Effect of Levofloxacin Prophylaxis on Rates of Febrile Neutropenia in Patients Receiving DA-EPOCH-R Chemotherapy for Aggressive Lymphomas

Abstract Introduction: Febrile neutropenia (FN) is a serious potential adverse event of myelosuppressive chemotherapy. Dose-adjusted EPOCH-R (DA-EPOCH-R: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab, with doses adjusted to induce neutropenia of < 0.5 x 10 9/L) is a chemoimmunotherapy regimen used for aggressive lymphomas including diffuse large B-cell lymphoma, double/triple hit, Burkitt, primary mediastinal, and HIV-associated large cell lymphoma. It is associated with high rates of FN (13-25% of cycles) despite use of prophylactic Septra and granulocyte colony stimulating factor (G-CSF). Fluoroquinolone antibiotics have been used in various hematological malignancies to reduce infection rates while on chemotherapy, but this strategy has never been reported with DA-EPOCH-R. This study was conducted to assess the impact of adding routine Levofloxacin prophylaxis on FN and infection rates in patients receiving DA-EPOCH-R. Methods: This is a combined cohort study comparing the patients who received DA-EPOCH-R for newly diagnosed aggressive lymphoma at the London Regional Cancer Program in London, Ontario, Canada before and after the initiation of routine Levofloxacin prophylaxis in July 2020. The prospective cohort received Levofloxacin 500 mg x 7 days with each cycle starting on cycle day 8 in addition to standard supportive care with Septra and G-CSF. The primary objective was the rate of febrile neutropenia. Secondary objectives included days hospitalized, deaths related to infections, and adverse events secondary to Levofloxacin. Results: Thirty patients who received DA-EPOCH-R in the 5 years preceding the initiation of routine prophylactic Levofloxacin were included in the retrospective cohort. Median age was 58 (range 18-79), 66% were male, and 90% had stage III/IV disease. Total number of cycles of DA-EPOCH-R received was 110, with a median of 4 cycles per patient (range: 1-6). FN developed in 14 patients (46%), and complicated a total of 20 cycles (18%) of DA-EPOCH-R. There were 19 hospital admissions due to FN, with a median duration of hospitalization of 12 days (range 3-120). Two patients died, both due to infection. Thirteen patients have been treated so far in the prospective cohort, 12 of whom received levofloxacin prophylaxis. Median age was 59 (range 23-69), 66% were male, and 76% had stage III/IV disease. Total number of cycles of DA-EPOCH-R received was 60, with a median of 5 cycles per patient (range: 1-6 ). Only 1 patient (8%) developed FN, which complicated a total of 3 cycles (5%) of chemotherapy. All 3 episodes of FN resulted in hospitalization for a median duration of 30 days (range 20-49). There have been no deaths due to infection in this cohort thus far. No concerning adverse effects from Levofloxacin have been observed. Conclusions: Although enrollment in the prospective cohort is ongoing, preliminary data are highly encouraging, with significantly lower rates of FN and death due to infection observed since the introduction of routine Levofloxacin prophylaxis. The addition of Levofloxacin to standard prophylaxis with Septra and G-CSF seems to be an effective way to mitigate the risks to patients on DA-EPOCH-R for aggressive lymphomas, and this strategy is worthy of further study. Disclosures Lam: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria.

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Quality of Life after Diagnosis in Survivors of Aggressive Lymphomas

Blood ◽

10.1182/blood-2020-134897 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Robert M. Kraft ◽

Melissa C. Larson ◽

Kathleen J. Yost ◽

Thomas M. Habermann ◽

Matthew J. Maurer ◽

...

Keyword(s):

United States ◽

General Population ◽

B Cell ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Advisory Committees ◽

Aggressive Lymphomas ◽

The Us

Background: Aggressive lymphomas are potentially curable; however, long-term effects of treatment and the disease may adversely affect patients' quality of life (QoL). We investigated QoL at baseline, and up to nine years after diagnosis in survivors of aggressive lymphomas. Methods: Patients newly diagnosed with lymphoma were prospectively enrolled within nine months of diagnosis in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) and systematically followed. Patients were enrolled from September 1, 2002 until June 30, 2015. Eligibility criteria included being a United States resident, English-speaking, no history of HIV, and aged 18 years and older. All pathology was reviewed by a lymphoma hematopathologist. Aggressive lymphoma subtypes included in this analysis were diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma grade III, Hodgkin lymphoma, T-cell lymphoma, other non-Hodgkin lymphoma not otherwise specified (NOS), other B-cell lymphoma NOS, and composite lymphomas. We assessed QoL using the Functional Assessment of Cancer Therapy-General (FACT-G) scale at baseline enrollment, and 1, 2, 3, 6, and 9 years post-diagnosis. FACT-G measures well-being (WB) in four domains-physical (PWB), social/family (SFWB), emotional (EWB), and functional (FWB), which are added to create a total (TOT) score. Those who completed <80% of FACT-G questions at any given time point were excluded. "Survivor" was defined as alive at 1, 2, 3, 6, and 9 year follow-up with no active disease or treatment within six months of a given time point. Because patients could be enrolled at any time within the first 9 months from diagnosis, the timing of initial QoL assessment was variable with respect to the start of lymphoma treatment. We estimated longitudinal change in QoL using mixed models incorporating scores from all available time points. The minimally important difference (MID) of 5 points for TOT and 2 points for each of the domains was used to determine clinical significance. Scores were compared to United States (US) general population normative data. All statistical analyses were performed using SAS (v 9.4). Results: From September 1, 2002 to June 30, 2015, 3,028 patients with aggressive lymphomas were prospectively enrolled in the MER, of which 2,018 completed the FACT-G baseline assessment (47% prior to therapy initiation). Of these patients, 1,144 at 1 year, 1,002 at 2 years, 943 at 3 years, 562 at 6 years, and 289 at 9 years post-diagnosis completed the FACT-G at both baseline and each of the respective time points after diagnosis, and met the definition of survivor. The median age at diagnosis of patients analyzed was 59 years (range 18-93). The cohort included 844 female patients (42%). DLBCL comprised 44% of cases, Hodgkin lymphoma 19%, T-cell lymphoma 11%, composite lymphomas 8%, other B-cell NOS 6%, other non-Hodgkin lymphoma NOS 7%, and Follicular lymphoma grade III 5%. QoL increased from baseline enrollment; the largest increase was seen from baseline to 1 year after diagnosis with a statistically and clinically significant mean TOT score difference of 6.7 points. This mean increase in TOT scores sustained over time with an increase of 7.8 points above baseline at 9 years after diagnosis. At baseline, PWB, EWB, and FWB scores were significantly lower in patients with aggressive lymphomas compared to the US general population, and SFWB scores were significantly higher (all p <0.01); however, only SFWB and EWB score differences were clinically significant as defined by MID. SFWB showed only a mild decline from baseline over the course of 9 years. Despite this, all SFWB scores were statistically and clinically significantly higher than the US general population at 1, 2, 3, 6, and 9 years after diagnosis (all p <0.01 and MID >2). Patients with aggressive lymphomas TOT scores at baseline did not differ from the US general population, while TOT scores at 1, 2, 3, 6, and 9 years post-diagnosis were statistically and clinically significantly higher. Overall, the results in the pre-treatment QoL subset were consistent with the cohort as a whole. Conclusions: In survivors of aggressive lymphomas, QoL improved primarily in the first year after diagnosis, and sustained over the course of nine years. QoL in survivors of aggressive lymphomas is higher than the United States general population at 1, 2, 3, 6, and 9 years after diagnosis. Figure Disclosures Maurer: Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Farooq:Kite, a Gilead Company: Honoraria. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding.

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Pillar-1: Multicenter Phase 2 Study of Everolimus for Patients with Mantle Cell Lymphoma Who Are Refractory or Intolerant to Bortezomib.

Blood ◽

10.1182/blood.v120.21.2751.2751 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2751-2751

Author(s):

Michael Wang ◽

Leslie Popplewell ◽

Robert H. Collins ◽

Jane N. Winter ◽

Andre Goy ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Median Duration ◽

Mtor Inhibitor ◽

Cell Lymphoma ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 2751 Background: Mantle cell lymphoma (MCL) is a rare, often aggressive form of B-cell lymphoma. In relapsed MCL, bortezomib is associated with an overall response rate (ORR) of 32% and a median time to progression of 6.7 months (Ann Oncol 2009;20:520-5). The mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in hematologic malignancies. In a phase 2 study of relapsed/refractory lymphomas, including MCL, reported by Witzig et al, the oral mTOR inhibitor everolimus showed antitumor efficacy and acceptable tolerability (Leukemia 2011;25:341-7). PILLAR-1 (PIvotaL Lymphoma triAls of RAD001-1) was a phase 2 study conducted to determine the efficacy and safety of everolimus monotherapy in patients with previously treated MCL refractory or intolerant to bortezomib. Methods: PILLAR-1 was a US, multicenter, open-label, 2-stage, single-arm, phase 2 study of oral everolimus 10 mg/day for adults with pathologically confirmed MCL who were refractory or intolerant to bortezomib and received ≥1 other antineoplastic therapy. Patients were considered refractory to bortezomib if they had documented radiological progression on or within 12 months of the last bortezomib dose when given alone or on or within 12 months of the last dose of the last component of a combination therapy that included bortezomib. Patients were considered intolerant to bortezomib if they discontinued bortezomib for toxicity (documentation was required). Primary endpoint was ORR assessed by the investigator according to the modified response criteria for malignant lymphoma. To declare a positive study, ≥8 responders out of 57 patients were required. Secondary endpoints included progression-free and overall survival (PFS and OS, respectively), duration of response (DOR), and safety. Results: Fifty-eight patients were enrolled between August 2008 and January 2011. Median age was 68 years (range, 50 to 83 years), 77.6% were male, 19.0% and 67.2% had stage III and IV disease, respectively, 20.7% received autologous stem cell transplant, 74.1% received ≥3 prior treatment regimens, 84.5% were bortezomib refractory, and 13.8% were bortezomib intolerant; 1 patient (1.7%) was considered neither bortezomib refractory nor intolerant as disease progression occurred >12 months after the last bortezomib dose. Median duration of follow-up was 23.2 months. As of April 20, 2012, all patients discontinued study treatment, most commonly due to disease progression (51.7%) or adverse events (AEs) (39.7%). Median duration of everolimus exposure was 2.9 months (range, 0.4 to 16.9 months). The study did not meet its primary objective as only 5 objective responses per local review (all partial responses [PR]) were observed, resulting in an ORR of 8.6% (90% confidence interval [CI], 3.5% to 17.3%). The DOR ranged from 21 to 338+ days. Per local review, 35 patients (60.3%) experienced stable disease (SD). The median duration of disease control in the 40 patients with PR or SD was 5.7 months (range, 1.7+ to 16.7+ months). Median PFS per local review was 4.4 months (95% CI, 3.5 to 6.1 months). In a sensitivity analysis based on central radiology review, 6 patients experienced PR (ORR, 10.3%; 90% CI, 4.6% to 19.4%), the DOR ranged from 49+ to 401+ days, 30 patients experienced SD (51.7%), and median PFS was 5.2 months (95% CI, 4.0 to 7.1 months). Median OS was 16.9 months (95% CI, 14.4 to 29.9 months). Four patients proceeded to stem cell transplantation. Grade 3/4 nonhematologic AEs were experienced by 70.7% of patients; those that occurred in ≥5% of patients were abdominal pain (8.6%), pneumonia (8.6%), fatigue (6.9%), hyperglycemia (6.9%), asthenia (5.2%), diarrhea (5.2%), dyspnea (5.2%), hyponatremia (5.2%), and pneumonitis (5.2%). Based on laboratory values, grade 3/4 thrombocytopenia and neutropenia occurred in 13.8% of patients each, and anemia occurred in 8.6%. Conclusions: In this phase 2 study, everolimus monotherapy demonstrated modest activity in heavily pretreated patients with bortezomib-refractory MCL. Future studies exploring everolimus as monotherapy in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted. Disclosures: Wang: Novartis: Research Funding. Off Label Use: Everolimus is an mTOR inhibitor indicated in the US for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with letrozole after failure of letrozole or anastrozole; adults with progressive pancreatic neuroendocrine tumors that are unresectable, locally advanced, or metastatic; adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib; adults with renal angiomyolipoma and tuberous sclerosis complex not requiring immediate surgery; and adults and children aged 3 years or greater with subependymal giant cell astrocytoma associated with tuberous sclerosis complex who require therapeutic intervention but are not candidates for curative surgical resection. Winter:Seattle Genetics: Consultancy; Talon: Consultancy; BMS: Consultancy; Sanofi-Aventis: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Caremark/CVS: Consultancy; Eisai: Consultancy; Novartis: Consultancy; TG Therapeutics: Consultancy; Spectrum: Consultancy; Teva: Consultancy; Medalis: Consultancy. Goy:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Robeva:Novartis: Employment. Pirotta:Novartis: Employment. Fan:Novartis: Employment. Klimovsky:Novartis: Employment.

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The Use of CEP (Lomustine, Etoposide and Prednisone), an All-Oral Palliative Chemotherapy Regimen, in Aggressive Lymphomas

Blood ◽

10.1182/blood-2019-126997 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4131-4131

Author(s):

Lakshman Vasanthamohan ◽

Brent Parker ◽

Joy Mangel ◽

Selay Lam ◽

Kang Howson-Jan ◽

...

Keyword(s):

Disease Control ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Multivariate Analyses ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Salvage Chemotherapy ◽

Advisory Committees ◽

Free Survival ◽

Aggressive Lymphomas

Background: There is no current standard of care therapy for the management of patients with aggressive lymphomas in the relapsed or refractory (R/R) setting who are not candidates for intensive salvage chemotherapy and/or autologous stem cell transplant (ASCT). The combination of lomustine (CCNU), etoposide and prednisone (CEP) is an oral chemotherapeutic regimen that is modified from CCEP used in Hodgkin Lymphoma (CCNU, chlorambucil, etoposide and prednisone). CEP consists of alternating A & B cycles as follows (Figure 1): 'A' cycles contain lomustine 80 mg/m2 on day 1 as well as etoposide 100 mg/m2 and prednisone 100 mg on days 1-7. 'B' cycles contain only the etoposide and prednisone. Cycles are given every 21 days apart. To date there has been no published data on CEP's efficacy and tolerability in aggressive R/R lymphoma. In this study, we describe our institutional experience with CEP at the London Regional Cancer Program (LRCP) in London, Ontario for patients with R/R aggressive lymphomas unable to tolerate intensive chemotherapy. Methods: We conducted a retrospective review of patients who received CEP at LRCP between January 2014 and May 2018 for R/R aggressive lymphomas. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and adverse effects related to CEP. Kaplan-Meier survival curves modeled PFS and OS. We also performed univariate and multivariate analyses to assess whether pre-specified variables (age, IPI score at diagnosis, LDH at time of treatment, and the number of prior lines of therapy) were independently associated with response to CEP (using linear regression) or progression-free survival (using the Cox proportional hazards model). IPI score (0-2 vs. 3-5) and the number of prior lines (1-2 vs. ≥ 3) were analyzed as binary variables due to the overall sample size. Results: 46 patients received CEP at LRCP during the study period. Diffuse large B-cell lymphoma was the most common diagnosis (70%) with Hodgkin lymphoma (6.5%) and peripheral T-cell lymphoma (6.5%) being the next most common. The median age of patients starting CEP was 76, with the median number of prior therapies being 2 (range 1-6). The primary outcome was ORR, which was 41% in our population, with a median time to response of 23 days. The median PFS was 2 months while the median OS was 4 months (Figure 2). The 2-year PFS and OS were both 8.7%. The median CEP treatment period was 1.5 full cycles while the longest CEP treatment period was 21 consecutive cycles. Univariate analysis revealed that lower IPI score (p=0.037) was significantly associated with ORR, while lower LDH (p=0.029) was significantly associated with PFS. Multivariate analyses revealed no factors associated with ORR, while lower LDH (p=0.017) and lower IPI (p=0.037) were associated with PFS. Toxicities were manageable with 48% with cytopenias of any grade and the most common grade 3-4 toxicity was febrile neutropenia in 13%. Conclusions: CEP is a safe, and convenient, all-oral palliative regimen for R/R aggressive lymphoma who are not eligible for intensive salvage chemotherapy or ASCT. The median OS in our population is comparable to pooled clinical trial and academic center data from non-transplant eligible patients with R/R DLBCL (Crump et al, Blood, 2017). Some patients even in spite of low performance statuses were able to tolerate many cycles of CEP with a long period of disease control, suggesting it is a reasonable treatment option for frail patients to balance disease control with an acceptable side-effect profile. Disclosures Lam: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Other: Education Grant; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Phua:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Ibrutinib in Association with R-DHAP/Ox for Patients with Relapsed/Refractory B-Cell Lymphoma: Preliminary Results of the Biblos Phase Ib Lysa Study

Blood ◽

10.1182/blood.v128.22.5384.5384 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5384-5384 ◽

Cited By ~ 2

Author(s):

Christophe Bonnet ◽

Thierry Lamy ◽

Christophe Fruchart ◽

Steven Le Gouill ◽

Katharina Gunzer ◽

...

Keyword(s):

Febrile Neutropenia ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hematological Toxicity ◽

Advisory Committees ◽

Cutaneous Eruption ◽

Phase Ib ◽

Hemorrhagic Events

Abstract Background: Ibrutinib is a first-in-class selective, irreversible inhibitor of Bruton's tyrosine kinase (BTK) approved for the treatment of patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) and R/R chronic lymphocytic leukemia. In heavily pretreated MCL, in monotherapy, an ORR of 68% was observed in a phase II study (Wang, 2013). Toxicity is mainly hematological and gastrointestinal. Safety profiles for combination of ibrutinib with R-CHOP or R-benda are acceptable and these combinations are under evaluation in phase III randomized studies (Younes, 2014; Maddocks 2015). We present here preliminary data of a phase Ib study evaluating the safety and tolerability of ibrutinib in association with R-DHAP or R-DHAOx for patients with B-cell lymphoma after first or second treatment failure who are candidates for autologous stem cell transplantation (ASCT). Patients & methods: Eligible patients were planned to receive 3 cycles, given every 21 days, of rituximab 375 mg/m² on day 1, dexamethasone 40 mg on days 1 to 4, cytarabine 2 g/m² bid on day 2 and cisplatin 100 mg/m² on day 1 (R-DHAP) or oxaliplatin 130 mg/m² on day 1 (R-DHAOx) in association with escalating doses of ibrutinib. The starting dose (dose level 1, DL1) was 420 mg/day on days 1 to 21. The dose-variation scheme followed a traditional "3+3" design (DL-1: 280 mg/day on days 1 to 21; DL2: 560 mg/day on days 1 to 21). Dose-limiting toxicities (DLT) were considered during the first cycle. DLT were defined as: non-hematological toxicity grade (Gr) 3-4 excluding alopecia, diarrhea and/or nausea/vomiting and/or fatigue/asthenia for less than 7 days; any Gr ≥ 2 hemorrhagic events; any Gr≥ 1 intracranial hemorrhage and any Gr≥ 4 hematological toxicity lasting more than 7 days. Results: Between May 2014 and July 2015, 25 patients have been treated (R-DHAP: 13, 1 non evaluable for DLT; R-DHAOx: 12). In the DL1 cohort (420 mg/day), DLTs assessed as related to ibrutinib were observed in 3/6 patients receiving R-DHAOx (Gr3 cutaneous eruption, Gr3 febrile neutropenia and prostatic infection, Gr4 thrombocytopenia) and in 3/6 patients receiving R-DHAP (Gr4 cutaneous eruption, Gr4 thrombocytopenia and Gr4 sepsis). According to protocol, ibrutinib dose was decreased to 280 mg/day. Thirteen patients were treated at DL-1 with 1 patient experiencing DLT in each cohort (1/6 evaluable patients in R-DHAP group: Gr4 thrombocytopenia and Gr4 gastric hemorrhage, Gr3 atrial fibrillation; 1/6 patient in R-DHAOx group: Gr3 epigastric pain). Six (50%) patients treated with ibrutinib at the dose of 420 mg and 10 (77%) of those treated at the dose of 280 mg received more than 80% of the planned dose before ASCT. All 25patients experienced one or more adverse events (AE). Diarrhea occurred in 8% of patients. All 25 patients presented Gr3-4 hematological adverse events (neutropenia: 17 patients, including 7 with febrile neutropenia; thrombocytopenia: 25). Three patients presented serious hemorrhagic events. Four patients developed cutaneous eruptions (all of them received prophylactic sulfamethoxazole-trimethoprim). There was 1 death attributable to cardiac toxicity (assessed as unrelated to ibrutinib). Nine patients discontinued ibrutinib (7 due to toxicities, including DLTs, and 2 due to patient's decision). Response to treatment (Cheson 2007 criteria) is currently evaluable in 16 patients (64%). Fourteen responded to the treatment: 8 CR (50%) and 6 PR (37%). Stem cells were harvested in 16 patients and all of them underwent ASCT (CD34+ cells > 3.0x106/kg in 94% of the collected patients after one sole apheresis). Conclusion: Our preliminary result show thatthe DHAP/Ox plus ibrutinib (administered continuously from D1-21) regimen led to several dose-limiting toxicities. Because the dose of 280 mg might be insufficient to improve the quality of response, the protocol was amended in October 2015 in order to change the schedule of Ibrutinib. A new escalation phase using ibrutinib only from day 5 to day 18 is currently ongoing. Pharmacokinetics analyses are also performed. Disclosures Bonnet: JANSSEN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SERVIER: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees. Karlin:takeda: Consultancy; amgen: Consultancy, Honoraria; janssen-cilag: Consultancy, Honoraria; celgene: Consultancy, Honoraria; Bristol: Consultancy. Dupuis:janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Salles:Roche/Genentech: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria.

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Abexinostat (S78454/PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose-Escalation Study in 35 Patients

Blood ◽

10.1182/blood.v120.21.3643.3643 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3643-3643 ◽

Cited By ~ 2

Author(s):

Franck Morschhauser ◽

Louis Terriou ◽

Bertrand Coiffier ◽

Gilles Salles ◽

Ioana Kloos ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Febrile Neutropenia ◽

Board Of Directors ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Abstract Abstract 3643 Background. Abexinostat is a new hydroxymate-based pan-HDAC inhibitor of class I and II that induces apoptosis and cell cycle arrest in various human tumor cell lines and inhibits tumor growth in several lymphoma xenograft models. Aim. The primary objective of the Phase I was to assess the safety profile and to determine the recommended Phase 2 dose (RP2D) as well as the optimal administration schedule of abexinostat in patients with refractory or relapsed lymphoma or chronic lymphocytic leukemia. The secondary objectives included assessment of pharmacokinetic and pharmacodynamic profiles and preliminary antitumor activity. Methods. Eligibility criteria included ECOG ≤ 1 and adequate hematological, renal and hepatic functions. This study used a 3+3 cohort expansion design to reach the RP2D. Three different 3-week schedules of abexinostat were tested: schedule 1 (S1) with 14 days of treatment (day 1 – day 14); schedule 2 (S2) with 10 days of treatment (day 1 – day 5 and day 8 – day 12); schedule 3 (S3) with 12 days of treatment (day 1 – day 4, day 8 – day 11 and day 15 – day 18). The schedules were evaluated at different dose levels of abexinostat b.i.d. (4 h apart): S1 at 30 mg/m2, and all 3 schedules at both 45 mg/m2 and 60 mg/m2. The following were considered DLTs if they occurred in cycle 1: ≥ grade 3 non-hematologic toxicity, prolongation of QTc interval and febrile neutropenia; grade 4 neutropenia or thrombocytopenia; and next cycle postponed by > 1 week. Results. A total of 35 patients were included. The median age was 61 (21–83). The sex ratio M/F was 22/13. The median number of prior therapies was 5 (2–11). Lymphoma subtypes were Hodgkin's lymphoma (HL) (n=11), follicular lymphoma (FL) (n=7), diffuse large B-cell lymphoma (DLBCL) (n=6), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) (n=4), marginal zone B-cell lymphoma (MZL) (n=3), mantle cell lymphoma (MCL) (n=3) and peripheral T-cell lymphoma (n=1). One DLT (thrombocytopenia) was observed in S2 at 45 mg/m2. At 60 mg/m2, 2 DLTs were observed in each schedule: thrombocytopenia in S1 and S2 (2 each), thrombocytopenia and febrile neutropenia (1 each) in S3. Grade 3 and 4 toxicities were exclusively hematologic: thrombocytopenia (G3: 31.4% patients, G4: 25.7% patients), neutropenia (G3: 11.4% patients, G4: 5.7% patients), febrile neutropenia (G3: 2.9% patients, G4: 2.9% patients), anemia (G3: 2.9% patients, G4: 2.9% patients) and leukopenia (G3: 2.9% patients). The other frequent drug-related adverse events were grade 1 and 2: asthenia (34.3% patients), gastro-intestinal disorders (60% patients) and dry skin (17.1% patients). No prolonged QTc intervals were observed in any schedule. A dose reduction occurred in 28.6% patients in S1, 33.3% in S2 and 37.5% in S3. S1 was selected for Phase 2 since it allowed a full week for platelets recovery, a longer drug exposure than S2 and a safety profile similar to the 2 other schedules. Cmax was reached after each administration with median tmax between 0.5 h and 1 h for each schedule and at each dose level. The median apparent terminal elimination half-life was around 4 h. These results are consistent with the limited accumulation of abexinostat with these dose regimens. There is no evidence of time dependent pharmacokinetics. No correlations have been demonstrated so far between histones H3 acetylation in peripheral blood mononuclear cells and PK parameters or clinical activity. Eight out of 29 (27.5%) evaluable patients achieved objective response: 2 complete responses (2 FL) and 6 partial responses (1 FL, 1 CLL, 1 MZL and 3 HL). At the time of data cut off, all but 1 (HL) responses were ongoing between cycle 6 and cycle 22 (median 13.5 cycles). One stable disease (1 MZL) was observed and was still ongoing after cycle 9. Nineteen patients withdrew for progressive disease, including 9 patients who withdrew after at least 2 cycles (4 HL, 2 DLBCL, 1 MCL, 1 MZL and 1 FL). Conclusion. Abexinostat is well tolerated and demonstrates promising durable responses (including CRs) in indolent lymphomas and Hodgkin's lymphoma patients. Enrollment in the Phase II part of the study is ongoing following S1 (3-week cycles – 14 days of treatment) at the RP2D (45 mg/m2b.i.d.). Disclosures: Terriou: Servier: Honoraria; Pfizer: Consultancy; Amgen: Honoraria; GSK: Honoraria. Coiffier:Servier: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kloos:Institut de recherches internationales Servier: Employment. Tavernier:Institut de recherches internationales Servier: Employment. Depil:Institut de recherches Internationales Servier: Employment. Ribrag:Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding.

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Phase I Study Of Inotuzumab Ozogamicin (InO) Combined With R-GDP For Relapsed/Refractory CD22+ B-Cell Non-Hodgkin Lymphoma (B-NHL)

Blood ◽

10.1182/blood.v122.21.1821.1821 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1821-1821

Author(s):

Randeep Sangha ◽

Andrew Davies ◽

Nam H. Dang ◽

Michinori Ogura ◽

David A. MacDonald ◽

...

Keyword(s):

Febrile Neutropenia ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase I Study ◽

Inotuzumab Ozogamicin ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Expansion Cohort ◽

Number Of Cycles

Abstract Background CD22 is expressed on most B-NHL. Inotuzumab ozogamicin (InO) is a humanized anti-CD22 antibody conjugated with calicheamicin, a potent cytotoxic antitumor antibiotic with activity in relapsed/refractory B-NHL. This study explored the safety, tolerability and preliminary efficacy of InO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) for subjects with CD22+ B-NHL. Methods Part 1 (dose escalation phase, n = 27) enrolled patients (pts) with relapsed or refractory CD22+ B-NHL treated with ≥1 prior R-chemo regimen using an up-and-down independent dose-escalation schema for G and P. InO (0.8 mg/m2 day 2) was combined with R-GDP (R 375 mg/m2, G, and P day 1; oral D 40 mg days 1-4) on a 21-day cycle for up to 6 cycles. R-GDP (R 375 mg/m2 day 1; G 1000 mg/m2 days 1 and 8; D 40 mg days 1-4; P 75 mg/m2 day 1) is a regimen used in some patients with relapsed/refractory B-NHL. Part 2 (MTD confirmation cohort, n = 10) enrolled additional pts to further evaluate the safety and tolerability of the MTD determined in Part 1. Confirmation of the MTD required a dose-limiting toxicity (DLT) rate of < 33% in Cycle 1 and < 4 pts discontinuing prior to Cycle 3 due to adverse event (AE). Part 3 (MTD expansion cohort, n = 18) enrolled additional pts to further evaluate the preliminary efficacy of InO when given in combination with R-GDP. Results Fifty-five pts were treated: 21 DLBCL, 14 FL, 12 MCL, 4 SLL, 1 MZL, and 3 other indolent B-NHL. Characteristics: aged 25 to 81 y (median 65 y); 51 with ECOG PS ≤1; median of 2 prior chemo regimens (range 1-6); 8 refractory to prior therapy. The dose-escalation phase (Part 1) identified the MTD as InO 0.8 mg/m2, R 375mg/m2, G 500 mg/m2 (day 1 only), D 40 mg, P 50 mg/m2. This MTD was confirmed in Part 2, in which 3 pts had DLTs (2 with grade 4 platelets, 1 with febrile neutropenia). The most common treatment-related grade ≥3 AEs included thrombocytopenia (69%), neutropenia (56%), lymphopenia (22%), leukopenia (18%), anemia (16%), and febrile neutropenia (11%). Twenty-one pts completed all 6 treatment cycles; the median number of cycles completed was 4 (range 1-6). The most common AEs leading to dose reductions and temporary dose delays included thrombocytopenia, febrile neutropenia, and neutropenia. For the 55 pts enrolled, the overall response rate (ORR) was 45% (n = 25), including 22% of pts (n = 12) who achieved a complete response (CR). Of the 55 pts enrolled, 46 had both a baseline and at least 1 post-baseline assessment reported. In this population to date, the ORR was 54%, including 26% who achieved a CR. 2 pts remain on treatment at the time of data collection. Additional efficacy data are summarized in Table 1 . Pharmacokinetic samples were collected for pts enrolled in the MTD confirmation and expansion cohorts. Fifty-three pts have discontinued treatment, including 21 who completed the planned number of cycles, 12 due to AE (including 8 pts with grade 2/3 thrombocytopenia that did not resolve to grade 1 or better within the 28-day dose delay window allowed per protocol, and 1 each grade 5 oesophageal obstruction, grade 2 skin lesion and grade 4 tumor lysis syndrome) and 12 due to PD. Fifteen deaths have been reported, 12 due to disease progression and 3 due to other causes, including graft-versus-host disease, toxicity after allograft, and sequelae of subdural hematoma not related to study drug (n = 1 each). Conclusions InO 0.8 mg/m2 with R-GDP is tolerable at reduced doses of G (500 mg/m2 day 1 only) and P (50 mg/m2). Preliminary efficacy in the MTD expansion cohort is encouraging. Follow-up for PFS and OS is currently ongoing. Disclosures: Sangha: Boehringer Ingelheim: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Pfizer: Honoraria. Off Label Use: This abstract presents findings from a phase I study of inotuzumab ozogamicin in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma; this drug is investigational and is not approved for use in any indication in any country. Davies:Pfizer: Research Funding; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Ogura:Eli Lilly: Research Funding. Volkert:Pfizer Inc: Employment. Ananthakrishnan:Pfizer Inc: Employment. Luu:Pfizer Inc: Employment. Boni:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment. Goh:Gilead Scienes: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Jannsen: Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Hospira: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Preclinical Evaluation of Gilteritinib on NPM1-ALK Driven Anaplastic Large Cell Lymphoma Cells

Blood ◽

10.1182/blood-2019-130633 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2865-2865

Author(s):

Sudhakiranmayi Kuravi ◽

Janice Cheng ◽

Kishore Polireddy ◽

Gabrielle Fangman ◽

Roy A Jensen ◽

...

Keyword(s):

Tyrosine Kinase ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Advisory Board ◽

Advisory Committees ◽

Apoptotic Protein ◽

Large Cell Lymphoma ◽

Alk Positive

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin's lymphoma (NHL) comprising 2-8% of adult and 10-20% of pediatric and adolescent NHL. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL express (nucleophosmin1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The self-dimerization of fusion kinase NPM1-ALK mediates constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for lymphoma cell proliferation and survival. The current standard treatment regimen for ALK+ ALCL is CHOP (cyclophosphamide, hydroxy doxorubicin, vincristine, prednisone) chemotherapy. Oftentimes, resistance and failure of remission occur with CHOP therapy, making it a suboptimal treatment regimen for many patients. Therefore, an alternative therapeutic approach is warranted to better address the needs of the ALK+ ALCL population. Gilteritinib is a recently FDA approved tyrosine kinase inhibitor for the treatment of FMS-like tyrosine kinase (FLT3) mutation-positive acute myeloid leukemia. Along with inhibition of FLT3, gilteritinib also inhibits other tyrosine kinases such as AXL and ALK. In this study, for the first time, we demonstrated gilteritinib mediated growth inhibitory effects on NPM1-ALK driven ALCL cells. We have used a total of five cell lines in our study: NPM1-ALK endogenously expressing human ALCL cell lines (SUDHL-1, SUP-M2, SR-786, and DEL), and our laboratory generated ectopically overexpressing Ba/F3-FG-NPM1-ALK, a murine cell line. Gilteritinib treatment (5-20 nM) inhibited NPM1-ALK fusion kinase phosphorylation, which resulted in downregulation of downstream survival signaling pathways including AKT, ERK1/2, and STAT3 leading to induced apoptosis and decreased clonogenic survival. Gilteritinib mediated apoptosis was associated with caspase 3/9 and poly (ADP-ribose) polymerase cleavage with increased pro-apoptotic protein BAD and decreased anti-apoptotic protein MCL-1. Increased expression of c-Myc is associated with ALK-positive ALCL and gilteritinib treatment decreased c-Myc levels in a dose dependent manner. Cell cycle analysis demonstrated gilteritinib treatment induced cell cycle arrest at the G0/G1 phase with a concomitant decrease in G2/M and S phases. In summary, our preclinical results suggest gilteritinib has therapeutic potential for the treatment of ALCL cells expressing NPM1-ALK and other ALK /ALK-fusion driven hematologic or solid malignancies. Disclosures Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study

Blood ◽

10.1182/blood-2020-139253 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 51-52

Author(s):

Sung-Eun Lee ◽

Joon Seong Park ◽

Young Rok Do ◽

Sung-Hyun Kim ◽

Dae Young Zang ◽

...

Keyword(s):

Prospective Study ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Kinase Inhibitor ◽

Molecular Response ◽

Close Monitoring ◽

Advisory Committees ◽

Deep Molecular Response ◽

Multicenter Prospective Study

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

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Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽

10.1182/blood-2019-124192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5263-5263

Author(s):

Karin Hohloch ◽

Christine Windemuth-Kieselbach ◽

Pier Luigi Zinzani ◽

Roberto E. Cacchione ◽

Wojciech Jurczak ◽

...

Keyword(s):

Follicular Lymphoma ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Therapy ◽

First Line ◽

Advisory Committees ◽

Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

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