scholarly journals General Characteristics and Association of Myeloid Neoplasm with Thyroid Cancer

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4634-4634
Author(s):  
Shehab Fareed Mohamed ◽  
Naveen Pemmaraju ◽  
Koji Sasaki ◽  
Gautham Borthakur ◽  
Tareq Abuasba ◽  
...  
Keyword(s):  
Overall Survival ◽  
Thyroid Cancer ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Myeloid Neoplasm ◽  
Significant Difference ◽  
The Relationship

Abstract Introduction Differentiated thyroid cancer (DTC) is the most common endocrine malignancy. Treatment options include surgery, radioiodine & hormonal therapy. Radioiodine therapy (RAI) is often used after surgery with the purpose of ablation of residual thyroid tissue, adjuvant therapy or clinically evident metastatic disease. However, the use of RAI carries a risk of secondary malignancies, such as leukemias. The 10-yr survival rate of patients with DTC > 90%. However, several studies showed those patients may be at risk for secondary cancers. Therapy related myeloid neoplasm (tMN) can develop after RAI exposure. The relationship between thyroid and myeloid neoplasm (MN) may not be fully explained by exposure to RAI. In this retrospective study, we investigated the association between MN & DTC. Methods This study included patients >18years with DTC and either MN ((Acute Myeloid Leukemia (AML), Myelodysplastic syndrome (MDS), Chronic myelomonocytic leukemia (CMML), or Myeloproliferative Neoplasms (MPN) who had been diagnosed and/or treated at UTMD Anderson Cancer Center from 1/2012-12/2020 Descriptive statistics were performed to define the demographic, clinical and biological characteristics of the patients included in the study. Results Fifty-four pts had both DTC and MN. The median age was 52 yrs (18-77). Most of the patients were white 41/54 (75.9%) with equal sex distribution and of the papillary subtype of DTC 48 (88.8%). DTC stages were I (15(42.86%), II -15 (42.86%) III & IV- 5 cases (14.29%). Of the MN patients, AML/MDS cases were 30 (56.36%), while MPNs cases were 24(43.64%). Majority were CML 13/24 (54%) (p =0.01). The most common cytogenetics karyotypes detected were diploid in 17 (30.91%) followed by complex in 8 patients (14.55%). The most frequent positive mutation was FLT3 in 6 cases (10%) followed by TP53 and ASXL1 with 5 (9.26%) patients respectively. While the mutation panel were negative in 16 patients (29.63%). RAI was used in 42(76.36%) patients, with a median dose 142 mCi (75-290). Thirty patients (70%) of those treated with RAI developed therapy related MN, while 12 patients had MN earlier occurred first in 34 patients (61.82%) (proceeded AML/MDS in 23 (74.19%) and 11(45.83%) (P= 0.005) in cases of MPNs. The median time lapse from developing thyroid to myeloid cancer was 4 years. Thyroid cancer proceeded AML or MDS by 2.5 years, while thyroid cancer happened around the same year (0.09) with MPNs (p= 0.04) Table 1 A hypomethylating agent (HMA) based therapy for myeloid neoplasm was the most commonly used in 15 (42.86%), other therapies included cytarabine (5), cladribine (4) & fludarabine (3) based .37 pts (67.27 %) achieved complete remission, while 18 (32.73%) underwent stem cell transplantation. Overall survival showed that 40 (74%) were still alive. Therapy related AML/MDS Overall survival were inferior to non-therapy related patient (p= 0.29) figure 1. Patients who had 3 or 4 types of cancer to the group who had only thyroid and myeloid cancer showed increase risk of death with a hazard ratio of 1.72 (0.62-4.77 however this was not statistically significant also (p= 0.30). Conclusion In our cohort patients who were exposed to Radioiodine (RAI) had developed therapy related myeloid neoplasm (t-MN) AML/MDS even with doses < 100 mCi. Median to develop neoplasm (t-MN) were 4 years, complex cytogenetics is frequent. No statistically significant difference in survival between therapy related and none therapy related group. DTC did occur with MPNs as well with CML most frequent subtype. Prospective studies need to be done to further elucidate the relationship between DTC & MPN. Figure 1 Figure 1. Disclosures Pemmaraju: ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Affymetrix: Consultancy, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; LFB Biotechnologies: Consultancy; MustangBio: Consultancy, Other; Plexxicon: Other, Research Funding; Aptitude Health: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Incyte: Consultancy; Sager Strong Foundation: Other; Daiichi Sankyo, Inc.: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; Samus: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Springer Science + Business Media: Other; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Verstovsek: Promedior: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

scholarly journals Outcomes of Abdominal Thrombosis in Patients with Myeloproliferative Neoplasms in a Single Center Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4307-4307
Author(s):  
Douglas Tremblay ◽  
Alexander Vogel ◽  
Erin Moshier ◽  
Ronald Hoffman ◽  
Marina Kremyanskaya ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hepatic Encephalopathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Single Center ◽  
Advisory Committees ◽  
Vein Thrombosis ◽  
Single Center Experience ◽  
Significant Difference

Abstract Background Abdominal thrombosis (AT) is a concerning complication of myeloproliferative neoplasms (MPNs), leading to significant morbidity and mortality. While the epidemiology of AT in MPNs has previously been described, outcomes based on timing of AT relative to MPN diagnosis are unknown. Additionally, it is unclear how the treatment of the MPN affects outcomes including esophageal variceal bleeding (EVB), development of ascites, and additional thrombosis. Methods We conducted a retrospective review of patients at a single tertiary care institution. Inclusion criteria included: 18 years or older, a diagnosis of an MPN, including polycythemia vera (PV), myelofibrosis (MF), essential thrombocythemia (ET), and AT, including portal vein thrombosis (PVT), Budd Chiari Syndrome (BCS), or other splanchnic vein thrombosis. Primary outcome measures included EVB, additional thrombosis, development of ascites, hepatic encephalopathy, and death due to any cause. Years to outcome events were calculated by Kaplan Meier analysis. Results Baseline disease characteristics are summarized in Table 1. Sixty-four eligible patients were identified, 46 (72%) were female. The median age at time of AT was 45 years (range, 18-89). PV was the most common MPN, followed by ET then MF. Sixty patients (95%) harbored a mutation in JAK2. Characteristics of the AT are summarized in Table 2. Twenty-nine patients (45%) were diagnosed with AT after the MPN, with a median of 44 months (1-288) between diagnoses. Nineteen patients (30%) were diagnosed with AT before MPN, a median of 4 months (1-90). Sixteen patients (25%) were diagnosed concurrently (within 1 month). There was no difference in age at diagnosis of MPN among the three groups, however, patients diagnosed with AT before MPN were significantly younger (37 [18-89]) than those diagnosed with an AT after MPN (52 [31-85]) or concurrently (48 [20-70]) (p=0.0045). There was no significant difference among these three groups with respect to other AT characteristics. The median overall survival (OS) of the cohort was not reached. Five-year OS probability was 98%. No significant difference in overall survival (OS) was observed among those diagnosed with an AT before, concurrent, or after being diagnosed with an MPN. Treatment of the AT was primarily with warfarin (39%), although 19% of patients were treated with a direct oral anticoagulant. Additionally, 20% of patients received a transjugular intrahepatic portosystemic shunt (TIPS). Seven patients (11%) received no treatment for their AT. Of the entire cohort, 16 patients (25%) experienced an EVB. For patients who were on MPN directed therapy at time of AT, the hazard ratio (HR) for years to bleeding event was 1.24 (0.28-5.57) as compared to those who were not treated (p=0.7798). Ten patients (15.6%) experienced a non-abdominal thrombosis, predominantly deep vein thrombosis or pulmonary embolism. Thirty patients went on to develop ascites. HR for years to ascites from thrombosis was 1.94 (0.17-21.64) in the MPN treated patients (p=0.5823). Six patients (9%) developed hepatic encephalopathy. There was no difference between the MPN treated patients and non-MPN treated patients in a composite outcome of EV bleed, additional AT, ascites, or hepatic encephalopathy. Conclusions In this single center experience, a significant portion of patients were diagnosed with an AT before their MPN diagnosis. Treatment of the MPN at time of AT diagnosis did not appear to affect outcomes including EVB, additional thrombosis, development of ascites, or hepatic encephalopathy. These results suggest that once developed, treatment of the underlying MPN may not decrease complication rates of an AT. Further analyses are underway to clarify whether this finding is true in each AT subtype. Disclosures Hoffman: Merus: Research Funding; Summer Road: Research Funding; Formation Biologics: Research Funding; Janssen: Research Funding; Incyte: Research Funding. Kremyanskaya:Incyte: Research Funding. Mascarenhas:Merck: Research Funding; Promedior: Research Funding; Novartis: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding.

Major Improvement of Invasive Aspergillosis Outcome Is Not Enough to Improve Overall Survival In Allogeneic Hematopoietic Stem Cell Transplant Recipients: Results From a Single-Center Retrospective Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1244-1244
Author(s):  
Géraldine Salmeron ◽  
Raphaël Porcher ◽  
Anne Bergeron ◽  
Marie Robin ◽  
Regis Peffault de Latour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
First Line Treatment

Abstract Abstract 1244 Background. Voriconazole (V) treatment has been shown to improve the 12 week (W) survival rate of hematological patients (pts) with invasive aspergillosis (IA), including recipients of allogeneic hematopoietic stem cell transplants (HSCT). We investigated whether this early survival advantage could translate into a significant increase in overall survival. Methods. We retrospectively reviewed all consecutive pts who received a transplant between Sept. 1997 and Dec. 2008 at Saint-Louis Hospital and were diagnosed as having IA. The temporal origin of the study was the date of IA diagnosis for each patient. Factors associated with survival were analyzed using Cox proportional hazard models. Separate models were estimated for survival up to 12 W and for survival between 12 W and 24 months (M) in pts surviving longer than 12 W. The deaths of pts with and without IA were analyzed with a competing risk framework. Cumulative incidence curves were compared using Gray's tests. Results. Our study examined 89 IA pts. The median follow-up was 70 M (range, 11–130 M). Two pts did not receive any antifungal treatment and were excluded from subsequent analyses. Of the 87 pts, 42 received first-line V and 45 primarily received a lipid formulation of amphotericin B (n=25), amphotericin B deoxycholate (n=10), caspofungin (n=8) or itraconazole (n=2). The primary characteristics of pts with IA and their causes of death, separated by V as first-line treatment, are shown in the table below. The median survival was 2.6 M, and the overall survival at 24 M was 19% (95% CI 12–30 M) (see figure). Overall, the survival rates of the two groups were significantly different (P= 0.010). However, the differences in survival were quite dramatic prior to 10 M, whereas both survival curves became very close after one year. At 18 M, the numbers of surviving pts were almost identical in the two groups [19% (95% CI: 11–34%) in pts who did not receive V as first-line treatment vs. 21% (95% CI 11–38%) in pts who did]. Pts who did not receive V as a first-line treatment displayed a higher probability of dying from IA than those who did (P=0.004), whereas opposite results were found for mortality in pts without IA (P=0.006). The 24-M cumulative incidence of death from IA was 47% (95% CI 31–61%) in the no V group and 19% (95% CI 9–33%) in the group treated with V. The 24-M cumulative incidence of death in pts without IA was 4% (95% CI 7–14%) in the no V group and 27% (95% CI 14–42%) in pts treated with V. The probability of death from another cause, with IA, was similar in both groups (29% vs. 36% at 24 M; P=0.46). After adjusting for donor type, conditioning regimen, progressive GVHD at diagnosis of IA and cumulated steroid dose (mg/kg) in the W preceding IA diagnosis, administration of V as first-line treatment was found to decrease the risk of death during the first 12 W by approximately 70% [HR=0.31 (95% CI 0.16–0.60); P=0.0005]. Conversely, analysis of mortality between 12 W and 24 M failed to identify any significant predictor of risk of death; however, only 24 pts died during this period. Conclusions. The finding that first-line treatment with V, which is associated with a tremendous improvement in IA outcome, does not translate into an increase in overall survival (even in the context of early diagnosis) is striking. Diagnosis of IA following HSCT, whatever the outcome, appears to be a strong marker for poor long-term prognosis. Disclosures: Bergeron: Pfizer: Speakers Bureau, none; Merck: Speakers Bureau, none; Schering: Speakers Bureau, none. Sulahian:Pfizer: Research Funding, non; Merck: Research Funding, none. Ribaud:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, none; Schering: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, none; Gilead: Speakers Bureau, none.

scholarly journals Impact of Bortezomib- or Lenalidomide-Based Induction Treatment on High Risk Cytogenetic Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Enrolled in the Gimema-MM-03-05 and EMN01 Trials

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 744-744 ◽  
Author(s):  
Alessandra Larocca ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Francesca Patriarca ◽  
Lorenzo De Paoli ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Significant Difference ◽  
Reduced Risk

Abstract Introduction : Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment. Methods : In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)). Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR). Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value. Results : 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p<0.001), ISS3 20% vs 27% (P=0.65), HiR patients were 29% vs 26%, StR patients were 71% vs 74% (p=0.32) and the median follow-up was 72.3 and 63.6 months, respectively. In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B). BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A). Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02. BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A). In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045. Conclusions : BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetics. Disclosures Larocca: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Janssen: Honoraria; Celgene: Honoraria. Patriarca: MSD Italia: Honoraria; Janssen: Honoraria. Corradini: Gilead: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Bosi: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Boccadoro: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria.

scholarly journals Different Treatment Approaches to Blast Phase-Myeloproliferative Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3641-3641
Author(s):  
Franco Castillo Tokumori ◽  
Najla Al Ali ◽  
Onyee Chan ◽  
David A. Sallman ◽  
Seongseok Yun ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Initial Treatment ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Myeloproliferative Neoplasms ◽  
Intensive Chemotherapy ◽  
Blast Phase ◽  
Advisory Committees

Abstract CONTEXT: Transformation to acute myeloid leukemia (AML) occurs in 5-20% of patients with myeloproliferative neoplasms (MPN). Overall survival in blast phase MPN (MPN-BP) is poor, usually in the range of 3 to 6 months, and is not significantly impacted by intensive chemotherapy. Current guidelines favor treatment with a hypomethylating agent (HMA), but survival remains poor, and allogeneic hematopoietic stem cell transplantation (AHSCT) holds the only potential for long term survival. OBJECTIVE: To describe the clinical characteristics and overall survival of MPN-BP according to different treatment approaches. DESIGN: Single-institution, retrospective analysis of 70 MPN patients that progressed to blast phase, who presented to our institution between 2001 and 2020. Transformation to AML defined as >20% myeloblasts in peripheral blood or bone marrow. We stratified the patients according to initial treatment strategy for AML. Baseline variables were compared between groups. Median overall survival (mOS) was measured from time of AML diagnosis to date of death. Kaplan-Meier plots were created to compare mOS. RESULTS: Among 70 MF patients that progressed to AML, initial treatment was: 19 best supportive care (BSC), 25 HMA (20 HMA only and 5 HMA + venetoclax), and 26 intensive chemotherapy (IC) [12 patients received standard "7+3" regimen with daunorubicin/idarubicin and cytarabine, 12 received high-dose cytarabine, cladribine +/- mitoxantrone (CLAG/CLAG-M), and 2 received CPX-351 (Vyxeos)]. Patients receiving IC were younger at time of leukemic transformation than those receiving BSC (median 63.9 years vs 72.9 years; p=0.029) or HMA (median 63.9 years vs. 69.0 years; p=0.026). Additionally, 70% of IC patients had an ECOG performance status of 0 or 1 compared to just 48% of patients receiving either BSC or HMA (p=0.088). Median OS for the entire cohort (n = 70) was 4.8 months. Compared to patients who received active treatment with HMA or IC, those treated with BSC had shorter survival (0.9 months vs 6.4 months; p=0.001). Median survival between patients treated with HMA and IC was not significantly different (4.5 months vs 9.6 months; p=0.13). Patients treated with IC were more likely to proceed to AHSCT (46% vs 5%; p < 0.001). Between HMA and IC groups, there was no difference in time from MPN-BP diagnosis to treatment (median 0.4 months vs 0.3 months; p=0.644) or total number of lines of treatment for MPN-BP. Focusing specifically on the role of AHSCT in patients treated with IC, we found that patients who received AHSCT had significantly longer mOS than those patients who did not (18.9 months vs 4.9 months; p=0.002), suggesting the beneficial role of intensive chemotherapy is critically tied to the ability to subsequently undergo AHSCT. Among patients who underwent AHSCT, 1-year and 2-year OS was 51% and 34%, respectively. In contrast, patients not receiving AHSCT had 1-year and 2-year OS of 14% and 2%, respectively. Independent of age, AHSCT (p=0.008) and receipt of therapy (p=0.017) significantly correlated with longer survival after AML diagnosis. Besides these factors, there were no significant differences in the clinical characteristics between the three groups. Acknowledging the limitations associated with small numbers, we did not note any difference in survival between patients who received HMA vs HMA + venetoclax (p=0.27). CONCLUSIONS: In MPN-BP, patients receiving treatment had superior outcomes to those that received BSC. Initial treatment with intensive chemotherapy was associated with non-significant improvement in survival; however, this appears to be critically linked to the receipt of AHSCT. In appropriate patients, intensive chemotherapy may be reasonable in an effort to provide an effective bridge to AHSCT. Still, this study reinforces the poor prognosis associated with MPN-BP and the desperate need for novel therapeutic approaches in this group of patients. Figure 1 Figure 1. Disclosures Sallman: AbbVie: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Sweet: Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Padron: BMS: Research Funding; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; Taiho: Honoraria; Stemline: Honoraria. Lancet: Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy; Astellas: Consultancy; Agios: Consultancy; ElevateBio Management: Consultancy; Jazz: Consultancy. Komrokji: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuykendall: Novartis: Honoraria, Speakers Bureau; Prelude: Research Funding; Incyte: Consultancy; PharmaEssentia: Honoraria; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Myelofibrosis in Real Life: Findings from the French Intergroup of Myeloproliferative Neoplasms (FIM) Registry

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3128-3128
Author(s):  
Brigitte Dupriez ◽  
Sylvie Chevret ◽  
Jean-Christophe Ianotto ◽  
Francoise Boyer ◽  
Pascale Cony-Makhoul ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Spleen Size ◽  
Biological Parameters ◽  
Advisory Committees ◽  
History Of

Abstract Background: Myelofibrosis (MF) is the less frequent Philadelphia-negative myeloproliferative neoplasms (MPN). We have included in a nationwide database primary (P), post-polycythemia (PPV) and post-essential thrombocythemia (PET) MF diagnosed in France since 2005. Methods: Inclusion criteria were: diagnostic of MF after 2005; according strictly to WHO (bone marrow biopsy mandatory); informed consent. The registry was launched in Oct. 2013, and 26 hematology centers included patients (pts). Summary statistics were reported, namely median [Interquartile range, IQR] or percentage. Baseline characteristics were compared across IPSS groups using chi-square test or Mann and Whitney test. Kaplan-Meier survival curves were plotted and compared by the log-rank test. Results: At time of analysis (June 2016) a total of 527 pts were included in the registry, complete baseline data were available in 499 (95%), and follow-up (FU) data in 433 (87%). Median [IQR] age and M/F sex ratio were 71 [63-78] years and 315/184 (1.7), respectively (resp). 301 (60%) pts had PMF, 182 (36%) had secondary MF (including 64 PPVMF and 118 PETMF) and 16 had pre-fibrotic MF. Five percent of pts had a familial history of hematologic malignancy, and 22% a history of thrombosis or hemorrhage. Splenomegaly was present in 386 (77%) with a median [IQR] spleen size of 4 cm [1-8] below costal margin, and was symptomatic in 11% of pts. Constitutional symptoms were present in 107 (21%) (weight loss in 56, night sweats in 61, fever in 14), and ECOG score was 0, 1, 2, and 3 in 53%, 36%, 11% and 0.3% of pts, resp. Median [IQR] Hemoglobin, WBC and platelet counts were 109 g/L [94-122], 9.3 G/L [5.7-16.0] and 257 G/L [138-430], resp. Circulating blast cells were present in 41%, LDH was above normal value in 95% of pts, median EPO level was 54 [11 - 57] U/L. Grade of fibrosis (WHO) was 1, 2, and 3 in 2%, 66% and 32% of pts, resp. Karyotype was done in 321 pts, normal in 173 (54%), abnormal with favorable prognostic value in 89 (30%) and unfavorable in 30 (10%) (29 failures). A total of 461 (92%) pts had molecular testing: 60% were JAK2V617F positive, 4% had MPL and 7% had CALR mutations, and 99 (28%) over the 352 pts with triple testing were triple negative. IPSS risk categories were low, int-1, int-2 and high in 68 (14%), 168 (34%), 158 (32%), and 105 (21%) pts, resp. In addition to constitutional symptoms, there was a significant increase in the prevalence of clinical signs across IPSS categories (from low to high risk): symptomatic spleen (p=0.016) -though no difference in spleen size was found (p=0.18)-, early satiety (p=0.013), ECOG score (p= 0.0001), bone pain (p=0.002). Moreover, among biological parameters, there was an increase across IPSS groups in WBC (p=0.029), LDH (p=0.0007), ferritin (p=0.003), circulating CD34+ cells (p=0.020), EPO level (p=0.035). In contrast, a decrease was seen for hemoglobin and platelets (p=0.0001 for both). Lastly, frequency of grade 3 fibrosis increased with IPSS (p=0.043), while no evidence of difference was found regarding abnormal karyotype and mutational pattern. Median FU was 33 months [9-63 months]. Among those 433 pts with FU data, median FU was 38 months [19-68], and 124 (29 %) pts had died at the time of analysis, including 13%, 17%, 31%, and 40% of pts from the Low, Int-1, Int-2, and High risk groups, resp (p= 0.0001, figure 1). In the 450 pts with treatment data, treatments received during FU included cytoreductive drug (41%), Jak-inhibitors (35%), Interferon alpha (18%), IMIDs (4%). Splenectomy was performed in only 14 (3%) pts. Forty percent of pts received packed red blood cells, and 12% platelets transfusions. 49 (11%) patients participated in a clinical trial, and 27 (6%) were allografted. Conclusion: This is the first analysis of the French MF observatory after inclusion of more than 500 pts diagnosed and treated during the past 10 years. Complete baseline data and follow-up information available for the majority of pts should allow for new studies of outcomes and influence of clinical and biological parameters, as well as reassessment of prognostic models in the era of new targeted therapies. Figure 1 Comparison of overall survival according to IPPS Figure 1. Comparison of overall survival according to IPPS Figure 2 Figure 2. Disclosures Etienne: Pfizer: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Tavitian:Novartis: Membership on an entity's Board of Directors or advisory committees. Ugo:Novartis: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Only Hotspot SF3B1 K700E Mutation Is an Independent Predictor of Overall Survival in Myelodysplastic Syndromes

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Rashmi Kanagal-Shamanna ◽  
Guillermo Montalban Bravo ◽  
Koji Sasaki ◽  
Carlos E. Bueso-Ramos ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
P Value ◽  
Aberrant Splice ◽  
Low Grade ◽  
Advisory Committees ◽  
Pathologic Features ◽  
Significant Difference ◽  
Advisory Role

SF3B1 mutated (SF3B1mut) MDS is associated with increased ring sideroblasts (RS) and favorable outcome. IWG-PM proposed that SF3B1mut MDS be considered a distinct entity in the absence of other unfavorable features. However, not all SF3B1mut MDS have similar clinical course. Hotspot K700E SF3B1mut leads to aberrant splice junctions and large-scale mRNA downregulation by activating a cryptic splice site. The functional effects of SF3B1mut outside of K700E is not clear. The outcome can also be altered by concomitant gene mutations and karyotype. In this study, we studied the clinical-pathologic features and outcome in a single-institutional series of 94 SF3B1mut and 415 SF3B1wt MDS, and explored the differences between K700E and non-K700E subgroups. All untreated MDS patients diagnosed over a 3-year duration who underwent NGS were selected. Overall survival was calculated from diagnosis to death/ last follow-up. Univariate (UVA) Cox proportional hazards regression was used to identify any association of variables with outcome followed by multivariate modeling (MVA) (p-value 0.200 cutoff). Of 509 patients, 94 (19%) had SF3B1mut: 59 men, 35 women; median age: 74 (39-92) years. Baseline characteristics: Table 1. Compared to SF3B1wt, SF3B1mut had a significantly higher median age (74 vs. 70, p=0.0008), MCV (105 vs. 96, p<0.0001), platelet count (188 vs. 78, p<0.0001) and lower BM blasts (2 vs. 4, p=0.003). SF3B1mut were less frequently therapy-related (18% vs. 34%, p=0.002), significantly enriched in R-IPSS VL/L and WHO MDS-RS and MDS with iso del(5q). Majority (~66%) had concomitant mutations: TET2 (25%), DNMT3A (21%), RUNX1 (15%), TP53 (10%), ASXL1 (7%), BCOR (4%), IDH1/2 (4%), SRSF2 (3%), RAS (3%) and EZH2 (3%) (Fig 1B). ~10% showed complex karyotype (CK). Among SF3B1mut, hotspot K700E mutation was seen in 55 (~60%). Non K700E mutations (n=39, 40%) frequently involved codons: H662, K666 and R625, seen in 8 patients each (Fig 1A). SF3B1 K700E showed a higher median RS% (50% vs. 34%; p=0.038), ANC (2.4 vs. 1.8, p=0.005) and a trend for higher platelet (196 vs. 124, p=0.05). SF3B1mut were less likely MDS-EB than non-K700E (22% vs. 49%, p=0.008). All 4 SF3B1mut patients that fit WHO criteria for MDS with isolated del(5q) had K700E (Table). The frequency of RUNX1 mutation was significantly higher in non-K700E cases (26% vs. 7.3%, p=0.012); mutations in BCOR (p=0.02), IDH2 (p=0.07) and SRSF2 (p=0.07) were exclusively noted in non-K700E cases (Fig 1C). There was no significant difference in TP53mut or CHIP-associated mutations DNMT3A, ASXL1 and TET2 or SF3B1 VAF. There was no significant differences in diploid vs. CK. However, K700E had lower CCCS categories (0/1, n=39; 2/3/4, n=10 vs. 0/1, n=19; 2/3/4, n=17); p=0.011). Majority were treated with HMA [16/17 (94%) K700E; 15/19 (79%) non-K700, 217/ 277 (78%) SF3B1wt]. SF3B1mut had better OS than SF3B1wt in all MDS (NR vs. 25.2 months, p=0.0003; fig 1D), low-grade MDS (NR vs. 41.3 months, p=0.0015; fig 1E) and MDS-RS (NR vs. 22.3 months, p=0.0004; fig 1F). Four (7.3%) K700E died compared to 9 (23%; p=0.036) non-K700E. The outcome of non-K700E was similar to SF3B1wt, in all MDS, low-grade MDS and MDS-RS (median OS, NR for both; p=0.021). By UVA, the following associated with worse outcome: higher BM blasts, lower hemoglobin, platelet and MCV, prior chemo-radiation, CK, higher R-IPSS, absence of mutations in SF3B1 K700E, TET2 and U2AF1 and presence of TP53mut. Non-K700E did not associate with OS. By MVA, lower hemoglobin, higher R-IPSS, absence of SF3B1 K700E and presence of TP53mut were independent predictors of worse OS. Within MDS-RS categories, independent prognostic factors of worse OS included lower platelet, presence of mutations in non-K700E SF3B1mut, ASXL1, SRSF2 and TP53. TP53mut/CK was seen in 10% SF3B1mut MDS. No survival differences were noted between SF3B1mut with or without TP53mut/CK (median OS, NR) and SF3B1wt without TP53mut/CK (44.3 months), but TP53mut/CK with SF3B1wt MDS had a worse outcome (median OS, 12.9 months, HR 1.46, p=0.001; fig 1G). Same findings were noted within low-grade MDS and MDS-RS, suggesting SF3B1mut negates the poor prognostic effect of TP53mut/CK. About 40% SF3B1mut MDS show non K700E mutations. K700E and non K700E SF3B1mut MDS show distinct clinical and mutational profiles, with K700E showing a significantly better OS compared to non K700E and SF3B1wt. Only SF3B1 K700E independently predicted for worse OS in MDS. Figure Disclosures Sasaki: Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Honoraria. Jabbour:Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding. Garcia-Manero:Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy.

scholarly journals Increased Interleukin-8 (IL8)-CXCR2 Signaling Promotes Progression of Bone Marrow Fibrosis in Myeloproliferative Neoplasms

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Andrew Dunbar ◽  
Min Lu ◽  
Mirko Farina ◽  
Young Park ◽  
Julie Yang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Private Company ◽  
Advisory Committees ◽  
Cd34 Cells

Introduction: Elevated pro-inflammatory cytokines are a hallmark feature of myeloproliferative neoplasms (MPNs). The pro-inflammatory cytokine interleukin-8 (IL8) is increased in patients with myelofibrosis (MF) and correlates with adverse outcome, including overall survival. Previously, the Levine/Fang labs identified increased IL8 secretion from individual CD34+ stem cells in a subset of MF patients. The role of IL8 and its cognate receptors CXCR1/2 in MF pathogenesis has not been delineated. Methods: Single-cell cytokine assays were performed on isolated CD34+ cells from 60 clinically annotated MPN patients (20 MF, 20 PV, 20 ET) using a previously described micro-chip platform (Kleppe et al, Can Disc 2013). 10 healthy donors (CD34+ cells from hip replacements) were used as controls. Integrated RNA-Seq and Assay for Transposase-Accessible Chromatin followed by next-generation sequencing (ATAC-Seq) was performed on CD34+ cells from MPN patients with and without expanded IL8 secreting clones for gene expression/chromatin accessibility analysis. To model the role of IL8-CXCR2 on fibrosis in vivo, the human MPLW515L transplant model (hMPLW515L) of MF was used. Specifically, wild-type (WT) murine bone marrow (Creneg-Cxcr2f/f; Cxcr2WT) or marrow lacking the CXCR2 receptor (VavCre-Cxcr2f/f; Cxcr2KO)were retrovirally infected with MSCV-hMPLW515L-IRES-GFP and transplanted into lethally irradiated WT recipient mice and monitored for disease. Blood counts, chimerism, and flow cytometry were assayed. Moribund mice were sacrificed and assayed for grade reticulin fibrosis and overall survival. Results: Single-cell cytokine assays confirmed an increased proportion of IL8-secreting CD34+ cells in MF patients (40%) in comparison to other MPN sub-types (10% PV/0% ET) (Figure 1A). MF patients with expanded IL8 secreting clones (defined as >50% of total CD34+ cells) had increased leukocytosis (p<0.0001), larger spleen sizes (p=0.0004), greater prevalence of constitutional symptoms (p=0.0084), and higher-grade reticulin fibrosis in marrow (Figure 1B) in comparison to MF patients without prevalent IL8 clones. IHC confirmed increased IL8 expression in marrow biopsies from 8/15 MF patients in comparison to 0/4 normal controls (Figure 1C), and high IL8 expression was also observed in MF splenic megakaryocytes (MKs) as well as in splenic stromal/endothelial cells not seen in normal spleen (Figure 1D). Integrated RNA-Seq/ATAC-Seq analysis of IL8-high MF patients confirmed up-regulation of IL8-CXCR2 signaling and enrichment in pro-inflammatory pathways (i.e TNFa, NFkB, etc) by GSEA, as well as increased expression/accessibility of pro-inflammatory genes S100A8 and S100A9-previously implicated in fibrosis development. Flow analysis of IL8-high MF CD34+ cells revealed enhanced surface expression of CXCR2 and its analog CXCR1, such that MF was characterized by increased IL8 ligand and receptor expression (Figure 1E) and coincided with enhanced NFkB pathway activity (Figure 1F). Consistent with this, colony forming assays of cultured MF CD34+ cells revealed enhanced colony output when cultured with IL8 compared to WT CD34+ cells-an effect ameliorated by co-treatment with the CXCR1/2 antagonist Reparixin (Figure 1G). In vivo, hMPLW515L adoptive transplant with Cxcr2KO hematopoietic donor cells demonstrated improved leukocytosis, thrombocytosis (Figure 2A) and splenomegaly in comparison to Cxcr2WT hMPLW515L recipient mice. Pathologic analysis revealed a reduction in reticulin fibrosis in bone marrow (Figure 2B) and spleen, translating into an improvement in overall survival (Figure 2C). Notably, a significant reduction in dysplastic MKs-a hallmark feature of MF-was also observed in Cxcr2KO hMPLW515L mice (Figure 2D) supporting a role for CXCR2 signaling in MK proliferation. Conclusion: IL8 secreting clones are associated with increased symptom severity and fibrosis grade in MF. Gene expression of MF CD34+ IL8 secreting clones shows up-regulation of inflammatory genes S100A8/A9, implicated in myofibroblast proliferation. Cxcr2 KO abrogates fibrosis formation and prolongs survival in the hMPLW515L model, and CXCR1/2 inhibition impairs colony forming capacity of MF CD34+ cells. These data suggest pharmacologic inhibition of this pathway should be investigated as potential therapy in MF and in PV/ET patients at high risk of fibrotic transformation. Disclosures Fan: IsoPlexis: Current Employment, Current equity holder in private company; Singleron Biotechnologies: Current Employment, Current equity holder in private company. Levine:Morphosys: Consultancy; Prelude Therapeutics: Research Funding; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Amgen: Honoraria; Astellas: Consultancy; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Lilly: Consultancy, Honoraria; Janssen: Consultancy. Hoffman:Protagonist: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy.

scholarly journals Interim or End of Treatment FGD-PET Complete Response Does Not Have Adequate Predictive Value in Mature T/NK Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1813-1813
Author(s):  
Tatyana Feldman ◽  
Larysa Sanchez ◽  
Patrick Toth ◽  
David Panush ◽  
Lori A Leslie ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Predictive Value ◽  
Research Funding ◽  
Nk Cell ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Significant Difference

Abstract Introduction: Cure rate of Mature T/NK cell lymphoma (TCL) is rather low and multiple trials are being conducted to improve frontline therapy outcomes. Consolidation with autologous stem cell transplant is becoming widely used as a mean of improving survival (SCT). Based on data from several retrospective trials, pts who achieve CR may not benefit from consolidative SCT. There is no data available on the role of PET-CR as defined by using Deauville criteria (which became standard in response assessment of NHL (The Lugano Classification 2014)). We performed retrospective analysis of 59 pts with TCL examining the correlation between PFS/OS and iPET and eotPET. Methods: 59 pts newly diagnosed pts with TCL treated between 2008-2016 for whom interim and eotPET scan were available. It was our routine practice to obtain baseline, interim (after 3 cycles of chemotherapy) and eotPET. Pathology slides of outside cases were centrally evaluated by a hematopathologist to confirm diagnosis. Baseline, interim and eotPET were centrally reviewed by a nuclear medicine radiologist blinded to clinical outcomes who assigned Deauville score (DS) to every PET. Responses were recorded according to the Lugano classification 2014. Descriptive statistics and Kaplan Meier method was used to calculate the Progression-free survival (PFS) and Overall survival (OS), two-sided Log-rank test was used to compare OS and PFS between PET groups. Results: Detailed demographic is presented in Table1. Median age at diagnosis is 59, sixty two percent males, 37% female; ALCL 34%, PTCLnos 22%, AITL 19%, and ATLL 10%; most of pts were advanced stage. Most common chemotherapy regimens used were CHOP/CHOEP, HCVAD, and CODOX, SMILE. Median follow up time for the entire cohort was 22.7mo. Forty nine percent of pts progressed and 29% of pts died during follow up. Cause of death for majority of pts was disease progression. Following Deauville scores were assigned on iPET and eotPET respectively: DS1 in 37% and 39%, DS2 in 30% and 35%, DS3 in 15% and 6%, DS4 in 9% and 4%, DS5 in 9% and 16%. We analyzed mPFS and mOS for PET-CR using DS1-2 or DS1-3 to define it. Sixty seven percent and 82% were considered in PET-CR on iPET based on DS 1-2 and DS 1-3 respectively. PET-CR went up to 77% and 83% respectively on eotPET. For final analysis, DS1-2 was used to define PET-CR as no statistically significant difference in mPFS and mOS was noted between DS1-2 and DS1-3. With median follow up of 22.7mo, two-year mPFS and mOS for the cohort were 50% and 74% respectively. Two- year mPFS for iPET-CR and eotPET-CR were 62%. Two-year mOS for iPET-CR and eotPET-CR were 86%% and 83%. Two-year mPFS for iPET-PR and eotPET-PR were 37% and 67%. Two-year mOS for iPET-PR and eotPET-PR were 70% and 100 % (not statistically significant difference with PET-CR mPFS and mOS). None of the pts with PD on iPET were alive at two year. Two-year mOS for eotPET-SD and eotPET-PD are 40%. Negative predictive value of iPET and eotPET is 61%, positive predictive value is 65% and 72% respectively. Conclusion: While PET-SD and PD is quite predictive of poor survivorship, significant number of PET-CR pts will relapse. Even though PET-CR rate to frontline therapy is high, it does not translate into durable responses for significant number of pts with TCL. Thus, PET-CR is not a sensitive enough measure to be considered as a predictor of long-term remission in TCL. It is important to develop response assessment tools which will correlate better with long term survivorship of TCL patients. Figure 1 Overall survival stratified on PET response Figure 1. Overall survival stratified on PET response Figure 2 Progression free survival stratified on PET response Figure 2. Progression free survival stratified on PET response Disclosures Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Pharmacyclics: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Mato:Theradex: Research Funding; TG Therapeutics: Research Funding; ProNAi: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma: Research Funding; Abbvie: Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Chow:Seattle Genetics: Speakers Bureau. Protomastro:COTA: Employment. Leslie:Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Sex Differences in Multiple Myeloma Biology and Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4374-4374 ◽  
Author(s):  
Sarah Anne Bird ◽  
David Cairns ◽  
Faith E. Davies ◽  
Kevin Boyd ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Sex Differences ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Significant Difference ◽  
Males And Females

Introduction: Multiple myeloma (MM) is more common in men than women but the mechanism(s) driving this are not understood. In our previous study (Myeloma IX) we found sex disparities in the cytogenetic lesions present in myeloma cells at the time of diagnosis and that female sex was associated with reduced overall survival in the context of treatment with traditional chemotherapy (CVAMP/MP) and thalidomide combinations. Here, we evaluate sex differences in almost 4000 patients recruited to the UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. Methods: Myeloma XI recruited newly diagnosed patients of all ages, with pathways for transplant eligible (TE) and ineligible (TNE) patients. An induction randomisation compared the triplet combination of cyclophosphamide, lenalidomide and dexamethasone to a similar combination with thalidomide (CRD vs CTD). Eligible patients underwent autologous stem cell transplant (ASCT) and in both pathways a maintenance randomisation compared lenalidomide (+/-vorinostat) until disease progression versus observation. We compared baseline characteristics of males and females using Fisher's Exact test for categorical characteristics and the Wilcoxon-Mann-Whitney test for continuous characteristics with p<0.05 the level considered statistically significant. We compared outcomes, progression-free (PFS) and overall survival (OS), using the log-rank test. Adverse cytogenetic lesions, analysed in a subset of 1610 patients, were defined as t(4;14), t(14;16), t(14;20), del(17p) and gain(1q). Standard risk (SR) was defined as the absence of any of these lesions, High-risk (HiR) as one lesion present and Ultra High-risk (UHiR) as >1 lesion present. Results: Of 3894 patients enrolled in the trial 2268 (58%) were male and 1626 (42%) were female, in keeping with the known sex disparity in MM. There was no difference in the median age, WHO performance status, ethnicity and most laboratory values of the two groups. Females were more likely to have the molecular risk lesions t(14;16) and del(17p) and had proportionately more HiR and UHiR disease, Table 1. Despite these differences, PFS and OS from induction randomisation did not significantly differ (PFS: Males 25 months, [95% CI 24, 26], Females 24 months, [95% CI 22, 25] and OS: Males 67 months, [95% CI 62, 70], Females 70 months, [95% CI 64, 74]). Molecular lesions that have been associated with outcome remained prognostic in both sexes, with a stepwise reduction in PFS and OS with cumulative risk lesions. PFS: Males SR 29 months, HiR 23 months, UHiR 16 months (p < 0.0001), Females SR 27 months, HiR 18 months, UHiR 17 months (p = 0.0007); OS: Males SR 77 months, HiR 59 months, UHiR 34 months (p < 0.0001), Females SR 82 months, HiR 54 months, UHiR 41 months (p < 0.0001). There was, however, no significant difference in PFS or OS when we compared males and females with a given cytogenetic lesion or cytogenetic risk. There was a significant difference in the proportion of patients of either sex who continued through the trial and underwent ASCT in the TE pathway (Males 72%, Females 67%; p = 0.031), but no significant difference in those that entered the maintenance randomisation (TE: Males 56%, Females 50%, p = 0.107; TNE Males 45%, Females 42%, p = 0.249). There was no significant PFS or OS difference by sex when analysed within each treatment pathway (TE, TNE), induction regimen (CTD, CRD) and maintenance approach (lenalidomide maintenance, observation). Conclusions: Females had a higher proportion of the adverse molecular risk lesions del(17p) and t(14;16) and were more likely to have HiR and UHiR disease. In the context of Myeloma XI trial treatment this did not correspond to a difference in PFS or OS, either overall or within the induction or maintenance randomisation treatment options (even though males were more likely to undergo ASCT). This suggests that in women the treatment delivered may have been able to overcome some of the adverse effect of the risk lesions present or that other factors affecting outcome were more important. on behalf of the NCRI Haematological Oncology Clinical Studies Group. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Davies:Janssen, Celgene: Other: Research Grant, Research Funding; Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Honoraria, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Gregory:Abbvie, Janssen: Honoraria; Amgen, Merck: Research Funding; Celgene: Consultancy, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Owen:Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses. Russell:DSI: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. OffLabel Disclosure: CTD/CRD induction therapy for myeloma, Lenalidomide maintenance 10mg 21/28 days

scholarly journals Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1956-1956
Author(s):  
Amy Wang ◽  
Justin Kline ◽  
Wendy Stock ◽  
Satyajit Kosuri ◽  
Andrew S. Artz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Stem Cell ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Checkpoint Inhibitors ◽  
Advisory Committees ◽  
Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

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