Phase I/II Study of Myeloablative Anti-CD20+ Radioimmunotherapy with I-131-Rituximab in High-Risk CD20-Positive Non Hodgkin Lymphoma

Abstract Abstract 3700 Background: Radioimmunotherapy (RIT) has been successfully used to treat primary and relapsed/refractory CD20+ Non-Hodgkin-Lymphoma (NHL). Myeloablative anti-CD20 RIT allows delivering high radiation doses to lymphoma sites when followed by autologous stem cell infusion (autoSCT). However, RIT is infrequently used at present and long-term data is lacking. Patients, Design and Methods: 23 patients with relapsed/refractory CD20+ NHL who did not achieve a complete response to salvage chemotherapy were enrolled in this Phase I/II trial to evaluate RIT with 131I-labelled Rituximab (131I-R) in a myeloablative setting between January 2000 and October 2004. Biodistribution and dosimetry studies were performed in all patients to determine 131I activity required to induce a total body dose of 21 to 27 Gy to the critical organs lung and kidney. In 6/23 patients RIT was combined with high dose chemotherapy (HD-CTx) followed by autoSCT. 8/23 patients received a sequential HD-CTx with a second autoSCT. The median follow-up is 9.5 years. Results: 188–525 mCi 131I were delivered to achieve the limiting organ dose. No grade 3/4 non-hematologic toxicity was seen with RIT alone. Significant grade 3/4 toxicity (mucositis, neutropenic fever, pneumonia, sepsis) including one therapy related death was observed in all patients treated with RIT combined with HD-CTx/autoSCT. The overall response rate was 87% (64% complete response rate). The median progression free (PFS) and overall survival are 47.5 and 101.5 months. After long-term follow up, 9 patients are progression free and 10 patients are alive. An elevated (>1) international prognostic index (IPI) was most predictive for overall survival. Conclusion: Myeloablative 131I-Rituximab RIT followed by autoSCT is feasible, well tolerated and effective in high risk CD20+ NHL and prolongs PFS compared to last standard chemotherapy. Patients additionally treated with high dose chemotherapy experienced significantly increased toxicity. Long-term results for progression free survival and overall survival in this trial are encouraging. Disclosures: No relevant conflicts of interest to declare.

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Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.0023 ◽

2014 ◽

Vol 32 (7) ◽

pp. 634-640 ◽

Cited By ~ 139

Author(s):

Antonio Palumbo ◽

Sara Bringhen ◽

Alessandra Larocca ◽

Davide Rossi ◽

Francesco Di Raimondo ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Response Rate ◽

Complete Response Rate ◽

Progression Free Survival ◽

Complete Response ◽

Free Survival ◽

Grade 3 ◽

To Receive

Purpose Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma. Patients and Methods We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance). Results In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients. Conclusion Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

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Ponatinib in Combination with FLAG-IDA Chemotherapy for Blast-Phase Chronic Myeloid Leukemia: Final Results of the Seamless Phase I/II Dose-Finding UK Trials Acceleration Programme (TAP) Matchpoint Trial

Blood ◽

10.1182/blood-2021-147972 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 312-312

Author(s):

Mhairi Copland ◽

Daniel Slade ◽

Graham McIlroy ◽

Gillian Horne ◽

Jennifer Byrne ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Chronic Phase ◽

Optimal Dose ◽

High Dose Chemotherapy ◽

Dose Finding ◽

High Dose ◽

Blast Phase

Abstract Background Outcomes for patients with blast-phase chronic myeloid leukaemia (BP-CML) are extremely poor, and allogeneic stem cell transplantation (alloSCT) represents the only opportunity for cure. Crucially, long-term survival post-transplant depends on first attaining a return to chronic phase though salvage treatment. Novel strategies that improve response and can optimise transplant outcomes are therefore required. In the era of tyrosine kinase inhibitors (TKIs), BP-CML has become an orphan disease. Consequently, the prospective trials needed to guide clinical practice are rarely attempted. We now report the final results of the prospective MATCHPOINT trial which uses an innovative EffTox design to investigate the activity and tolerability of the TKI ponatinib in combination with high-dose chemotherapy, to improve remission status and transplant outcomes in BP-CML. Methods and patients Between March 2015 and April 2018, 17 patients were recruited through the UK Trials Acceleration Programme to this dose-finding, seamless phase I/II trial of daily ponatinib combined with fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (PON-FLAG-IDA) salvage therapy. We employed EffTox, an advanced Bayesian method to simultaneously consider response to treatment (efficacy) and dose-limiting toxicity (DLT) in all treated patients, providing a single measure of clinical utility, which then informed the subsequent dose level recommendation. The primary objective was to determine the optimal dose of ponatinib, in combination with chemotherapy, as determined by the EffTox model. The primary outcomes were attainment of a second chronic phase and occurrence of a DLT. Secondary outcomes investigated the toxicity of combination therapy, alloSCT outcomes, and survival. The median follow-up of trial patients is 41 months. Results Nine patients completed one cycle of PON-FLAG-IDA, a further eight patients completed both planned cycles. Using an EffTox analysis, the optimal dose of ponatinib was determined as 30mg once daily. Eleven patients achieved a return to chronic phase and four experienced a DLT, fulfilling the pre-specified criteria for clinically relevant efficacy and toxicity. After PON-FLAG-IDA salvage, eight patients attained complete cytogenetic response and five major molecular response (MMR). The most common grade 3-4 non-hematologic toxicities were febrile neutropenia (29% of patients), lung infection (24%), fever (18%) and hypocalcaemia (18%). Three patients experienced treatment-related mortality. Twelve patients proceeded to alloSCT, of whom seven are alive after median 36 months post-transplant follow-up. Only one of the five patients achieving MMR relapsed post-alloSCT, neither of the other relapsing patients achieved a second chronic phase pre-transplant. Median overall survival (OS) of the whole cohort was 12 months (95% confidence interval 6 months to non-calculable), median OS of patients undergoing alloSCT has not been reached. Conclusions Ponatinib has shown that it can be safely combined with high-dose chemotherapy to achieve a return to chronic phase in patients with BP-CML, and represents an effective novel treatment strategy in this high-risk population. Responding patients subsequently undergoing alloSCT can benefit from long-term disease-free survival. The EffTox method enabled very efficient data usage from this high-risk patient population, and is a model for investigating novel therapies in other ultra-orphan cancers. Figure: Overall survival of the MATCHPOINT cohort Figure 1 Figure 1. Disclosures Copland: Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding. Byrne: Incyte: Honoraria. Rothwell: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria. Brock: Eli Lily: Honoraria; Invex Therapeutics: Honoraria; Merck: Honoraria; Roche: Honoraria; AstraZeneca: Current holder of individual stocks in a privately-held company; GSK: Current holder of individual stocks in a privately-held company. De Lavallade: Pfizer, Novartis.: Honoraria; Bristol Myers Squibb, Incyte: Honoraria, Research Funding. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Clark: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Smith: Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Honoraria. Milojkovic: Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Yap: Faron Pharmaceuticals: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Ponatinib for the treatment of blast-phase CML

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NCOG-36. LONG-TERM SURVIVAL AND COGNITIVE FUNCTION FOLLOW UP OF PRIMARY CNS LYMPHOMA TREATED WITH R-MVP FOLLOWED BY HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL TRANSPLANT CONSOLIDATION

Neuro-Oncology ◽

10.1093/neuonc/noab196.626 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi159-vi160

Author(s):

Kate Therkelsen ◽

Christian Grommes

Keyword(s):

Stem Cell ◽

Complete Response ◽

High Dose Chemotherapy ◽

High Dose ◽

Consolidation Therapy ◽

Term Survival ◽

Stem Cell Rescue ◽

Long Term Follow Up

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare central nervous system malignancy, and long-term follow up studies are uncommon. First line therapy is based on high-dose methotrexate and different consolidation therapy options. This is a long-term follow up study of PCNSL patients enrolled in a prospective trial using R-MPV chemotherapy regimen followed by high dose chemotherapy and autologous stem cell rescue to determine long-term survival and cognitive effects. METHODS From June 2005 to September 2011, 32 newly diagnosed immunocompentent PCNSL were enrolled. Patients received 5-7 doses of rituximab (500mg/m2), methotrexate (3.5 gm/m2), procarbazine (100mg/m2), and vincristine (1.4mg/m2) (R-MVP). Consolidation therapy consisted of high dose chemotherapy (HDC) with thiotepa (250 mg/m2), busulfan (3.2 mg/kg), and cyclophosphamide (60 mg/kg), followed by autologous stem cell rescue (ASCT) in those with partial or complete response to R-MVP. Long-term follow-up status including disease status, cognitive status (KPS, NANO score), and leukoencephalopathy (modified Fazkas Scale) were collected. RESULTS 26 of 36 underwent HDC and ACST. Of those, 3 died due to treatment related effects; 2 died of disease progression within two years after ASCT. After a median follow-up of 10.5 years, none of the remaining 21 patients progressed. At the time of last follow up, the median KPS was 90, compared to 80 at time of ASCT. The median NANO score and leukoencephalopathy score post ASCT and at follow-up did not change. Of note, 2 of 4 patients with a partial or complete response to R-MVP that elected not to proceed with HDC-ASCT consolidation, experienced progression at a mean of 52 months. CONCLUSION Long-term follow up demonstrates that treatment was tolerated well with stable leukoencephalopathy on MRI and good performance status. Disease recurrence 2 years after HDC with ASCT consolidation was not observed.

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Vinblastine, Mitoxantrone and Prednisone (MVP) Followed by Involved Field Radiotherapy (IF-XRT) for Early Clinical Stage Hodgkins’s Lymphoma: Long Term Follow-Up.

Blood ◽

10.1182/blood.v106.11.2677.2677 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2677-2677

Author(s):

Danielle Shafer ◽

Hossein Borghaei ◽

Michael Millenson ◽

Nicos Nicolaou ◽

Tahseen I. Al-Saleem ◽

...

Keyword(s):

Overall Survival ◽

Early Stage ◽

Survival Rates ◽

Complete Response ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Combined Modality Treatment ◽

Grade 3

Abstract Background: The treatment of early stage Hodgkin’s lymphoma (HL) continues to evolve in attempt to improve the safety profile of the regimens and decrease their long-term toxicities. Treatment related mortality exceeds that from HL after 12 to 15 years. In light of the potential long-term complications associated with irradiation and chemotherapy, particularly pulmonary and cardiac toxicity, alternative approaches minimizing exposure to drugs with long-term organ toxicity have been examined. Objectives: We evaluated a novel regimen of MVP and IF-XRT for non-bulky early-stage HL. The primary outcomes were response rate and freedom from disease progression. Secondary outcomes were toxicity, specifically pulmonary and cardiac dysfunction. Methods: Patients were enrolled in this multi-site phase 2 study between 1995 and 1999. Eligible patients were 18 years of age or older, had ECOG performance status 0–2 and pathologically confirmed, clinically staged non-bulky Stage I or II HL. Patients received a minimum of four cycles of mitoxantrone 8mg/m2 and vinblastine 6 mg/m2 intravenously on days 1 and 15 of each 28-day cycle. Prednisone 100mg was given orally days 1 to 5 and 15 to 19. Chemotherapy was continued for two additional cycles after complete response, up to eight cycles. Patients then received IF-XRT (30.6 Gy-39.6 Gy) four weeks after completion of chemotherapy. G-CSF was not used as primary prophylaxis. Results: Thirty-four patients were evaluated for response in a final review. A total of 32 patients (94%) achieved a complete remission after combined therapy. Thirty patients (88%) achieved a complete response after chemotherapy alone. At a median follow-up of 49 months (range 16.9–79.7 months), 10 patients had relapsed, and three deaths were documented. None of the deaths occurred during treatment. The median time to progression was 30 months. The overall survival and disease-free survival rates at 5 years were 90% (95% confidence interval [CI], 73–97%) and 78% (95% CI, 58–89%), respectively. The treatment was well tolerated without significant grade 3/4 toxicity. (Grade 3/4 leukopenia 18% of patients; neutropenia 28%) There were no significant changes in DLCO or left ventricular ejection fraction at 12 months observed after chemotherapy. Twenty-one patients received only 4 cycles of chemotherapy; the median dose intensity for the entire group was 85%. Conclusions: As the management of early-stage HL continues to evolve in attempt to reduce long-term toxicity, this trial serves as a reminder of the balance required between efficacy and toxicity in this largely curable population. In this relatively well-tolerated regimen, there was minimal long-term toxicity, but a high number of relapses, most of which were successfully salvaged with resultant excellent 5-year overall survival rates. As the treatment for early-stage HL moves forward, there will undoubtedly be further attempts to modify the ABVD backbone. We await those results as well as long term data from the German Hodgkin Study group investigating reduction of combined modality treatment (HD10) in a similar patient population.

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Primary Clinical Response of Relmacabtagene Autoleucel in Adults with Relapsed/Refractory Follicular Lymphoma (r/r FL) in China

Blood ◽

10.1182/blood-2021-150085 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2434-2434

Author(s):

Yuqin Song ◽

Zhitao Ying ◽

Haiyan Yang ◽

Ye Guo ◽

Wenyu Li ◽

...

Keyword(s):

Overall Survival ◽

Median Duration ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

Complete Response ◽

High Dose ◽

Free Survival ◽

Duration Of Response

Abstract Background Most patients (pts) with r/r FL remain incurable and eventually relapse or progress. Previously, a Ph1 study of relma-cel (NCT03344367) had demonstrated preliminary safety and efficacy in r/r B-NHL pts, including those with r/r FL. A Ph2 pivotal study in r/r FL pts had been enrolled and preliminary efficacy, safety and PK was presented. Methods Adult pts were eligible with histologically confirmed grade (Gr)1-3a r/r FL on the basis of the 2016 WHO Classification, having failed ≥ 2-line prior therapies or relapsed after auto-HSCT, without allogeneic transplant within 90 days or primary central nervous system (CNS) lymphoma, and with ECOG performance score of 0-1. Pts were randomized to receive either 100×10 6 (low dose) or 150×10 6 (high dose) relma-cel (1:1) following fludarabine 25 mg/m 2 & cyclophosphamide 250 mg/m 2 daily×3. Pts were evaluated for efficacy (Cheson, 2014), toxicity (cytokine release syndrome [CRS] by Lee 2014, and others by CTCAE v4.03), and PK (by qPCR and flow cytometry). Primary endpoint was complete response rate (CRR). Secondary endpoints included objective response rate (ORR), frequency/severity of AEs, duration of response (DOR), duration of complete response (DoCR), duration of partial response (DoPR), time to primary remission (TTR), time to primary complete remission (TTCR), progression free survival (PFS), overall survival (OS), and CAR-T cell expansion. Disease response was by investigator assessment, a sensitivity analysis was also conducted using an independent review committee. Results Between June 2018 and June 2021, 28 r/r FL pts were enrolled and treated. As of the data cut-off of June 11, 2021, 20 pts were treated with relma-cel with ≥ 1 month of follow-up. Among these 20 pts, the median age was 54.5 years (range, 36-71), 50% of pts were male, 85% had ECOG 0, 10% had a sum of perpendicular diameters (SPD) ≥ 5000 mm 2, and 36% (5/14) had a FLIPI2 score≥ 3. Pts had received a median of 3.5 prior lines of therapy, 6 (30%) pts had received at least five lines of treatment and 65% were refractory to last prior treatment, 85% were relapsed, 50% were both relapsed and refractory. Relma-cel was successfully manufactured in all pts. Best ORR was 100% (19/19), and best CRR was 95% (18/19). For the mITT (n=19, one pt who developed gastric adenocarcinoma, was excluded, but also achieved CR), ORR at 1 month was 100%(19/19) and CRR was 63% (12/19). CRR at 3 months for 17 pts > 3 months post treatment, was 82%(14/17). At a median follow-up of 8.9 months, the median duration of response [DOR], progression-free survival (PFS) and overall survival (OS) were not reached. Twenty pts who received relma-cel were evaluable for safety. Gr ≥3 AEs related to relma-cel occurred in 80% of pts, most commonly neutrophil count decreased (35%), lymphocyte count decreased (30%) and white blood cell count decreased (25%). CRS occurred in 35% (all Gr 1), and only 2 pts received tocilizumab. Median CRS onset was 7 days (range, 5-9), with median duration of 5 days. Two (10%) pts experience neurotoxicity (NT), both Gr 1, with onsets of 4 and 9 days, and duration of 25 and 7 days, respectively. No deaths occurred. Safety data, tocilizumab/steroids usage and PK parameters are shown in the Table. Conclusion With median follow-up of 8.9 months, relma-cel treatment in r/r FL pts had resulted in high tumor remission rates and a manageable toxicity profile in the first 20 pts treated. Data for additional patients will be presented. Table： The summary of AEs (AE, TEAE, CRS, NT), the usage of tocilizumab/steroids and PK Parameters Figure 1 Figure 1. Disclosures Yang: JW Therapeutics: Current Employment. Zhang: JW Therapeutics: Current Employment. Ma: JW Therapeutics: Current Employment. Zhou: JW Therapeutics: Current Employment. Zheng: JW Therapeutics: Current Employment.

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Prolonged Overall Survival (OS) in a Subset of Responders to the Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma (HL): Results of an International Multi- Center Phase I/II Experience

Blood ◽

10.1182/blood-2018-99-117251 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2907-2907 ◽

Cited By ~ 1

Author(s):

Ahmed Sawas ◽

John Kuruvilla ◽

Jennifer Kimberly Lue ◽

Changchun Deng ◽

Jennifer E Amengual ◽

...

Keyword(s):

Research Funding ◽

Response Rate ◽

Phase 1 ◽

Median Number ◽

High Dose Chemotherapy ◽

Brentuximab Vedotin ◽

High Dose ◽

Refractory Hodgkin Lymphoma

Abstract Introduction Prognosis for patients who fail to respond to high-dose chemotherapy or progress after high dose chemotherapy and autologous stem cell transplant (ASCT) is particularly poor, with a recent study reporting 71% of patients dying in year 1 and 90% by year 2, with a median -progression survival of 1.3 years [1]. In our study of brentuximab vedotin plus bendamustine (BvB) in patients with relapsed or refractory Hodgkin's lymphoma, we recently reported an overall response rate (ORR) and complete response rate (CR) of 71% and a 32% respectively (N=65) in a heavily treated patient population [2]. Having noted several patients with a progression free survival (PFS) of 1 year or longer, we reviewed all enrolled patients for protracted duration of benefit, raising the question as to whether these patients may have been cured by BvB in the salvage setting. (ClinicalTrials.gov #NCT01657331). Methods Among 65 enrolled patients we identified 23 with a PFS of more than one year after treatment with BvB. Patients had received Bv on Day 1 with B on Days 1 and 2 of a 3-week cycle for up to 6 cycles. In the Phase 1 study 4 dose levels were evaluated: (1) Bv = 1.2mg/kg; B = 70mg/m2; (2) Bv = 1.2mg/kg; B = 80mg/m2; (3) Bv = 1.8mg/kg; B = 80mg/m2; and (4) Bv = 1.8mg/kg; B = 90. Accrual followed a classic Fibonacci dose escalation, with 3 patients being treated at each dose level. Dose Limiting Toxicity (DLT), defined as any CTC version 4 Grade 3 or 4 toxicity led to expansion of the dose cohort. The recommended phase II dose was Bv 1.8 mg/kg on Day 1 and B 90 mg/m2 on Days 1 and 2. The Phase 2 portion of the study accrued an additional 37 patients. Response was assessed by the investigator per Cheson 2007 after cycles 2 and 6. Patients were followed post completion of therapy every 3 month until disease progression and imaging was conducted every 3- 6 months. Study procedures and follow-up were concluded on June 30th 2018. In addition, plasma and serum biomarkers were prospectively collected for correlation with toxicity and response. Results With a median follow-up of 33 months (range 20-58 month) we identified 23/65 patients (43% male) with a median age of 34 years (range, 18-55) who experienced a PFS of 1 year or more. The median number of prior systemic therapies was 3 (range 1-6); with 11 patients having had prior ASCT and 10 patients receiving prior radiation therapy. Median number of BvB cycles administered was 4 (range 2-6). A best response of CR was documented for 17 patients (74%) and partial response (PR) was documented for 6 patients (26%). Consolidation with HDCT-ASCT was performed in 10 patients, 3 of whom received maintenance Bv post-transplant. The median duration of response (DOR), PFS and OS among this group was 28, 32 and 34 months, respectively. All responses are ongoing with no evidence of relapse. Long term survival with no further therapy after a median of 6 cycles of BvB ( range 2-6) was observed in 13 patients (20% of the treated population) (median post-BvB PFS 36 months, range 20-58). Exploratory analysis of the correlation between disease outcome and changes from baseline in select biomarkers demonstrated a significantly lower mean baseline sCD30 level among long term responders (p=0.01). No correlations were noted between other clinical outcome metrics and sCD30, nor with other biomarkers including TARC, CD163, or galectin. Conclusion In this heavily treated population with HL, the combination of BvB represents an effective and tolerable outpatient salvage regimen with long term response and protracted survival among a subset of patients, and raises the prospect that these patients, with a historically poor outcome may be cured with BvB. We intend to follow these patients to obtain additional information on their longer term outcome. ReferencesZagadailov, E.A., et al., Real-world effectiveness of brentuximab vedotin versus physicians' choice chemotherapy in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplantation in the United Kingdom and Germany. Leuk Lymphoma, 2018. 59(6): p. 1413-1419.O'Connor, O.A., et al., Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1-2 trial. Lancet Oncol, 2018. 19(2): p. 257-266. Disclosures Kuruvilla: Princess Margaret Cancer Foundation: Research Funding; Merck: Consultancy, Honoraria; Leukemia and Lymphoma Society Canada: Research Funding; Lundbeck: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria. O'Connor:ADC Therapeutics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding.

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Radioimmunotherapy-Based Conditioning with Yttrium-90 Ibritumomab Tiuxetan Plus High Dose BEAM for Non-Hodgkin Lymphoma: Does the Regimen Matter?

Blood ◽

10.1182/blood.v126.23.3179.3179 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3179-3179

Author(s):

Amrita Y. Krishnan ◽

Joycelynne Palmer ◽

Auayporn P. Nademanee ◽

Robert Chen ◽

Leslie L. Popplewell ◽

...

Keyword(s):

Complete Remission ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

High Dose Chemotherapy ◽

High Dose ◽

Poor Risk ◽

Non Hodgkin Lymphoma ◽

Grade 3 ◽

Induction Failure

Abstract Background: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) has played an important role in the treatment of relapsed or refractory non-Hodgkin lymphoma (NHL). Several studies demonstrate that standard-dose 90Y ibritumomab tiuxean (0.4 mci/kg) (Zevalin) plus high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (ZBEAM) is a well-tolerated HCT preparative regimen. Herein we report the outcomes of a prospective single-arm phase II study of ZBEAM conditioning in three CD20+ NHL histologic strata: mantle cell (MCL), diffuse large B cell (DLBCL), and follicular (FL)/transformed (TF). The study was designed to detect a 20% improvement in PFS, within each stratum, over historical rates for BEAM alone at 2-years post HCT with ~80% power, α=0.05. Patients and Methods: Patients with histologically confirmed CD20+ MCL, DLBCL, FL, or TF were eligible if they failed induction therapy, had relapsed disease or poor risk disease (Table 1). Patients with DLBCL or FL were classified as poor risk if they failed to achieve a complete response after induction chemotherapy or had high-/high-intermediate-risk features per the age-adjusted International Prognostic Index (IPI) at diagnosis. All MCL and TF lymphomas were considered poor risk, including those in first remission. Results: The median follow-up for surviving patients: 43 months (range: 3-79). The estimated PFS and overall survival (OS) probabilities at 3 years were between 47-75% and 82-91%, respectively (Table 2); non-relapse mortality (NRM) was <1% overall. Adverse events ≥ grade 3 within the first 100-days included grade 3 infection (n=8) per CTCAE 3.0, grade 3 GI toxicity (n=1) per Bearman Toxicity Scale and grade 4 infection (n=1) per CTCAE 3.0. Conclusion: Across histologies, high OS and low NRM confirm the safety and tolerability of the regimen, while improvements in 2-year PFS compared to historical controls in DLBCL and MCL are notable1-4 leading us to conclude that, in the case of MCL and DLBCL, RIT based conditioning improves outcome compared to high dose chemotherapy alone. The strikingly high PFS within the DLBCL subgroup, even though this strata had the highest percentage of induction failure patients serve as a basis for an ongoing multinational randomized phase III trial comparing ZBEAM to BEAM for the treatment of relapsed/ IF DLBCL. Table 1. Patient and Disease Characteristics (#/% or median/range) Variable All N = 116 MCL N = 32 DLBCL N = 46 FL N = 20 TF N = 18 Disease status at HCT 1st complete remission 1st partial remission 1st relapse 2nd complete remission ≥3rd complete remission Induction failure 29 (25) 7 (6) 20 (17) 20 (17) 3 (3) 37 (32) 23 (72) 4 (13) 0 (0) 1 (3) 0 (0) 4 (13) 4 (9) 1 (2) 8 (17) 12 (26) 0 (0) 21 (46) 0 (0) 1 (5) 6 (30) 4 (20) 1 (5) 8 (40) 2 (11) 1 (6) 6 (33) 3 (17) 2 (11) 4 (22) Prior regimens 2 (1-7) 1 (1-3) 2 (2-7) 3 (1-4) 2 (1-3) Age at transplant, yr 57 (23-75) 60 (43-72) 48 (23-75) 57 (43-67) 58 (41-65) Maintenance rituximab No Yes N/Aa 103 (89) 12 (10) 1 (1) 23 (72) 9 (28) 0 (0) 44 (96) 2 (4) 0 (0) 20 (100) 0 (0) 0 (0) 16 (89) 1 (6) 1 (6) Abbreviations: MCL, mantle cell lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; TF, transformed lymphoma; HCT, hematopoietic cell transplantation; N/A, not available. a) The follow-up time for 1 patient had not reached Day +30 post-HCT at the time the analytical data were locked. Table 2. Outcomes, % (95% CI) AllbN = 115 MCL N = 32 DLBCL N = 46 FL/TF, combinedbN = 20/17, 37 BEAM, historical estimates: 2-yr PFS N/A 35 45 45/35, 40 ZBEAM, trial estimates: 2-yr PFS 70 (61-78) 78 (57-89) 78 (62-87) 54 (30-73)/57 (31-77), 56 (38-70) 3-yr PFS 66 (56-74) 69 (54-79) 75 (63-83) 47 (36-58)/57 (42-70), 52 (35-67) 3-yr OS 85 (77-91) 91 (72-98) 83 (70-90) 85 (65-94)/82 (60-92), 83 (67-92) Abbreviations: PFS, progression-free survival; OS, overall survival. b) At the time of abstract submission, the follow-up time for 1 of the 116 patients was not sufficient for outcomes to be reported (<100 days post-HCT). References 1) Mills W, et al. J Clin Oncol 1995;13:588-595. 2) Shimoni A, et al. Cancer 2012;118:4706-4714. 3) Kolstad A et al. Blood 2014;123:2953-2959. 4) Berger MD et al. Hematol Oncol 2015; doi:10.1002/hon Disclosures Krishnan: celgene: Consultancy, Equity Ownership, Speakers Bureau; millennium: Speakers Bureau; onyx: Speakers Bureau; jannsen: Consultancy; jazz: Consultancy; spectrum: Consultancy. Off Label Use: Zevalin combined with BEAM. Nademanee:Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics Inc.: Research Funding; Spectrum: Research Funding. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Forman:Mustang: Research Funding; Amgen: Consultancy.

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Long-term neuropsychological follow-up of young children with medulloblastoma treated with sequential high-dose chemotherapy and irradiation sparing approach

Journal of Neuro-Oncology ◽

10.1007/s11060-017-2409-9 ◽

2017 ◽

Vol 133 (1) ◽

pp. 119-128 ◽

Cited By ~ 15

Author(s):

Taryn B. Fay-McClymont ◽

Danielle M. Ploetz ◽

Don Mabbott ◽

Karin Walsh ◽

Amy Smith ◽

...

Keyword(s):

Young Children ◽

High Dose Chemotherapy ◽

High Dose

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Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

Blood Advances ◽

10.1182/bloodadvances.2020002583 ◽

2020 ◽

Vol 4 (17) ◽

pp. 4091-4101

Author(s):

Arne Kolstad ◽

Tim Illidge ◽

Nils Bolstad ◽

Signe Spetalen ◽

Ulf Madsbu ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Overall Response Rate ◽

Response Rate ◽

Phase 1 ◽

B Cell Lymphoma ◽

Complete Response ◽

Hematologic Toxicity ◽

Overall Response ◽

Non Hodgkin Lymphoma ◽

Anti Cd20

Abstract For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

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