A Detailed Evaluation of Transplant-Related Toxicities and Outcome for Patients with CNS Lymphoma (CNSL) Consolidated with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT) Using Thiotepa, Busulfan (Bu), Cyclophosphamide (TBC) Conditioning

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4354-4354
Author(s):  
Michael Scordo ◽  
Valkal Bhatt ◽  
Meier Hsu ◽  
Antonio M. Omuro ◽  
Matthew J. Matasar ◽  
...  
Keyword(s):  
Research Funding ◽  
Secondary Malignancy ◽  
Cns Lymphoma ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Kaplan Meier ◽  
Clinically Significant ◽  
Grade 3

Abstract Background: HDT-ASCT with TBC conditioning has emerged as a common consolidation strategy for patients (pts) with relapsed/refractory (rel/ref) primary (PCNSL) or secondary (SCNSL) (Welch et al, Leuk & Lymph 2014). In a prospective study, chemosensitive PCNSL pts in first remission after induction with R-MPV (rituximab, MTX, procarbazine and vincristine) proceeding to HDT-ASCT with TBC conditioning, experienced an encouraging 2-year PFS and OS of 75% and 81%, respectively (Omuro et al, Blood, 2015). Three of these patients experienced transplant-related mortality (TRM, 11.5%), which appears greater than HDT-ASCT for other lymphomas. The purpose of this report is to correlate characteristic toxicities of TBC conditioning for CNSL to pre-HDT-ASCT clinical variables. Methods: The MSKCC IRB approved this retrospective chart review. Eligible pts (n=34) were ≥ 18 years of age with PCNSL or SCNSL that was chemosensitive to induction therapy after which they proceeded to HDT-ASCT conditioned with TBC between December 2006 and April 2015. All pts included were treated outside of prospective clinical trials. Clinically significant grade 3-5 non-hematologic toxicities per CTCAE 4.0 occurring in >20% of pts were recorded from the initiation of conditioning until 6 months post ASCT (Figure 1). Pre-HDT-ASCT variables for analysis include: age, gender, disease (PCNSL or SCNSL), Karnofsky performance status (KPS), hematopoietic cell transplant comorbidity index (HCT-CI), number of prior regimens, prior use of whole-brain radiotherapy (WBRT), and disease status prior to HDT-ASCT (CR/CRu or PR). We evaluated the association of these pre-HDT-ASCT characteristics with the number of clinically significant grade 3-5 non-hematologic toxicities (≥4 vs. <4) using FisherÕs exact test. We further estimated progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods. Results: Thirty-three patients (97%) experienced ≥ 1 grade 3-5 non-hematologic toxicity. Febrile neutropenia (grade 3) occurred in 32 pts (94%). Of all pre-HDT-ASCT variables, only the number of prior regimens (>2) was significantly associated with incurring more grade 3-5 non-hematologic toxicities, p=0.04 (Table 1). With a median follow-up for survivors of 12 months (range, 1.5-86.2 months), PFS was 79% (95% CI, 65-96) and OS was 82% (95% CI, 68-98) at 1 year (Figures 2 and 3). During the follow-up period, there were 7 pt deaths: 4 died of disease, 2 died secondary to TRM (5.9%), and one died of a secondary malignancy (squamous cell carcinoma) 86.2 months after HDT-ASCT. There were no progression events beyond 12 months. In a limited subset analysis wherein n=22 had first dose bu pharmacokinetics evaluated, pre-HDT-ASCT variables were not associated with higher bu AUC levels, though 64% of these pts required a dose reduction. Conclusions: We reaffirmed that HDT-ASCT with TBC conditioning is effective consolidation for CNSL, but it is associated with more grade 3-5 non-hematologic toxicity in pts having had >2 prior regimens. Risk-adapted dose attenuation of TBC conditioning for this group of pts may mitigate observed toxicity. Table 1. Association of Pre-ASCT Variables & Grade 3-5 Non-hematologic Toxicities Number of Clinically Significant Grade 3-5 Toxicities Pre-ASCT Variables All (N=34) Fewer than 4 (N=21) 4 or more (N=13) p-value Age 0.71 <60 23 (68%) 15 (71%) 8 (62%) ≥60 11 (32%) 6 (29%) 5 (38%) Gender 0.72 Female 13 (38%) 9 (43%) 4 (31%) Male 21 (62%) 12 (57%) 9 (69%) Disease 0.30 PCNSL 19 (56%) 10 (48%) 9 (69%) SCNSL 15 (44%) 11 (52%) 4 (31%) KPS 0.99 ≥80 32 (94%) 20 (95%) 12 (92%) <80 2 (6%) 1 (5%) 1 (8%) BMT HCT CI 0.99 ≤2 17 (50%) 11 (52%) 6 (46%) >2 17 (50%) 10 (48%) 7 (54%) Number of Prior Regimens 0.04 ≤2 21 (62%) 16 (76%) 5 (38%) >2 13 (38%) 5 (24%) 8 (62%) WBRT 0.17 No 28 (82%) 19 (90%) 9 (69%) Yes 6 (18%) 2 (10%) 4 (31%) Disease state prior 0.99 CR/CRu 29 (85%) 18 (86%) 11 (85%) PR 5 (15%) 3 (14%) 2 (15%) Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 2. Kaplan-Meier Curve for PFS Figure 2. Kaplan-Meier Curve for PFS Figure 3. Kaplan-Meier Curve for OS Figure 3. Kaplan-Meier Curve for OS Disclosures Bhatt: Spectrum: Consultancy. Moskowitz:GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4639-4639 ◽  
Author(s):  
Jakub Svoboda ◽  
Lauren E. Strelec ◽  
Daniel J. Landsburg ◽  
Sunita Dwivedy Nasta ◽  
Anthony R. Mato ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Grade 3 ◽  
Historical Controls

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

scholarly journals Initial Results of a Phase II Study of Sequential Chemotherapy and Lenalidomide Followed By Rituximab and Lenalidomide Maintenance for Untreated Mantle Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2880-2880 ◽  
Author(s):  
Anita Kumar ◽  
Andrew D. Zelenetz ◽  
Connie Lee Batlevi ◽  
Philip Caron ◽  
Ahmet Dogan ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Tp53 Mutation ◽  
High Dose ◽  
Cell Transplant ◽  
Ki 67 ◽  
High Risk Disease ◽  
Mantle Cell ◽  
Grade 3

Abstract Introduction: Cytarabine-containing induction chemotherapy followed by high dose therapy and autologous stem cell transplant (ASCT) is currently a standard treatment approach for younger patients with mantle cell lymphoma (MCL). This approach, however, may be associated with lesser efficacy in patients with high-risk disease biology (i.e. with elevated proliferative index, blastic morphology, or TP53 alteration). Older patients are treated with rituximab-based chemotherapy regimens without stem cell transplant. In this single-center prospective phase II study, we treated MCL patients, irrespective of their age, with immunochemotherapy combined with lenalidomide without ASCT to evaluate the safety and efficacy of this regimen. Methods: Treatment consisted of 3 parts: A) 4 cycles of lenalidomide (15mg orally days 1-14) and standard RCHOP chemotherapy in a 21-day cycle B) rituximab and high-dose cytarabine (RHIDAC) administered at a dose of 1,000-3,000 mg/m2 every 12 hours x 4 doses for a total of 2 cycles C) rituximab plus lenalidomide maintenance for 6 months. Eligible patients were untreated MCL, stage II-IV, KPS≥70%, and with adequate organ function. We enriched study enrollment for high risk patients, 31 of a total 47 patients, as defined by Ki-67 ≥30% and/or blastic/blastoid/pleomorphic morphologic subtype. PET/CT after each phase of treatment was completed and interpreted with the 5-point Deauville scale (negative=1-3). The primary endpoint of the study was to evaluate the 3-year progression free survival. Herein we are presenting preliminary data on the end-of-treatment (EOT) response rate and the toxicity of the regimen, including the interim and EOT PET data. Results: Interim data (as of June 1, 2018) for the first 45 of a planned 47 patients are presented here. Median age was 63 (range 30-79); 82% stage IV; MIPI low, intermediate and high risk were 31%, 31%, and 38%, respectively; 64% of patients had high-risk disease per our definition (28 patients with a Ki-67 ≥30% and 6 patients with blastic morphology). Of the 39 patients who completed Len-RCHOP induction, 85% were PET-negative and after RHIDAC, 95% of patients achieved a negative PET scan (Figure 1). Of the 26 patients who have completed Len-R maintenance, 92% were PET-negative, 8% PET-positive (Table 1). At EOT, 24 patients (92%) achieved a complete remission, 1 patient achieved a partial response, and 1 patient had progressive disease. Among the 24 patients who achieved a CR, the median follow-up is 9 months. Two relapses have occurred at 18 months and 25 months. The patients with a treatment failure (one PR at EOT, one progressive disease at EOT, and 2 relapses), occurred in patients either with a TP53 mutation (3/3 tested, 1 pending) or blastic morphology (3/4 patients). Overall the treatment program was well-tolerated and predominantly hematologic toxicities were observed, particularly during the RHIDAC phase consistent with past experience with this treatment regimen in MCL. During each phase (Len-RCHOP, RHIDAC, and Len-R maintenance), grade 3/4 neutropenia was observed at a rate of 13%, 52%, 16%, respectively; febrile neutropenia 1%, 4%, 0%, respectively; grade 3/4 anemia 11%, 32%, 1%, respectively; and grade 3/4 thrombocytopenia 8%, 75%, 2%, respectively. Comparing to our historical data in a cohort of 23 MCL patients (57% low risk), Len-RCHOP resulted in a higher PET-negative rate compared to RCHOP alone, 85% versus 65%, respectively. Conclusion: The addition of lenalidomide to RCHOP chemotherapy appeared to increase the rate of PET-negativity compared to historical results with RCHOP alone. Toxicity occurred as expected and was manageable. Early failures were observed in patients with TP53 mutation or blastic morphology. Although follow-up is limited, early results with this approach are promising. Disclosures Kumar: Seattle Genetics: Research Funding; Abbvie Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Zelenetz:Novartis/Sandoz: Consultancy; Amgen: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Abbvie: Research Funding; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Hamlin:Portola: Consultancy. Matasar:Seattle Genetics: Honoraria. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Takeda: Honoraria; Merck: Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Straus:Bayer: Consultancy; Medical Crossfire: Speakers Bureau; DAVA Oncology: Consultancy, Honoraria; JUNO: Consultancy; Millenium (Takeda): Consultancy, Research Funding; Seattle Genetics: Consultancy; Onco Tracker: Consultancy; Roch China: Speakers Bureau; InPractice Elselvier: Consultancy; Memorial Sloan Kettering Cancer Center: Employment. Younes:BMS: Honoraria, Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Roche: Honoraria, Research Funding; Novartis: Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria; J&J: Research Funding; Curis: Research Funding; Incyte: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria.

scholarly journals Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Lenalidomide Refractory Myeloma: Long Term Follow up and Comparison of 2 Mg Vs 4 Mg Doses

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4780-4780
Author(s):  
Martha Q. Lacy ◽  
Betsy R. LaPlant ◽  
Kristina M Laumann ◽  
Shaji Kumar ◽  
Morie A Gertz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Cell Transplant ◽  
Survival Curves ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Grade 3 ◽  
Dose Levels

Abstract Background: Pomalidomide has demonstrated excellent activity in patients with relapsed, lenalidomide refractory, multiple myeloma (MM). Between November 2007 and March 2012, we enrolled 285 patients with relapsed MM on 5 sequential phase 2 trials; patients received pomalidomide at 2mg or 4 mg daily with weekly dexamethasone (Pom/dex). The approved dose of pomalidomide is 4 mg for 21 of 28 days. We wished to compare efficacy, tolerability and long-term outcomes between cohorts treated with 2 mg or 4mg daily continuously and 4mg daily for 21/28 days. Methods: After excluding two ineligible patients, 283 patients with lenalidomide refractory, relapsed MM from 5 sequential cohorts were analyzed. These patients were divided into 3 groups: Group1 received Pom 2mg for 28/28 day cycle (N= 69), Group 2 received Pom 4 mg for 28/28 day cycle (N= 95) and Group 3 received Pom 4mg for 21/28 day cycle (N= 119). All patients received oral dexamethasone given 40 mg daily on days 1, 8, 15, and 22. Response was assessed by the IMWG Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis or full dose anticoagulation. Results: The median age was 63 years (32-85); 35% were female. The median time from diagnosis was 53 months and the median number of prior regimens was 4. 127 (46%) had high-risk molecular markers. Prior therapies (% received) included lenalidomide (100%), thalidomide (46%), bortezomib (78%), autologous stem cell transplant (71%), and allogeneic transplant (4%). The median follow-up is 16.4 months (3.2-64.4). Forty eight percent are alive and 26% remain progression free; 15 patients are continuing to receive treatment. Frequency of AEs by groups are shown in Table 1. The most notable difference is grade 3+ neutropenia seen in 39% of group 1 and 56% and 57% of groups 2 and 3. Confirmed responses of PR or better were seen in 29% (group1), 35% (group2) and 24% (group3). Median duration of response (DOR) was 14.1 months (group1), 14.5 months (group2) and 10.2 months (group3). Median PFS was 5.5 months (group1), 6.9 months (group2) and 4.3 months (group3). Although the dose level cohorts were sequential rather than randomized, we compared OS between the dose levels in an exploratory manner. There was no significant difference in OS between dose levels (p=0.26). Median overall survival (OS) was 16.6 months (group1), 21.9 months (group2) and 16.0 months (group3). Conclusions: Pom/dex is active and well tolerated even in heavily pretreated patients Responses are durable. Response rates and overall toxicity are similar between the 2 mg and 4 mg doses. Neutropenia is more common in those receiving doses of 4mg daily or for 21/28 days compared to those receiving 2 mg daily. Table 1. All Grades Grade 3+ 2mg 28 Day 4mg 28 Day 4mg 21 Day 2mg 28 Day 4mg 28 Day 4mg 21 Day Anemia 68% 58% 74% 14% 15% 27% Lymphopenia 22% 51% 11% 16% 32% 8% Neutropenia 71% 82% 77% 39% 57% 56% Thrombocytopenia 51% 61% 63% 10% 9% 23% Leukopenia 59% 77% 72% 26% 38% 39% Pneumonia 7% 11% 12% 6% 7% 11% Fatigue 51% 65% 60% 9% 5% 8% Neuropathy 28% 32% 28% 0% 3% 0% Elevated Blood Glucose 10% 21% 8% 4% 6% 3% Pneumonitis 3% 2% 3% 3% 1% 1% VTE (Thrombosis) 3% 3% 3% 1% 3% 3% Secondary Malignancy 0% 2% 1% 0% 2% 1% Figure1. Kaplan Meier Overall Survival Curves Figure1. Kaplan Meier Overall Survival Curves Disclosures Lacy: Celgene: Research Funding. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Stewart:Novartis: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Array BioPharma: Consultancy; Sanofi: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

scholarly journals Initial Treatment Patterns and Survival Outcomes of Mantle Cell Lymphoma Patients in China in the Rituximab Era

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3994-3994
Author(s):  
Yun Li ◽  
Meng Wu ◽  
Huiqiang Huang ◽  
Wei Xu ◽  
Haiwen Huang ◽  
...  
Keyword(s):  
Research Funding ◽  
Autologous Stem Cell Transplant ◽  
Low Risk ◽  
Rank Test ◽  
High Dose ◽  
Cell Transplant ◽  
First Line ◽  
Kaplan Meier ◽  
Ecog Ps

Introduction:Mantle cell lymphoma is an uncommon subtype of B-cell non-Hodgkin lymphoma with variable initial treatment strategies defined by disease risk factors, patient preferences and access to medical care. There is a paucity of reported data on treatment patterns and clinical outcomes in Chinese patient populations managed in the rituximab era. The study aim was to evaluate and compare outcome in relation to prognostic factors and first-line treatment in patients with MCL managed in real-world academic medical centers in China. Methods:Retrospective data were collected from 5 major Chinese Hematology Centers in Beijing, Guangzhou, Nanjing, Shanghai and Suzhou from the period of 2007 to 2017. Diagnosis for MCL was based on characteristic immuno-phenotype and CyclinD1 immunohistochemistry staining. Overall Survival (OS) time was calculated from date of diagnosis to date of death or date of last follow-up, whichever comes first. Kaplan-Meier estimator was used to estimate survival probability. Median follow-up time was estimated on overall survival by reverse Kaplan-Meier method. Survival difference between groups was evaluated by log-rank test for statistical significance. Results:A total of 605 patients with newly diagnosed MCL were included in the analysis. The median follow-up time of the whole group was 38 months. The median age was 58 years (range 28-83) with 59% patients under age 60; the M:F ratio was 3.5:1; 76% presented with ECOG PS of 0-1. Eighty-three percent patients had stage 3-4 disease, 38% had intermediate and high risk MIPI scores, and 30% had IPI scores of 3-5. Ki-67 was <30% in 39% patients. Overall, 75% patients received rituximab-containing combination chemotherapy regimens, with the rest receiving chemotherapy without rituximab. The most common chemotherapy in partnership with rituximab was CHOP-based regimens (51%), followed by HyperCVAD (17%), bendamustine (12%), and DHAP (9%). High dose cytarabine was utilized in 30% patients, delivered primarily with the HyperCVAD, DHAP and Nordic MCL regimens. Forty patients (7%) received novel agent-containing induction regimens, including VRCAP with bortezomib and BR plus ibrutinib. Seventy-one patients (12%) moved onto to consolidative autologous stem cell transplant (ASCT) after induction chemotherapy at selected centers. The 3-year OS and 5-year OS were 75.5% and 63.5%, respectively. Clinical parameters such as age <60, ECOG PS 0-1, normal LDH, and absence of BM involvement were significantly associated with improved OS in log-rank test analysis (p<0.001, p<0.001, p<0.001, p<0.001, respectively). Ki67 <30% was associated with improved survival compared to Ki67>30 (p=0.003). OS correlated with MIPI and IPI scores. The 3-year OS rates were 39.7%, 67.7% and 86.7% respectively for high-, intermediate- and low-risk MIPI scores (p<0.001), while 3-yr OS were 25.6%, 51.2%, 78.7% and 93.0% respectively for high-, high-intermediate-, low-intermediate, and low-risk IPI scores (p<0.001). The 5-year OS rates were 32.1%, 58.8% and 67.2% respectively for high-, intermediate- and low-risk MIPI scores (p<0.001), while 5-yr OS were 19.2%, 36.3%, 58.7% and 81.7% respectively for high-, high-intermediate-, low-intermediate, and low-risk IPI scores (p<0.001). Inclusion of rituximab with chemotherapy and consolidative ASCT were significantly associated with improved OS (p=0.016, p<0.001, respectively), while inclusion of high dose cytarabine was associated with improved OS with borderline significance (p=0.065). Conclusions:This large retrospective dataset of MCL patients who received contemporaneous real-world management in Chinese Hematology Centers confirmed the survival advantage afforded by rituximab-containing chemo-immunotherapy and consolidative autologous stem-cell transplant in first-line setting. The majority of patients seeking care at major medical centers were younger than 60 years of age with good performance status and lower risk MIPI/IPI scores, which correlated with more favorable survival. Incorporation of novel agents signaled infrastructural readiness to explore novel agents and combination in both first-line and relapsed settings. Disclosures Ruan: Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Juno: Consultancy; Kite: Consultancy.

Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Florence Cymbalista ◽  
Véronique Leblond ◽  
Alain Delmer ◽  
Dirk Winkler ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference ◽  
Ultra High Risk ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

Obesity and Hepatitis B Infection and Risk Of Primary CNS Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4298-4298
Author(s):  
Chia-Ching J. Wang ◽  
Paige M Bracci ◽  
James L. Rubenstein
Keyword(s):  
Risk Factors ◽  
Hepatitis B ◽  
Research Funding ◽  
Hbv Infection ◽  
Cns Lymphoma ◽  
High Dose ◽  
Hepatitis B Infection ◽  
Dose Methotrexate ◽  
Hep B

Abstract Introduction The incidence of primary central nervous system lymphoma (PCNSL) has markedly increased during the past three decades. Advanced HIV disease, as well as congenital and iatrogenic immunodeficiency states are the only established risk factors. While the incidence of PCNSL continues to rise among older patients (>60), the vast majority of newly-diagnosed PCNSL patients are not overtly immune suppressed. The goal of this study is to identify novel risk factors for PCNSL that may explain the continued rise in incidence among non-HIV infected, immunocompetent populations. Methods A cohort of 72 HIV-negative patients diagnosed with primary and secondary CNS lymphoma who received ambulatory follow-up evaluation at University of California at San Francisco between 2009-2013 were frequency-matched to Bay Area population-based controls by age-group, sex and race with 1:4 case:control ratio. We regarded HBsAg positivity at baseline as evidence of chronic HBV infection, and HBcAb positivity at baseline as prior HBV infection. Body mass index (BMI) was modeled as normal (reference,<25), overweight (25-30) and obese (30+). Multivariable unconditional logistic regression was used to compute odds ratios (OR) as estimates of relative risk. Models were adjusted for matching factors and statistical significance was based on a two-sided p<0.05. Having been born in a country with a high prevalence of HBV was assessed as a potential confounder. Results 64 patients with PCNSL were identified. Among these, 28 (44%) were male, 69% Caucasian, median age at diagnosis was 61.5 years, 6 (10%) died during the follow-up period, and 7 (11%) had intraocular involvement. HBV infection (chronic or prior) and increased BMI were independently associated with increased risk of PCNSL; HBV infection: OR=14.8 (5.0-44), p<0.0001; BMI: obese vs. normal, OR=2.8 (1.2-6.5), p for trend=0.04. There was no evidence of confounding and no statistical interaction between HBV and BMI (p=0.72). HCV positivity also was assessed but analysis was constrained as only 3 patients were HCV antibody positive (1 also HBV positive). Results from descriptive analyses of intraocular involvement provided some evidence that these PCNSL patients were more likely to have been born in a country with moderate/high HBV prevalence (chi-square p=0.006). Obese PCNSL patients were statistically significantly younger (median age 54) than other patients (overweight median age 64.5, normal 63). Interestingly the Asian patients were younger (median age 57) than Caucasian (median age 62). Hep B patients were older (median age 66) compared with non Hep B (median age 56) but the difference was not statistically significant. All PCNSL patients were treated with high dose methotrexate-based systemic chemotherapy. 37 (58%) were determined to be in complete remission at the end of the follow-up period. For B-cell PCNSL patients who were treated with high-dose methotrexate (n=55), those who were obese had improved progression-free survival (PFS) compared to non-obese (P<0.04; HR 0.3). In contrast, a history of hepatitis B infection was associated with shorter PFS (P=0.04; HR 2.7). Notably, the apparent risk factors of obesity and/or hepatitis B impact approximately half of the 55 non-HIV-infected PCNSL patients in this analysis. Conclusions We believe this to be the first report of associations among obesity, hepatitis B infection and PCNSL. These findings may partly explain the increasing incidence of this subtype of NHL. We hypothesize that both hepatitis B infection as well as obesity may each promote inflammatory states that contribute to CNS lymphomagenesis. Further studies are warranted to confirm these findings and to explore underlying mechanisms of pathogenesis. Supported by Leukemia and Lymphoma Society and NIH R01CA139-83-01A1. Disclosures: Rubenstein: Genentech: Research Funding; Celgene: Research Funding.

5-Azacytidine (AZA) in Combination with Ruxolitinib (RUX) As Therapy for Patients (pts) with Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 823-823 ◽  
Author(s):  
Naval Daver ◽  
Guillermo Garcia-Manero ◽  
Jorge E. Cortes ◽  
Lingsha Zhou ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Single Agent ◽  
Myeloproliferative Neoplasm ◽  
Hematological Toxicity ◽  
Cell Transplant ◽  
Bone Marrow Biopsies ◽  
Baseline Characteristics ◽  
Grade 3

Abstract Background: Clinical trials exclusively focusing on pts with MDS/MPN are lacking. AZA is a DNA methyltransferase (DNMT) inhibitor approved for the therapy of MDS while RUX is a JAK inhibitor approved as therapy for primary myelofibrosis and polycythemia vera. RUX and AZA may target distinct clinical and pathological manifestations of MDS/MPNs. Aim: To determine the efficacy and safety of RUX + AZA in pts with MDS/MPN requiring therapy including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia BCR-ABL1 negative (aCML), and myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)(ClinicalTrials.gov Identifier: NCT01787487). Methods: A sequential approach with single-agent RUX 15 mg orally twice daily (if platelets 100-200) or 20 mg twice daily (if platelets >200) continuously (pts with platelets below 50 were not eligible) in 28-day cycles for the first 3 cycles followed by the addition of AZA 25 mg/m2 on days 1-5 of each 28-day cycle starting cycle 4 was adopted. The AZA dosage could be gradually increased to a maximum of 75 mg/m2. The AZA could be started earlier than cycle 4 and/or at a higher dose in pts with proliferative disease or elevated blasts. Results: 24 pts were enrolled between March 1, 2013 and April 1, 2015. Baseline characteristics are summarized in table 1. 17 pts remain alive after a median (med) follow-up of 6.0 (3.7 - 21.3+) months. Responses were evaluated by the MDS/MPN IWG response criteria (Savona et al., Blood 2015, 125(12):1857-65). Responses were noted in 12 (50%) pts. Details of responses are shown in table 2. Med time to responses was 1.8 mos (0.7 - 5.5+) and the med duration of response is 7.0 mos (1.8 - 17.6+). Additionally, 9 pts had >5% pretreatment BM blasts: 6 of these pts had follow-up BM evaluations and 3 achieved a reduction in blasts to <5% with a med time to blast reduction of 5.5 mos (5.5 - 11.2+). Serial evaluation of bone marrow biopsies documented reduction in EUMNET fibrosis score in 3 of 11 (27%) evaluable pts after a med of 5.5 mos (2.1 - 5.6+) on therapy. The reduction was by one grade in all 3 pts (MF-2 to MF-1 in 2 pts, MF-1 to MF-0 in 1 pt) and was confirmed on a subsequent BM biopsy in 2 pts. No pts experienced grade 3/4 non-hematological toxicity. New onset grade 3/4 anemia and thrombocytopenia were seen in 12 (50%; of which 5 had a 2+ grade change) and 8 (31%) pts, respectively. The med overall survival is 15.1+ mos. 7 pts have died: pneumonia (n=3), sepsis (n=2), progression to AML (n=1), and transition to hospice (n=1). The AZA was started in cycle 4 in 12 pts (50%). The AZA was started earlier due to leukocytosis or increased blasts in 11 pts (46%), in cycle 1 (n=6), cycle 2 (n=4), and cycle 3 (n=1). 13 pts have discontinued protocol therapy due to leukocytosis (n=6), progression to AML (n=1), lack of response (n=3), pneumothorax (n=1), stem cell transplant (n=1), and loss of insurance (n=1), respectively. Conclusion: Concomitant administration of RUX with AZA was feasible and effective in pts with MDS/MPNs, with expected myelosuppression as the only significant toxicity. This combination warrants further evaluation. Table 1. Baseline characteristics (N = 24) Characteristic N (%) / [range] Med age, years 71 [55 - 79] Prior treatment 9 (38) Diagnosis MDS/MPN-U CMML aCML 11 (46) 10 (42) 3 (12) MF - DIPSS Int-1/ Int-2/ High 4(17)/ 11(46) / 9(37) MDS - IPSS Low/ Int-1/ Int-2/ High 9(38) /12(50) / 2(8) / 1(4) Splenomegaly 12 (50) Med WBC x 109/L 26.3 [3 - 123.2] Peripheral blood blasts >/= 1% 17 (71%) LDH 1040 [409 - 3567] EUMNET fibrosis grade MF-1/ MF-2/ MF-3 10(42)/ 6(26)/ 1(4) JAK2 + 6 (25) Med JAK2 allele burden 42.2 [3 - 90] Karyotype Diploid Abnormal 18 (75) 6 (25) 28-gene molecular panel in 23 pts*, (1 pt not done) ASXL1 DNMT3A TET2 KRAS/NRAS PTPN11 IDH 2 4 (17) 4 (17) 3 (13) 2(8) / 2(8) 2(8) 2 (8) *Mutations identified in only 1 pt included EZH2, GATA2, RUNX1, MPL, KIT. Table 2. Response evaluation by the MDS/MPN IWG 2015 criteria Response category Evaluable pts Responders/Evaluable (%) *All responses, some pts have > 1 response All 12/24 (50) Clinical improvement (CI) spleen Pts with palpable spleen > 5 cm 8/11 (73) CI total symptom score Pts with baseline TSS > 20 3/12 (25) CI Hemoglobin (HGB) Baseline HGB < 10 g/dL 1/7 (15) CI Transfusion independence History of transfusion dependence 1/5 (20) Partial marrow response Baseline and follow-up BMs 5/11 (45) Optimal marrow response Baseline and follow-up BMs 1/11 (9) *No CR or PR documented Disclosures Daver: ImmunoGen: Other: clinical trial, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. DiNardo:Novartis: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

A Phase Ib/II Study of Combined Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2051-2051 ◽  
Author(s):  
Januario E. Castro ◽  
Michael Y. Choi ◽  
Carlos I. Amaya-Chanaga ◽  
Natalie Nguyen ◽  
Colin MacCarthy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Free Survival ◽  
Phase Ib ◽  
High Dose Methylprednisolone ◽  
Grade 3

Abstract High-dose methylprednisolone (HDMP) and rituximab (R) is an effective non-myelosuppressive treatment regimen for patients (pts) with chronic lymphocytic leukemia (CLL). Also, this combination has shown activity even in pts who have adverse leukemia-cytogenetics, such as del17p. Phase III studies have demonstrated that CLL pts treated with chlorambucil and obinutuzumab-Gazyva (G), another anti-CD20 mAb, had a superior outcome than comparable pts treated with R-chlorambucil. We hypothesized that G-HDMP is well-tolerated and effective in the treatment of pts with CLL. Accordingly, we initiated an open-label phase Ib/II clinical study. A total of 40 pts were enrolled in two cohorts of 20 pts each (previously untreated (PU) and relapsed/refractory (RR) CLL) and treated with HDMP 1 g/m2on Day 1-3 of cycles 1-4 (28 days/cycle) and G administered based on FDA dosing recommendations for 6 cycles. The pts had a median age of 67 years + 9.1 in the RR cohort and 63 years + 8.3 in the PU cohort. The median baseline absolute lymphocyte count was 30.7 + 7.3 x1,000/mm3 for pts in the RR cohort and 47.6 + 19.7 x1,000/mm3for pts in the PU cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 30% RR vs. 0% PU, del(13q) in 60% RR vs. 70% PU, del(11q) in 20% RR vs. 35% PU, and trisomy 12 in 15% RR vs. 20% PU. Most AEs were grade 1-2 (RR=87%; PU=93%) without development of dose-limiting toxicities. Only two pts needed therapy discontinuation. One pt due to pulmonary embolism and the second pt due to asymptomatic gastrointestinal bleeding that required blood transfusion and resolved spontaneously. Grade 1-2 G-infusion-related reactions (IRR) were observed in 40% and 80% of pts in the RR and PU cohorts, respectively. Grade 3-4 IRR were observed in 10% of pts in the PU cohort only. We observed cytopenias (neutropenia grade 3-4: RR=55%, PU=40%; thrombocytopenia grade 3-4: RR=35%, PU=20%; and anemia grade 3-4: RR=0%, PU=0%). There were no cases of febrile neutropenia. Two pts (10%) in the RR cohort and one pt (5%) in the PU cohort developed infection grade 1-2 that was treated with oral antibiotics but did not require study treatment discontinuation. The most frequent non-hematological adverse events (AEs) were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). There were no treatment related deaths in either cohort. The response assessment was performed in all 40 pts by iwCLL criteria. The ORR was 100% in the PU cohort and 95% in the RR cohort. 70% of the pts in the PU cohort and 85% of the pts in the RR cohort achieved a PR. CR was observed in 30% and 10% of the pts in the PU and RR cohorts, respectively. One pt (5%) in the RR cohort and four pts (20%) in the PU cohort achieved MRDneg status (<0.01% CLL in the bone marrow by multiparameter flow cytometry). Only one pt in the RR cohort achieved SD. At a median follow-up of 12.2 months, the RR cohort had a median Progression Free Survival (PFS) of 13.6 months and median Treatment Free Survival (TFS) of 14.7 months; the median Overall Survival (OS) has not been reached. In the PU cohort, the median PFS, TFS and OS have not been reached. One pt from the RR cohort and one pt from the PU cohort died during the follow-up period due to disease progression. G-HDMP was well tolerated and all 40 pts showed hematological and clinical responses during the study treatment without development of unexpected AEs. In both cohorts, most of IRR were grade 1-2 and severe IRR (grade 3-4) were much less compared with previously published data (G-chlorambucil / CLL-11 study). Compared to pts in the CLL-11 study, cytopenias appeared to be more frequent, however, the rate of infection and need for IV antibiotics or hospitalizations was lower. Of note, the eligibility criteria allowed pts with severe cytopenias and transfusion requirement to participate in our study. Response in PU pts were higher in terms of ORR, CR and CR-MRDnegativecompared with the data from the CLL-11 study and suggests a possible synergistic activity between G and HDMP. Overall, G-HDMP was well tolerated in the PU and RR CLL pts with a lower rate of IRR making this regimen more manageable in the outpatient setting. Responses were higher than previously reported in PU pts. Responses in RR pts appear to be comparable to our previous studies using R-HDMP. Our data supports G-HDMP as an alternative combination regimen for the treatment of CLL pts. Disclosures Kipps: Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

A Phase 1 Trial of Inotuzumab in Combination with CVP (Cyclophosphamide, Vincristine, Prednisone) for Relapsed/ Refractory CD22+ Acute Leukemia (SWOG 1312)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1634-1634 ◽  
Author(s):  
Anjali S. Advani ◽  
Anna Moseley ◽  
Michaela Liedtke ◽  
Margaret O'Donnell ◽  
Megan Othus ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Grade 3 ◽  
Mixed Phenotype

Abstract The prognosis of patients (pts) with relapsed/ refractory acute lymphoblastic leukemia (ALL) remains poor and novel therapies are needed. The anti-CD22 immunoconjugate inotuzumab ozogamicin (INO) has demonstrated promising results in both phase 2 and 3 trials (Kantarjian et al. Lancet Oncology 2012; 13(4): 403-11). Pre-clinical studies have demonstrated superior anti-tumor activity when INO is co-administered with cyclophosphamide (C), vincristine (V), and prednisone (P). In this study, SWOG 1312, we assess the safety of INO in combination with CVP and determine the maximum tolerated dose (MTD) of INO in this regimen for patients with relapsed or refractory (R/R) CD22+ acute leukemia (B-ALL, mixed phenotype, and Burkitts). Here, we present our toxicity results. Methods: Pts were treated at limited SWOG institutions from Apr 2014 to present. INO was supplied by Pfizer and an IND was approved by the FDA. The protocol was reviewed and approved by each institutional review board. Eligibility criteria included: age > 18 years (yrs), > 20% blasts expressing CD22, R/R CD22+ acute leukemia (B-ALL, mixed phenotype, or Burkitts), and adequate organ function. All pts received treatment with C (750 mg/m2) intravenous (IV) Day 1, V (1.4 mg/m2) (max 2 mg) IV Day 1, P (100 mg) orally Days 1-5 and IO (dose escalated as in Table 1) IV Days 1, 8, and 15. Each cycle was 28 days, and a maximum of 6 cycles could be administered. Dose escalation was performed using a standard 3x3 design; with the plan to treat 12 pts once the MTD was defined. Dose limiting toxicities (DLTs) were considered: (1) > Grade 4 non-hematologic toxicities with the exception of nausea, vomiting and toxicities secondary to neutropenia and sepsis; (2) prolonged myelosuppression [absolute neutrophil count (ANC) < 500/ uL or platelet count < 25,000/uL] in a bone marrow with < 5% blasts and no evidence of leukemia that lasts > 35 days beyond the most recent dose of IO; (3) any grade 3 non-hematologic toxicity (excluding peripheral neuropathy, hyperglycemia, and toxicities secondary to neutropenia, thrombocytopenia, and sepsis) that does not resolve to Grade 2 or better by 7 days beyond the most recent dose of IO; (4) any > Grade 3 elevation in SGOT/ SGPT or bilirubin lasting ≥ 7 days; (5) any IO-related toxicity resulting in permanent discontinuation of IO. Results: As of 7/14/2016, 24 pts have been enrolled: 2 pts were ineligible and 3 pts are currently receiving treatment and are not evaluable for toxicity. Of the 19 evaluable pts, the median age was 49 yrs (range 21-75), 10 (53%) were male, and the median WBC at registration was 9.4 K/uL (range 0.9-59.6). All pts had B-ALL. The median time from initial diagnosis to registration was 774 days. Five pts were in 1st relapse, 8 in 2nd relapse, 3 in 3rd relapse, 1 in 4th relapse, and 2 pts were primary refractory. Five pts had received prior allogeneic hematopoietic stem cell transplant (AHSCT); 7 pts had poor risk cytogenetics (Ph+, -7, +8, complex, or hypodiploid). One death occurred during treatment and was attributed to pneumonia. Grade 3-4 hematologic toxicity related to treatment was common: neutropenia (11 pts), thrombocytopenia (7 pts), and anemia (6 pts). Grade 3-4 non-hematologic toxicities were almost exclusively febrile neutropenia. One DLT occurred at Dose Level 3: prolonged myelosuppression. No cases of hepatic veno-occlusive disease (VOD) occurred during treatment, and 1 pt experienced Grade 3 alkaline phosphatase at Dose Level 1. Three pts proceeded to AHSCT after study treatment; 1 pt developed VOD post AHSCT however, this fully resolved. Currently, 3 pts have been enrolled to Dose Level 4. Conclusion: The combination of CVP/IO is well tolerated and only 1 significant hepatic event (which subsequently resolved) was observed despite a heavily pre-treated group of patients. Further toxicity results and dose escalation will be presented at the meeting. Response data will also be presented if enrollment is complete. Disclosures Advani: Pfizer: Consultancy, Research Funding. Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Erba:Pfizer: Consultancy; Juno: Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Agios: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy; Celator: Research Funding; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Jannsen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Ariad: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Ariad: Consultancy; Astellas: Research Funding; Astellas: Research Funding; Celator: Research Funding; Agios: Research Funding; Agios: Research Funding; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy.

High-dose imatinib mesylate treatment in patients (Pts) with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6535-6535 ◽  
Author(s):  
E. Aoki ◽  
H. Kantarjian ◽  
S. O’Brien ◽  
M. Talpaz ◽  
F. Giles ◽  
...  
Keyword(s):  
Standard Dose ◽  
Chronic Phase ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Molecular Responses ◽  
Pre Treatment ◽  
Grade 3

6535 Background: The standard dose (SD) of imatinib for CP CML is currently 400 mg daily, but higher doses (HD) may be more effective. We conducted 2 consecutive trials using HD imatinib (i.e., 400mg twice daily) in previously untreated early CP CML pts. This is an updated analysis of the longer follow-up. Methods: A total of 175 previously untreated pts received HD imatinib. We compared the results with a previous study using SD imatinib (400mg/day) in untreated pts with early CP CML (N=50). Results: Cytogenetic and molecular responses were evaluable in 222 pts (N=49 at SD, 173 at HD) and 217 pts (N=46 at SD, 171 at HD), respectively. In HD group, Sokal risk classification was good in 69%, intermediate in 29%, and poor in 11% of pts. There were no differences in pre-treatment characteristics between two groups. The median age was 48 years in both groups. Median follow-up is 53 months for SD and 30 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (90% vs 78% with SD, p=0.03) and these occurred earlier, with 69% achieving this response after 6 months of therapy vs 45% with SD (p=0.001). The cumulative incidence of major molecular response was significantly better in HD group (p=0.03), and this response was also observed earlier in HD group: at 12 months 54% in HD and 24% in SD group had achieved this response (p=0.001). At 24 months, 19/70 (27%) evaluable pts with HD versus 3/31 (10%) of pts in SD group achieved complete molecular remission. Four pts (2%) in HD group and 4 pts (8%) in SD group have progressed to advanced phases (p=0.05). There was a trend in favor of the HD group for transformation-free-survival but it was not statistically significant (p=0.07). Overall survival is excellent in both groups (24 month survival, 99% with HD vs 98% with SD; p=0.24). Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in two groups. The median actual dose in HD group was 800 mg at 12 months, with 39% patients requiring dose reduction at some point. Conclusions: High-dose imatinib provides higher rates of complete cytogenetic responses and earlier molecular responses with some increase myelosupression. The long-term benefit of earlier responses remains to be demonstrated. [Table: see text]

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