Early Safety and Efficacy Analysis of a Phase II Study of Sequential R-CHOP and Yttrium-90 Ibritumomab Tiuxetan (Zevalin®) for Elderly High Risk Patients with Untreated DLBCL.

Abstract Introduction: Elderly patients (pts) with high risk DLBCL represent an increasing demographic, are often underserved in clinical trials, and need improved therapies. By the age-adjusted international prognostic index (aaIPI), pts >60 years (yrs) with high-intermediate (HI) and high risk (H) disease had 5 yr survival (OS) rates of 37%, and 21%, respectively. Rituximab’s addition to CHOP has improved responses and outcomes, but >50% of high risk pts still relapse. We are investigating the safety and efficacy of sequential RCHOP followed by Yttrium-90 ibritumomab tiuxetan (Zevalin ®) radioimmunotherapy (RIT) in an effort to improve these results. An early safety analysis of this sequential program is presented here. Methods: Untreated ASCT-ineligible pts >60 yrs, with aaIPI HI or H risk DLBCL are eligible for study. Induction: pts receive R-CHOP chemotherapy at standard doses q 21 days x 6 cycles with prophylactic pegfilgrastim (or G-CSF) and darbepoetin alfa (Aranesp ®) support. Consolidation: pts with ≥ stable disease at post RCHOP restaging are eligible for 90Y-90 ibritumomab tiuxetan, given 6–9 weeks post RCHOP; For platelet (plt) counts ≥ 150K → 0.4 mCi/kg dose, plt counts of 100–149K → 0.3 mCi/kg. Weekly CBC’s are performed until week 12–13 restaging. Results: 26 pts have been enrolled as of July 12th, 2005. Median age is 75 (range 65–85; male:female 9:17); KPS <80% in 55% (median 70%, range 60–90%); LDH > nl: 89% (range 150–804); Stage III/IV: 11.5% / 88.5 %; Extranodal sites are >1 in 50%; B symptoms in 54%; aaIPI HI (2 factors) = 46%, H (3 factors) = 54%; 18/26 pts have completed RCHOP; 8 pts are off study before RIT for: 4 cardiovascular events (1 CHF,1 Non-Q-wave MI, 1 sudden death, 1 V. Fib arrest), 3 neutropenic sepsis (1=grade 4, 2=grade 5), 1 leptomeningeal progression; 14 pts have received RIT. Median nadir counts during RIT occur at week 6–7: absolute neutrophil count (ANC) = 850 cells/mm3 (0.3–5.4), Hemoglobin (Hgb)= 10.1 gm/dl (6.6–14.6), plt = 28K cells/mm3 (7–103); Grade 3 and 4 ANC = 39%/39%, Hgb 39%/0%, Plt 46%/15%; During RIT, blood and Plt transfusion occurred for 46% and 31%, respectively; colony stimulating factor and erythropoietic support was used in 39% and 31%, respectively. One pt had delayed count recovery post RIT (448 days, transfusion independent from week 12→). Non-hematologic serious adverse events after RIT include: two grade 3 neutropenic infection (1 without fever), 1 grade 5 sudden death at week 7 (autopsy refused). OS and EFS for all pts by intent to treat is 60% and 55%, respectively, with 14 months median followup. Of pts post-RIT >12 weeks (11 pts), none have relapsed with 21 months median follow-up. Conclusions: Treatment of elderly aaIPI HI and H risk DLBCL pts with sequential RCHOP followed by 90Y ibritumomab tiuxetan is feasible and associated with manageable toxicity. Hematologic toxicity with RIT is similar to single agent toxicity, with slightly greater thrombocytopenia that warrants careful follow-up. Toxicity during RCHOP induction is significant in high risk elderly patients and cycle one modification is being implemented. Accrual continues to evaluate the potential long term impact of RIT on EFS and OS.

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Final Results of a Phase II Study of Sequential R-CHOP and Yttrium-90 Ibritumomab Tiuxetan (RIT) for Elderly High Risk Patients with Untreated Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽

10.1182/blood.v116.21.1793.1793 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1793-1793 ◽

Cited By ~ 6

Author(s):

Paul A. Hamlin ◽

Maria Alma Rodriguez ◽

Ariela Noy ◽

Carol S. Portlock ◽

David Straus ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

B Cell Lymphoma ◽

Phase Iii ◽

Ibritumomab Tiuxetan ◽

Grade 5 ◽

Yttrium 90

Abstract Abstract 1793 Introduction: Elderly patients (pts) with high risk DLBCL are one of the fastest growing demographics of pts, but advances over RCHOP21 have not been realized. These pts are often under-represented in clinical trial secondary to comorbidity, ageism, and eligibility requirements. By the age adjusted international prognostic index (aaIPI), pts >60 years (yrs) with high-intermediate (HI) and high (H) risk disease had 5 yr survival (OS) rates of 37% and 21%. Even in the RCHOP era, high risk elderly patients have event-free-survival of roughly 50%. We report the mature data from a phase II study investigating sequential RCHOP followed by yttrium-90 ibritumomab tiuxetan radioimmunotherapy (RIT) in an effort to improve these results. Methods: Untreated ASCT-ineligible pts >60 yrs, with aaIPI HI and H risk DLBCL were eligible for study. Pts received RCHOP21 × 6 cycles at standard doses with prophylactic GCSF and darbepoetin alfa. Pts with responding (CR/PR) or stable disease post RCHOP received RIT, given 6–9 weeks post chemotherapy at 0.4 mCi/kg for platelets (plt) ≥150K and 0.3 mCi/kg for plt 100–149K. Weekly CBCs were performed for 12–13 weeks or until count resolution. Rituximab levels were assessed pre-RIT in a subset of pts. Primary end-points were PFS and OS, with intent-to-treat (ITT) analysis performed for all patients. Statistics anticipated 2/3 of pts (n=43) receiving RIT, with power to demonstrate a 20% improvement in PFS/OS at 2 yrs. Results: 65 pts were consented, with 2 pts having progression prior to a single cycle on protocol, leaving 63 evaluable pts. The median age was 75 (62-86), median KPS 70% (50-100%), Stage III/IV 23/74%, LDH>ULN 91%, ENS>1=45%, BM positive=11%; aaIPI HI/H 45%/55%. Moderate or greater comorbidity was present in 86% of pts (n=65) by NIA/NCI scale. 86% of pts completed RCHOP, with overall response rate (ORR) of 83% (CR/Cru 75%, PR 8%) (Cheson 1999). Fifty pts by ITT were eligible for RIT following RCHOP chemotherapy, with 44 pts ultimately treated. Reasons for discrepancy included low bone marrow cellularity (2pt), AFIB/CHF post day 0 (1 pt), abnormal baseline FISH/cytogenetics (2 pts), withdrawal of consent (1pt). Rituximab levels in 30 pts are available pre-RIT: mean 112 mcg/ml (range 41–196) and did not correlate with outcome. The RIT dose was 0.4 mCi/kg in 38 patients and 0.3 mCi/kg in 6 patients. No patient had altered biodistribution on imaging. RIT was generally well tolerated with expected hematologic nadirs at weeks 6–7. Grade 3/4 non-heme toxicity during RIT included neutropenic fever (2), transient EF decline >20% (1), hip fracture (1), anthracycline induced cardiomyopathy (grade 5), suspected CNS bleed (grade 5). Response post RIT (n=44) was CR/CRu 86%, PR 2%. Response improvement (PR->CR or CRu->CR) occurred in 7 pts (16%). Median followup for surviving pts is 42 months, with median OS and PFS not reached (0.5-74.4). KM estimates of OS and PFS at 42 months by ITT: 64% and 62% respectively. OS and PFS at 42 months for RIT treated pts (n=44): 83.5% and 74.5%. There have been only two relapse >12 months after RIT. The aaIPI (HI vs H) predicted outcomes: OS 75% vs. 49% (p=.008), PFS 68% vs. 45% (p=.01). Conclusion: Sequential RCHOP21 × 6 cycles followed by RIT in an elderly, high comorbidity, high risk DLBCL cohort is associated with very encouraging outcomes by ITT and specifically in the RIT treated pts with long term follow-up. Therapy was well tolerated in this age group and given lack of late relapses, one may hypothesize RIT is addressing minimal residual disease typically associated with recurrence. Outcome is very favorable when compared to historical controls. A prospective Phase III study is needed to confirm these results. Disclosures: Hamlin: Genentech: Honoraria, Speakers Bureau; Biogen Idec: Honoraria, Speakers Bureau; Spectrum: Consultancy, Research Funding; CTI: Consultancy, Research Funding. Off Label Use: Y-90 ibritumumab tiuxetan is not approved for use in DLBCL; it is FDA approved for NHL/indolent lymphoma. Rodriguez:CTI: Research Funding. Noy:Spectrum: Consultancy. McLaughlin:Spectrum: Consultancy. Pandit Tasker:CTI: Research Funding; Spectrum: Research Funding. Zelenetz:GSK: Consultancy; CTI: advisory board.

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R-FND Followed by Radioimmunotherapy for High-Risk Follicular Lymphoma

Blood ◽

10.1182/blood.v112.11.3056.3056 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3056-3056 ◽

Cited By ~ 7

Author(s):

Peter McLaughlin ◽

Sattva Neelapu ◽

Michelle Fanale ◽

Maria Rodriguez ◽

Ana Ayala ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

Ibritumomab Tiuxetan ◽

Free Survival ◽

Grade 3 ◽

Anti Cd20 ◽

Better Than

Abstract Follicular lymphoma (FL) patients, (pts) with high-risk features using the FL International Prognostic Index (FLIPI) have an expected 5-year survival of only about 50% with conventional therapy. With the incorporation of anti-CD20 monoclonal antibody (mAb) therapy, results are improving (e.g., Buske, Blood2006; 108: 1504). Starting in 2003, we have treated high-risk (FLIPI ≥3) FL pts with R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone) for 4 cycles, followed by radioimmunotherapy (RIT) with ibritumomab tiuxetan, and subsequent rituximab maintenance. Results for the first 35 pts are: complete (CR) and partial (PR) remission 83% and 14%; 3-year overall (OS) and failure-free survival (FFS) 89% and 74% (median follow-up 24 mo.). RIT converted 5 PR pts to CR. Toxicity was mainly hematologic. Five pts did not receive RIT, one because of neutropenia after R-FND. Following RIT, platelet and neutrophil nadirs were 28 and 0.3, occurring at 4–7 weeks. 16 pts required transfusions, and 27 received growth factors. 13 pts had infections, only 2 of which were grade 3. Recovery occurred by 3 weeks in most, with prolonged cytopenias in 6. There has been 1 case of myelodysplasia. In conclusion, the additional complexity of this RIT intensification strategy is warranted in this high-risk FL population, resulting in OS and FFS outcomes that are better than non-mAb therapies, and at least as good as published chemotherapy-rituximab combination therapy.

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Frontline Combined Chemoimmunotherapy with Fludarabine, Cyclophosphamide, Alemtuzumab and Rituximab (CFAR) in High-Risk Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.208.208 ◽

2009 ◽

Vol 114 (22) ◽

pp. 208-208 ◽

Cited By ~ 2

Author(s):

Sameer A Parikh ◽

Michael Keating ◽

Susan O'Brien ◽

Alessandra Ferrajoli ◽

Stefan Faderl ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Hematologic Toxicity ◽

Frontline Therapy ◽

Grade 3 ◽

Tract Infections ◽

Cmv Reactivation

Abstract Abstract 208 Background: Combined chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has excellent clinical activity as frontline therapy for patients (pts) with chronic lymphocytic leukemia (CLL). In a subset of pts who exhibited high-risk features, such as serum beta-2 microglobulin (B2M) ≥4 mg/L; the complete remission (CR) was lower and time to progression (TTP) and overall survival (OS) were shorter; therefore characterizing these pts as high-risk. Alemtuzumab (A) has activity as a single-agent and in combination with F in pts with relapsed/refractory CLL. To improve the CR and OS for pts with high-risk CLL, we added A to the FCR regimen (CFAR) as frontline therapy in a Phase II clinical trial. Methods: All pts who met NCI-WG criteria to initiate therapy, were < 70 years and had a B2M ≥4 mg/L were eligible for the study. Frontline CFAR consisted of C-200 mg/m2 D3-5, F-20mg/m2 D3-5, A-30mg IV D1,3,5, and R-375–500 mg/m2 D2. Courses were repeated every 28 days for a total of 6 courses. All pts received pegylated filgrastim 6mg SC with each course of therapy. All pts received allopurinol for tumor lysis prophylaxis. Antibiotic prophylaxis with TMP/SMX DS and valacyclovir or valganciclovir was also given to all pts. CMV antigenemia was monitored before each course. Results: A total of 60 pts were enrolled from July 2005 through August 2008 (Table). One pt was lost to follow-up. The median age was 59 yrs (range 42–69) and 44 (75%) were male. Median B2M was 5.1 mg/L (4–11.6); HGB was 11.5gm/dL (5.5–15.1); PLT was 139 k/μL(41–446); WBC was 100k/μL (5–665); ALC was 92k/μL (4–619); and 30 pts (51%) were Rai stage III-IV. The median number of courses administered was 4 (2–6); reasons for not completing 6 courses included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and pt. choice (2). CR was achieved in 70%, nPR in 3%, PR in 18%, and 7% pts did not respond, leading to an ORR of 92% (Table). There was no significant correlation between CR or OR with Rai Stage, IgVH mutation status, FISH status, ZAP70 and CD38 expression. After a median follow-up of 24 months (3–49), 19(32%) pts have progressive disease. Patients with 17p deletion and unmutated IgVH had significantly shorter TTP as shown in the >Table. Eleven (19%) pts have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 transformed into AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. In a historic cohort of high-risk pts treated with FCR, grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 10% courses; and major and minor infections were seen in 15% and 23% pts respectively, all comparable to that seen with frontline CFAR. A-associated infusion reactions occurred in 42 (71%) pts. CMV reactivation occurred in 7 (12%) pts, all of whom were on valacyclovir prophylaxis. There was 1 death due to CMV pneumonia; all other episodes of CMV reactivation were promptly treated with valaganciclovir leading to resolution of fever and/or antigenemia. The median OS for all pts has not been reached (49+mo) and the median TTP is 38 months. Conclusion: CFAR is an active frontline regimen in high-risk pts with CLL. Although CR rates in pts with other high-risk features such as 17p deletion and unmutated IgVH were >50%, TTP was significantly shorter for these pts than for pts without these features. With current follow-up, OS, TTP, infectious complications and grade 3/4 hematologic toxicity are comparable to historic high-risk pts treated with FCR. Disclosures: Keating: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Consultancy, Honoraria; Genzyme: Research Funding.

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RIT with 90Y Ibritumomab Tiuxetan in Agressive Non-Hodgkin Lymphoma. Evaluation of Recent Outcomes in a Single Institution

Blood ◽

10.1182/blood.v120.21.4883.4883 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4883-4883

Author(s):

Anel Montes ◽

Ma Andrade ◽

Ilda Murillo ◽

Luis Lopez-Gomez ◽

Teresa Baringo ◽

...

Keyword(s):

Median Time ◽

Hematologic Toxicity ◽

Consolidation Therapy ◽

Ibritumomab Tiuxetan ◽

Score Distribution ◽

Non Hodgkin Lymphoma ◽

Grade 3 ◽

Relapsed Disease ◽

Active Disease

Abstract Abstract 4883 Diffuse Large B Cell (DLBC) and Mantle Cell Lymphoma (MCL), are two subtypes of aggressive non-Hodgkin lymphoma (A-NHL),that frequently present as advanced systemic disease limiting the use of involved field radiation. They are also predominant in advanced age population non suitable for intensive therapy such as stem cell transplantation. Their aggressive systemic behavior, confer high rates of relapse and short overall survival. The development of radioimmunotherapy brings a new therapeutic approach for both types of A-NHL. We present the results derived from a single-institute use of 90Y-Ibritumomab Tiuxetan (90Y-IT) (Zevalin®) in DLBC and MCL, both as consolidation therapy in first complete response (C-1CR) after chemoimmunotherapy and as second line treatment in relapsed disease (RD). Patients and Methods: we included 19 patients with A-NHL, 10 MCL and 9 DLBCL, treated with 90Y-IT according to a multidisciplinary clinical protocol, between September 2005 and February 2012. Inclusion criteria were: histological confirmed CD20+ MCL or DLBCL, with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, absolute platelet count (APC) ≥ 100 × 109/L, ≤ 25% bone marrow CD20+ lymphocytes, in Complete Remission (CR) after first line chemoimmunotherapy or with relapsed disease. All patients received two prior 250 mg/m2 Rituximab doses, followed by 0.4 mCi /kg IV 90Y-IT. Response was evaluated by PET/TC 12 weeks after treatment. Major endpoints were: objective response rate (ORR), overall survival (OS), progression free survival (PFS), and safety. Other clinical prognostic factors were taken into account upon their possible influence in treatment value. Results: 18 of 19 patients treated with 90Y-IT completed follow-up and were taken into analysis, 10 MCL (52.6%) and 9 DLBCL (47.4%); M/F distribution 10/9 (73.6/26.4%); Overall ECOG 0–1 82.35%. Mean follow-up time: 46.8 months. 8 patients were treated as C-1CR, 4 MCL and 4 DLBCL. For MCL mean age was 66.9 (53–79) years. MIPI score distribution: 0–3 (70.0%), >3 (30.0%). Status before 90Y-IT was: C-1CR 3; relapsed in CR after chemotherapy 3; relapsed/refractory with active disease after chemotherapy (PR) 4. Previous chemotherapeutic schedules: ≤2 (50 %). Overall response (80.0%) 7 CR; 1 PR. Mean estimated OS since 90Y-IT: 57.0 months (52.4–61.6), median OS: 59 months (34.8–86.1) and mean PFS: 24.9 months (95% CI: 14.3–35.6); median PFS: 22 months (95% CI: 1.9–42.0). For DLBCL: mean age 53 (35–87) years. IPI-R score distribution: 0–2 (33.3%), >2 (66.7%). Status before 90Y-IT was: C-1CR 5; relapse/refractory with active disease after chemotherapy (PR) 4; Previous chemotherapeutic schedules ≤2 (77.8%). Overall responses (88.8%) 5 CR; 3 PR. Mean OS since 90Y-IT: 49.2 months (42.8–55.6); median OS: NR and mean PFS: 39 months (95% CI: 22.6–55.4). Until analysis 11 patients have relapsed (57.8%), 8 MCL (80%) and 3 DLBCL (37.5%). Four patients had died, 3 because of disease progression even after several chemotherapeutic treatments. In respect to safety: thrombocytopenia was the most frequent hematologic toxicity presented in 63.1%, grade 3–4 in 21%, with median time to presentation of 2.8 weeks and median time for recovery of 3 weeks. Neutropenia occurred in 52.6%, grade 3–4 in 21%, with median time for recovery of 2 weeks. 1 patient (5.2%) required red cell transfusion and 4 (21.5%) needed platelet transfusion. The most frequent non hematologic toxicity was asthenia. One MCL patient who relapsed 28 months and received 2 more chemotherapy schedules has been diagnosed, four years after 90Y-IT as lung carcinoma. Conclusions: 90Y-IT is a safe and effective consolidation therapy in A-NHL, that allows sustained CR and extends PFS with a low toxicity profile. There are needed further studies to evaluate the impact of radioimmunotherapy in A-NHL. This worh has bee partially sponsored by a grant from FEHHA Disclosures: No relevant conflicts of interest to declare.

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Comparison Of Sequential Vs Alternating Administration Of Bortezomib, Melphalan and Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) In Elderly Patients With Newly Diagnosed Multiple Myeloma (MM) Patients: GEM2010MAS65 Trial

Blood ◽

10.1182/blood.v122.21.403.403 ◽

2013 ◽

Vol 122 (21) ◽

pp. 403-403 ◽

Cited By ~ 4

Author(s):

Maria-Victoria Mateos ◽

Joaquín Martínez-López ◽

Miguel T. Hernandez ◽

Rafael Martinez ◽

Laura Rosiñol ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Research Funding ◽

Risk Groups ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Sequential Scheme ◽

To Receive

Abstract Background VMP and Rd are two of the most efficient and widely accepted regimens in the treatment of elderly newly diagnosed MM patients. In order to further improve the outcome of elderly patients, one possibility would be to use regimens including all these drugs simultaneously, but this may result into high toxicity. Alternatively, the use of these regimens (VMP and Rd) in a sequential or alternating scheme could improve the treatment of elderly patients. We hypothesized the alternating scheme would minimize the emergence of resistant clones, and would reduce the cumulative toxicity. In order to test this hypothesis we decided to compare VMP and RD in a sequential vs an alternating scheme. Patients and methods 241 patients were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd (half of the patients started by VMP and half by Rd) up to 18 cycles). VMP included the iv administration of bortezomib 1.3 mg/m2 twice weekly for 1 six-weeks cycle, followed by once weekly for 8 four-weeks cycles in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. Results 121 patients were allocated to receive the sequential scheme and 120 the alternating regimen. Both arms were well balanced according to the baseline characteristics. 52% patients in the sequential arm and 55% in the alternating and had high risk cytogenetic abnormalities (t(4;14), t(14;16), del17p or 1q gains). After 9 cycles of treatment, in the sequential arm, 35 out of 66 (54%) achieved at least VGPR vs 51 out of 65 patients (78%) in the alternating arm (p=0.002), including sCR/CR rate of 28% vs 38% in the sequential and alternating arms, respectively (p=NS). Seven patients in each arm achieved immunophenotypic CR. Moreover, while four patients progressed in the sequential arm under treatment with VMP, no patients in the alternating scheme developed disease progression during the first 9 cycles, After a median follow up of 12 months, there was a trend for shorter TTP in the sequential as compared with the alternating scheme (18 m-TTP of 83% vs 89% (p=NS)). In terms of OS, 83% of patients in the sequential arm were alive at 18 m versus 93% in the alternating (p=NS). Patients who achieved sCR/CR had a significantly longer 18 m-TTP as compared with patients who didn’t achieve it in both sequential (100% vs 71%; p=0.006) and alternating arms (100% vs 79%; p=0.006) and this translated into a significant benefit in OS. No differences were observed in overall response rates and CR rates in standard and high risk patients. The 18 m-TTP was similar in standard and high risk groups in both sequential (86% vs 81%) and alternating arms (84% vs 94%), noting that 94% of patients receiving the alternating scheme were progression-free at 18 months. Regarding hematologic toxicity, the frequency of G3-4 neutropenia was slightly lower in the sequential than in the alternating arm (16% and 23%) and the same trend was observed for G3-4 thrombocytopenia (16% vs 20%). Concerning non-hematologic toxicity, 5% and 4% of the patients in the sequential and alternating arms developed G3-4 infections, respectively; the rate of G3-4 skin rash was 4% in the sequential and 3% in the alternating arm; 4% of patients in the sequential arm developed G3-4 peripheral neuropathy and 3% in the sequential arm. The rate of grade 3-4 thrombotic events was 2% in both arms. Nevertheless, the detailed evaluation of the toxicity will be done at the completion of the trial when all patients will have received the same amount of drugs in either a sequential or an alternating scheme (at the present time, 42 patients in the sequential arm were not yet at risk for the development of lenalidomide-related side effects). Conclusions The administration of melphalan, bortezomib, lenalidomide and steroids in elderly MM patients in a sequential or alternating scheme is feasible. Although longer follow-up is necessary, the alternating scheme may be superior in terms of response rate and outcome, as result of the early exposure of the plasma cell to different agents. Toxicity profile is acceptable. Aparently both schemes of therapy seems to overcome the poor prognosis of high risk cytogenetic. Disclosures: Mateos: Janssen, Celgene: Honoraria. Off Label Use: Lenalidomide plus dexamethasone is not approved for newly diagnosed MM patients. Ocio:Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding. San Miguel:Janssen, Celgene: Membership on an entity’s Board of Directors or advisory committees.

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Long-Term Outcome of Patients with Marginal Zone Non-Hodgkin Lymphoma (MZL) Treated with Yttrium-90 Ibritumomab Tiuxetan: The Mayo Clinic Experience

Blood ◽

10.1182/blood-2019-130384 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1544-1544

Author(s):

Muhamad Alhaj Moustafa ◽

Ricardo Parrondo ◽

Gregory Wiseman ◽

Jennifer Peterson ◽

Thomas E. Witzig ◽

...

Keyword(s):

Median Time ◽

Research Funding ◽

Low Grade ◽

Ibritumomab Tiuxetan ◽

Term Outcome ◽

Long Term Outcome ◽

Grade 3 ◽

Yttrium 90

Background MZL is a low-grade non-Hodgkin's lymphoma (NHL) which involves lymph nodes, extranodal sites, or spleen. It is sensitive to radiation therapy, which is used in localized disease with curative intent. Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) that targets CD20. It is approved for relapsed/refractory low grade and follicular NHL. The data on its use in MZL is limited. We present long-term outcome of the largest reported cohort of MZL patients who received (90)Y-IT. Methods Medical records of patients who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2004 and December 2018 were analyzed. We selected patients with MZL and reviewed clinical data including age, gender, MZL type, clinical stage (Ann Arbor Staging System), treatment response, (90)Y-IT related adverse effects (AEs), as well as lymphoma and treatment related events. All patients received (90)Y-IT according to the standard treatment guidelines. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Twenty-one patients were identified (Table 1). The median age at diagnosis was 60 years (range, 11-81) and 71% (15/21) were female. 52% (11/21) were previously-untreated (UMZL) while 48% (10/21) were relapsed (RMZL). The median number of pretreatments in RMZL patients was 2 (range, 1-3). ECOG performance status at the time of treatment was 0 in 90% (19/21) and 1 in 10% (2/21). 62% (13/21) were stage III/IV disease at the time of (90)Y-IT therapy. The median follow-up was 8.5 years (95% CI; 4.5, 12.4); 17 (81%) patients remain alive. The ORR was 91% (19/21) with the two non-responders being in the RMZL group. The CR rate was 81% (17/21) and 65% (11/17) remain in CR at a median follow-up of 5.7 years (95% CI; 1.4, 11). Nine (43%) patients had a relapse during the study period. More relapses occurred in the RMZL group (7/10; 70%) compared to (2/11; 18%) in the UMZL group. Median PFS (whole cohort) was 10 years (95% CI; 2.1, NR) and TTNT (whole cohort) was not reached (NR) (95% CI; 2.1 years, NR). Median PFS was significantly higher in UMZL group compared to RMZL group NR (95% CI; 2.5 years, NR) vs 2.1 years (95% CI; 0.17, 9.9), respectively (Figure 1-A).Median OS (whole cohort) was 19.3 years (95% CI; 8.9, 19.3) without statistical difference in between UMZL group and RMZL group NR (95% CI; NR, NR) vs 16.6 years (95% CI; 9, 19.4), respectively (Figure 1-B). None of the 11 UMZL patients died at median follow up of 4.7 years (95% CI; 1.6, 9.2). All 4 deaths were in the RMZL group with 3 dying of transformation to high-grade lymphoma at 8, 22, and 25 months post-(90)Y-IT treatment. One patient died of myelodysplastic syndrome 7.3 years post-(90)Y-IT treatment while in CR. Toxicities were primarily hematologic. Grade ³3 neutropenia was observed in 6/21 (29%) patients with median time to nadir of 48.5 days (range, 19-70) and median time to recovery to normal absolute neutrophil count of 39.5 days (range, 7-476). Grade ³3 thrombocytopenia was observed in 3 (14%) patients with median time to nadir of 35 days (range, 19-357) and median time to recovery of 21 days (range, 2-538). Grade ³3 anemia was observed in only one patient. Only two patients required transfusions and growth factor support. Non-hematologic AEs included mild to severe fatigue in 4 patients. Conclusion RIC with (90)Y-IT is efficacious and well-tolerated in patients with previously untreated as well as relapsed MZL. As expected it appears to be more efficacious in previously untreated patients. Long-term complete remission (>5 years) was observed in 52% of the study population (43% of UMZL and 9% of RMZL). Combination of efficacy, tolerability, and treatment schedule most convenient for patients makes (90)Y-IT a reasonable alternative to systemic therapy with immunotherapy, chemotherapy, or chemo-immunotherapy in management of MZL. Figure 1: (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UMZL) and patients with relapsed MZL (RMZL), (B) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UMZL patients and RMZL patients. Disclosures Tun: Curis: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: The use of Yttrium-90 ibritumomab tiuxetan as a first line treatment for marginal zone lymphoma

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Lenalidomide Maintenance after Autologous Stem Cell Transplant in Patients with High-Risk Relapsed/Refractory Lymphomas Is Feasible and Compares Favorably to Historical Controls: Results of a Phase I/II Trial

Blood ◽

10.1182/blood.v128.22.4639.4639 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4639-4639 ◽

Cited By ~ 2

Author(s):

Jakub Svoboda ◽

Lauren E. Strelec ◽

Daniel J. Landsburg ◽

Sunita Dwivedy Nasta ◽

Anthony R. Mato ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Hematologic Toxicity ◽

Cell Transplant ◽

Grade 3 ◽

Historical Controls

Abstract Background: Lymphoma patients with residual hypermetabolic lesions on FDG-PET imaging after salvage chemotherapy have poor outcomes following autologous stem cell transplant (ASCT). We have previously shown progression free survival (PFS) of only 5 months (range: 1-19) in this population with only 7% of patients without progression at 12 months (Svoboda et al, BMT 2006). We hypothesized that these high-risk patients may benefit from continued therapy after ASCT. Lenalidomide is an immunomodulatory agent which has been used as maintenance in other hematologic malignancies, but its toxicity and efficacy have not been well described in lymphoma patients following ASCT. Methods: We are conducting a phase I/II prospective, open-label trial of lenalidomide maintenance after ASCT in lymphoma patients at high risk for relapse defined by residual FDG-PET positive lesions (SUV ≥ 2.5) immediately prior to ASCT. The primary objective of phase I was to determine the safety and dose-limiting toxicity (DLT) of lenalidomide maintenance. A 3+3 de-escalation design was used with a starting dose of lenalidomide at 10 mg on days 1 through 28 of each 28-day cycle. Lenalidomide was initiated 28-100 days post-ASCT and planned for up to 24 cycles. DLT was defined as non-hematologic toxicity ≥ grade 3 or hematologic toxicity ≥ grade 4 during the first 28 days of lenalidomide. The primary objectives of phase II were PFS and overall survival (OS). Survival outcomes were calculated from the date of ASCT. Enrollment began in 5/2012; we report data through 7/2016. Results: Fourteen patients were enrolled and 11 were evaluable (one patient withdrew consent and two progressed prior to initiation of lenalidomide). Eight (73%) evaluable patients had diffuse large B-cell lymphoma (DLBCL): 4 with germinal center (GC) origin and 4 non-GC by Hans algorithm. Three (27%) patients had Hodgkin lymphoma. Median age was 44 years (29-61), ECOG PS 0 (0- 1), prior therapies 2 (2-5). Median follow-up was 24 months (range 8-44), and median time on lenalidomide was 13 cycles (1-24). No DLTs were observed in phase I, and the dose of 10 mg daily was determined to be appropriate for phase II. Six (55%) patients discontinued lenalidomide: 3 due to disease progression, 2 at investigator's discretion (1 subsequently progressed), and 1 due to grade 3 rash possibly related to lenalidomide. Of 3 patients who discontinued lenalidomide due to progression, 1 (non-GC DLBCL) died of disease progression, 1 (GC DLBCL) achieved complete remission (CR) with allotransplant, and 1 (non-GC DLBCL) remains on another active therapy. Overall, 8 (73%) patients remain in CR following ASCT, including 3 patients who discontinued lenalidomide. Of note, 1 patient developed adenocarcinoma of the colon 1 year after completion of lenalidomide, and 1 patient developed therapy-related acute myeloid leukemia at 10 months after discontinuing lenalidomide. At a median follow-up of 24 months, PFS of the complete cohort was 62.3% (95% CI: 0.28-0.84; Figure 1) and median PFS was not reached. OS was 75% (95% CI: 0.30-0.93; Figure 2) and median OS was not reached. When compared to the reported PFS of 7% at 12 months in the historical controls with identical high risk pre-transplant characteristics, the PFS of 62.3% (95% CI: 0.28-0.84) at 12 months was significantly improved (Z-test, p<0.05). Conclusion: We established feasibility of lenalidomide maintenance at 10 mg daily after ASCT in patients with relapsed/refractory lymphomas. Preliminary clinical outcomes observed in this phase I/II trial are very encouraging when compared to historical controls. To better understand the toxicity profile and validate the promising clinical benefit, the strategy of utilizing immunomodulatory agents as post-transplant maintenance should be studied in a larger cohort of high-risk lymphoma patients. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Svoboda: Pharmacyclics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding. Nasta:Millennium Pharmaceuticals: Research Funding. Mato:Abbvie: Research Funding; Acerta Pharma: Research Funding; Gilead Sciences: Research Funding; ProNAi: Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Theradex: Research Funding; TG Therapeutics: Research Funding; Gilead Sciences: Consultancy; Abbvie: Consultancy. Hwang:Novartis: Research Funding. Schuster:Janssen Research & Development: Research Funding; Gilead: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; Hoffman-LaRoche: Research Funding; Merck: Research Funding.

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Efficacy and Safety of FCR (Fludarabine, Cyclophosphamide, Rituximab) Followed by Yttrium-90 Ibritumomab Tiuxetan in Relapsed Follicular Lymphoma (FL) Patients

Blood ◽

10.1182/blood.v112.11.5003.5003 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5003-5003

Author(s):

Francesco Pisani ◽

Carlo Ludovico Maini ◽

Rosa Sciuto ◽

Laura Dessanti ◽

Antonio Spadea ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Efficacy And Safety ◽

Ibritumomab Tiuxetan ◽

Prior Therapy ◽

Number Of Patients ◽

Grade 3 ◽

The Impact ◽

Yttrium 90

Abstract Background: FCR regimen has provided encouraging results in FL and Yttrium-90 Ibritumomab Tiuxetan (90Y-RIT) has been reported to be effective in patients with relapsed or refractory FL. Our study investigates the efficacy and safety of 90Y-RIT consolidation in relapsed FL patients, responding to second-line with FCR. Methods: At date reporting for this abstract we have recruited 10 patients median age 63 yrs (range 46–77). All enrolled patients were relapsed patients with histologically confirmed CD20-positive (grade 1 or 2) FL according to WHO classification. Major inclusion criteria were: age ≥ 18 years, WHO performance status of 0, 1 or 2, no prior therapy with Rituximab for 3 months and at the completion of FCR, patients achieving at least PR, with < 25% bone marrow involvement, with neutrophil count ≥ 1500/microlitre and platelet count ≥ 100000/microlitre. All patients at relapse received every 28 days FCR: F (25mg/m2×3 days), C (1gr/m2day1) and R (375mg/m2day4) for 4 cycles. Patients were restaged 4 to 8 weeks after the last course of FCR; who achieved at least a partial remission was eligible for Yttrium-90 Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg (0.3–0.4 mCi/Kg) up to a maximum dose 1184 MBq at 3 months after the completion of FCR. The patients were restaged with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy at 4 to 8 weeks after the last cycle of FCR. A complete blood cell count was obtained once a week for 12 weeks after 90Y-RIT treatment. A history and physical examination were performed together with renal and liver function once a months for 3 months after 90Y-RIT. All patients received prophylaxis with trimethoprim-sulfamethoxazolo and valacyclovir from initiation of therapy until 3 ≥ months following therapy with 90Y-RIT. Results: Between August 2005 and March 2008 nine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 0.4 mCi/Kg, 3 patients at 0.3 mCi/Kg) and one patient is under treatment. All 10 patients were relapsed patients: 6 patients received 1 or 2 prior therapy regimens and 4 patients had received 3 to 5 regimens. Eight of them were previously treated with Rituximab plus chemotherapy, 2 patients had no previous Rituximab treatment history, one also had ABMT. After FCR 6 patients obtained CR and 3 PR; after 90Y-RIT treatment the ORR was 100% and CCR was 100% with median follow up of 13 months (range 5–26) and all patients are alive in CR; 3 patients in PR after FCR regimen converted to CR by 90Y-RIT. The most common grade 3 or 4 adverse events were hematologic: grade 3 or 4 neutropenia occurred in 10/10 patients treated with FCR and grade 3 or 4 neutropenia and thrombocytopenia in 9/9 patients assessable after 90Y-RIT. Following treatment with 90Y-RIT the median neutrophil nadir was 0.5 × 109/L (range 0.3 – 1.09 ×109/L) at week 5; the median platelet count nadir was 40 × 109/L ( range 12–81 × 109/L ) at week 6. One patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungus infection. No other severe infection have been recorded, no nonhematologic adverse event have been registered so far. Conclusion: Our experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with FL. Hematologic toxicity occurring with FCR or with radio-immunotherapy are clinically controllable and acceptable in the population composed mainly of patients with a history of prior treatment using rituximab plus chemotherapy. A longer follow up and a larger number of patients with relapsed FL are required to determine the impact of this regimen on long-term duration of response and EFS.

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Safety and Efficacy of CEEP (Cyclophosphamide, Epirubicin, Etoposide, Prednisolone) with or without Rituximab in Elderly Patients (>70) with Diffuse Large B-Cell Lymphoma (DLBL): A Retrospective Single Center Experience

Blood ◽

10.1182/blood.v118.21.4957.4957 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4957-4957

Author(s):

Danny Hsu ◽

Ibrahim Tohidi-Esfahani ◽

Christina Brown ◽

Scott Dunkley ◽

Stephen Robert Larsen ◽

...

Keyword(s):

Elderly Patients ◽

Haematological Toxicity ◽

The Other ◽

Single Center ◽

Safety And Efficacy ◽

Single Center Experience ◽

Comorbidity Index ◽

Grade 3 ◽

Relapsed Disease

Abstract Abstract 4957 Background Over 40% of patients with the most common lymphoid malignancy worldwide, DLBL, are over the age of 70. Although R-CHOP is inarguably the mainstay of therapy for DLBL patients, a significant number of elderly patients do not tolerate the regimen due to underlying frailty and/or co-morbidities. Most elderly patients with significant co-morbidities have limited treatment options and are not offered anthracycline-containing chemotherapy due to concerns regarding toxicity. Here we describe our single center experience with CEEP, a lower intensity regimen for elderly patients with newly diagnosed or relapsed DLBL whom are deemed inappropriate for CHOP-based chemotherapy. Method All patients >70 years old (median 78.5, range 71 – 85) with histologically proven DLBL treated with CEEP ± Rituximab (R) at Royal Prince Alfred Hospital from 2000 to 2010 were retrospectively reviewed. Modified CEEP, Cyclophosphamide 300mg/m2 Day 1 (D1) and D15, Epirubicin 50mg/m2 D1 and D15, Etoposide 100mg/m2 D1 and D15, and Prednisolone 50mg D1-D5 (reduced dose from original CEEP protocol) was administered every 2 weeks. Rituximab 375mg/m2 (when approved for use in Australia) was administered every 28 days. As per institutional protocol, all patients received Bactrim prophylaxis for Pneumocystis. Baseline characteristics, Charlson Comorbidity Index, Revised International Prognostic Index (RIPI), the number of CEEP cycles, treatment response and toxicity from treatment were identified and reviewed. Results A total of 22 patients were identified, 10 were male. 15 received CEEP as initial therapy, and 7 for relapsed disease. 23% (n=5) had an ECOG score ≥ 2. 55% (n=12) had RIPI ≥ 3. All patients had a Charlson Comorbidity Index ≥ 2, with 23% (n=5) ≥ 5, which was considered sufficient to preclude conventional CHOP-based chemotherapy. Median cardiac ejection fraction was 62% (range 55 – 85%). 73% (n=16) received Rituximab and 50% (n=11) received primary GCSF prophylaxis. The median number of CEEP ± R cycles was 6 (range 2 – 9 cycles). 5% (n=1) required dose reduction and 9% (n=2) required delays in treatment due to haematological toxicity. Median follow-up was 10.0 months (range 1 – 92.7 months). At completion of therapy, complete responses (CR) were demonstrated in 10 patients (45%), with partial responses (PR) seen in 32% (n=7). 18% (n=4) demonstrated progressive disease (PD) despite therapy. Of the 7 patients with relapsed disease prior to CEEP ± R, CR was seen in 2 cases, both of whom had previous exposure to R-CVP (cyclophosphamide, vincristine, prednisolone) chemotherapy. At most recent follow up, 32% (n=7) have remained in CR with a median follow up period of 28.1 months (range 13 – 92.7 months), 36% (n=8) had disease progression, 9% (n=2) demonstrated stable residual disease, while 23% (n=5) have died. Of the 5 deaths, 3 were attributed to progressive DLBL. The other deaths were a result of complications following further salvage chemotherapy. Grade 3 – 4 haematological toxicity was observed in 72% (n=16) of patients. Febrile neutropenia occurred in 41% (n=9). Overall, 50% (n=11) required at least one re-admission to hospital. Non-haematological grade 3 – 4 toxicity was detected in 2 patients, one of whom suffered unstable angina in the setting of anaemia, the other an acute cerebrovascular event in the setting of new atrial flutter post-chemotherapy. Discussion Although limited by a small sample size, our retrospective single center experience demonstrates that CEEP ± R chemotherapy can be administered to elderly patients with significant co-morbidities. Our cohort was all aged >70, with medical co-morbidities leading to the unsuitability of conventional CHOP-based therapy. Whilst an overall response rate of 77% (CR + PR) was observed, on prolonged follow up, 32% of patients remained in CR. Significant haematological toxicity (72%) and infectious complications (41%) were observed, however no deaths were directly attributed to the chemotherapy. Future prospective studies are required to further evaluate the safety and efficacy of R-CEEP in the elderly. Disclosures: No relevant conflicts of interest to declare.

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Old Does Not Necessarily Mean Worse: Standard Stupp Regimen for Elderly Patients (≥ 70 years) with Newly Diagnosed Glioblastoma

10.21203/rs.3.rs-233647/v1 ◽

2021 ◽

Author(s):

Loig Vaugier ◽

Loïc Ah-Thiane ◽

Maud Aumont ◽

Emmanuel Jouglar ◽

Mario Campone ◽

...

Keyword(s):

Elderly Patients ◽

Real Life ◽

Treatment Decision ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Class Iii ◽

Newly Diagnosed Glioblastoma ◽

Grade 3 ◽

Neurological Disabilities

Abstract Introduction Glioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard Stupp regimen in particular, although this is the mainstay for younger (<65 years) patients. Methods All patients with newly diagnosed GBM and age ≥ 70 who were referred to our institution for Stupp treatment were reviewed from 2004 to 2018. MGMT status was not available for treatment decision. The primary endpoint was overall survival (OS). Secondary outcomes were relapse-free survival (RFS), early (≤ 1 month after RCT) adverse neurological events (symptoms of intracranial hypertension and/or use of corticosteroids and/or hospitalization) and temozolomide hematologic toxicity assessed by CTCAE v5. Results 128 patients were included. The median age was 74.1 (IQR: 72-77). 15% of patients were ≥80 years. 62.5% and 37.5% of patients fulfilled the criteria for RPA class I-II and III-IV, respectively. 81% of patients received the entire RCT and 28% completed the maintenance temozolomide. With median follow-up of 11.7 months (IQR: 6.5-17.5), median OS was 11.7 months (CI95%: 10-13 months). Median RFS was 9.5 months (CI95%: 9-10.5 months). 60% of patients had early adverse neurological events, of whom 44% had progression and 8% experienced grade ≥3 hematologic adverse events. RPA class III-IV and occurrence of neurological events were associated with lower OS rates, whereas post-operative neurological disabilities were not. Age ≥80 was not associated with worsened outcomes. Conclusions Stupp radiochemotherapy was feasible and effective for “real-life” elderly patients diagnosed with glioblastoma, even in the case of post-operative neurological disabilities.

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