), self-limited transaminase elevation (30% G2, 6% G3), and self-limited elevation of bilirubin not associated to VOD (22% G2, 16% G3). There were no cardiac, pulmonary, renal or CNS toxicities. There was no QT prolongation detected after SAHA. Neutrophils and platelets engrafted promptly at median days +10 (range, 8-13) and +12 (range, 8-55), respectively. This toxicity profile is undistinguishable from the one we previously described with Gem/Bu/Mel. Activity and patient outcomes at median follow-up of 8 months (1-23) are shown on Table 2 and Figures: Conclusions Concurrent administration of SAHA with high-dose GemBuMel is feasible up to a daily dose of SAHA of 1,000 mg, with no increased toxicities compared to Gem/Bu/Mel alone. Early results indicate that SAHA/Gem/Bu/Mel is highly active in refractory or poor-risk relapsed HL and DLCL and warrants further study in earlier disease stages. Longer follow-up is needed to confirm these findings. Disclosures: Nieto: Otsuka Pharmaceuticals: Research Funding. Off Label Use: Vorinostat not approved for DLCL or Hodgkin's lymphoma. Qazilbash:Otsuka Pharmaceuticals: Research Funding. Andersson:Otsuka Pharmaceuticals: Research Funding.

Description: The malignant Hodgkin and Reed-Sternberg (RS) cells of Hodgkin lymphoma (HL) reside among an overwhelming number of benign stromal cells. The majority of the cells in this microenvironment are T and B lymphocytes. Both B and T cells have been reported to express growth and survival factors that may support HRS cells survival. Specifically, we and others reported that B cells in HL lesions express CD30 ligand and CD40 ligand that are known to activate NF-kB and provide survival and resistance signals to HRS cells. To determine the contribution of benign B-cells to the survival of RS cells in vivo, we have recently conducted a pilot study using rituximab alone in patients with relapsed classical HL. Depleting benign B cells from HL lesions produced an overall response rate was 23% in heavily pretreated patients (response rate was 50% when patients with no extranodal site involvement). We therefore hypothesized that depleting benign B cells from HL lesions by rituximab may deprive HRS cells from critical growth and survival factors which may synergizes with chemotherapy. To test this hypothesis, we evaluated the safety and efficacy of the novel combination of rituximab and gemcitabine chemotherapy in patients with relapsed/refractory classical HL. Rituximab was given at 375 mg/m2 weekly for 6 weeks to rapidly deplete B lymphocytes, while gemcitabine was given at a 1 gm/m2 on day 1 and 8 of a 21-day cycle. The first dose of rituximab was given concurrently with the first dose of gemcitabine. Patients were eligible if they had biopsy-confirmed relapsed/refractory classical HL irrespective of CD20 expression on HRS cells, bidimensionally measurable disease that is confined to lymph nodes, adequate bone marrow reserve (ANC 〉 1,000/uL, Platelet 〉 100,000/uL) and adequate cardiac and renal functions. Patients with prior autologous stem cell transplantation were eligible. Patients were excluded if they had extranodal disease, HIV infection, or were pregnant women. To date 29 patients are enrolled, of whom 26 are evaluable for treatment response. Median age 32 years (range 19–73), 11 were females and 15 males. The median number of prior treatment regimens was 4 (Range 1–6), and 17 (65%) were refractory to their last regimen. Fourteen patients (54%) received prior stem cell transplantation. Twenty-one patients (81%) were previously treated with platinum-based therapy. Treatment was reasonably well tolerated with the most frequent toxicity being thrombocytopenia and neutropenia. Thirteen patients (50%) responded to therapy irrespective of CD20 expression by HRS cells. Our results compare favorably with the reported single agnet activity of gemcitabine in less heavily pretreated patients. This encouraging results warrants evaluating this novel therapeutic concept in less heavily pretreated patients, perhaps in a randomized phase II design to shed more light on the potential contribution of rituximab to gemcitabine.

Description: Introduction: Mantle cell lymphoma (MCL) is a rare and incurable subtype of B-cell lymphoma. Intense chemo-immunotherapy with 8 cycles of Rituximab-HyperCVAD alternating with Rituximab-Methotrexate-Ara C is associated with an overall survival of 10.7 years but the 10-year cumulative incidence of therapy-related myeloid neoplasm was 6.2%. The ibrutinib-rituximab combination has produced durable responses in 88% of patients with relapsed and refractory MCL with acceptable toxicity. This gives rise to a "Window" of opportunity to use chemotherapy-free induction with ibrutinib plus rituximab followed by fewer cycles of chemo-immunotherapy consolidation in young and fit patients with newly-diagnosed, untreated MCL. Methods: Enrolment began in June 2015 for a Phase II single-center clinical trial consisting of an initial chemotherapy-free phase (window) of ibrutinib and rituximab combination treatment in Part 1 until best response, followed by a shortened course of intense chemo-immunotherapy in Part 2 among young newly diagnosed MCL patients of ≤65 years. The primary objective was to evaluate the response rate of ibrutinib plus rituximab. The secondary objectives were to evaluate the progression free survival (PFS) of ibrutinib plus rituximab after consolidation with a shortened number of cycles of intense chemo-immunotherapy, and to further evaluate the toxicity profile. Ibrutinib is dosed at 560 mg orally, daily, continuously. Rituximab is dosed at 375 mg/m2 IV weekly x 4 during cycle 1 (28 days cycle), then day 1 of cycles 3-12. Intense chemo-immunotherapy consists of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD); alternating every 28 days with rituximab plus high-dose methotrexate-Ara C. If in complete remission (CR) after initial ibrutinib and rituximab treatment, a total of 4 additional treatments of intense chemo-immunotherapy are given. If the patient is in partial response or progression, and if responding to intensive chemo-immunotherapy, a total of 2 cycles of chemo-immunotherapy therapy are administered beyond achievement of CR. Results: As of August 2, 2016, we have completed the target enrolment by accruing 50 out 50 patients with newly-diagnosed untreated MCL. Forty one (n=41) patients have begun treatment and 36 are evaluable for response. Of the 36 evaluable patients, overall response rate (ORR) to Part 1 alone (Ibrutinib plus rituximab) is 100% (n=36) with PR in 28% (n=10) and CR in 72% (n=20). Nineteen 19 patients have completed both Part 1 (ibrutinib and rituximab) and Part 2 (chemo-immunotherapy). The ORR to both Part 1 and Part 2 (n=19) was 100% and was equal to the CR rate (100%, n=19), i.e. all have achieved a CR to Part 1 and Part 2. Toxicities are recorded as the number of patients experiencing a certain adverse event. Regardless of their relation to study drug in Part 1, the most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=40), diarrhea (n=25), rash (n=24), myalgia (n=22), oral mucositis (n=17), peripheral neuropathy (n=15), nausea (n=14), blurred vision (n=14), edema (n=13), constipation (n=12), headache (n=11), dry eyes (n=9), dizziness (n=9) and watery eyes (n=6). Grade 3 non-heme AEs included fatigue (n=3), nausea (n=0), rash (n=1), pleural effusion (n=1), infection (n=2) and dyspnea (n=1). There was no grade 4 or grade 5 non-heme toxicities in Part 1. In part 2, common grade 1-2 hematological (heme) AEs was anemia (n=13). Grade 3-4 haematological AEs included neutropenia (n=2), ALT increase (n=1) and febrile neutropenia (n=1). In Part 2, there was no grade 5 hematologic toxicity. The toxicity after intensive immune-chemotherapy in shortened cycles are much improved compared to historical controls but longer follow-up is needed. Conclusions: Preliminary data indicate that the chemotherapy-free induction with ibrutinib and rituximab in newly diagnosed, young MCL patients was efficacious and well-tolerated. This unprecedented efficacy and safety may provide a window of opportunity for less chemo-immunotherapy needed for consolidation. Table Preliminary findings form the Window Study: a phase II clinical trial Table. Preliminary findings form the Window Study: a phase II clinical trial Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding.

Description: Both non-Hodgkin lymphoma (NHL) and HL are radiosensitive tumors. Although the efficacy of radioimmunotherapy (RIT) targeting CD20 antigen has been established in several types of B-cell NHL, no data exisit on the potential use of this approach in classical HL. The malignant Hodgkin and Reed-Sternberg (HRS) cells of HL infrequently express CD20 suggesting that classical HL may not be the optimal tumor to be targeted by this approach. However, HRS cells are frequently surrounded by reactive B lymphocytes that express CD20. Therefore, we hypothesized that targeting reactive B cells in HL microenvironment by RIT could deliver effective radiation dose to HL lymph nodes killing HRS cells by cross-fire effect. To test this hypothesis, we treated 4 patients with relapsed classical HL with Zevalin RIT. During the imaging phase, patients received a slow intravenous infusion of rituximab (250 mg/m2) followed by an intravenous injection of 4–5 mCi of In-111 labeled anti-CD 20 (In-111 Zevalin). Whole-body scans were performed at 2–4 hours and 40–48 hours after injection using a Siemens dual-head gamma camera. Simultaneous anterior and posterior projections were obtained at these time points. After ruling out any unfavorable biodistribution of Zevalin was confirmed on images at both time points, patients underwent the treatment phase which consisted of rituximab (250 mg/m2) followed by Y-90 anti-CD 20 (Y-90 Zevalin). To-date 4 patients are enrolled on study (ages 25, 31, 65, and 74 years). Two patients received prior ASCT, and 2 were treated after failing ABVD chemotherapy alone. All patients received 0.4 mCi/Kg up to a maximum dose of 32 mCi. Normal biodistribution of Zevalin was confirmed in all 4 patients during the imaging phase. No Zevalin-avid lesions was noted in one patient. There was faint visualization of some of the known lesions (by Ga-67 SPECT, CT or F-18 FDG PET) in the axilla and abdomen in 2 of the 4 patients. Intense Zevalin-uptake sites were identified in the supraclavicular, infraclavicular, mediastinal, hepatic and abdominal lymphatic chains in another patient. Imaging results and treatment responses are shown in the following table: Patient Response Prior ASCT In-111 Zevalin-avidity Clinical 1 Yes none PD 2 No faint, right axilla PD 3 Yes very faint, abdomen NC 4 No intense NC Treatment was well tolerated with hematologic toxicity similar to those observed in NHL patients. Our preliminary results suggest that RIT targeting reactive B cells in classical HL is feasible and safe. Future studies should incorporate pretreatment evaluation of a selected lymph node by fine needle aspiration to determine the fraction of reactive B cells in the microenvironment prior to treatment with RIT targeting CD20.