Poor Outcomes with Hyper CVAD Induction for T-Cell Lymphoblastic Leukemia/Lymphoma

Abstract Background: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in adults is an aggressive bone marrow malignancy that historically has a poor prognosis. Hyper-CVAD/methotrexate-cytarabine (hyper CVAD) regimen is a commonly used induction regimen following the protocol developed at MD Anderson Cancer center. Recent reports from Swedish Cancer Registry showed that relapse rates were much higher than expected with this regimen. We report our retrospective experiences across three different centers, Winship Cancer Institute of Emory University (Atlanta), University of Alabama Cancer Center (Birmingham) and Moffitt Cancer Center, (Tampa), with the use of this regimen for management of T-ALL/LBL. Methods: We conducted a retrospective chart review of all adult T-ALL/T-LBL cases at three large cancer centers between the years 2005-2015, treated at the physician's discretion. Data collected included patient demographics, tumor characteristics (white count at diagnosis, flow cytometry, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. Since hyper CVAD is a commonly used regimen outside of clinical trials, we focused our analysis on outcomes with this regimen. This regimen consisted of 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8). CNS prophylaxis was given to all patients as per standard of care recommendations. All patients eligible for maintenance received 2 years of POMP (6 mercaptopurine, methotrexate, vincristine and prednisone) maintenance. Relapse-free survival (RFS) and overall survival (OS) were examined looking at medians and interquartile ranges of times to events. Kaplan Meier curves provided a graphical representation of the survival probability. Results: The final analysis included 95 adult patients with 64/95 (67%) patients receiving hyper-CVAD induction. Among the hyper-CVAD patients the median age at diagnosis was 30 (range 17-74). 71% of patients were male. Median white cell count (WBC) was 13.6/mm3 (1.7-500). Cytogenetic analysis revealed diploid in 36, complex (1 or more abnormalities in 16) and was not available in 12. WBC count was > 100,000/mm3 in 9 patients. 14 patients had mediastinal disease while 7 had CNS disease at diagnosis. Hyper-CVAD was the primary induction regimen in 56/64. Other patients either started on non-hyper CVAD induction prior to switching (n=3) or had asparaginase added to induction (n=5). The median number of cycles given as 7 (range 2-10) with 27(45%) patients receiving the planned 8 cycles. 37 patients did not complete 8 cycles due to stem cell transplant in remission (n=12), progressive disease (n=10) and unclear reasons (n=15). After induction therapy, remission status was unknown in 3 patients while 43/61 patients (70%) achieved remission. Maintenance with POMP was started in 21 patients that were in remission while 12 patients were taken to transplant without starting on maintenance. At the time of analysis, 23/64 (35%) patients are alive. The median relapse free survival was 387 days (12.9 months) and the median overall survival was 536 days (17.6 months). Excluding one patient lost to follow up, 44/63 (69.8%) relapsed. There was no difference in relapse versus non relapse patients in terms of median age (30 vs 33 years), median WBC at diagnosis (13.2 vs 13.6 mm3). Relapse rate was lower in patients with diploid karyotype (22/36, 61%) as compared to those with complex karyotype (14/16). Median survival in patients post relapse was 150 days. Only 9 patients were able to go for transplant after relapse with post transplant survival also being low (6 deaths). For the entire group, the two year survival was 35%. Conclusion: Our multi-institutional retrospective review shows that outcomes are poor across various centers in patients outside of clinical trials. This is the largest reported series of patients with adult T-ALL/T-LBL treated with hyper-CVAD outside of clinical trials. This data warrants investigation with newer agents to improve outcomes in this disease. Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Disclosures Kota: Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hathaway:OnQ Health: Research Funding. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acetylon: Membership on an entity's Board of Directors or advisory committees; PLexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria; Rosetta Genomics: Research Funding; Seattle Genetics: Research Funding. Jillella:Seattle Genetics, Inc.: Research Funding. Borate:Genoptix: Consultancy; Seattle Genetics: Research Funding; Gilead: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau.

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Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽

10.1182/blood-2018-99-120155 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3011-3011 ◽

Cited By ~ 1

Author(s):

Lucia Masarova ◽

Jorge E. Cortes ◽

Keyur P. Patel ◽

Susan M. O'Brien ◽

Graciela M. Nogueras González ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research ◽

Phase 2 Study ◽

Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

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Event-Free Survival at 24 Months Following Autologous Stem Cell Transplant in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2019-124579 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2896-2896

Author(s):

Seth M Maliske ◽

Matthew J. Maurer ◽

Carrie A. Thompson ◽

Luis Porrata ◽

Ivana Micallef ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Salvage Chemotherapy ◽

Newly Diagnosed ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research

Introduction: Front-line immunochemotherapy (IC) with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is expected to cure 60-70% of newly diagnosed DLBCL. Up to one third of newly diagnosed DLBCL patients will have relapsed or refractory (r/r) disease.1 Current standard of care for these patients is salvage chemotherapy and, if chemosensitive, to be followed by high dose chemotherapy with hematopoietic cell rescue (autoHCT).2,3 Event-free survival at 24 months (EFS24) after frontline IC is associated with excellent long-term outcomes with overall survival (OS) similar to that of age- and sex-matched controls.4 In comparison, those achieving EFS24 following autoHCT for relapsed or refractory disease may have increased risk for late-mortality compared to the general population with advanced age and intensive salvage therapy contributing to the risk of late complications.5 We sought to better characterize EFS24 after autoHCT to determine the utility of this end-point for informed clinical decisions, patient management, and future clinical trials. Methods: Patients were prospectively enrolled onto the Molecular Epidemiology Resource (MER) of the University of Iowa/ Mayo Clinic Specialized Program of Research Excellence (SPORE). Patients were followed for relapse, retreatment, and death; all events were validated by medical record review. For this analysis patients were included if they were consented within 9 months of initial diagnosis of DLBCL between 2002-2012, had received anthracycline-based IC (R-CHOP, or similar), and eventually had undergone autoHCT for r/r DLBCL. Patients with primary central nervous system (CNS) lymphoma or post-transplant lymphoproliferative disorders (PTLD) were excluded. Overall survival (OS) was defined as time from autoHCT until death due to any cause. Event-free survival (EFS) was defined as time from autoHCT until progression, relapse, retreatment, or death due to any cause. OS from achieving EFS24 after autoHCT was compared to age- and sex-matched general US population. Results: 108 patients underwent autoHCT for relapsed DLBCL between 2002 and 2017. Median age at autoHCT of the patients was 60 years (range 20-78) and 72 (67%) were male. The most common transplant conditioning regimen was BEAM (82%). At a median follow-up after autoHCT of 85 months (range 1-171), 72 patients (67%) had an event and 64 patients (59%) had died. Kaplan-Meier estimates for EFS and OS at 24 months from the time of autoHCT were 49% (95% CI: 40-59) and 61% (95% CI: 52-71), respectively. 52 patients had a progression within 24 months of autoHCT; OS from progression was poor (median OS=2.8 months, 95% CI: 1.8-6.0; 5 year OS = 9%, 95% CI: 2-22). 48 patients achieved EFS24 after autoHCT; median OS from achieving EFS24 was 136 months (95% CI: 92-NE) and 5 year OS was 79% (95% CI: 68-93). This was inferior to the background population (Figure 1, SMR=3.64, 95% CI: 2.11-6.27, p<0.0001). Eight patients had a progression after achieving EFS24 from autoHCT. OS from progression in these 8 patients (median OS=27.3 months, 95% CI: 14.4-NE; 5 year OS = 16%, 95% CI: 3-93) was improved compared to progression within 24 months of autoHCT (p=0.072, figure B). Cause of death (COD) in EFS24 achievers was progression of lymphoma (n=6), infection (n=1), secondary malignancy related to therapy (n=3), heart disease (n=1), and unknown (n=1). Conclusions: Patients achieving EFS24 after salvage chemotherapy and autoHCT have a favorable long-term prognosis; however, overall survival remained inferior to the general population. Most common COD after achieving EFS24 was progression of lymphoma. In spite of this, EFS24 remains a valuable end-point for informed clinical decisions, patient management, and future clinical trials. Figure 1 Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Nanostring: Research Funding. Ansell:Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding.

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Clonal Hematopoiesis Is Frequent and Associated with Inferior Survival Irrespective of Transplantation Strategy in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2021-148050 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1127-1127

Author(s):

Adam S. Sperling ◽

Robert Redd ◽

Christopher J. Gibson ◽

Peter G. Miller ◽

Jill Corre ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Autologous Transplantation ◽

Newly Diagnosed ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Clonal Hematopoiesis

Abstract Background: The acquisition of somatic clonal mutations in the blood of healthy individuals is referred to as clonal hematopoiesis (CH) and is associated with increased age, risk of hematologic malignancy, and non-malignant inflammatory outcomes. The presence of CH in patients with non-Hodgkin lymphoma (NHL) has been associated with adverse outcomes and decreased overall survival (OS) especially in the setting of autologous transplantation. In multiple myeloma (MM), the presence of CH at the time of stem cell collection was associated with decreased OS only in those patients who did not receive thalidomide analog maintenance. However, the clinical significance of CH in patients with newly diagnosed MM undergoing autologous transplant has not been assessed. We sought to determine the frequency and clinical outcome of CH in patients with newly diagnosed MM. The IFM 2009 study randomized 700 newly diagnosed patients with MM to lenalidomide, bortezomib and dexamethasone (RVd) versus RVd plus high-dose therapy (HDT). This patient cohort provides a unique opportunity to examine the prevalence of CH in newly diagnosed MM patients and assess its influence on clinical outcomes, including early transplantation, in a homogeneously treated population of MM patients. Methods: We performed targeted error-corrected next generation sequencing of 100 genes recurrently mutated in hematologic malignancies in 377 patients with newly diagnosed MM who were part of the IFM 2009 study (additional patient samples are pending analysis). CH was defined as the presence of any pathogenic mutation with a variant allele fraction (VAF) ≥ 0.005. Sample DNA was collected from peripheral blood of subjects at the time of screening/diagnosis. The median age at sample collection was 59 years. Median follow-up was 7.8 years. Results: We identified CH in 188 (48%) patients with VAF ≥ 0.005, in 119 (32%) patients with VAF ≥ 0.01 and in 59 (16%) patients with VAF ≥ 0.02. Because prior studies have primarily assessed clinical significance of VAF ≥ 0.02, further analysis was restricted to this threshold. Consistent with prior reports DNMT3A (30 patients), TET2 (11 patients) and ASXL1 (3 patients) were the most commonly mutated genes. The presence of CH was associated with increased median age (61 vs 59 years, p = 0.003), ISS stage III (p = 0.007) and increased LDH (p = 0.006), but not with sex, monoclonal protein isotype, b2-microglobulin level, or assignment to RVd or HDT arms. As previously reported, randomization to the early transplant arm was associated with increased relapse free survival but not with improved OS. Across the entire cohort, the presence of CH was associated with inferior OS (p = 0.003), but had no association with relapse-free survival or time to relapse. The decrement in OS was seen equally in both the RVd and HDT arms of the study. The presence of mutant clones smaller than a VAF < 0.02 was not associated with adverse clinical outcomes. Fourteen patients developed a second primary malignancy (SPM), only two of which were hematologic neoplasms. There was no difference in the frequency of SPM development in those patients with or without CH. Conclusions: In patients with newly diagnosed multiple myeloma, the presence of CH at a VAF ≥ 0.02 is frequently observed and is associated with decreased overall survival regardless of transplantation strategy. The presence of CH did not affect the risk of developing an SPM. Taken together, these data suggest that while CH is associated with decreased survival the presence of CH should not alter eligibility of patients for autologous transplantation. Figure 1 Figure 1. Disclosures Sperling: Adaptive: Consultancy. Miller: Foundation Medicine: Consultancy. Moreau: Amgen: Honoraria; Celgene BMS: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria. Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Other: Stock ownership. Ebert: Celgene: Research Funding; Skyhawk Therapeutics: Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Deerfield: Research Funding. Munshi: Amgen: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Pfizer: Consultancy; Adaptive Biotechnology: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Legend: Consultancy; Bristol-Myers Squibb: Consultancy.

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Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽

10.1182/blood-2020-139661 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Philip C. Amrein ◽

Karen K. Ballen ◽

Kristen E. Stevenson ◽

Traci M. Blonquist ◽

Andrew M. Brunner ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Survival Estimate ◽

Grade 3 ◽

Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

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Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment

Blood ◽

10.1182/blood-2020-137489 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-30

Author(s):

Josep-Maria Ribera ◽

Olga García ◽

Pau Montesinos ◽

Pilar Martinez ◽

Jordi Esteve ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Molecular Response ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Allogeneic Hsct ◽

Central Artery

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was <2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

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Early Allogeneic Stem Cell Transplantation and Use of Asparaginase during Induction Chemotherapy Appear to Improve Otherwise Poor Outcomes in Adult T-Cell Acute Lymphoblastic Leukemia/Lymphoma (T-ALL/T-LBL) Patients: A Multi-Institutional Review

Blood ◽

10.1182/blood.v126.23.4869.4869 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4869-4869 ◽

Cited By ~ 1

Author(s):

Uma Borate ◽

Amanda Redden Hathaway ◽

Deniz Peker ◽

Bradford E Jackson ◽

Vamsi K Kota ◽

...

Keyword(s):

Board Of Directors ◽

Treatment Regimen ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Rank Test ◽

P Value ◽

Advisory Committees ◽

Treatment Regimens ◽

Genetics Research ◽

Institutional Review

Abstract Background: AdultT-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) is a rare, aggressive bone marrow malignancy with a historically poor prognosis despite use of various chemotherapies. Methods: After institutional review board approval, we compiled a database of all adult T-ALL/T-LBL cases at three large cancer centers between the years 2005-2015, treated at the physician's discretion. Data collected included patient demographics, tumor characteristics (white cell count at diagnosis, blast phenotype, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. Relapse-free survival (RFS) and overall survival (OS) were examined looking at medians and interquartile ranges of times to events. Kaplan Meier curves provided a graphical representation of the survival probability. Moreover, we provided estimates of the 50th percentile along with corresponding 95% confidence intervals (CIs). We also used Univariate and Multivariable Cox Regression to estimate unadjusted and adjusted Hazard Ratios (HRs) and their 95% CIs. Stratified analysis was also performed using the Mann-Whitney U-test to compare median survival times, and the Log-rank to compare survival curses for RFS and OS. Results: The final analysis included 95 adult patients. Median age at diagnosis was 32 (range 17-75). 71.6% of patients were male. 49.5% of patients were white, 14.7% were black, 6.3% were Hispanic, 7.4% were Asian and in 22.1% of patients the race was unknown. Multiple frontline treatment regimens were used with 60% of patients treated with Hyper-CVAD, an additional 5.3% of patients received Hyper-CVAD with asparaginase, 24.2% of patients were treated on a pediatric-based protocol, 4.2% on a clinical trial, and 6.3% received other regimens. In total, 40 patients (42.1%) received asparaginase at some point during treatment regimen with 27 patients (28.4%) receiving it in the initial treatment regimen. After induction therapy, 65 patients (68.4%) achieved remission. Twenty-eight patients (29.5%) underwent transplant (8 matched-related donors, 10 matched unrelated donors, 5 mismatched unrelated donor, 2 cord transplants, 2 autologous, and 1 haplo-identical transplant). Ten patients (10.5%) underwent transplant in first complete remission (CR1) while two patients (2.1%) proceeded to transplant with minimal residual disease following induction. Despite therapy, 59 patients (62.1%) had known disease relapse or progressive disease. 16 patients (16.8%) underwent transplant after disease relapse. At time of analysis, 57 patients (60.6%) died. In the entire cohort, median RFS was 12.9 months and median OS was 19 months. In patients with a very high white count (>100 x 103/cmm at presentation) there was a trend toward earlier relapse when compared to patients presenting with white counts in the normal range (HR 2.27, p-value 0.085). Patients who received asparaginase in their initial treatment regimen have statistically improved RFS (HR 2.65, p-value = 0.014) and OS (HR 2.3, p-value=0.017). When adjusting for the presence of the covariates of age, sex, and WBC, patients who received initial asparaginase still had significant improvement in RFS (HR 3.18, p-value 0.033). In overall survival, significant benefit was seen in the addition of asparaginase in patients under 40 (HR 3.4, CI 1.22-9.5), however in patients greater than 40, asparaginase use seemed to decrease survival (HR 0.24, CI 0.03-1), although this did not reach statistical significance. All patients who underwent transplant had an improvement in OS, with median survival in the transplant group of 27 months compared to 18.2 months in the non-transplanted patients (log-rank test p-value = 0.048). Patients who received a transplant in CR1 had a trend towards improvement in RFS of 6.3 months (17.8 months versus 11.5 months in non-transplanted patients; log-rank test p-value = 0.03). Conclusion: Overall, adult T-ALL/T-LBL has a poor prognosis. Our multi-institutional retrospective review showed that OS and RFS may be improved by incorporating asparaginase use in front line therapy and by transplanting patients in first CR. Our data is limited in that actual dosing of asparaginase was not examined and that relatively few patients > 40 yrs old received asparaginase (4 pts) or SCT (5 pts). More prospective studies are needed in older adult T-ALL/LBL patients using these approaches to possibly improve their outcomes. Disclosures Borate: Gilead: Speakers Bureau; Genoptix: Consultancy; Seattle Genetics: Research Funding; Novartis: Speakers Bureau; Amgen: Speakers Bureau; Alexion: Speakers Bureau. Hathaway:OnQ Health: Research Funding. Kota:Pfizer: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding. Shah:DeBartolo Institute for Personlaized Medicine: Research Funding; Rosetta Genomics: Research Funding; Acetylon Pharmaceuticals, INC: Membership on an entity's Board of Directors or advisory committees; Plexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Speakers Bureau; Bayer: Honoraria; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Research Funding; SWOG: Consultancy; NCCN: Consultancy. Jillella:Leukemia Lymphoma Society: Research Funding. Heffner:Amgen: Consultancy. Erba:Novartis; Incyte; Celgene: Consultancy, Patents & Royalties; GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Seattle Genetics; Amgen: Consultancy, Research Funding; Millennium/Takeda; Celator; Astellas: Research Funding; Sunesis;Pfizer; Daiichi Sankyo; Ariad: Consultancy.

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Single UM171 Expanded Cord Blood Permits Transplantation of Better HLA Matched Cords with Excellent Gvhd Relapse Free Survival

Blood ◽

10.1182/blood-2018-99-110188 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4658-4658 ◽

Cited By ~ 2

Author(s):

Sandra Cohen ◽

Jean Roy ◽

Silvy Lachance ◽

Anne Marinier ◽

Jean-Sébastien Delisle ◽

...

Keyword(s):

Board Of Directors ◽

Culture System ◽

Research Funding ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Cell Dose ◽

Equity Ownership

Abstract Cord blood (CB) transplants have fallen into disfavor in large part due to low cell dose leading to prolonged hospitalizations and high transplant related mortality (TRM). UM171, a novel and potent agonist of hematopoietic stem cell (HSC) self-renewal could solve this major limitation, allowing for CB's important qualities of lower risk of chronic GVHD and relapse to prevail. In addition, UM171 could permit transplantation of smaller, better HLA matched cords, associated with lower TRM. Hence, we initiated a clinical trial to test the safety and efficacy of UM171 expanded CB (eCB). Our goal was to design a clinically viable eCB transplant with a TRM as low or lower than other HSC sources all the while maintaining CB's low relapse rate. Patients (pts) received a myeloablative conditioning regimen. On day (D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on D+1. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Between 7/16-6/18, 21 adult pts (median age 44 years) were transplanted with an eCB. Median final culture volume and net viable CD34 fold expansion were 670 mL and 35, respectively. Median 1st day of 100 and 500 neutrophils were D+10 and D+18, respectively. Achieving 100 neutrophils was 5 days faster than seen with our pts receiving peripheral blood (PB) or marrow (BM) and appeared cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on cell dose. More importantly, pts appeared to derive clinical benefit beyond neutrophil engraftment (defined as 500 neutrophils). Pts' median last day of fever prior to 500 neutrophils was D+8, much earlier than engraftment and 4 days earlier than seen with our PB-BM pts. We offer 2 hypotheses as explanation: i) 100 neutrophils, which are attained early, provide significant defense against infection, ii) the graft contains a significant proportion of dendritic cell precursors (30-40%) which offer mucosal protection during severe neutropenia. Duration of hospitalization was shorter by 12 days and longer by 2 days compared to our non eCB and PB-BM transplants, respectively. In addition, because cell dose requirements were lower, 12/21 pts received a better HLA matched CB, thus >80% of patients were transplanted with a ≥6/8 HLA matched eCB. As a result of lower minimal cell dose criteria, we can now use ∼half the CBs in the banks instead of only 5% for a 70 kg patient. Platelet engraftment occurred at a median of 42 days. With a median follow up of 14 months, there has been no CMV disease, no PTLD, 2 adenovirus cystitis, 2 (10%) grade 3-4 acute GVHD, no moderate/severe chronic GVHD and 1 TRM (5%) despite a median comorbidity index of 2 (0-5). Full donor chimerism was achieved in all cell subsets. Immune recovery was faster than seen in our unrelated donor transplants who routinely receive ATG prophylaxis with 196, 300 and 413 CD4+/µL at 3, 6 and 12 months, respectively. Interestingly, transcriptome analysis of UM171-eCB cells shows an enhanced lymphoid progenitor-associated gene signature when compared to DMSO exposed cells. Animals transplanted with UM171-eCB cells showed a 20 to 35-fold increase in thymic cellularity at 8 weeks post-transplant. Despite some very high risk pts in our trial, only 3 relapsed. Overall, progression free, and GVHD/relapse free survival (GRFS) are excellent at 95, 77 and 67%, respectively, at 12 months. A 7 day UM171 single eCB protocol is feasible and provides clinical benefits beyond faster engraftment with fewer infectious complications, better HLA matching and very low TRM, all the while saving production and hospitalization costs. Nevertheless, longer follow up will be required to better assess relapse howbeit encouraging preliminary results. Furthermore, patients' quality of life is paramount and best evaluated by GRFS which is excellent thanks to a very low rate of significant chronic GVHD all the while maintaining a low risk of relapse. In conclusion, this 1st trial documents the potency of UM171 and positions UM171-eCB as a promising HSC source which could compete with the current standard of care. Figure. Figure. Disclosures Cohen: ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent; Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Caudrelier:ExCellThera: Employment. Zandstra:ExCellThera: Equity Ownership. Sauvageau:ExCellThera: Employment, Equity Ownership.

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Does Trial Participation Improve Outcomes for Higher-Risk Myelodysplastic Syndromes (MDS) Patients Treated at Specialty Centers?

Blood ◽

10.1182/blood-2018-99-117174 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3096-3096

Author(s):

Sudipto Mukherjee ◽

David P. Steensma ◽

Rami S. Komrokji ◽

Amy E. DeZern ◽

Gail J. Roboz ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Wald Test ◽

Genetic Alterations ◽

Cancer Center ◽

Trial Participation ◽

Advisory Committees ◽

Risk Categories

Abstract Background: For some rare cancers, better outcomes have been reported for patient (pts) treated at high volume or specialty centers compared to pts who did not receive such care. Greater availability of interventional clinical trials may be one of the drivers of better outcomes in specialty centers. However, not all pts referred to specialty centers are eligible or willing to participate in trials, and it is not known how outcomes compare for pts treated at specialty centers on clinical trials versus standard of care. In this study, we compared the outcomes of higher-risk MDS pts treated in and out of clinical trials at MDS specialty centers. Methods: Pts treated at MDS Clinical Research Consortium institutions (Moffitt Cancer Center, Cleveland Clinic, MD Anderson Cancer Center, Cornell University, Dana-Farber Cancer Institute, and Johns Hopkins) from 2006-2016 were included. Pts were diagnosed with MDS according to 2008 WHO criteria and identified as having "higher-risk" disease based on the revised IPSS (IPSS-R) criteria that included Intermediate, High and Very high risk categories. All pts treated outside clinical trials received hypomethylating agents (HMAs), either azacitidine (AZA) or decitabine (DAC). Trial and non-trial pts were matched 1:1 based on age, sex, number of treatment regimens prior to HMA (for non-trial pts) or experimental regimen (for trial pts) and IPSS-R categories. All non-trial pts included in the analysis received at least 4 cycles of AZA or DAC at the same institution. Transplant rates and overall survival (OS) were evaluated for association with trial participation. OS was estimated by the Kaplan-Meier method and compared using Cox proportional hazard regression with two-sided Wald test with adjustment for matching variables. The relative odds of transplant following initial treatment were estimated using logistic regression and compared with two-sided Wald test. Results: Of 774 pts in the MDS CRC database for whom complete data were available, 323 were treated in clinical trials and 451 were treated with AZA or DAC. The trial and non-trial MDS cohorts were well matched with regards to median age (68.5 vs 68.2 yrs; P=0.65), females (28.4% vs 29.9%, P=0.75), numbers of regimens (3 vs 3, P=0.77) and IPSS-R risk categories (P=0.86). Estimated median OS of pts treated in and out of clinical trials was 44.5 and 50.6 months (P=0.67), respectively. Compared to standard of care, trial participation was not associated with any survival advantage [Hazard ratio (HR), 95% CI, 0.94 (0.72-1.24), P=0.67] (Figure 1). Clinical trial participation did not significantly increase the odds of proceeding to transplant [Odds Ratio (OR) (95% CI), 1.5 (0.68, 1.61), P = 0.83)]. As shown in Table 1, in multivariate analyses, among all factors, increasing number of regimens received was significantly associated with better survival, possibly reflecting a bias towards healthier pts who survived longer to receive multiple regimens. Conclusions: In a matched-pair analysis, we found comparable survival outcomes between trial and non-trial higher-risk MDS pts treated at specialty centers. Our matched analysis failed to identify any statistical evidence to suggest that an average patient benefited from trial participation within the MDS CRC sites. Additional research is necessary to interrogate these comparisons for specific patient subpopulations by genetic alterations, co-morbidities and regimen sequence, for which trial participation may have been beneficial. Based on the population-average findings, however, we expect any improvement in survival to be modest. Disclosures Komrokji: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Roboz:Orsenix: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Celgene Corporation: Consultancy; Orsenix: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Argenx: Consultancy; Otsuka: Consultancy; Aphivena Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Cellectis: Research Funding. Nazha:MEI: Consultancy. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

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Progression-Free Survival and Overall Survival Among a Patient Cohort of Relapsed/Refractory Mycosis Fungoides in France, Germany, Italy, Spain and the United Kingdom

Blood ◽

10.1182/blood-2019-126246 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5879-5879

Author(s):

Martine Bagot ◽

Timothy Illidge ◽

Nicola Pimpinelli ◽

Mehul Dalal ◽

Athanasios Zomas ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Mycosis Fungoides ◽

Systemic Therapy ◽

Research Funding ◽

Index Date ◽

Progression Free Survival ◽

High Rate ◽

Advisory Committees ◽

Free Survival

Background and Aim: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL) wherein those with advanced stage have a poor prognosis. The objective of this study was to describe clinical characteristics and survival in MF patients who were refractory or had relapsed after a first systemic therapy. Methods: A retrospective chart review study was conducted at 27 sites in Europe. Patients enrolled had a diagnosis of MF and proved to be relapsed/refractory (R/R) prior to 1-Jan-2016 after a first systemic therapy. Overall survival (OS) and progression-free survival (PFS) were estimated from the date of R/R event (defined as the index date) using Kaplan-Meier estimates. PFS was defined as death, progression, second relapse or refractory, or presence of subsequent treatment after index date. Results: This study included 104 advanced R/R MF patients with a median age of 54.5 years (range: 21-82). The median follow-up was 3.5 years (range: 0-20.7) after index date. In total 80% of patients experienced a second R/R, with a median time to second R/R of 15.8 months (range: 0.6-174.6). The median age at death was 65 years (range: 42-85). In total 39 deaths (37.5%) were observed. Among those patients who had a known cause of death (N=35), 18 died of CTCL progression, 11 of CTCL complication or drug toxicity and 7 of other causes. The estimated median OS was 11.5 years (95% CI: 6.5 - not reached). The median PFS was 1.3 years (95% CI: 1.0-2.1). Conclusions: The high rate of R/R and low PFS suggest that the clinical burden of R/R MF is significant in five European countries, and recently approved targeted therapies have the potential of improving outcomes. Disclosures Bagot: Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illidge:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Div of Cancer Sciences, Faculty of Biology, Medicine and Health, Univ of Manchester, National Institutes of Health and Research Biomedical Research Center, Manchester Academic Health Sciences, Christie Hospital National Health Service Foundation Trust: Employment. Dalal:Takeda: Employment. Zomas:Takeda: Employment. Trinchese:Takeda: Employment. Little:Takeda: Employment. Bent-Ennakhil:Takeda Pharmaceuticals International AG: Employment. Ortiz-Romero:Actelion: Consultancy, Membership on an entity's Board of Directors or advisory committees; 4SC: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; miRagen: Membership on an entity's Board of Directors or advisory committees; PLCG1: Patents & Royalties; Kyowa: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; MEDA: Research Funding.

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African American Race Is Associated with Decreased Relapse-Free Survival in Immune Thrombotic Thrombocytopenic Purpura

Blood ◽

10.1182/blood-2019-131064 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1066-1066

Author(s):

Angela Liu ◽

Marshall Mazepa ◽

Elizabeth Davis ◽

Andrew Johnson ◽

Ana G Antun ◽

...

Keyword(s):

Clinical Trial ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

First Episode ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Count Recovery ◽

White Patients

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ impairment. The incidence of iTTP is higher among African-Americans (AA), however, differences in presentation and outcomes have not been fully investigated. In a multi-center cohort of patients with iTTP from the United States Thrombotic Microangiopathy (USTMA) Consortium, we tested the hypothesis that AA race is an independent predictor of poor outcomes including iTTP related mortality and relapse. Methods: We queried data from the USTMA iTTP registry, which currently includes data from 785 individual patients from 15 institutions across the United States. Data from at least one iTTP episode are available for 734 patients. The cohort is 35.1% (N = 272) White, 58.7% (N = 455) African American, 0.4% (N=3) Asian, 1.8% (N=14) Hispanic, and 4.0 % (N=31) other/unknown race. We restricted our analyses to AA and White participants because of small numbers in the other groups. We compared presenting features and treatments using the chi-squared test and t-test for categorical and continuous variables, respectively. A relapse was defined as a recurrent iTTP episode occurring at least 30 days after last therapeutic plasma exchange. To evaluate relapse-free survival, we included only patients enrolled in the registry at their first TTP episode (144 White and 246 AA) since patients presenting with a relapse as their index episode are already confirmed to have relapsing iTTP. Kaplan Meier analysis was used to compare relapse-free survival in White and AA patients, and a Cox regression model was developed to evaluate the independent effect of race on relapse, adjusting for potential confounders including age, sex, and the use of rituximab. Results: Demographics and presenting features of 390 individuals (144 White and 246 AA) presenting with a first episode of iTTP are shown in Table 1. Presenting symptoms including fever, confusion, seizure, memory deficits, stupor, headache, stroke, chest pain, abdominal pain, fatigue, and dark urine were similar between Whites and AA except for petechiae, which were more frequently documented in Whites (28.8% vs 17.7%, p=0.011). Presenting laboratory studies were also comparable though AA had a higher rate of elevated serum troponin (50.6% vs 32.5%, p=0.003), lower hemoglobin level (8.27 ± 0.13 vs 8.81 ± 0.19, p=0.0176) and platelet count (20.3 ± 1.2 vs 26.2 ± 3.2, p=0.0432). In addition to therapeutic plasma exchange and corticosteroids, rituximab was administered to 23.7% of White patients and 22.7% of AA during their first iTTP episode (P=0.815). Median time to platelet count recovery (days of daily plasma exchange until normal platelet count for two consecutive days) was shorter in AA compared with White patients [5 (IQR 4, 10) vs. 8 (IQR 5, 14), log rank P = 0.004]. AA race remained a significant predictor of the shorter time to platelet count recovery [HR 1.44 (95% CI 1.12, 1.85), P=0.004] after adjusting for rituximab therapy [HR 0.60 (95% CI 0.0.46, 0.80), P<0.001], female sex [HR 0.95 (95% CI 0.73, 1.22), P=0.669], age [HR 0.99 (95% CI 0.99, 1.01), P=0.682], platelet count [HR 1.00 (95% CI 0.99, 1.04), P=0.820] and LDH at presentation [HR 1.00 (95% CI 1.00, 1.00), P=0.525]. Death during the first episode occurred in 8.9% of White patients and 5.5% of AA patients (P=0.206). Relapse-free survival after the first episode of iTTP was lower in AA than White patients (Figure 1). AA race was associated with the reduced relapse free survival [HR 1.79 (95% CI 1.08, 2.98), P=0.024] in a Cox regression model adjusted for age [HR 1.00 (95% CI 0.98, 1.01), P=0.683], sex [HR 0.96 (95% CI 0.60, 1.54), P=0.867], and rituximab therapy [HR 0.93 (95% CI 0.55, 1.59), P=0.806]. Conclusion: African Americans with iTTP have a higher relapse rate and shorter relapse free survival after the first episode of the disease compared with Caucasian patients, which is independent of age, sex and rituximab therapy. Contrary to our hypothesis, acute outcomes of iTTP (time to platelet count recovery and mortality) were not worse in AA patients. The factors contributing to the higher relapse rate in AA with iTTP need to be further investigated. Our findings suggest that AA patients may also benefit from closer follow up. Disclosures Farland: Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Shire: Other: PI on clinical trial Sickle cell ; Imara: Other: PI on Clinical trial- Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Zheng:Alexion: Speakers Bureau; Ablynx/Sanofi: Consultancy, Speakers Bureau; Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy.

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