RBC Alloimmunization Burden Is High in Regularly RBC-Transfused Myelodysplastic Syndrome (MDS) Patients: A Report from South Australian-MDS Registry

Abstract Introduction: Anemia is one of the commonest presenting features of MDS and approximately 30-40% of patients require regular RBC-transfusion. RBC-transfusion dependency (RBC-TD) is a poor-prognostic factor independent of revised International Prognostic Scoring System (IPSS-R) (Hiwase et al ASH 2014). Although RBC transfusion increases the risk of alloimmunization, there is limited literature characterizing this risk in MDS patients as compared to other hematological disorders (such as thalassemia). Methods: This retrospective study assessed the alloimmunization rate in 784 MDS and AML (20-30% blasts) patients registered in the South Australian-MDS registry (SA-MDS registry) between 1991 and 2015. RBC-TD was defined as ≥1 unit of RBC transfused every eight weeks for four months according to WHO based Prognostic Scoring System. The cumulative incidence of RBC-alloimmunization was calculated using competing risk analysis (death being the competing risk). Factors associated with increased rate of RBC antibody formation were investigated by Cox regression analysis. Results: The median age of the 784 patients at diagnosis was 75 years with 66% males. The estimated median follow up time was 7.3 years. 70% of patients (549/784) were diagnosed with primary MDS, while the remaining patients were diagnosed with AML (20-30% blasts; n=57), CMML (n=91) or therapy-related myeloid neoplasm (T-MN; n=87). At last follow-up 30% patients were alive, 67% were deceased and 3% were lost to follow-up. During the study period, 658 (84%) patients required ≥1 unit of RBC transfusion and median RBC units transfused were 29 (range 0-708). The WPSS definition of RBC-TD was met in 47% (366/784 patients), while 36% (282/784) patients required intermittent RBC-transfusions (RBC-TI). During follow up, 83 (13%) patients formed 155 RBC-alloantibodies and 50% of these cases (42/83) developed >1 RBC-alloantibody. Autoantibodies were also detected in 31 cases, mainly in association with RBC-alloantibodies (n=27; complex alloimmunization) while 4 cases had only autoantibodies. Interestingly, in 19/27 of cases autoantibodies were detected only after alloimmunization. The pathophysiologic mechanism of this remains unclear. The most common alloantibody specificities were Rh (57%) and Kell (21%) (Table 1). The median interval between 1st RBC transfusion and antibody detection was 10 (0.2-225) months. In 9 cases (6 females) alloantibodies were detected prior to the 1st unit of RBC-transfused. The incidence of RBC alloimmunization reached a plateau at 16% by 100 units of RBC (Fig. 1A), however 80% of antibodies were detectable by 30-40 RBC units transfused. It indicates that most "responders" will form antibodies during the first 30-40 units of RBC transfused. Since most chronically transfused MDS patients do not form RBC alloantibodies it is important from a clinical and resource-utilization standpoint to identify who is at greatest risk of RBC alloimmunization. Multivariate analysis using Cox-regression model was performed. The only factor which was associated with significantly higher risk of RBC alloimmunization was RBC-TD (HR 2.52; p=0.0005). Age, sex, IPSS-R category and number of RBC units transfused did not independently predict alloimmunization rate. Using competing risk analysis, the cumulative incidence of RBC-alloimmunization was significantly higher in RBC-TD group compared to RBC-TI group (p=0.0004; Fig. 1B). Conclusion: RBC-alloimmunization is a substantial risk in MDS patients, especially in RBC-transfusion dependent cases. Extended phenotype matching (D,C,c,E,e and Kell) could have prevented alloantibody formation in 79% of alloimmunized MDS patients. Table 1. Specificity of 155 RBC-alloantibodies Table 1. Specificity of 155 RBC-alloantibodies Disclosures Yeung: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Eculizumab Protects Against TE and Prolongs Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Study

Blood ◽

10.1182/blood.v120.21.3480.3480 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3480-3480

Author(s):

Gérard Socié ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Jeffrey Szer ◽

Alvaro Urbano-Ispizua ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Advisory Committees ◽

Significant Protective Effect ◽

Rbc Transfusion

Abstract Abstract 3480 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic and life-threatening hematopoietic stem cell disorder characterized by uncontrolled complement-mediated hemolysis. PNH, in large part due to chronic hemolysis and platelet hyperactivation, is associated with thromboembolism (TE), one of the leading causes of disease mortality. Eculizumab, a monoclonal antibody that inhibits terminal complement activation, has been shown in clinical trials to reduce hemolysis and the incidence of TE. The International PNH Registry provides the opportunity to understand from real world experience the impact of eculizumab on TE reduction in PNH patients. Aim: To assess the risk factors for TE and mortality in PNH patients enrolled in the Registry and to assess the effectiveness of eculizumab in reducing PNH-associated TEs. Methods: Patients are eligible for the Registry if they have a detectable PNH clone, regardless of disease severity, comorbidities, or treatments (past, current or planned). As of June 30, 2012, there were 1547 patients enrolled from 25 countries on 5 continents. Patients were excluded from analysis if they were missing key demographic variables or dates of eculizumab use, or did not yet have follow-up information. The cumulative incidence of TE was determined using competing risks methods to take into account bone marrow transplantation and death, while Kaplan-Meier methods were used for the cumulative incidence of mortality. Risk factors for TE and mortality were explored using a Cox proportional hazards model with stepwise selection (the significance level was relaxed to P=0.20 due to the small number of events for analysis). Variables examined in the models included: ethnicity; prior TEs, bone marrow disorders, impaired renal function, impaired hepatic function (IHF), abdominal pain, dysphagia, dyspnea, easy bruising/bleeding, fatigue, headache, hemoglobinuria, Karnofsky performance score, granulocyte clone size and lactate dehydrogenase (LDH) at enrollment, red blood cell (RBC) transfusions 6 months prior to enrollment as a marker for hemolysis, and treatments after enrollment (eculizumab and warfarin/heparin). Results: The mean age of the 1047 patients eligible for analysis was 45 years; 537 patients (51.3%) were female and 868 were Caucasian (82.9%). Anti-coagulants (heparin/warfarin) were used by 28% of patients and eculizumab was used by 51% during follow-up (18% used both). During a mean (SD) follow-up of 22.5 (18.4) months, 16 patients had a TE and 51 were deceased. Patients taking eculizumab during follow-up had a cumulative incidence of TE at 1 year of 0.41% and 1.35% at 2 years, while patients not taking eculizumab had TE incidence of 1.70% and 2.61% at 1 and 2 years, respectively. In the multivariate Cox model, the greatest associations with TE were RBC transfusions in the 6 months before enrollment (hazard ratio [HR]=9.61), history of IHF (HR=4.78), dyspnea (HR=2.42) and headache (HR=2.33) at enrollment. While controlling for these variables, eculizumab had a significant protective effect (HR=0.23, 95% CI = 0.08–0.66). The cumulative incidence of mortality in eculizumab-treated patients was 2.31% and 4.21% at 1 and 2 years, while in untreated patients it was 4.40% and 7.01%, respectively. In the multivariate model of mortality, the greatest associations were age 60+ years (HR=4.72), Karnofsky score <80 (HR=2.34), fatigue at enrollment (HR=1.94), and recent RBC transfusion (HR=1.75). While controlling for these variable, eculizumab had a significant protective effect (HR=0.41, 95% CI = 0.23–0.73). Conclusions: This analysis of a large international cohort of ‘real world’ patients with PNH showed that eculizumab is associated with a significantly reduced risk of TE and mortality, consistent with prior research. Recent RBC transfusion, a surrogate marker for hemolysis, was associated with increased risk of TE and mortality. Several symptoms and hepatic dysfunction also showed increased risks for these outcomes. As might be expected, older age and low performance status were associated with mortality. These data should be interpreted within the context of a contemporary cohort of PNH patients who may or may not be treated (with either eculizumab and/or anticoagulation). These analyses are limited due to small number of TE and mortality outcomes. Disclosures: Muus: Alexion Pharmaceuticals : Sat on advisory board of Alexion Pharmaceuticals. Other. Urbano-Ispizua:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Kanakura:Shire: Consultancy. Rosse:Alexion Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara:Alexion Pharmaceuticals, Inc: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Long-Term Outcomes of Patients with Systemic Light Chain Amyloidosis (AL) Treated At Diagnosis with Risk-Adapted Stem Cell Transplant and Consolidation with Novel Agents.

Blood ◽

10.1182/blood.v120.21.3150.3150 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3150-3150 ◽

Cited By ~ 4

Author(s):

Raymond L. Comenzo ◽

Daniel E Fein ◽

Hani Hassoun ◽

Christina Bello ◽

Joanne F Chou ◽

...

Keyword(s):

Board Of Directors ◽

Light Chain ◽

Cumulative Incidence ◽

Research Funding ◽

Initial Therapy ◽

Novel Agents ◽

Cell Transplant ◽

Advisory Committees ◽

Hematologic Response

Abstract Abstract 3150 Background: AL is a plasma cell dyscrasia characterized by the pathologic production of monoclonal light chains which misfold, deposit in various organs, including the heart, and can cause early death. High dose melphalan with stem cell transplant (SCT) results in high hematologic response rates and is a standard treatment for eligible patients. Achieving a complete hematologic response (CR) to SCT results in extended event-free and overall survival (OS), up to 8 and 13 years respectively in one large series. (Blood 2011; 118:4346) We have studied the addition of novel agents as consolidation following risk-adapted SCT (RA-SCT) in order to improve hematologic response (HR) rates and therefore outcomes. (Br J Haem 2007;139:224; Amyloid 2010;17:80a) In this report we examine the long-term outcomes of patients who received initial therapy with RA-SCT followed by consolidation for hematologic response less than CR (HR < CR). Methods: We performed a retrospective study to assess the HR rates, incidence of hematologic progression and overall survival (OS) of AL patients enrolled at diagnosis on two consecutive phase II trials using RA-SCT with consolidation for HR < CR (NCT01527032 and NCT00458822). OS was calculated from date of transplant to date of death or last follow up. Median event free survival (EFS) and OS were estimated by the method of Kaplan Meier. Cumulative incidence function was used to estimate the incidence of progression and death. Results: Between 2002 and 2011, 83 patients were enrolled and underwent RA-SCT on these trials and, following RA-SCT, those with HR < CR received consolidation with thalidomide and dexamethasone (TD) in the first and bortezomib and dexamethasone (BD) in the second trial. Thirty-six patients had cardiac involvement (43%) and all patients had free light chain measurements employed to score hematologic response and progression using consensus criteria (Am J Hematol 2005;79:319; Blood 2010;116:1364a). The frequency of CR following SCT was 24% and increased to 48% with post-SCT consolidation. The CR rates increased at 1 year compared to 3 months post-SCT from 21% to 36% with TD and from 28% to 62% with BD. With a median follow up of 5.1 years, the EFS is 4.5 years (95% CI: 2.6 to not reached) and the OS of all patients has not been reached (Figure 1). Sixteen patients died prior to hematologic progression and 26 patients have progressed with a cumulative incidence of hematologic progression of 8%, 18%, and 29% at 1, 2 and 3 years, respectively (Figure 2). Thirty-one percent (8/26) of relapsed patients have not required second-line therapy while among those who have, 78% (14/18) have responded including 44% (8/18) with CR. The median OS following hematologic progression was 5 years (95% CI: 2.6–5.8). Conclusions: Half of the AL patients on initial therapy trials employing RA-SCT and consolidation for HR < CR achieved CR with 36% of pts on the TD and 62% on the BD consolidation trial in CR at 1 year post-SCT respectively. At 3 years post-SCT the cumulative incidence of relapse was 29% and a third of relapsed patients did not require therapy, likely due to the very sensitive serum free light chain assay that detects low level hematologic progression in the absence of organ progression. Almost 80% of patients requiring second-line therapy responded, over half with CR, and median OS after relapse was 5 years. These results indicate that initial therapy with RA-SCT and consolidation is an effective initial treatment strategy for patients with AL in the era of novel agents. With over 5 years of follow up the median OS has not been reached. Disclosures: Comenzo: Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

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Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽

10.1182/blood.v124.21.1992.1992 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1992-1992 ◽

Cited By ~ 1

Author(s):

Eugen Tausch ◽

Christina Galler ◽

Richard Schlenk ◽

Peter Hillmen ◽

Fritz Offner ◽

...

Keyword(s):

Prognostic Factors ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Gene Mutations ◽

Phase Iii ◽

Response To Treatment ◽

Prognostic Impact ◽

Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Pegylated Interferon-Alpha 2a in Combination with Nilotinib As First-Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (Nilopeg trial). Four-Year Follow-up Results

Blood ◽

10.1182/blood.v126.23.1578.1578 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1578-1578 ◽

Cited By ~ 1

Author(s):

Franck E. Nicolini ◽

Gabriel Etienne ◽

Viviane Dubruille ◽

Lydia Roy ◽

Françoise Huguet ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Chronic Phase ◽

Pegylated Interferon ◽

Molecular Response ◽

Advisory Committees ◽

Molecular Responses ◽

Log Reduction

Abstract Background & aims In the Nilopeg trial (EudraCT 2010-019786-28), we have previously demonstrated that the combination of nilotinib (Tasigna® Novartis), a second generation inihibitor (TKI2), combined to pegylated interferon-alpha 2a (Peg-IFN, Pegasys®, Roche) in de novo chronic phase chronic myeloid leukemia (CP-CML) patients is able to induce high rates of molecular responses with an acceptable additional toxicity (F. E. Nicolini et al. Lancet Haematology 2015) within 24 months of follow-up. We report here the ≥4-year follow-up of such patients for toxicity and efficacy. Methods In a phase 2 study, newly diagnosed CP-CML patients were assigned to a priming strategy by Peg-IFN (± HU) for a month at 90 mg/wk, prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 micro.g/wk for ≥ 1 year, maximum 2 years. After 2 years nilotinib was continued alone. The primary endpoint was the rate of confirmed molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in % for 2 years and then performed in each center [all expressed in % on the international scale (IS)]. All data presented here are in intention-to-treat. Events were defined as death, progression to AP or BC, failure on nilotinib or nilotinib treatment discontinuation for any cause excluding treatment-free remission (TFR). Results Fourty-two patients were enrolled in this trial (one withdrawn its consent prior to treatment initiation), and the median follow-up is now 50.7 (47.8-52.8) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. The median age at treatment initiation was 53 (23-85) years, 2 patients had a masked Philadelphia chromosome, 3 a variant form, and 1 additional chromosomal abnormalities, all patients had "major" BCR-ABL1 transcripts. The rates of Complete Cytogenetic Responses (CCyR) at "6", and "12" months of combination (i. e. at 5 and 11 months of TKI2) were 71%, and 100% respectively. Eighty seven percent of patients had a BCR-ABLIS ≤10% at M3 (i. e. after 2 months TKI). The rates of molecular responses respectively at 12, 24, 36 and 48 months were 76%, 78%, 83%, 73% for MMR, 51%, 58.5%, 66%, 58.5% for 4 log reduction (MR4), 17%, 34%, 34%, 44% for 4.5 log reduction (MR4.5), 12%, 32%, 29%, 41.5% for ≥5 log reduction (MR5), shown as cumulative incidence curves for MR4.5 in figure 1. The median doses of Peg-IFN delivered to the patients during the first year were 45 (0-45) micro.g/wk, and for nilotinib 600 (300-600) mg daily. Interestingly, logistic regression analysis adjusted on MR4.5 responses showed a significant relationship with the mean doses of Peg-IFN delivered to the patients at 12 months (p=0.003, OR = 1.09 [1.03-1.16]), 24 months (p=0.005, OR = 1.08 [1.02-1.14]) and 48 months (p=0.024, OR = 1.09 [1.01-1.17], but not with the mean doses of nilotinib [p=0.84, OR = 0.99 [0.99-1.01], p=0.087, OR = 1 [0.99-1.01], and p=0.88, OR = 1 [0.99-1.01] respectively. Eight patients (19.5%) were in TFR for a median of 6.8 (0.5-9.5) months after 2-year consecutive MR4.5, and none lost MMR yet at last follow-up. One patient died of progression (unmutated myeloid blast crisis at M6, who relapsed after unrelated allogeneic stem cell transplantation). There was no additional grade 3-4 hematologic or biochemical toxicities occurring after 24 months. At last follow-up 10 patients switched for another TKI (2 for dasatinib, 5 for imatinib, and 3 for imatinib followed by dasatinib), for unsufficient cytogenetic or molecular response (2 patients) or for toxicity (7 patients). Overall, 4 patients presented some cardio-vascular events 3 coronary stenoses, one brain stroke). Conclusion Despite additional initial toxicities Peg-IFN priming strategy, followed by the combination of nilotinib and Peg-IFN during the first year induces very high rates of durable deep molecular responses (MR4 and MR4.5) at later time-points, offering TFR for number of patients. To date, no emerging severe adverse events occurred. However, to confirm these promising results, a randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is absolutely warranted and in progress. Figure 1. Cumulative incidence of MR4.5 Figure 1. Cumulative incidence of MR4.5 Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Huguet:Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; PFIZER: Consultancy, Speakers Bureau. Legros:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Rea:Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Amé:BMS: Speakers Bureau; Novartis: Speakers Bureau. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis: Speakers Bureau; BMS: Speakers Bureau. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Mahon:ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria.

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Solid Tumors in Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: A Study on 2220 Patients

Blood ◽

10.1182/blood-2018-99-115318 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3039-3039

Author(s):

Barbara Mora ◽

Elisa Rumi ◽

Paola Guglielmelli ◽

Daniela Barraco ◽

Margherita Maffioli ◽

...

Keyword(s):

Polycythemia Vera ◽

Board Of Directors ◽

Solid Tumors ◽

Essential Thrombocythemia ◽

Cumulative Incidence ◽

Research Funding ◽

Time Dependent ◽

Jak Inhibitors ◽

Advisory Committees

Abstract Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) that can progress to post-PV (PPV) myelofibrosis (MF) and post-ET (PET) MF, from now on referred to as secondary myelofibrosis (SMF). Recent studies have shown an increased risk of developing solid tumors (ST) in MPN patients in comparison to the general population. Information on development of ST in SMF is scant. Objectives of this study are to investigate ST in SMF correlating clinical phenotypes and treatments and to evaluate differences in the incidence of ST between PV and ET patients who developed SMF and those who did not. Methods: The SMF group (including only PV and ET who developed SMF) was from the MYSEC cohort with ST-data collected (n=768 SMF); the PV/ET group including only patients who did not evolved into SMF at the time of this analysis was from the Pavia cohort (n=1452, 611 PV and 841 ET). SMF diagnosis was performed according to the IWG-MRT criteria (2008), PV and ET diagnosis was reviewed according to the most recent WHO criteria. We performed time-to-event analysis with Cox regression models using either the time elapsed after ET or PV diagnosis or the time elapsed after SMF diagnosis, events being defined as the diagnosis of ST. Concomitant JAK inhibitor therapy was considered a dynamic (time-dependent) covariate present from the date of drug start. Likewise, the pre- and post-SMF periods were compared considering SMF as a time-dependent state. This study was approved by the Review Board of each Institution and conducted in accordance with the Declaration of Helsinki. Results: Within 768 SMF, 394 were PET and 374 PPV MF. Median follow up time was 14.5 years (range, 0.9-45.9) from ET/PV diagnosis and 3.0 years (range, 0.6-27.3) from SMF diagnosis. We identified 71 patients (9.2% of the entire cohort) who developed a ST (included one multiple myeloma and four lymphoproliferative disorders). We excluded from the analysis myelodysplastic syndromes, acute leukemias, carcinomas in situ, breast fibroadenomas, superficial bladder carcinoma and non-melanoma skin cancers. The most frequent (≥10%) ST subtypes were: breast (17 cases), prostatic (10) and kidney cancer (7). In 11 patients the date of ST occurrence was unreported and therefore they were excluded from time dependent analysis. As for the other 60 cases, 13 (21.7%) were diagnosed before ET/PV development, 22 (36.7%) during the ET/PV phase and 25 (41.6%) after SMF transformation. The cumulative incidence of ST was 0.44% person-year of follow up for ET/PV developing SMF and 0.98% person-year of follow up for SMF. There was a trend of association between male gender and ST occurrence after ET/PV (P=0.054) and after SMF diagnosis as well (P=0.055). No other statistically significant differences in demographics, driver mutations, karyotype, bone marrow fibrosis, and MYSEC-PM strata were found at the time of SMF diagnosis between SMF patients with and without ST. Then, we focused on 165 SMF patients treated with JAK inhibitors (of whom 10 during ET and 15 during PV phase): 128 received ruxolitinib, 11 fedratinib, 11 momelotinib, one XL019 and 14 JAK inhibitors sequentially. We did not find any correlation between JAK inhibitors treatment given at any time point of the follow-up and occurrence of ST (Log-rank P=1). Of note, the four patients with lymphoma did not receive JAK inhibition. In the Pavia cohort, within a median follow up of 4.7 years (range, 0.6-39.7), 24 (3.9%) PV and 40 (4.8%) ET patients developed a ST. The incidence of ST in the Pavia dataset was 0.74% person-year of follow up. We eventually merged the MYSEC and the Pavia cohorts. As for the latter dataset we can not exclude SMF evolution with a longer follow-up, we treated SMF occurrence of the merged group as a time dependent covariate. The probability of developing ST was similar in the group of patients evolved into SMF and in those who did not (P=0.7, Figure 1). Conclusions: This study provides evidence that: 1) the cumulative incidence of ST is about 1% person-year of follow up in SMF patients; 2) JAK inhibitors given during ET/PV or SMF phase are neutral for ST development within the limit of current follow up; 3) developing SMF in patients with PV or ET does not imply a higher risk of ST. These findings highlight the need of studies aimed at identifying patients at higher risk of ST occurrence. Disclosures Rambaldi: Roche: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Amgen Inc.: Consultancy; Pfizer: Consultancy. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. Gotlib:Kartos: Consultancy; Promedior: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Deciphera: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Kiladjian:Celgene: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cervantes:Hospital Clinic Barcelona: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees. Devos:Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Palandri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Janssen: Consultancy, Speakers Bureau; Roche: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

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Fertility Rates in Young Hodgkin Lymphoma Survivors: A Danish Nationwide Cohort Study of 769 Patients

Blood ◽

10.1182/blood-2019-122642 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2841-2841

Author(s):

Andreas Kiesbye Øvlisen ◽

Lasse H. Jakobsen ◽

Kristian Hay Kragholm ◽

Martin Hutchings ◽

Henrik Frederiksen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Index Date ◽

Cox Regression ◽

Fertility Rates ◽

Grant Funding ◽

Advisory Committees ◽

First Child ◽

Funding Research

Introduction: The vast majority of young adults with Hodgkin lymphoma (HL) are cured by contemporary first line treatments. Treatment-related long-term toxicities can have a negative impact on survivorship and the risk of infertility may be particularly pertinent to young HL survivors. This study aimed to investigate the fertility rate (rate of first child after index date) over time in patients with HL compared to the matched controls. Methods: All Danish patients with HL, including classical and lymphocyte predominant HL, diagnosed in the period 2000-2015 were identified in the Danish Lymphoma Registry. Patients aged 18-40 years at diagnosis with documented complete remission after first line therapy were included. Patient data were merged with the Danish Fertility Database and the Medical Register of Births and Deaths. For each HL patient, five random Danish citizens alive at the index date of the HL patient were matched on birth date, sex, and parenthood status (categorical; with children vs without children at the index date). Follow-up was measured from 9 months post diagnosis (index date) until the time of first child, relapse, death, or censoring, whichever came first. Patients with progression/relapse within the first 9 months after diagnosis were excluded. Cumulative incidences of first living child after the index date were computed for the entire cohort and stratified on sex using the Aalen-Johansen estimator with death or relapse before first child after index date as competing events. Cox regression was used to compare the rates of first child of HL patients and matched controls by clinical subgroups and estimated for males and females separately. Results: A total of 769 HL patients were included (male:female ratio 1.2, median age 30 years) and median follow-up was 9.9 years. The mean numbers of children per person at start of follow-up were similar in patients and matched controls (female HL patients 0.64 vs matched controls 0.63 children per individual; male HL patients 0.56 vs matched controls 0.54 children per individual). At the end of follow-up, average numbers of children were higher in male and female HL patients (female HL patients 1.22 children per individual; matched control 1.14 children per individual) and males (HL patients 1.00 children per individual; matched controls 0.92 children per individual). The cumulative incidence of first child after index date in female HL patients was lower during the first three years of follow-up compared to the matched controls. However, beyond three years of follow-up the cumulative incidences of first child after index date were similar (Figure 1A). Among male HL patients the cumulative incidence of first child after index date was higher than that of the matched controls throughout the entire follow-up (Figure 1B). Overall, fertility rates were higher in HL patients (males, 36.7 per 1,000 person years; females, 41.7 per 1,000 person years) as compared to the matched controls (males, 24.2 per 1,000 person years; females, 33.0 per 1,000 person years). The Cox regression showed that both male and female patients with HL had higher fertility rates as compared to matched controls (males, HR 1.5, p-value < 0.001; females, HR 1.2, p-value = 0.012; Table 1). This was also observed in specific clinical subgroups, i.e. ages 18-30 years, CCI 0, no children prior to diagnosis, and limited stage disease. Moreover, among patients receiving 6+ cycles of chemotherapy, fertility rates were not lower than expected (Table 1). Conclusion: The fertility rates for long-term HL survivors without progression/relapse were higher than in matched controls, in particular for male HL patients. Elevated fertility rates as compared to the matched controls were observed for lower age (<30 years), limited stage disease, and for patients without children at the time of diagnosis. No clinical subgroup did significantly decrease the fertility rates. Disclosures Hutchings: Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Novartis: Research Funding. Frederiksen:Abbvie: Research Funding; Alexion: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Janssen: Research Funding. Eloranta:Karolinska Institutet: Other: coordinator for a public-private real world evidence; Janssen Pharmaceuticals.: Other: project coordinator for a public-private real world evidence. Glimelius:Janssen Pharmaceuticals: Honoraria. Ekstroem Smedby:Janssen Cilag: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Takeda: Honoraria, Other: Grant funding, Research Funding. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

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Prognostic Factors of Long-Term Outcomes In Low- or Int-1-Risk MDS with del5q Treated with Lenalidomide (LEN): Results From a Randomized Phase 3 Trial (MDS-004)

Blood ◽

10.1182/blood.v116.21.4027.4027 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4027-4027

Author(s):

Pierre Fenaux ◽

Aristotles Giagounidis ◽

Odile Beyne-Rauzy ◽

Ghulam Mufti ◽

Moshe Mittelman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 3 ◽

Advisory Committees ◽

Free Survival ◽

Lower Baseline ◽

Younger Age ◽

Equity Ownership ◽

Rbc Transfusion

Abstract Abstract 4027 Background: Transfusion dependence is a significant negative predictor of overall survival (OS) and risk of AML-progression in MDS (Malcovati L, et al. JCO 2007;25:3503-10). LEN 5 mg and 10 mg induced significant RBC-transfusion independence (TI) versus placebo (PBO) in a randomized, phase 3, multicenter, double-blind (DB) study (MDS-004) in RBC transfusion-dependent patients (pts) with Low- or Int-1-risk MDS with del5q (Fenaux P, et al. Blood 2009;114:Abstract 944). The aim of this analysis is to identify prognostic factors for AML-free survival and OS during LEN treatment in the MDS-004 study after prolonged follow-up (pts enrolled between July 8, 2005 and July 26, 2007; last pt visit June 14, 2010; final data cutoff July 9, 2010). Methods: LEN-naïve pts with RBC transfusion-dependent Low- or Int-1-risk del5q MDS were randomized to receive LEN 5 mg on days 1–28 or LEN 10 mg on days 1–21, both of every 28-day cycle, or PBO. First response was assessed at 16 wks. Responders continued DB treatment for up to 52 wks, until erythroid relapse or disease progression. Pts who completed 52 wks of therapy could enter an open label (OL) extension phase at their current LEN dose. PBO and LEN 5 mg recipients who did not respond by wk 16 or who had erythroid relapse could receive LEN 5 or 10 mg, respectively, in the OL phase. This analysis included data through completion of the OL phase for pts randomized to LEN 5 and 10 mg combined in the DB phase; pts randomized to PBO were excluded as all except 11 pts crossed-over to LEN 5 mg. LEN 5 and 10 mg dose groups were comparable, allowing data for the two groups to be combined. A Cox proportional hazard model was used to evaluate effect of potential baseline risk factors, with RBC-TI ≥ 26 wks and cytogenetic response (CyR) as time-dependent covariates on AML-free survival and OS. The full model with all covariates and the final model, based on backward model selection method, are presented. Results: All 138 pts randomized to LEN who received ≥ 1 dose were included: median age 68 y (range 36–86); 74% of pts were female; 66% had an isolated del5q abnormality and 28% had ≥ 1 additional abnormality; and 43% of pts had WHO-based Prognostic Scoring System (WPSS) low/int risk, 32% high/very high, and 25% missing data. At baseline, median time since diagnosis was 2.7 y (range 0.2–29.2) and median RBC transfusion requirement was 6 units/8 wks (range 1–25). Duration of LEN was 12.9 mo (range 0.3–36.7); 54 of 62 responders entered the OL phase. Median follow-up for the cohort was 36 mo (range 0.4–59.4). Overall, 31 (22%) pts progressed to AML (median time to AML progression 4.01 y; 95% confidence interval [CI] 3.17–4.03) and 66 (48%) died (median OS 3.68 y; 95% CI 2.93–not estimable). The cumulative 3-year AML-progression rate was 34.8% and the 3-year OS rate was 56.0%. Multivariate results are presented in the Table. Achieving RBC-TI ≥ 26 wks was associated with a 45% and 51% reduction in the risk of AML progression (P=0.022) and death (P=0.008), respectively. Lower baseline ferritin level and younger age were associated with a reduced risk of AML-progression and death. Conclusion: Achievement of RBC-TI with LEN was associated with a significantly reduced risk of AML progression and death. Other predictors for longer AML-free survival and OS were lower baseline ferritin levels and younger age. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; J&J: Honoraria; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Beyne-Rauzy:Amgen: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Backstrom:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Hellström-Lindberg:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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EBMT Risk Score for Pre Transplant Risk Assessment in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v120.21.3094.3094 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3094-3094 ◽

Cited By ~ 1

Author(s):

Zartash Gul ◽

Hasan Khan ◽

Qaiser Bashir ◽

Nina Shah ◽

Simrit Parmar ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Risk Score ◽

Cumulative Incidence ◽

Research Funding ◽

Advisory Committees ◽

All Cause Mortality ◽

Response Status

Abstract Abstract 3094 Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for patients with multiple myeloma (MM) but its use is limited by high non-relapse mortality (NRM). European Group for Bone Marrow transplant (EBMT) risk score is a validated predictor of outcome for patients undergoing allo-HCT for hematological malignancies. It takes into consideration patient's age, donor's gender and type, disease status and the interval from diagnosis to allo-HCT, with the score ranging from 0 to 7. We assessed the impact of EBMT risk score in MM patients undergoing allo-HCT. Methods: A total of 189 patients with MM who underwent HSCT between November 1985 and June 2010 at MD Anderson Cancer Center were included in the analysis. Results: Patient characteristics are summarized in Table 1. There were 110 males (58%) and 79 females (42%) with a mean age of 50 years (range 28–70). Donors were related in 146 patients (HLA-identical=131, 1 antigen mismatched (AGMM) = 5, 2 AGMM =1, 3AGMM=1, syngeneic=8) and unrelated in 43 patients (HLA identical= 37, 1AGMM=4, 2AGMM=1, unknown=1). One-hundred and twelve patients had prior autologous transplants (auto-HCT). Of these 83 had 1, 28 had 2 and 1 had 3 prior auto-HCT, respectively. Median time from diagnosis to allo-HCT was 24.7 months (range 3.3–232) and median overall follow up was 13 months (0.2–266). Overall 94 patients (49%) had progressed before last follow-up. Incidence of all-cause mortality was 138 (73.4%) with 69 (36%) of all deaths attributed to NRM. KM estimates of 2-year PFS and OS were 25% and 42%, and 5-year PFS and OS were 16% and 27%, respectively. Cumulative incidence (CI) of grade 2–4 and grade 3–4 acute graft versus host disease (aGVHD) was 33% and 13%, respectively. Cumulative incidence of overall and extensive chronic GVHD (cGVHD) was 47% and 17%, respectively. EBMT risk score was, 0–3 for 41 (21.7%), 4 for 72 (38.1%) 4 and 5–7 for 76 (40.2%) patients. EBMT risk score was higher for males, African-Americans and older allo-HCT recipients, patients with higher LDH levels (>618mg/dl), ß2-microglobulin >3.5mg/dl and patients with bone marrow plasmacytosis. Median PFS in patients with EBMT scores 0–3, 4 and 5–7 were 10.1, 8.4 and 6.4 months, respectively (P=0.0036). Median OS in patients with EBMT scores 0–3, 4 and 5–7 were 39, 15.8 and 9.6 months, respectively (p=0.001). Cumulative NRM in patients with EBMT scores 0–3, 4 and 5–7 were 37% (15/41), 36.1% (26/72) and 37.3% (28/75), respectively (p= 0.234). Cumulative incidence of progression in patients with EBMT scores 0–3, 4 and 5–7 were 36.5% (15/41), 50% (36/72) and 56.5% (43/76), p=0.119. Compared to those with EBMT risk score (0–3), individuals with EBMT risk scores >5 had a higher risk of all-cause mortality (HR 2.34, 95% CI 1.44–3.80), and disease progression (HR 3.06, 95% CI 1.67–5.61). Addition of ß2-microglobulin, BM plasma cells or prior response status alone or in combination with EBMT risk score significantly improved the discrimination properties of the model containing EBMT score alone (p<0.05). Conclusions: EBMT risk score is an independent predictor of survival in MM patients undergoing allo-HCT. Addition of myeloma-specific factors predictors (ß2-microglobulin, plasma cell infiltration and prior response status) to EBMT score significantly improves its prognostic impact. Disclosures: Giralt: Millenium: 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; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Could Chronic Gvhd Overcome the Poor Prognosis of Patients with MDS and TP53 Undergoing Allogeneic HSCT?

Blood ◽

10.1182/blood.v126.23.2890.2890 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2890-2890

Author(s):

Juan Carlos Caballero ◽

Mercedes Sánchez-Barba ◽

Mónica Del Rey ◽

Kamila Janusz ◽

Eva Lumbreras ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Somatic Mutations ◽

Advisory Committees ◽

Poor Outcome

Abstract Background and Aim Although new agents have been approved for the treatment of MDS, the only curative approach for these patients is allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, in these patients this approach has only obtained 40-60% of overall survival. Somatic mutations in MDS have recently been analyzed in order to confirm clonally and also prognostic impact in MDS patients. In this regard, TP 53 mutated gene is present in MDS in less than 10% of patients and is associated with advanced disease and high-risk features. Recent studies confirms poor outcomes in patients with TP 53 mutated receiving allogeneic stem cell transplantation1,2. The present study try to analyze if the development of chronic graft versus host disease (cGVHD) could modify, due to graft versus leukemia effect, the adverse prognosis of these high-risk patients (TP53 mutated patients). Design and Methods <>Results of HSCT in 92 MDS patients from 5 centers in Spain were retrospectively studied. Samples were collected 1 month prior to transplant. 280ng of the genomic DNA from BM cells was screened for somatic mutations in TP53 gene. The study was done by NGS on a GS Junior Instrument (Roche) according to an amplicon sequencing design. For each sample, eight exons (4-11) were amplified with preconfigured primer plates provided within the IRON II study network. Data analysis, were carried out using the Sequence Pilot software version 3.5.2 (JSI Medical Systems) and GS Amplicon Variant Analyzer software, versions 2.7 and 2.9 (Roche Applied Science). Minimum coverage of sequenced exons was 100 reads and the sensitivity of variant detection was set to a lower limit of >2% for bidirectional reads. Only those variants that resulted in amino acid change in the protein sequence were considered. OS and RFS were calculated using the Kaplan-Meier method. The log-rank test was used for comparisons. All calculations were done using SPSS 18.0. Cumulative incidence of relapse was also calculated by xlstat version 2014 program. <>Results Median age was 54 years (17-69), 71.7% were "de novo" MDS and regarding IPSS, 53% were in the int-2/high-risk category. Other characteristics were in Table 1. In the pre-transplant evaluation, 15 patients out of 92 (16,3%) were TP 53 mutated. The mutations were located in exons 5, 6, 7, 8 and 10. These variations were present in a variable percentageof the cell population (3 to 84%). All mutations were specific nucleotide changes except for two cases. At the time of the last update, 16 patients had relapsed (17.4%) and 40 had died (43.5%). After a median follow up of 15.5 months, OS was 56.5%. Median OS for patients with mutated TP53 trend a toward to be shorter than survival for patients without mutated TP53 (median of 7 mo vs median not reached, respectively, p=0.156). Multivariate analysis for OS confirmed complex karyotype (HR 5,588, 95CI 1,794-17,407, p=0.003) and no developement of cGVHD (HR 3,531, 95IC 1,634-7,632, p=0.001) as predictors for poor outcome. Cumulative incidence of relapse was 20.3% (+/-4.3%) at 1 years. Mutational status of TP53 significantly influenced on relapse (53.3% +/-12.9% vs 13.7% +/-4% at 1 year for patients with vs without TP 53 mutation (Gray test=0.001, Figure 2). Regarding Relapse Free Survival (RFS), after a median of follow up of 17 months, RFS was 67.9% and as previously suggested, the presence of TP 53 mutation had an impact on RFS (41.7% for mutated (median RFS of 6 months) and 75% for non mutated patients (median RFS not reached), p=0.009). Multivariate analysis for RFS confirmed age (HR 1.054, 95CI 1.005-1.106, p=0.032) and TP 53 mutated (HR 3.054, 95IC 1.145-8.149, p=0.026) as predictors for lower RFS. Regarding 15 patients with mutated TP 53, 7 did relapsed and 9 had died. Developement of cGVHD showed a trend toward to improve outcome among TP 53 mutated patients, with a better OS and RFS for those developing cGVHD as compared to those who did not (OS of 55% vs 17% for patients with and without cGVHD, p=0.039, Figure 2 and RFS of 71% vs 50%, respectively, p=0.3). <>Conclusions Mutated TP53 pre-allo patients presents poor outcome as compared to not mutated, as previously described Bejar1 and Kim2. Nevertheless, the developement of cGVHD could overcome the adverse impact of this factor due to the developement of graft versus tumor efect, improving survival curves (OS and RFS) as compared to previous published results. Study supported by GRS-1033/A/14 P53. 1.-BŽjar, JCO 2014, 32(25). 2.-Kim, BBMT 2015, Epub ahead of print. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sanz: JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Valcarcel:AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Díez-Campelo:CELGENE: Research Funding, Speakers Bureau; JANSSEN: Research Funding; NOVARTIS: Research Funding, Speakers Bureau.

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Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naive

Blood ◽

10.1182/blood-2018-99-114877 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 463-463 ◽

Cited By ~ 5

Author(s):

David P. Steensma ◽

Uwe Platzbecker ◽

Koen Van Eygen ◽

Azra Raza ◽

Valeria Santini ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership ◽

Grade 3 ◽

Rbc Transfusion

Abstract BACKGROUND: Patients with TD lower-risk (LR)-MDS relapsed or refractory to ESA have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase, characteristics observed in some MDS patients. IMerge is an ongoing global study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1). In the first 32 patients enrolled, 8-week TI rate was 34%, with 24-week TI of 16%, and HI-E of 59%. The most frequently reported adverse events were reversible grade ≥3 cytopenias (Fenaux et al EHA 2018 Abstr S1157). Higher response rates were observed in patients (n=13) who were LEN and HMA naïve without del(5q). We report here results in an additional 25 LEN and HMA naïve patients without del(5q), with longer term follow-up of the 13 initial patients meeting the same criteria. METHODS: IMerge is a phase 2/3 trial (NCT02598661) that includes LR-MDS patients with a high transfusion burden (≥4 units / 8 weeks) who are relapsed/refractory to ESA or have sEPO >500 mU/mL. The additional 25 were required to be LEN and HMA naïve and lack del(5q). Imetelstat 7.5 mg/kg was administered IV every 4 weeks. In addition to the key endpoints noted above, secondary endpoints include safety, time to and duration of TI. Biomarkers are also being explored, including telomerase activity, hTERT, telomere length, and genetic mutations. RESULTS: Overall, for the 38 LEN/HMA naïve and non-del(5q) patients, median age was 71.5 years and 66% were men. 63% of patients were IPSS Low and 37% Int-1. Median prior RBC transfusion burden was 8.0 (range 4-14) U, and 71% had WHO 2008 RARS or RCMD-RS. 9/37 (24%) patients with evaluable sEPO levels had baseline level >500 mU/mL. As of July 2018, with a median follow-up of 25.8 months for the initial 13 patients, and 5.2 months for the 25 recently included patients, the 8-week RBC-TI rate was 37% (14/38). Durability of 24-week TI responses was demonstrated, with a median duration of 10 months and the longest ongoing response now >2 years. Among the patients achieving durable TI, all showed a Hb rise of ≥3.0 g/dL compared to baseline during the transfusion-free interval. Response rates were similar in RARS/RCMD-RS (33% [9/27]) and other patients (27% [3/11]), and those with baseline EPO levels >500 mU/mL (33% [3/9]) and ≤500 mU/mL (32% [9/28]). Reversible grade ≥3 neutropenia and thrombocytopenia were each reported in 58% of the patients. Liver function test (LFT) elevations were mostly grade 1/2. Reversible grade 3 LFTelevations were observed in 3 (8%) patients on study. An independent Hepatic Review Committee deemed the observed LFT elevations were not imetelstat-related hepatic toxicities. SUMMARY / CONCLUSIONS: In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to LEN/HMA, single-agent imetelstat yielded a TI rate of 37%, with a median duration of 10 months and limited side effects. Durable responses were characterized by transfusion independence >24 weeks and accompanied by Hb rise. Updated data will be presented. Disclosures Steensma: Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Platzbecker:Celgene: Research Funding. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Raza:Kura Oncology: Research Funding; Onconova: Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Speakers Bureau; Geoptix: Speakers Bureau; Janssen: Research Funding; Syros: Research Funding. Santini:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Font:Celgene: Membership on an entity's Board of Directors or advisory committees. Samarina:Janssen: Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bussolari:Janssen: Employment, Equity Ownership. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Fenaux:Roche: Honoraria; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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