Long-Term Follow-up of the Randomized Controlled Study in Patients with Newly Diagnosed Severe Aplastic Anemia Treated with ATG, Cyclosporine, with or without G-CSF: On Behalf of the SAA Working Party of the EBMT

Abstract Introduction The prospective randomized study on treatment of 192 severe aplastic anemia (SAA) patients with ATG and Cyclosporine (CSA) with and without G-CSF showed that G-CSF added to ATG/CSA decreases the rate of early infection episodes and days of hospitalization in very SAA (vSAA) patients, but has no significant impact on overall survival (OS), event free survival (EFS), relapse, or death rates (Blood, 2011;17:4434). The number of secondary MDS/AML was low, however with a short observation time. Now, 16 years after initiation of the study, a follow-up was planned to evaluate long-term outcome, comparing patients with and without G-CSF. Patients and Methods A total of 192 patients with newly diagnosed SAA, not eligible for stem cell transplantation (SCT) were entered into this prospective randomized multi-center study to receive ATG/CSA with (49.5%) or without G-CSF (50.5%). In 2011, 44 of the 192 patients had died. For the present study the follow-up of the 148 patients alive at time of first publication were requested. There were 49% males (49% G-CSF; 48% no G-CSF), 36% with vSAA (32% G-CSF; 41% no G-CSF). The median age at randomization was 46 years (2-80), 47 (2-80) for the G-CSF and 44 (7-80) for the non-G-CSF group. The median follow-up using reverse KM method was 11.7 years (10.9-12.5). Results Among the 110 survivors (17 missing), 71 (65%) were in CR, 33 (30%) in PR and 6 not in remission (5%), without any difference between the G-CSF and non-G-CSF group (P=0.523). At last follow-up 65 (34%) of the patients have died. Causes of death were infection (26), bleeding (3), SAA unspecified (3), MDS/AML (4), solid cancer (3), transplant related mortality (8), cardiovascular/aging (7), or unspecified (11). There was no difference in the causes of death between patients treated with or without G-CSF. OS at 15 years was 57±12% for the G-CSF and 63±12% for the non-G-CSF group (P=0.927). EFS, including SCT, relapse, non-response at day 120, second MDS/AML, PNH or death as an event, was 24±10% for the G-CSF, and 23±10% for the non-G-CSF group (P=0.367). Nine patients developed florid or morphological signs of MDS/AML, 9 clonal cytogenetic anomaly only, 7 a solid cancer, 18 clinical PNH, 8 avascular osteonecrosis, and 12 chronic kidney disease (No difference between patients treated with or without G-CSF). Cumulative incidence (CI) at 15 years of MDS/AML (isolated cytogenetic anomalies not included) was 5.0±2% (G-CSF) and 7.3±3% (no G-CSF), respectively (P=0.693); for clinical PNH it was 10.1±5% and 13.3±7% (P=0.499), for relapse of responding patients at day 120, 29.8±22% and 25.1±17% (P=0.545), and for chronic kidney failure 16%±12% and 13%±12% (P=0.513), respectively. Forty patients needed a second line immunosuppressive therapy (IST) for relapse (17), refractory disease (8), cyclosporine dependence (6) or isolated cytopenia (9) (G-CSF 26; no G-CSF 16; P=0.291); 16 patients needed a third line IST for relapse (5), refractory disease (7), isolated cytopenia (4) (G-CSF 12; no G-CSF 4; P=0.647). Twenty-eight patients were treated with allogeneic SCT in second or subsequent line (G-CSF 12; no G-CSF 16). CI at 15 years of SCT (competing risk, death without SCT) was 14±8% (G-CSF) and 22%±10% (no G-CSF), respectively (P=0.380). OS at 10 years since SCT was 46±24%. The most important risk factors for patients treated with ATG/CSA with or without G-CSF were age and severity of the disease at randomization: OS at 15 years was 89±12% (<20 years), 81±13% (20-40 years), 55±15% (40-60 years), and 32±16% (>60 years of age), respectively (P>0.001), and 64±5% and 52±7% for patients with SAA and vSAA, respectively (P=0.021). There was no difference between patients treated with or without G-CSF. Finally, the lack of neutrophil response by day 30, which was significant at first evaluation, is still associated with borderline lower survival (46.6±14% versus 67.1±9%; P=0.058). Conclusion: Long-term outcome of SAA patients treated with ATG/CSA was not influenced by supplementing G-CSF in term of OS, EFS, death rates, relapse, PNH, secondary MDS/AML, solid cancer and non-malignant late complications. Due to the pre-cancer nature of the disease and its long-lasting treatment, patients treated with IST are at risk for a number of malignant and non-malignant late complications. It is somewhat disappointing that in this careful followed cohort less than 25% of patients are alive and event-free 10-15 years after initial treatment. Disclosures Peffault De Latour: Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hoechsmann:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Schrezenmeier:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Bader:Neovii: Research Funding; Cellgene: Consultancy; Riemser: Research Funding; Medac: Patents & Royalties, Research Funding; Novartis: Consultancy, Speakers Bureau. Risitano:Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Long-Term Outcome Following B-Cell Depletion Therapy with Rituximab In Children and Adults with Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v116.21.72.72 ◽

2010 ◽

Vol 116 (21) ◽

pp. 72-72 ◽

Cited By ~ 1

Author(s):

Vivek L. Patel ◽

Matthieu Mahévas ◽

Roberto Stasi ◽

Susanna Cunningham-Rundles ◽

Bertrand Godeau ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Initial Response ◽

Response Rates ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

One Year

Abstract Abstract 72 Background: Studies of B-cell depletion using Rituximab in adults with ITP report responses lasting at least one year in almost all of the 30–40% of patients with complete responses (CR: platelet count >150 × 109/l) and also a small fraction of patients with partial responses (PR: platelet count 50–150 × 109/l). However data describing patients with ITP who are relapse-free and off-treatment beyond 1–2 years from initial Rituximab are almost entirely anecdotal and comparable response data are even less available for children. This study assessed the duration of unmaintained platelet response following rituximab treatment in 72 adults and 66 children with ITP, all of whom had had at least an initial response to rituximab. Long-term outcome was estimated from these data. Methods: Seventeen published studies including 486 patients, 376 adults and 110 children, were used to obtain the initial response rates to standard-dose rituximab treatment (375mg/m2 weekly for 4 weeks) in adults and children. Only 1 included study did not use the standard dose of rituximab. The Godeau study (Blood, 2008) was used to estimate the one-year response rate in adults with ITP. Only those adults whose responses persisted at least one year had follow up assessed whereas children who demonstrated even ephemeral responses were included. Only verified counts were used in this IRB-approved multicenter study. Results: 138 subjects with CR's or PR's after rituximab were included. All patients had starting platelet counts <30×109/l and 131 (95%) had ITP of > 6 months duration. Thirty-three (24%) had undergone splenectomy. Using the data from prior publications to obtain the initial response rates, children had a 56% initial response rate to rituximab treatment and adults had a 57% rate. Taking initial responders and then using the Godeau data for adults and Kaplan-Meier analysis of our data for children, 38% one-year response rates were obtained for both children and adults treated with rituximab. Both age groups also showed remarkable similarity at two years with 30% relapse-free response rates. However, all of the 26 eligible children maintained their response beyond two years whereas adults continued to relapse. Therefore the five-year response rate was 30% for children and only 21% for adults. Sex, duration of ITP, and age among adults did not affect long-term outcome. The rate of relapse was almost identical for splenectomized patients and non-splenectomized ones but the splenectomized patients appeared to relapse sooner (Figure). Patients with CR's (55 of the 72 adults with responses lasting at least one year were CR's) had better long-term outcomes than did patients with PR's even more than one year from initial treatment. B-cells returned significantly sooner to higher levels in subjects who relapsed compared to those whose responses were ongoing. No clinical long-term toxicity was observed but 2 patients were identified to have mild hypogammaglobulinemia > 30 months from initial treatment. Conclusions: In summary, only approximately 1 in 5 adults treated with rituximab will have an at least five-year relapse-free response rate which is disappointingly low; children have only a slightly higher five-year relapse-free response rate. A pilot study to improve outcomes using either R-CVP or double dose rituximab was unsuccessful (Hasan, Am J Hematol,2009) Current efforts to improve long-term response rates have focused on the combination of high dose dexamethasone and rituximab (or even by providing maintenance treatment with rituximab). A better understanding of the mechanism of effect of rituximab in patients with ITP might allow an improved treatment strategy to be developed. Fortunately, the toxicity of rituximab treatment in patients with uncomplicated ITP appears to be low; however, yearly testing for immunoglobulins for a minimum of five years might be appropriate. Disclosures: Neufeld: Novartis. Inc: Research Funding. Shenoy:Novartis Oncology: Honoraria. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy.

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Long-Term Outcome of Myelodysplastic Syndromes (MDS) Patients Treated with Erythropoiesis Stimulating Agents (ESAs)

Blood ◽

10.1182/blood.v126.23.1696.1696 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1696-1696 ◽

Cited By ~ 1

Author(s):

Mikkael A. Sekeres ◽

Katrina Zell ◽

John Barnard ◽

Amy E. DeZern ◽

David P. Steensma ◽

...

Keyword(s):

Board Of Directors ◽

Median Survival ◽

Lower Risk ◽

Research Funding ◽

Advisory Committees ◽

Term Outcome ◽

Median Response ◽

Long Term Outcome ◽

Medical Need

Abstract Background: The majority of MDS patients (pts) have anemia and are treated initially with ESAs. Particularly for lower-risk MDS pts (International Prognostic Scoring System (IPSS) Low and Int-1), once ESAs are no longer effective, treatment options are limited to drugs commonly used for higher-risk MDS, such as hypomethylating agents, or off-label use of immunomodulatory drugs. As a result, most pts receive only transfusion support post-ESA, representing a pt group with an unmet medical need frequently targeted for drug development, for whom long-term outcome is unknown. Methods: We studied pts diagnosed with lower-risk MDS from 1997-2014 at MDS CRC institutions and treated with ESAs (epoetin alpha (epo) or darbepoetin (darb)). The best response to treatment was categorized per International Working Group 2006 response criteria (hematological improvement (HI), complete response (CR), or partial response (PR)). The primary endpoint was overall survival (OS) at the time of ESA failure, defined as cessation of treatment due to relapse or refractoriness; a secondary endpoint was time to AML transformation or death, from time of response (for responders) or failure (for nonresponders) determination. Descriptive statistics were used for baseline characteristics. The Kaplan Meier method was used to estimate OS and a log rank analysis was used to compare response categories. Cox regression analysis was performed for multivariable analysis. Results: Of 206 patients included in analyses, median age was 71.6 years (range: 25.3-88.1), 36% were female, 5% were African-American, and 11% had t-MDS. WHO categories included RA (14%), RARS (16%), RCMD (42%), MDS-u (6%), del (5q) (4%), RAEB-1 (9%), RAEB-2 (2%), RARS-T (2%), MDS/MPN-u (3%), and CMML-1 (2%), with pts classified as IPSS Low (39%), Int-1 (61%), or IPSS-R Very Low (16%), Low (55%), Intermediate (26%), and High (4%). IPSS cytogenetic risk groups were Good (72%), Intermediate (22%), and Poor (6%). Baseline median hemoglobin was 9.4 g/dl (range: 5.5-14.2), serum epo level was 97.2 (range: 14.2-3899.0), and 11% were transfusion-dependent. Treatment included darb (59%) and epo (41%) at median doses of 300 mcg (range: 100-500) and 40,000 units (range: 5,000-80,000), respectively. Pts remained on therapy for a median of 30.4 weeks (range: 0.0-447.7) and had a median follow-up of 28.4 months (95% confidence interval (CI): 24.5, 45.4). First treatments following ESA failure included azacitidine (41.7%), decitabine (10.2%), lenalidomide (16.6%), experimental drugs (3.1%), other growth factors (13.6%), ATG and/or other immunosuppressants (8%), chemotherapy (0.1%) , transplant (0.1%) and others (6.6%). The overall response rate (ORR) to ESAs was 18.8%, with 0% achieving CR; 0.1% PR; and 18.7% HI. Responses for epo were 17.3% and for darb were 19.8% (p=.67 for difference). For both ESAs, 81.2% of patients had disease refractory to treatment: 69.4% with stable disease and 12% with progressive disease with no significant differences between epo and darb by responder status. Median response duration for epo and darb were 21.9 weeks (range: 3.0 - 447.7) and 39.1 weeks (range: 0.0 - 350.7) respectively (p=0.045). Median survival from the date of diagnosis was 28.4 months (95% CI: 24.5, 45.4), and from ESA failure was 23.9 months (95% CI: 19.9, 33.0): 21.6 months (95% CI: 15.6, 39.2) for epo and 28.8 months (95% CI: 21.2, 39.7) for darb (p=0.99) (Figure). Median time to AML transformation or death was 17.4 Months (95% CI: 14.1, 22.9): 25.4 months for responders and 16.8 months for non-responders (p=.069). For patients who received ESAs for a minimum of 4 months (39% of pts for epo and 61% for darb), ORR was 16.5%, and median survival from ESA failure was 23.0 months (95% CI: 14.7, 33.0): 22.3 months (95% CI: 13.1, NA) for epo and 24.7 months (95% CI: 14.3, 39.7) for darb (p=0.87). Conclusion: In this large, but uncontrolled cohort, response rates were similar for lower-risk MDS patients treated with epo and darb, though duration was longer for darb. There was a trend for improved outcomes in patients who responded to ESAs. Lower-risk MDS patients treated with ESAs have an OS of less than 2 years from the time of failure, and can thus be considered a high-risk MDS group for whom subsequent therapies are not standardized, representing an unmet medical need. Figure 1. Figure 1. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Komrokji:Incyte: Consultancy, Honoraria, Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Speakers Bureau.

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Frontline Treatment With Imatinib Mesylate in Chronic Myeloid Leukemia Patients in Early Chronic Phase: a Very Long-Term Analysis by the GIMEMA CML Working Party

Blood ◽

10.1182/blood.v122.21.258.258 ◽

2013 ◽

Vol 122 (21) ◽

pp. 258-258 ◽

Cited By ~ 2

Author(s):

Fausto Castagnetti ◽

Gabriele Gugliotta ◽

Massimo Breccia ◽

Giorgina Specchia ◽

Tamara Intermesoli ◽

...

Keyword(s):

Board Of Directors ◽

Chronic Phase ◽

Working Party ◽

Molecular Response ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

Free Survival

Abstract Background The chronic myeloid leukemia (CML) therapeutic scenario has been enriched by the approval of second generation TKIs as frontline treatment of early chronic phase (ECP) patients, but imatinib mesylate (IM) still represents the standard for many patients. The long term outcome is extremely important to assess the treatment efficacy and to decide on the allocation of resources. The phase 3 trials comparing second generation TKIs versus standard-dose IM have not still demonstrated a clear improvement in terms of progression-free survival and overall survival. In the IRIS trial, at 8 year, 55% of patients were still on IM and the overall survival (OS) was 85%. Other published reports have shorter follow-up. Aims and Methods To assess the very long-term outcome of CML patients treated frontline with IM, we analyzed 559 patients enrolled within 3 multicentric prospective studies conducted by the GIMEMA CML Working Party (NCT00514488, NCT00510926, observational trial CML023). Definitions: major molecular response (MMR), BCR-ABLIS ratio <0.1%; deep molecular response (MR4.0), detectable disease ≤ 0.01% BCR-ABLIS or undetectable disease with ≥10,000 ABL transcripts; progression, transformation to accelerated or blastic phase; failure, according to 2013 ELN criteria; event, treatment discontinuation for any reason or lost to follow-up. Information on survival and progression were regularly collected. All deaths, at any time and for any reason, were included. All the analysis have been made according to the intention-to-treat principle. Results Baseline demographics characteristics: median age: 52 years (extremes 18-84 years); male sex: 60%; high Sokal, high Euro and high EUTOS scores: 22%, 7% and 7%, respectively; clonal chromosomal abnormalities (CCA) in Ph+ cells: 4% (not evaluable in 32% of patients for insufficient number of metaphases); e13a2 BCR-ABL transcript: 36%. Median follow-up: 76 (7-99) months. The cumulative incidence of complete cytogenetic response (CCyR), MMR and MR4 was 88%, 85% and 61%, respectively. The median time to CCyR, MMR and MR4 was 6, 7 and 42 months, respectively. Patients with high Sokal, high Euro and high EUTOS scores had significantly lower overall estimated probability of CCyR and MMR with respect to low and intermediate risk patients. A high Sokal score also predicted a significantly inferior probability of MR4; patients with high Euro and high EUTOS score had lower overall estimated probability of MR4, but the difference were not statistically significant. The reasons for IM discontinuation were: lack of efficacy (19%), toxicity or death (9%), withdrawal of informed consent (3%); 4% of patients were lost to follow-up. The 8-year event-free survival (EFS), failure-free survival (FFS), progression-free survival (PFS) and OS were 55% (95% CI: 51-60%), 66% (95% CI: 61-70%), 84% (95% CI: 78-89%) and 85% (95% CI: 79-90%), respectively. A high Sokal and a high Euro scores were able to identify patients with significantly lower probability of EFS, FFS, PFS and OS with respect to the other patients. High EUTOS score patients had significantly poorer EFS and FFS, but PFS and OS differences were not significant. Age, performance status and e13a2 transcript resulted independent prognostic factors on PFS and OS. Conclusions Until now, the available data on the very long-term outcome of newly diagnosed chronic phase CML patients treated frontline with imatinib are limited to a company sponsored study (IRIS study). The GIMEMA CML Working Party provided an unbiased overview of the long-term imatinib therapeutic effects in a multicentric nationwide experience. These results should be taken into consideration to make treatment decision concerning the choice of the first line TKI, particularly in low risk patients. Acknowledgments University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo. Disclosures: Castagnetti: Novartis Farma: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Abruzzese:BMS, Novartis: Consultancy. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Cavo:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Blood ◽

10.1182/blood-2020-139921 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 44-45

Author(s):

Franck E Nicolini ◽

Vincent Alcazer ◽

Pascale Cony-Makhoul ◽

Stephanie Dulucq ◽

Sandrine Hayette ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chronic Phase ◽

Molecular Response ◽

Newly Diagnosed ◽

Front Line ◽

Advisory Committees ◽

Long Term Outcome

Nilotinib (NIL) 600 mg daily has demonstrated its superiority over Imatinib 400 mg daily in terms of response and incidence of deep molecular response in the front-line chronic phase (CP) CML setting. In this observational study we have retrospectively analyzed the outcome of in- and out-study 202 patients (pts) treated in this setting with NIL 600 mg front-line, in "real-life" conditions. All pts with newly diagnosed adult CP-CML receiving NIL 300 mg BID alone front-line between 10/2007 and 06/2020, were eligible for this study. Data were retrospectively collected according to the current French regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2003, 2006, and 2009 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) in case of TFR. In this regard, a TKI was resumed if loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. The primary endpoints were the rate of molecular responses in the long-term and the (vascular) safety of Nilotinib. Secondary endpoints were the kinetics of molecular response, survival and safety of Nilotinib. Survival (OS, PFS & EFS) was defined according to ELN (J. Guilhot et al. Blood 2012). Two hundred and two patients were reported with 44% females and 56% males with a median age at diagnosis of 50.4 (17.5-83) years, and 26% of them had cardiovascular risk factors at onset (tobacco abuse 11%, hypercholesterolemia 9.3%, diabetes 1.45%, none with past history of cardiovascular events [CVE]). ELTS scores were high in 14%, intermediate in 31% and low in 55% of pts. Twenty-four (12%) pts harboured additional chromosomal abnormalities at diagnosis. The median follow-up after NIL initiation was 61.5 (1-147.5) months. At last follow-up 113 pts (55%) are not on NIL anymore for toxicities, TFR or resistance reasons. Twenty-eight (14%) pts present an arterial event on NIL (18% PAOD, 14% angina pectoralis, 7% myocardial infarction, 14% stroke, 47% others such as atrial fibrillation, cardiomyopathy...), that occurred after a median of 26 (0.6-98.5) months on NIL. Forty-six (22.5%) pts reached TFR criteria and stopped NIL after a median of 58.5 (27-126) months. The cumulative incidence (CI) rates of MMR at 1, 2 and 5 years were 64 (57-71)%, 79.4 (75.45-83.35)% and 95 (92-98.5)% respectively. For MR4, those were 35.5 (29-42)%, 60 (52-67)% and 82 (74.5-89)% respectively; and for MR4.5, were 14 (9-19)%, 31 (24-28)% and 62 (54-70.5)% respectively. The CI of sustained MR4.5 (i. e. patients eligible for TFR: MR4.5 ≥2 years) was observed in 30 (23-37)% at 3 years, 45.5 (36-55)% at 5 years and 52.5 (41.5-64)% at 6 years (Figure). The CI of patients entering TFR was 16.75 (10.5-23)% at 5 years and 51.94 (37.31-66.57)% at 10 years with a survival without MMR loss of 70.7 (58- 86)% at 1 year and 65.26 (50.6-84)% at 5 years. Nine (4.5%) pts progressed towards accelerated phase (4 pts) or BC (2 lymphoid, 3 myeloid) responsible for 5 deaths at latest follow-up. Among NIL resistant patients screened, 15 were harbouring ABL1 mutations (5 Y253H, 3 E255K, 3 T315I, 1 M244V, 1 G250E, 1 F359V, 1 V299L). Overall, 10 patients died (5 from CML, 5 from unrelated causes). The probability of OS was 95.75 [95%CI: 92.9-98.7]% at 2 years and 94.8 [91.5-98.3]% at 5 years, for PFS it was 94.92 [91.7-98.2]% at 2 years and 89.5 [84.7-94.6]% at 5 years, and EFS it was 78 [72.3-84]% at 2 years and 60.25 [53.3-68.1]% at 5 years. Regarding sustained MR4.5, univariate analysis showed that female gender (HR=2.46 [1.50-4.02], p<0.001) and low ELTS (HR=0.41 [0.22-0.76], p<0.004) had a significant impact, while multivariate analysis confirmed the role of these 2 factors (HR=2.31 [1.41- 3.79], p=0.001 and HR= 0.52 [0.30- 0.90], p=0.02) in addition to high ELTS (HR= 0.28 [0.14- 0.58], p<0.001). Univariate and multivariate analyses demonstrated that only age impacted on the CI of CVE (HR= 1.07 [1.04-1.10], p<0.001, and HR=1.07 [1.04-1.10], p<0.001). NIL first-line efficiently limits progression of newly diagnosed CP-CML patients and provides high rates of sustained MR4.5, allowing TFR in a substantial proportion of pts. However, the onset of arterial occlusive events, especially in the elderly is a matter of concern in the choice of this compound at treatment initiation. Disclosures Nicolini: Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Cony-Makhoul:BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Dulucq:Incyte: Speakers Bureau; Novartis: Speakers Bureau. Cayuela:Novartis: Speakers Bureau; Incyte: Speakers Bureau. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mahon:ARIAD: Honoraria; Pfizer: Honoraria; Novartis Pharma: Honoraria, Research Funding; BMS: Honoraria. Etienne:Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

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Incidence, Risk Factors, Treatment and Long Term Outcome of Refractory and First Relapse AML Patients in the OSHO Studies

Blood ◽

10.1182/blood-2019-125262 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1358-1358

Author(s):

Dietger Niederwieser ◽

Rainer Krahl ◽

Christoph Kahl ◽

Hans-Heinrich Wolf ◽

Sebastian Scholl ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Remission Induction ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

Advisory Boards

Introduction: Outcome of patients (pts) with refractory AML or following relapse is considered dismal and usually reported as refractory/relapsed. Here we analyzed long term outcome of refractory and relapsing pts separately over a 10 year (y) period from two prospective, non-age-limited, adult AML studies. Results have been published or presented previously as part of the German AML Intergroup studies1,2. However, incidence, characteristics, treatment and outcome of refractory and relapsed pts have not been evaluated. Patients and Methods: A total of 1621 pts from the OSHO 2002 ≤60 y (n=740) and 2004 >60 y (n=881) with newly diagnosed AML (except acute promyelocytic leukemia) and eligible for chemotherapy were analyzed. The gender was male in 51.7% of pts. AML type was de novo in 66.6%, followed by secondary AML in 25.8% and therapy related in 7.6%. Cytogenetic risk status was normal in 47.9%, intermediate in 16.3%, unfavorable in 15.3%, monosomal in 12.6% and favorable in 7.9%. Molecular analysis revealed wildtype (wt) FLT3 in 80.9% and FLT3 ITD mutated (mut) in 19.1% of pts. NPM was mutated in 30.2% of 1124 pts. In the AML 2002 and 2004 studies (NCT 01414231; NCT 01497002; NCT00266136), pts were randomly (9:1) assigned to remission induction by cytarabine (1 g/m2 bid d 1, 3, 5, 7) and Idarubicin (AML 2002) 12 mg/m2/d d 1-31 or mitoxantrone (AML 2004) 10 mg/m2/d iv d 1 - 32 or to a common arm consisting of a 3+7 scheme 3. Pts in complete remission (CR) received consolidation and stem cell transplantation (HSCT) according to cytogenetic risk and donor availability1,2. Pts with partial remission (PR) or non-response (NR) to two induction cycles were considered refractory. Pts achieving CR and relapsing thereafter were considered relapses and treated with MitoFlag or Flag-Ida4. Results: The majority of pts [median age 62 (range 17-87) y] entered CR or CRi after one or two induction cycles (n=1144; 70.6%). OS was 31.9 (29.5-34.4) % @5y and 26.0 (23.4-28.9) % @10y. Results were age dependent and superior in younger pts with an OS of 46.8 (43.1-50.7) % @5y compared to 19.3 (16.7-22.4) % @ 5y in elderly. Age, cytogenetics and NPM1 were determinants for CR and WBC (p<0,001), gender (p<0,05) and AML type (p<0,01) for OS. FLT3-ITD mut was an important determinant for relapse free survival in pts ≤60y. A total of 238 (14.7%) of 1621 pts, 23.5% in the younger and 76.5% in the elderly study, were refractory (PR 60.1%, NR 39.9%). Pts had a median age of 66 (range 23-83)y. OS of refractory pts was 11.4 (7.9-16.6)% @5y, and dependent upon PR [(13.1 (8.1-21.1) % @10y] and NR [5.2 (2.1-12.6) % @5y; p=0.0003]. Intensive chemotherapy ± HSCT and hypomethylating agents (HMA) were able to induce CR in 24.8% of pts. CR and non-CR pts had an OS of 42.7 (31.4-58.2) % @5y and an OS of 3.7 (1.7-8.0) % @2y, respectively. Risk factors for OS in refractory pts were age and type of therapy (p<0.0001). Almost all long term survivors were treated with HSCT. Of the 1144 CR/CRi pts, 582 relapsed 1-121 months (mts) after CR. Relapse occurred in 34.0% ≤6 mts, in 38,8% between 7-18 mts and in 12,2% >18 mts. Age, cytogenetic risk, type of AML, interval CR to relapse and HSCT were the dominant factors for relapse. CR2 was achieved after intensive chemotherapy ± HSCT, ± DLI and HMA in 227 pts (39.0%), 54.5% in the AML 2002 and 28.4% in the AML 2004. OS of relapsed pts was 13.8 (11.1 - 17.3) % @5y and 10.9 (7.4 - 16.2) % @10y and was higher in the younger with 23.4 (18.2-29.9) % @5y as compared to elderly pts 6.9 (4.4 - 11.0) % @5y. Pts with CR2 had a LFS of 24.9 (19.5-31.7) % @5y and was highest in patients <60y when intensive chemotherapy followed by HSCT was involved. Independent risk factors for OS in relapsed pts were age, cytogenetic risk, interval CR1 to relapse and type of therapy. Relapsed pts with HSCT in CR1 showed a trend for reduced survival. Conclusions Outcome of pts with refractory and relapsed AML is unsatisfactory but consistent >10% @5y. A differential response is observed in refractory and relapsed pts and is dependent upon PR, NR and the achievement of CR. Increase of CR rate in younger but especially in elderly pts with second generation TKI, reduction of TRM using FLT3-inhibitor monotherapy and the option to treat pts ineligible to chemotherapy promise better outcome in refractory and relapsed AML. 1Büchner et al. JCO 2012; 2Niederwieser et al Blood 2016; 3Mayer et al. NEJM 1994; 4Thiel et al. Ann Oncology 2015 Disclosures Niederwieser: Daichii: Speakers Bureau; Cellectis: Consultancy. Scholl:Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards; Pfizer: Other: Advisory boards; Novartis: Other: Project funding. Zojer:Amgen: 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. Sayer:Novartis: Other: none. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, 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; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Rituximab Plus Three Cycles of Dexamethasone In the Treatment of Immune Thrombocytopenia (ITP): a Pilot Study.

Blood ◽

10.1182/blood.v116.21.3697.3697 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3697-3697

Author(s):

Rebecca Elstrom ◽

Soo Y. Lee ◽

James B. Bussel

Keyword(s):

Platelet Count ◽

Pilot Study ◽

Board Of Directors ◽

Initial Treatment ◽

Research Funding ◽

Advisory Committees ◽

Equity Ownership ◽

Almost All

Abstract Abstract 3697 Introduction: Rituximab has been a useful treatment for patients with ITP; many hundreds of patients have been treated. 30–40% of patients will achieve a complete remission (CR: platelet count >150 × 109/l) with initial treatment and, of this group, the CR will last at least a year in almost all patients. However, emerging data suggests that at least 40% of these patients in CR will relapse between 1 and 3 years from initial treatment suggesting that long-term “cures” only occur in 20% of the initial patients. Therefore it would be desirable if CR's could be achieved in more patients and especially if these would be durable in more than 20%. One approach would be to use rituximab maintenance, however it results in suppression of B-cells for more than 2 years. Dexamethasone has also been used to achieve “cure” in ITP especially in adults at or near diagnosis. Cheng's study suggested that approximately 50% of patients would achieve a long-term response with only one 4-day cycle of high dose (40 mg/day) dexamethasone (N Engl J Med, 2003). A follow up study from GIMEMA suggested that 3–4 cycles of dexamethasone would be better than 1 cycle (Blood, 2007). Finally, Zaja's study suggested that rituximab plus one cycle of dexamethasone was superior to dexamethasone alone with a > 50% CR rate at 6 months (Blood, 2010). Therefore, we elected to perform a pilot study to explore the combination of rituximab with three cycles of dexamethasone at 14 day intervals. Methods: Patients with ITP with platelet counts < 30,000 off therapy and in need of treatment were enrolled. The standard dose (4 infusions of 375mg/m2) rituximab was given on days 1, 8, 15 and 22 and dexamethasone 40 mg (adjusted for size) on days 1–4, 15–18, and 29–32. Results: Fourteen patients between the ages of 4 and 53 years with ITP were treated with rituximab and dexamethasone (R&D) (Table 1). All had received previous steroid therapy as well as other treatments. The median platelet count was 40,000 at initiation of rituximab (range 7,000-230,000); several patients with low counts started with dexamethasone prior to initiating Rituximab to sustain their counts during initial treatment. Patients received rituximab weekly for between 2 and 4 doses and dexamethasone for either 2 or 3 courses at intervals between 1 and 8 weeks (median 2 week intervals). A summary of the results is shown in table 2 demonstrating short-lived platelet increases in response to dexamethasone in almost all patients. With short follow up, there were 7 CR's, 3 PR's and 4 NR's. If this was divided by duration of ITP prior to R&D, there were 4 CR's and 1 NR for ≤ 12 months and 3 CR, 3 PR, and 3 NR for > 12 months. More of the children who were treated had chronic disease than did adults explaining their apparently poorer response. Observed toxicities included hyperglycemia, grade 1 and 2 liver function abnormalities, weight gain, and 1 episode of colitis requiring hospitalization. Three patients opted to skip the third cycle of dexamethasone. Conclusion: A regimen of rituximab + 2–3 courses of dexamethasone is active in patients with pretreated ITP with appreciable but usually manageable toxicity. It appears to yield superior results if administered to patients within one year of diagnosis. This combination merits further exploration in a prospective clinical trial. Disclosures: Bussel: Portola: Consultancy; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc.: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; Genzyme: Research Funding.

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Stem Cell Transplantation Can Provide Durable Disease Control in Blastic Plasmacytoid Dendritic Cell Neoplasia (BPDC): A Retrospective Study From the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v118.21.3077.3077 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3077-3077

Author(s):

Sascha Dietrich ◽

Damien Roos-Weil ◽

Ariane Boumendil ◽

Emanuelle Polge ◽

Jian-Jian Luan ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Nk Cell ◽

Plasmacytoid Dendritic Cell ◽

Advisory Committees

Abstract Abstract 3077 Blastic plasmacytoid dendritic cell neoplasm (BPDC), formerly known as blastic NK cell lymphoma, is a rare hematopoietic malignancy preferentially involving the skin, bone marrow and lymph nodes. The overall prognosis of BPDC is dismal. Most patients show an initial response to acute leukemia-like chemotherapy, but relapses with subsequent drug resistance occur in virtually all patients resulting in a median overall survival of only 9–13 months. However, anecdotal long-term remissions have been reported in young patients who received early myeloablative allogeneic stem cell transplantation (alloSCT). We therefore performed a retrospective analysis of patients identified in the EBMT registry in order to evaluate the outcome of autologous stem cell transplantation (autoSCT) or alloSCT for BPDC. Eligible were all patients who had been registered with a diagnosis of BPDC or Blastic NK cell lymphoma and had received autologous stem cell transplantation (autoSCT) or alloSCT in 2000–2009. Centres were contacted to provide a written histopathology and immunophenotyping report and information about treatment and follow-up details. Patients who did not have a diagnostic score ≥ 2 as proposed by Garnache-Ottou et al. (BJH 2009) were excluded. RESULTS: Overall, 139 patients could be identified in the database who fulfilled the inclusion criteria (alloSCT 100, autoSCT 39). Of 74 patients for whom the requested additional information could be obtained, central review confirmed the diagnosis of BPDC in 39 patients (34 alloSCT, 5 autoSCT). The 34 patients who had undergone alloSCT had a median age of 41 years (range: 10–70 years), were transplanted from a related (n=11) or unrelated donor (n=23); received peripheral blood stem cells (n=9), bone marrow stem cells (n=19) or cord blood (n=6); and had been treated with a reduced intensity conditioning regimen (RIC, n=9) or myeloablative conditioning (MAC, n=25). Nineteen of 34 patients were transplanted in CR1. After a median follow up time of 28 months (range: 4–77+ months), 11 patients relapsed (median time to relapse: 8 months, range: 2–27 months) of whom 8 died due to disease progression. 9 patients died in the absence of relapse. No relapse occurred later than 27 months after transplant. Median disease free survival (DFS) was 15 months (range: 4–77+ months) and median overall survival (OS) was 22 months (range: 8–77+ months; Figure 1a). However, long-term remissions of up to 77 months after alloSCT could be observed. Patients allografted in CR1 tended to have a superior DFS (p=0.119) and OS (p=0.057; Figure 1b). MAC was associated with a better OS (p=0.001) which was attributable to the significantly higher non-relapse mortality (NRM) rate of patients after RIC (p=0.014), who had been significantly older (age RIC: 56 years, age MAC: 36 years, p=0.0014). The relapse rate was not different in patients after RIC and MAC, respectively. However, there was no survivor after RIC. Median age in the autoSCT group was 47 years (range: 14–62 years). Three of 5 patients were transplanted in CR1 of whom 1 patient relapsed after 8 months, 1 patient experienced treatment related mortality and 1 patient remained in CR for 28 months. The 2 remaining patients had more advanced disease at autoSCT and relapsed 4 and 8 months thereafter. CONCLUSION: AlloSCT is effective in BPDC and might provide curative potential in this otherwise incurable disease, especially when performed in CR1. However, it remains to be shown by prospective studies if the potential benefit of alloSCT in BPDC is largely due to conditioning intensity, or if there is a relevant contribution of graft-versus-leukemia activity. Disclosures: Tilly: Seattle Genetics, Inc.: 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, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses; Genentech: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Janssen Cilag: Speakers Bureau.

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