Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience

Background Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL) and most common of the clinically indolent NHLs. Although often considered an incurable disease, overall survival has increased significantly with refinement in diagnostic techniques and the addition of rituximab. The course of FL is quite variable and presence of symptoms, organ dysfunction, cytopenias, aggressiveness of tumor are all taken into consideration when deciding individual treatment. In this study, we evaluated a large patient cohort with FL treated over a 35 year period for progression free survival (PFS), overall survival (OS) based on FLIPI score, tumor grade, and treatment regimen and also looked at causes of late failures. Methods We evaluated 1037 patients (pts) from the Nebraska Lymphoma Study Group that were diagnosed with FL between the years of 1983-2020. Descriptive statistics were stratified according to age, histological subtype, treatment regimen, FLIPI category, presence and type of secondary malignancy. PFS was calculated from the time of diagnosis to progression or death and OS was the time from diagnosis to death from any cause. PFS and OS were plotted as Kaplan-Meier curves with statistically significant p<0.05. Results The median age at diagnosis and treatment was 61 years (yrs, range 17-91). A total of 9.1% were characterized as FLIPI high risk, 37.8% intermediate risk, and 33.6% low risk, 19.5% unavailable. Among the histological grade, 23.1% had FL- grade 1, 30.2% FL-2, 27.3% FL-3A, 2.5 % FL-3B and 16.9 % Composite Lymphoma. Anthracycline + rituximab was given in 24.5% of pts, whereas 43.8% of pts received an anthracycline based regimen without rituximab, 9.8% received rituximab without an anthracycline and 10.6% received neither of these agents. 6.75% (70 pts) were later found to have secondary malignancies of which 11 pts had myelodysplastic syndrome, 10 pts had acute leukemia and 9 pts had lung cancer. With a median follow up of 9.2 yrs and a maximum of 36 yrs, 29.7% (308 pts) had not relapsed. The median PFS across all groups was 4.6 yrs (Fig 1) and OS was 12.1 yrs. Median OS was significantly longer in patients that received rituximab at 16.1 yrs as compared to patients that did not receive rituximab at 9.89 yrs (Fig 2). PFS was 8.6 yrs, 3.6 yrs and 2.1 yrs and OS was 15.1 yrs, 11.7 yrs and 4.9 yrs in FLIPI low, intermediate and high risk groups respectively (p=<0.001) (Fig 3), suggesting that survival was influenced by FLIPI score. Median PFS in FL-3B and FL-3A was 9.2 yrs and 5.2 yrs respectively which is longer than 4.7 yrs and 4.2 yrs for FL-1 and FL-2 (p=0.24). OS in FL-3A and FL-3B subgroups was 10.8 yrs while it was 11.6 yrs and 14.3 yrs in FL-2 and FL-1 (P=0.081). PFS is significantly longer at 10.6 yrs in pts treated with both anthracycline and rituximab containing regimen as compared to 5.3 yrs in pts treated with rituximab alone and 3.05 yrs in pts that had only anthracycline based regimen (p=<0.001) (Fig 4). The median OS also was significantly higher in the combination regimen group at 18.8 yrs as compared to 11.3 yrs in rituximab only group and 9 yrs in anthracycline based regimen group (p=<0.001). When pts with FL-3A and FL-3B were grouped together and stratified according to treatment regimen, the group that received anthracycline and rituximab combination has highest PFS and OS at 13.3 yrs and 18.8 yrs (p<0.001). when pts with FL-3A were analyzed separately and stratified by treatment regimen, the results of PFS and OS were similar and statistically significant. However, of the 24 pts in FL-3B group, analysis revealed that PFS and OS was longer in anthracycline based regimen only group, however results were not statistically significant. Among the pts that relapsed/died after 10 years (n=190), the cause of death was relapsed lymphoma in 13.7%, unknown in 55.8%, secondary malignancies in 4.2%, treatment related in 2.6% and not related to disease in 23.7%. A total of 278 pts survived > 10 yrs, and of these pts, 119 (30%) had not relapsed at the last follow up. Conclusion The addition of rituximab to standard anthracycline based chemotherapy has resulted in significant improvements in the PFS and OS rates of FL. These results also support the prognostic value of the FLIPI in patients treated in the rituximab era. Late relapses after 10 yrs from disease can occur, but 11.5% of patients had not relapsed with long term follow up. Secondary malignancies are also an important consideration in the long term survivors. Disclosures Lunning: Acrotech: Consultancy; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; Verastem: Consultancy, Honoraria; ADC Therapeutics: Consultancy. Armitage:Trovagene/Cardiff Oncology: Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Consultancy; Ascentage: Consultancy. Vose:Bristol-Myers Squibb: Research Funding; Karyopharm Therapeutics: Consultancy, Honoraria; Seattle Genetics: Research Funding; Allogene: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding; Wugen: Honoraria; Novartis: Research Funding; Celgene: Honoraria; Incyte: Research Funding; Roche/Genetech: Consultancy, Honoraria, Other; Verastem: Consultancy, Honoraria; Miltenyi Biotec: Honoraria; Loxo: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Epizyme: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria.

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Evaluating Gvhd Outcomes Using Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil As Gvhd Prophylaxis Compared with Methotrexate/Tacrolimus in Matched-Related and Matched-Unrelated Hematopoietic Stem Cell Transplant in Relation to the Haplo-Identical Setting: A Single Center Experience

Blood ◽

10.1182/blood-2020-141659 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-6

Author(s):

Mindy Hsiao ◽

Preet M. Chaudhary ◽

George Yaghmour

Keyword(s):

Stem Cell ◽

Mycophenolate Mofetil ◽

Board Of Directors ◽

Relapse Free Survival ◽

Advisory Committees ◽

End Points ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Grade 3 ◽

Haplo Group

Background: The use of post-transplant cyclophosphamide (PTCy)/tacrolimus/mycophenolate mofetil (MMF) for GVHD prophylaxis has improved outcomes in haploidentical hematopoietic cell transplantation (haplo-HCT). PTCy is now being evaluated in matched-related (MRD) and matched-unrelated (MUD) allo-HCT. Previous studies demonstrated improved GVHD-free/relapse-free survival (GRFS) when PTCy was combined with two immunosuppressive agents and PTCy has also been associated with better relapse-free survival (RFS) as demonstrated in De Jong et al 2019, though only one immunosuppressive agent was used. Currently, there is limited published data comparing outcomes using PTCy/tacrolimus/MMF to standard MRD/MUD GVHD prophylaxis of methotrexate (MTX)/tacrolimus. The importance of studying this comparison may help to improve GVHD outcomes in MRD and MUD allo-HCT. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 19) who received allo-HCT from 2018 to 2020. The primary end-points assessed were incidence and severity of 1-year aGVHD and cGVHD. Secondary end-points included day+100 mortality, 1-year overall survival (OS), 1-year RFS, 1-year transplant-related mortality (TRM), and 1-year GRFS, defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the 1-year post-HCT period. Results: A total of 65 adult MRD and MUD allo-HCT recipients and 53 haplo-HCT patients were reviewed. Of the MRD/MUD patients evaluated, approximately 51% (n = 33) were female and 49% (n = 32) were male. The age range was 20-69 years old (median = 46), and the most common diseases included ALL (46%), AML (31%), MDS (11%), and others (i.e. lymphoma, aplastic anemia (AA), myelofibrosis) (12%). 34% (n = 22) of patients received PTCy on D+3 and D+4 with tacrolimus/MMF/ on D+5 as GVHD prophylaxis and 66% (n = 43) of patients received MTX/tacrolimus on D+1, +3, +6, and +11 as GVHD prophylaxis. All haplo-HCT patients received standard PTCy/tacrolimus/MMF. Stem cell source was primarily PBSC except in HLH and AA patients. The PTCy group had more MUD allo-HCT (64%), degree of antigen mismatch (56%), and median age of 50.5 years compared with the MTX group at 44%, 47%, and 44 years respectively. 70% in the MTX group received MAC compared with 45% in the PTCy group. The haplo group had similar demographics to the MTX group. The mean CD34 cell doses in the PTCy, MTX, and haplo groups were 4.87, 5.36, and 7.24x106 cells/kg respectively. Incidences of total GVHD, aGVHD, and aGVHD grade 3 or 4 in the PTCy group were 55%, 50%, and 4.5% respectively compared with 65%, 35%, and 7% in the MTX group, though not significant. The haplo group had 68%, 55%, and 1.9% respectively. Incidence of total cGVHD and cGVHD requiring systemic therapy in the PTCy group was 4.5% and 0% respectively compared with 30% (p = .02) and 23% (p =.01). The haplo group had 13% and 1.9% respectively. Day+100 mortality, 1-year OS, 1-year RFS, 1-year TRM, and 1-year GRFS in the PTCy group were 0%, 80%, 60%, 0%, and 64% respectively compared with 7%, 88%, 90%, 7.3%, and 59%. The haplo group had 3.8%, 86%, 89%, 14%, and 66%. In a univariate analysis, factors significantly associated with GVHD were disease status (p = .0.12) and CD34 dose (p = 0.015) and antigen mismatch (p = 0.04) was associated with increased mortality. Discussion: Our results demonstrate improved overall and extensive cGVHD outcomes in the PTCy group and thus an improvement in 1-year GRFS. Furthermore, incidence and severity of 1-year cGVHD in this group are improved when compared with previously reported outcomes. 1-year GRFS reported in De Jong et al 2019 was 45% and 1-year GRFS reported for all groups in our study is higher at 66%, 64%, and 59% for the haplo, PTCy, and MTX groups respectively. Although this was not significant, it may be clinically meaningful given the significant improvement in extensive GVHD and improvement in all other secondary end-points except 1-year OS and RFS. Furthermore, the PTCy group had a higher percentage of mismatched antigens yet demonstrated superior outcomes. 1-year OS and RFS were superior in the MTX group however this is likely due to sample size differences. The improved extensive cGVHD and GRFS outcomes observed using PTCy/tacrolimus/MMF in the MRD/MUD setting should continue to be evaluated and currently there is an ongoing prospective, randomized study to further investigate. Disclosures Yaghmour: Jazz: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group

Blood ◽

10.1182/blood-2008-10-183392 ◽

2009 ◽

Vol 113 (19) ◽

pp. 4505-4511 ◽

Cited By ~ 116

Author(s):

Verena Ingeborg Gaidzik ◽

Richard Friedrich Schlenk ◽

Simone Moschny ◽

Annegret Becker ◽

Lars Bullinger ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Negative Impact ◽

Serum Lactate Dehydrogenase ◽

Study Group ◽

Prognostic Impact ◽

Relapse Free Survival ◽

Free Survival ◽

Acute Myeloid

AbstractTo evaluate the incidence and clinical impact of WT1 gene mutations in younger adult patients with cytogenetically normal acute myeloid leukemia (CN-AML), sequencing of the complete coding region was performed in diagnostic samples from 617 patients who were treated on 3 German-Austrian AML Study Group protocols. WT1 mutations were identified in 78 (12.6%) of the 617 patients; mutations clustered in exon 7 (54 of 78) and exon 9 (13 of 78), but also occurred in exons 1, 2, 3, and 8. WT1 mutations were significantly associated with younger age, higher serum lactate dehydrogenase levels, higher blood blast counts, and the additional presence of FLT3-ITD (P < .001) and CEBPA mutations (P = .004). There was no difference in relapse-free survival and overall survival between patients with (WT1mut) or without WT1 mutations. Subset analysis showed that patients with the genotype WT1mut/FLT3-ITDpos had a lower complete remission rate (P = .003) and an inferior relapse-free survival (P = .006) and overall survival (P < .001) compared with those with the genotype WT1mut/FLT3-ITDneg. In conclusion, in our large cohort of younger adults with CN-AML, WT1 mutation as a single molecular marker did not impact on outcome. However, our data suggest a negative impact of the genotype WT1mut/FLT3-ITDpos.

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Phase II trial of hyperfractionated accelerated radiation therapy for nonresectable non-small-cell lung cancer: results of Eastern Cooperative Oncology Group 4593.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.11.3518 ◽

1998 ◽

Vol 16 (11) ◽

pp. 3518-3523 ◽

Cited By ~ 47

Author(s):

M P Mehta ◽

S P Tannehill ◽

S Adak ◽

L Martin ◽

D G Petereit ◽

...

Keyword(s):

Lung Cancer ◽

Radiation Therapy ◽

Survival Rate ◽

Response Rate ◽

Small Cell ◽

Small Cell Lung ◽

Relapse Free Survival ◽

Free Survival ◽

Grade 3 ◽

Accelerated Radiation Therapy

PURPOSE To assess the feasibility, toxicity, and efficacy of hyperfractionated accelerated radiation therapy (HART) for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Thirty patients from six institutions with stage IIIA or IIIB NSCLC were enrolled between November 1993 and August 1995. Radiation therapy (total dose, 57.6 Gy in 36 fractions) was delivered over 15 days with the use of three daily fractions with a 4-hour interval between fractions and an 8-hour interval between on-cord fields. Patients were not treated on weekends. RESULTS Twenty-eight patients (93%) completed radiation therapy. Treatment-related toxicities of grade 3 or greater included esophagitis in six patients and grade 3 skin reaction in three patients. The overall objective response rate was 54%, and the response rate within the radiation field was 64%. With a minimum follow-up of 19 months in surviving patients, the median survival and 1-year survival rate are 13 months and 57%, respectively. The median relapse-free survival and 1-year relapse-free survival rate are 7 months and 23%, respectively. No transverse myelitis or late toxicities of grade 4 or greater have been observed. CONCLUSION HART, delivered to a total dose of 57.6 Gy over 15 total days, is practical and well tolerated. Survival appears similar to that seen with modern combined modality regimens. A phase III trial is under way.

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Allogeneic Stem Cell Transplantation for Relapsed Follicular Non-Hodgkin’s Lymphoma: Single Centre Experience.

Blood ◽

10.1182/blood.v110.11.5054.5054 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5054-5054

Author(s):

Amir Peyman ◽

Stephen Couban ◽

Kara Thompson ◽

Louis Fernandez ◽

Donna L. Forrest ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Follicular Lymphoma ◽

Cell Transplantation ◽

Chronic Gvhd ◽

Disease Free Survival ◽

High Dose ◽

Hematopoietic Stem ◽

Free Survival ◽

Grade 3

Abstract Between 1993 and 2005, 57 patients with follicular lymphoma underwent high-dose chemo/radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), 49 Allogeneic, (16 Bone Marrow and 33 Peripheral Blood), 6 MIN, 2 MUD. Median age was 47 years. Median days to neutrophil and platelet engraftment after HSCT were 18 and 13 days respectively. Twenty-five patients experienced Acute GVHD and thirty-four had Chronic GVHD (12 mild and 22 extensive). Thirty-three patients were in grade 1, 17 in grade 2, 4 in grade 3 and 3 grade 4. As of their FLIPI score, 4, 14, 21 and 18 patients were calculated to have score of 0, 1, 2 and 3 respectively. Forty-one patients are alive. Two patients have relapsed, one a year and the other two years after HSCT. The 5 year survival was 71.9% (95% CI 57.5–82.2%) and 5 year survival was 67.2% (95% CI 52.3–78.5%). Transplant related mortality rate (TRM) in 5 year was 22.4% (95% CI 63.6–86.8%). No significant differences was found among FLIPI groups 0,1,2 and 3 in terms of overall, relapse-free survival, TRM Allogeneic HSCT for patients with progressive follicular lymphoma is feasible and may result in prolonged disease-free survival.

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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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