Interim Analysis of Phase II Study of the Bortezomib-Melphalan-Prednisolone Induction Therapy Followed By Lenalidomide-Plus-Dexamethasone Consolidation and Lenalidomide Maintenance in Non-Transplant Eligible Patients with Newly Diagnosed Symptomatic Multiple Myeloma.

Abstract Background In Japan, the phase II study of bortezomib-melphalan-prednisolone (VMP) for NDMM using the same protocol of VISTA trial revealed that there were more treatment discontinuation in this study than in the VISTA study. We planned five cycles of reduced intensity VMP therapy as an induction. And it is reported that lenalidomide plus low dose dexamethasone (Rd) therapy is very effective regimen after VMP therapy. In order to further improve its outcome, patients are treated with six cycles of Rd and maintenance of lenalidomide after VMP induction. Patients and methods We included 82 pts with NDMM. Pts were received 5 cycles of VMP followed by 6 cycles of Rd. After Rd, pts received maintenance of lenalidomide. VMP included the IV or SQ administration of weekly bortezomib at 1.3 mg/m2 in combination with oral melphalan 6 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4 of a 35-day cycle. Rd treatment consisted of lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly of a 28-day cycle. Lenalidomide maintenance therapy consisted of lenalidomide 10 mg daily on days 1-21 of a 28-day cycle. Results In total, 82 pts were recruited in the trial by 27 Japanese centers between 10/2012 and 8/2014. Median age were 73.5 years (range 61-84), 37.8% were 75 years of age or older, 45.1% were male, 48.8% had International Staging System (ISS) stage II and 20.7% had ISS stage III. Fifty four patients had IgG-type myeloma (65.8%), 19 had IgA-type (23.2%), and 9 had Bence Jones-type (11%). Of the cases analyzed by FISH (N=80), 16.3% had t(4;14), 10% had del 17p and 41.3% had +1q21. Eight patients (10%) had t(4;14) and +1q21, five patients (6.3%) had del 17p and +1q21 and only one patient (1.3%) had t(4;14), del 17p and +1q21. The best response during VMP therapy (the maximum treatment number was 5 cycles) could be evaluated. After five course of VMP therapy, the rates of partial response (PR) or better were 68% including sCR (5%), CR (6%),VGPR (20%) and PR (37%). The best response rate after VMP+Rd (maximum treatment number of Rd was 6 cycles) was also evaluated. The rates of PR or better were 90% including sCR (6%), CR (16%), VGPR (39%) and PR (29%). The most commonly observed grade 3 or higher adverse events during VMP therapy were anemia (30%), neutropenia (16%), thrombocytopenia (5%) and GI toxicity (6%). Summary The induction therapy of reduced intensity VMP was safe and effective. The best response rate after VMP+Rd was very effective. However, we need to evaluate consolidation of Rd and maintenance of lenalidomide after longer follow up. Disclosures Ishida: Takeda: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria. Sunami:Ono: Research Funding; Takeda: Research Funding.

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A Phase II Study of Lenalidomide for Previously Untreated Deletion (del) 5q Acute Myeloid Leukemia (AML) Patients Age 60 or Older Who Are Not Candidates for Remission Induction Chemotherapy (Southwest Oncology Group Study S0605)

Blood ◽

10.1182/blood.v116.21.332.332 ◽

2010 ◽

Vol 116 (21) ◽

pp. 332-332

Author(s):

Mikkael A. Sekeres ◽

Holly Gundacker ◽

Jeffrey Lancet ◽

Anjali Advani ◽

Stephen Petersdorf ◽

...

Keyword(s):

Induction Chemotherapy ◽

Phase Ii ◽

Induction Therapy ◽

Stable Disease ◽

Research Funding ◽

Response Rate ◽

Phase Ii Study ◽

Single Agent ◽

World Health ◽

Remission Induction

Abstract Abstract 332 Background: Older patients (pts, ≥60 years [yrs]) with AML have a dismal prognosis; the majority are not treated with any type of chemotherapy. Many have antecedent myelodysplastic syndromes (MDS), and 20–30% harbor chromosome 5 abnormalities. Lenalidomide (LEN) yields hematologic responses in 67% of lower-risk MDS pts with the del(5q) cytogenetic lesion, and complete responses (CRs) in 20% of higher-risk del(5q) MDS pts, all with isolated lesions. This Phase II study explores the safety and efficacy of single agent LEN in previously untreated older pts with AML and the del(5q) abnormality. Method: Untreated older pts with AML defined by 2001 World Health Organization criteria (without t(15;17)) who harbored a del(5q) cytogenetic abnormality (alone or in combination with other abnormalities) and who declined or were felt to be poor candidates for intensive induction chemotherapy were eligible. Pts were treated with LEN 50mg daily for up to 28 days as induction therapy. Concomitant cytotoxic or growth factor therapies were not allowed. Pts achieving stable disease or better per day 28 bone marrow assessment received post-remission LEN 10mg daily for 21 days of a 28-day cycle until disease progression or unacceptable toxicities. Enrollment from October 2006 through June 2010 was in 2 stages: 20 pts were registered; if at least 1 CR/CRi was observed using International Working Group response criteria, another 20 pts were to be enrolled. The study was designed with a critical level of 4.7% (erroneously concluding the regimen warrants further study if the true response rate is 5% or less) and power of 92% (probability of concluding that a response rate of 20% warrants further study). Result: Of 41 patients enrolled, 4 were excluded (2 without AML, 1 without del(5q), and 1 died prior to receiving therapy), leaving 37 for toxicity and efficacy analyses. Median age was 74 yrs (range, 60–94), 21 (57%) were female, 33 (89%) white, and 19 (51%) had prior MDS. Median presenting white blood cell count was 2,600 mcl (range, 600–658,000), and 30 (81%) had a performance status of 1. Of the 37 evaluable pts, 29 had pretreatment cytogenetic studies evaluated centrally. Two pts displayed no demonstrable abnormalities (but had del(5q) by fluorescence in situ hybridization); 5 had isolated del (5q); and 22 (76%) had complex karyotypes (≥3 abnormalities). Seven patients were removed from protocol therapy due to toxicities (infection, renal, respiratory, gastrointestinal, and rash), and 4 deaths occurred that were at least possibly related to therapy: 2 respiratory, 1 cardiac, and 1 febrile neutropenia. Five additional patients had grade 4 non-hematologic toxicities: hypocalcemia (2), fatigue (2), infection (1). Fourteen pts (38%) completed protocol induction therapy. Four pts (11%) of the 37 evaluable pts achieved CR/CRi following induction therapy, all of whom had complex karyotypes; 3 of the 4 relapsed after 1, 2, and 4 months, and the 4th died 13 months after CR without a report of relapse. Thirteen (35%) pts had stable disease following induction therapy; 8 went on to protocol post-remission therapy. Thirty-three of the 37 pts have died and the median overall survival was 2 months (95% CI, 1 to 4 months). The follow-up time of the 4 survivors was between 6 and 23 months. Conclusion: LEN as a single agent has modest activity and expected toxicity in older del(5q) AML pts, particularly when compared to other single-agent molecularly-targeted approaches, such as FLT3 inhibitors. Future trials will combine LEN with cytoxic or hypomethylator therapies in older del(5q) AML pts. Disclosures: Sekeres: Celgene: Honoraria. Off Label Use: Lenalidomide in (del)5q AML. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.

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The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽

10.1182/blood.v114.22.1661.1661 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1661-1661 ◽

Cited By ~ 6

Author(s):

Brad S Kahl ◽

Hailun Li ◽

Mitchell R Smith ◽

Randy D. Gascoyne ◽

Elisabeth Paietta ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Complete Response Rate ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Complete Response ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

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A Phase II Expansion Study Of Vorinostat In Combination With Idarubicin and Cytarabine For Patients With Acute Myelogenous Leukemia (AML) With FLT3 Molecular Alterations

Blood ◽

10.1182/blood.v122.21.2684.2684 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2684-2684 ◽

Cited By ~ 1

Author(s):

Koichi Takahashi ◽

Elias Jabbour ◽

Farhad Ravandi ◽

Gautam Borthakur ◽

Jorge E. Cortes ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Response Rate ◽

De Novo ◽

Phase Ii Study ◽

High Response Rate ◽

Myelogenous Leukemia ◽

Abnormal Karyotype ◽

Npm1 Mutation ◽

Acute Myelogenous

Abstract Background The combination of vorinostat, idarubicin and cytarabine (IA+vorinostat) is associated with high response rate in patients with newly diagnosed acute myelogenous leukemia (AML) or higher-risk myelodysplastic syndromes (MDS) (JCO 2012;30:2204). In that study, presence of FLT3-ITD was associated with 100% overall response rate (ORR) in 11 patients. To confirm the efficacy of this combination, we extended the phase II study to treat 2 additional cohorts: one for patients with newly diagnosed (untreated cohort) and the other with relapsed and refractory (R/R cohort) AML or higher-risk MDS with FLT3 alteration (both ITD and D835 mutation). Methods Patients with the above diagnosis, ages 15 to 65 years, with appropriate organ function (measured cardiac ejection fraction ≥ 50%, serum creatinine ≤ 2 mg/dl, total bilirubin ≤ 2 mg/dl, and GPT/GOT ≤ 2.5 x upper limit of normal) whose eastern cooperative group (ECOG) defined performance status ≤ 2 were eligible for the study. Study treatment comprised of vorinostat 500 mg orally three times a day (days 1 to 3), idarubicin 12 mg/m2 intravenously (IV) daily x 3 days (days 4 to 6), and cytarabine 1.5 g/m2 IV as a continuous infusion daily x 3 - 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy with lower dose combination and up to 12 months of maintenance therapy with single-agent vorinostat. Result Untreated cohort included 26 patients, whereas 13 patients were treated in R/R cohort (total 39 patients). Thirty six patients had de novo AML, 1 had de novo MDS and 2 had therapy-related AML. For the R/R patients, the median number of prior therapies was 3 (range: 1-6). The median age of the entire study group was 49 (range: 19-64) and 17 (44%) were male. Among the patients whose cytogenetic result were available, 20 (51%) patients had normal and 15 (39%) had abnormal karyotype. By Medical Research Council (MRC) criteria, 30 (77%) patients had intermediate risk and 9 (23%) had poor risk karyotype. Thirty three (85%) patients had FLT3-ITD only, 4 (10%) had both FLT3-ITD and D835 mutation, and 2 (5%) had D835 mutation only. Seventeen (44%) patients had NPM1 mutation. In untreated cohort (N = 26), CR and CRp were documented in 21 (80%) and 2 (8%) patients, respectively (ORR = 88%). In R/R cohort (N = 13), overall response (OR) was observed in 4 (30%) patients (CR in 2 [15%] and CRp in 2[15%]). Of those 4 patients who had OR in R/R cohort, 2 patients were refractory to other high-dose cytarabine-based regimen. The median duration of CR or CRp was 9.2 months (range: 0.1-48.4) in untreated cohort and was 2.9 months (range: 1.6-4.7) in R/R cohort. Twelve (46%) patients in the untreated cohort were bridged to stem cell transplant (SCT) while they were in 1st CR. None of the patients in R/R cohort were bridged to SCT. No difference in response was observed in 1) younger (Age < 60) vs. older patients, 2) normal vs. abnormal karyotype, 3) intermediate vs. poor risk cytogenetics by MRC criteria, 4) presence of RAS mutation, 5) presence of NPM1 mutation, or 6) de novo vs. therapy-related disease. The median overall survival (OS) was 21.7 months (95% CI: 8.1-35.3) in the untreated cohort and was 4.9 months (95% CI: 0.1-10.4) in the R/R cohort. Early treatment related mortality (defined by the death within 4 weeks of the induction) was documented in 1 (4%) patient in the untreated cohort and 2 (15%) patients in the R/R cohort. Toxicity profiles were similar to that reported in the original phase II study (JCO 2012;30:2204). Discussion Vorinostat in combination with IA provides high response rate and durable remission in previously untreateed AML or higher risk MDS patients with FLT3 alteration but is less effective in patients with R/R disease. Phase III randomized study of IA+/- vorinostat in previously untreated AML patients is ongoing (SWOG S1203). Disclosures: Off Label Use: vorinostat in MDS and AML. Cortes:Ambit: Research Funding; Astellas: Research Funding; Argo: Research Funding; Novartis: Research Funding.

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Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study

Blood ◽

10.1182/blood.v124.21.303.303 ◽

2014 ◽

Vol 124 (21) ◽

pp. 303-303 ◽

Cited By ~ 6

Author(s):

Rachid Baz ◽

Thomas G. Martin ◽

Melissa Alsina ◽

Kenneth H. Shain ◽

Hearn J. Cho ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Advisory Committees ◽

Overall Response ◽

Best Response ◽

Randomized Phase Ii ◽

Grade 3

Abstract Background: Pomalidomide-dexamethasone results in an overall response rate of 33% and median PFS of 4.2 months in patients with prior lenalidomide and bortezomib (Richardson et al. Blood 2014). In this randomized phase II trial, we compared pomalidomide-dexamethasone (arm B) versus the addition of oral weekly cyclophosphamide to pomalidomide-dexamethasone (arm C) in patients with lenalidomide-refractory multiple myeloma (MM). We have previously reported that the recommended phase II dose of cyclophosphamide with standard-dose pomalidomide + dexamethasone was 400 mg PO D1, 8, 15. Patients and Methods: Eligible patients had relapsed and refractory MM after at least 2 prior therapies and were lenalidomide refractory. Patients had a platelet count ≥ 50,000/mm3 and ANC ≥ 1,000/mm3 (patients with ≥50% bone marrow plasmacytosis were allowed if platelet count was ≥ 30,000/mm3and ANC could be supported with GCSF during screening and therapy). Patients were randomized (1:1) to receive pomalidomide 4 mg PO D1-21 and dexamethasone 40 mg PO D1, 8, 15, 22 (20 mg if older than 75 years) (arm B) with or without oral cyclophosphamide 400 mg PO D1, 8, 15 of a 28-day cycle (arm C). Patients randomized to arm B were allowed to cross over to arm C in the event of disease progression. Thromboprophylaxis was mandated with aspirin, warfarin, or LMWH. The primary endpoint was overall response rate using IMWG criteria. Secondary endpoints included an evaluation of PFS, OS and safety of the two arms. Results: Between 7/2012 and 3/2014, 36 patients were randomized to arm B and 34 to arm C. Patients characteristics were not different between the 2 arms (table below). The median number of prior therapies was 4 (2-12). All patients were lenalidomide refractory and none received prior pomalidomide. After a median follow up of 15 months, the overall response rate (partial response or better) was 39% and 65% (p=0.03) for arm B and C, respectively. The clinical benefit rate (minimal response or better) was 64% and 79% (p=0.2) for arm B and C, respectively. The median PFS was 4.4 months (95% CI 2.3-5.9) for arm B and 9.2 months (95% CI 4.6-16) for arm C (log rank p=0.04). As of July 2014, 28 patients had died (16 arm B, 12 arm C) with median overall survival of 10.5 versus 16.4 months (p=0.08) for arm B and C, respectively. Hematologic grade 3/4 adverse events were more frequent in arm C, although this was not statistically significant (see table). Thirteen patients crossed over and oral weekly cyclophosphamide was added to their tolerated dose of pomalidomide dexamethasone. For those patients, the best response was as follows: 2 PR, 2 MR, and 6 SD, 3 PD. Conclusions: Pomalidomide-dexamethasone in combination with oral weekly cyclophosphamide resulted in a superior response rate and PFS compared to pomalidomide-dexamethasone alone in patients with relapsed and refractory MM. The increased hematologic toxicities, as a result of the addition of oral cyclophosphamide, were manageable. Table Arm B (N=36) Arm C (N=34) P value Age, years, median (range) 63 (50-78) 64 (47-80) 0.7 Male, n (%) 23 (64) 18 (53) 0.3 Number of prior therapies, median (range) 4 (2-12) 4 (2-9) 0.5 Bortezomib refractory, n (%) 28 (78) 24 (71) 0.3 Carfilzomib refractory, n (%) 16 (44) 13 (38) 0.5 Prior high-dose therapy, n (%) 27 (75) 28 (82) 0.6 Prior alkylating agent, n (%) 32 (89) 32 (94) 1 B2-microglobulin, median (range) 3.2 (1.6-10) 3.6 (1.5-13.9) 0.5 Serum creatinine, median (range) 1 (0.5-2.3) 0.9 (0.6-2.1) 0.6 High-risk cytogenetics, n (%) 5 (24) 6 (28) 0.8 Deletion 17p, n (%) 3 (14) 4 (20) 0.8 t(4;14), n (%) 3 (14) 3 (14) 0.9 Trisomy or tetrasomy 1q, n (%) 11 (55) 6 (33) 0.4 Best response (partial response or better), n (%) 14 (39) 22 (65) 0.03 Clinical benefit rate (MR or better), n (%) 23 (64) 27 (79) 0.2 Grade 3/4 neutropenia, n (%) 12 (33) 17 (50) 0.2 Grade 3/4 febrile neutropenia, n (%) 4 (11) 6 (18) 0.5 Grade 3/4 thrombocytopenia, n (%) 2 (5) 5 (15) 0.2 Grade 3/4 anemia, n (%) 3 (8) 7 (20) 0.2 Grade 3/4 pneumonia, n (%) 4 (11) 3 (9) 1 Grade 3/4 fatigue, n (%) 2 (5) 4 (12) 0.4 Number of serious adverse events 17 20 Disclosures Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Karypharm: Research Funding; Sanofi: Research Funding. Off Label Use: Pomalidomide cyclophosphamide dexamethasone in relapsed refractory myeloma. Martin:Sanofi: Research Funding; Novartis: Speakers Bureau. Alsina:Triphase: Research Funding; Millenium: Research Funding. Shain:Onyx / Amgen: Research Funding; Treshold: Research Funding. Chari:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

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Final Results of the Phase I/II Study of Chemosensitization Using the CXCR4 Inhibitor Plerixafor in Combination with Bortezomib in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.4256.4256 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4256-4256 ◽

Cited By ~ 1

Author(s):

Irene M. Ghobrial ◽

Kenneth H. Shain ◽

Jacob Laubach ◽

Patrick Henrick ◽

James Vredenburg ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Plasma Cells ◽

Response Rate ◽

Phase Ii Study ◽

Median Number ◽

Recommended Dose ◽

Advisory Committees

Abstract PURPOSE: This study aimed to determine activity and safety of the CXCR4 inhibitor plerixafor in combination with bortezomib and dexamethasone in patients with relapsed or refractory Multiple Myeloma (MM). This was based on our preclinical studies showing that plerixafor (Mozobil, Sanofi Corporation) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. PATIENTS AND METHODS: Theprimary endpoint of the phase I study was the maximum tolerated dose (MTD) and for the phase II study, the safety and response rate of the combination. Eligibility criteria included patients with relapsed or relapsed/refractory MM with 1-5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib). The phase I included 8 cohorts with different doses and two treatment schedules. In cohorts 1-5, patients received plerixafor at the recommended dose sq on days 1-6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. In cohort 5b-6, plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. For the phase II portion patients received plerixafor at the MTD established in phase I of trial, 320 mcg/kg sq on days 1, 2, 3, 6, 10, and 13. Bortezomib was given 1.3 mg/m2 IV or sq twice a week on days 3, 6, 10, 13, every 21 days. Dexamethasone was given at 40mg on days of Bortezomib. RESULTS: A total of 58 patients were enrolled on this study from June 2009 to March 2015, with 25 on the phase I and 33 on the phase II study. In the phase I study, the median age was 60 years (range, 43-85), the median number of prior therapies was 2 (range, 1-4), with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 4 (1-12). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). Therefore, 3 additional patients were enrolled at dose level 5b (plerixafor 0.32 mg/kg and bortezomib 1.3 mg/m2). There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). Twenty-three patients were evaluable for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response (VGPR), 1 partial remission (PR) and 2 (9%) MR, and 15 (65%) having stable disease with only 3 (13%) progressive disease (PD). In the phase II study, the median age was 63 (46-83). The median number of prior therapies was 2 (1-5), with 22 (66%) who have received prior bortezomib. The median number of cycles on therapy is 5 (1-24). The response rate included 5 VGPR (16%), 11 PR (35%) with an overall response rate of 51% and another 11 (35%) stable disease. Grade 3/4 toxicities included thrombocytopenia (68%), lymphopenia (6%), hypophosphatemia (2%), anemia (4%), infections (4%), hyponatremia (2%), hypercalcemia (2%) and neurological toxicity (2%). We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. CONCLUSIONS: The combination of plerixafor and bortezomib is generally well tolerated with minimal neuropathy or other toxicities seen to date. The responses observed are strongly encouraging with 51% ORR in this relapsed and refractory population. This study was supported by R01CA133799-01, and by Sanofi and Takeda Corporations. Disclosures Off Label Use: Plerixafor in myeloma. Azab:Verastem: Research Funding; Selexys: Research Funding; Karyopharm: Research Funding; Cell Works: Research Funding; Targeted Therapeutics LLC: Other: Founder and owner . Schlossman:Millennium: Consultancy. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: 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; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees.

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AGMT MALT-2: A Phase II Study of Rituximab Plus Lenalidomide in Patients with Extranodal Marginal Zone B-Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT lymphoma)

Blood ◽

10.1182/blood.v126.23.3973.3973 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3973-3973 ◽

Cited By ~ 3

Author(s):

Barbara Kiesewetter ◽

Richard Greil ◽

Wolfgang Willenbacher ◽

Peter Neumeister ◽

Michael A. Fridrik ◽

...

Keyword(s):

Adverse Events ◽

B Cell ◽

Phase Ii ◽

Malt Lymphoma ◽

Research Funding ◽

Systemic Treatment ◽

Phase Ii Study ◽

Gastric Malt Lymphoma ◽

Best Response ◽

Disseminated Disease

Abstract Background: Chemotherapy-containing regimens are effective for the treatment of advanced MALT lymphoma. However, due to the indolent course of this disease immunomodulatory strategies appear reasonable. Lenalidomide was active as monotherapy for MALT lymphoma and addition of rituximab (R) achieved promising results in several B-cell malignancies. Methods: The AGMT MALT-2 study is a multicenter phase II study for the treatment of MALT lymphoma with R-lenalidomide (also referred to as "R2"). Treatment consisted of R 375 mg/m2 day 1 and lenalidomide 20 mg day 1-21 in a four-week cycle. In the case of gastric MALT lymphoma and Helicobacter pylori (HP)-infection patients had to be refractory to HP-eradication prior to inclusion. HP-negative or extragastric patients were directly eligible. In case of complete remission (CR) after 6 courses treatment stopped while those with partial remission (PR) or stabilization (SD) were eligible for 8 courses. All patients received prophylactic ASA (100 mg/day) during treatment and allopurinol (300 mg/day) for the first 8 weeks. The primary endpoint of the study was the objective response rate (ORR) defined by radiological or GELA histological response criteria, respectively. The secondary endpoint was safety. These are our final results. Results: A total of 50 patients were enrolled but four patients were excluded and replaced according to protocol, including two patients who withdrew informed consent before the first dose of treatment due to personal reasons. Of 46 evaluable patients 28 (60.9%) were female while 18 (39.1%) were male. Median age at initiation of treatment was 64 years with an interquartile range of 53-72 years. 28.3% (13/46) of patients had primary gastric MALT lymphoma while the majority of patients i.e. 71.7% (33/46) had primary extragastric manifestations (28% ocular adnexa, 11% lung, 11% disseminated disease, 7% parotid gland and 15% other localizations). 63.0% (29/46) of patients had localized disease and 37.0% (17/46) presented with advanced/ disseminated disease. ECOG status was 0 or 1 in 97.8% (45/46) of patients. 23.9% (11/46) of patients had received prior systemic treatment including one patient pretreated with lenalidomide and 9 pretreated with R-containing regimens. Treatment with R-lenalidomide resulted in an ORR of 80.4%. 54.3% (25/46) achieved CR, 26.1% (12/46) PR, and 17.4% (8/46) SD as best response. One patient progressed at cycle three but received successful salvage treatment. Median time to best response was 5.2 months (95% CI; 2.8-5.7). The mean number of applied treatment cycles was 6 (95% CI; 5.6-6.6). Fourteen patients (30.4%; 14/46) benefited from the extended treatment phase and converted to a deeper response between restaging at cycle three and restaging at cycle 6 (11/14) or 8 (3/14), respectively. Univariate analysis for response according to gender (male vs. female) (p = 0.691), primary localization of MALT lymphoma (gastric vs. extragastric) (p = 0.654), prior systemic treatment (p = 0.895), and localized vs. disseminated disease (p = 0.197) was not significantly different for groups. 48 patients received at least one dose of R-lenalidomide and were included in the toxicity analysis. Tolerability in terms of non-hematologic adverse events was good with no toxicity grade IV reported. 37.5% (18/48) of patient experienced mild infusion reactions following R. Common adverse reactions to lenalidomide consisted of mild fatigue in 33.3% (grade I/II = 16), musculoskeletal pain in 41.7% (I/II = 18, III = 2), cough or respiratory infections in 33.3% (I/II = 13, III = 3), diarrhea in 22.9% (I/II = 10, III = 1) and mild vertigo in 22.9% (I/II = 9, III = 2). Typical lenalidomide-associated exanthema occurred in 45.8% patients but was usually mild (I/II = 19, III = 3). Hematologic adverse events were rare with a rate of grade III/IV neutropenia below 20% (18.8%; 9/48). Dose reduction of lenalidomide due to adverse events was necessary in 34.8% (15 mg = 12, 10 mg = 4). Four patients discontinued treatment early due to adverse events. After a median follow-up of 27.2 months (range; 13.2-36.3) three patients have relapsed at 5.0-8.8 months suggesting durable responses in the majority of cases. No second malignancies were observed. Conclusion: This is the first study on efficacy of R-lenalidomide for MALT lymphoma. With an ORR of 80% and a CRR of 54% we could improve the results achieved with lenalidomide-monotherapy in a prior pilot trial. Disclosures Off Label Use: lenalidomide for MALT lymphoma. Greil:AOP Orphan: Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Merck: Honoraria; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding; Celgene: Consultancy; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche, Celgene: Honoraria, Research Funding. Willenbacher:Roche, Celgene: Consultancy, Honoraria, Research Funding. Fridrik:Roche: Consultancy, Honoraria. Markus:Celgene, Roche, EISAI, Novartis, IPSEN: Honoraria.

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Amonafide L-Malate (AS1413) in Combination with Cytarabine Is Equally Effective in Older and Younger Patients with Secondary Acute Myeloid Leukemia (AML); Final Data From a Phase II Study.

Blood ◽

10.1182/blood.v114.22.1047.1047 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1047-1047 ◽

Cited By ~ 2

Author(s):

Harry P Erba ◽

Margaret O'Donnell ◽

Steven L Allen ◽

Maria R Baer ◽

Bayard L Powell ◽

...

Keyword(s):

Complete Remission ◽

Phase Ii ◽

Induction Therapy ◽

Research Funding ◽

Phase Ii Study ◽

Phase Iii ◽

Remission Induction ◽

Younger Patients ◽

Poor Risk ◽

Hematopoietic Recovery

Abstract Abstract 1047 Poster Board I-69 Background: A major issue in the treatment of AML is the low response rate achieved with standard remission induction therapy in patients with “poor-risk” prognostic factors. One such poor-risk factor is secondary AML (sAML), AML following myelodysplasia or cytotoxic therapy for other malignancies. sAML is strongly associated with multi-drug resistance (MDR) mechanisms: up to 70% of sAML patients show overexpression of P-glycoprotein (Pgp) or other MDR mechanisms. Amonafide L-malate (amonafide, AS1413) is a unique DNA intercalator that is not a substrate for MDR, unlike anthracyclines commonly used in the treatment of AML. This phase II study evaluated amonafide in combination with cytarabine in patients with sAML. Methods: Patients received amonafide 600 mg/m2/day IV on days 1-5 and cytarabine 200 mg/m2/day IV by continuous infusion on days 1-7. Induction was repeated if leukemia persisted on day 14 marrow examination. Consolidation consisted of hematopoietic stem cell transplant (HSCT; n=10) or intermediate-dose (n=13)/high-dose (n=7) cytarabine, depending on age and HSCT donor availability. Bone marrows were centrally reviewed. The primary endpoint was complete remission with (CR) or without (CRi) hematopoietic recovery; secondary endpoints were duration of remission (DOR), survival and safety. Results: 88 patients with a median age of 62.5 years (range 23-87) were treated; Of these, 45 (51%) had received prior leukemogenic therapy (tAML) and 43 (49%) had prior MDS; 1 (1%) had favorable, 36 (41%) had intermediate and 42 (48%) had unfavorable cytogenetics. Overall CR + CRi rate was 42% (CRi 3%); median duration of remission (DOR) was 312 days. CR rates and DOR among age <60 and ≥60, 13/33 (39.4%), 312 days and 24/55 (43.6%), 316 days; among tAML and prior MDS, 18/45 (40%), 512 days and 19/43 (44.2%), 186 days; intermediate and unfavorable cytogenetics, 23/36 (61.1%), 282 days and 10/42 (23.8%), 322 days. Median overall survival for the whole population was 200 days and for responders 435 days. Non-hematologic grade ≥ 3 adverse events included febrile neutropenia (35%), hypotension (16%), pneumonia (14%), respiratory failure (11%), and bacteremia (11%). The death rate within 28 days of induction therapy was 20.5%. Median time to hematopoietic recovery of neutrophil count > 500/cmm and platelets of 20,000/cmm was 29 and 28 days, respectively. Conclusions: Amonafide produced a high complete remission rate and durable responses in both older and younger patients with sAML. Efficacy was maintained across several poor-prognosis subgroups frequently characterized by MDR, for which amonafide is not a substrate. A phase III study (ACCEDE) is evaluating amonafide + cytarabine vs. daunorubicin + cytarabine in patients with sAML. Disclosures: Erba: Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria; Pharmion: Honoraria; MGI Pharma: Honoraria; Cephalon: Honoraria, Research Funding; Wyeth: Research Funding; Antisoma: Research Funding; Lilly: Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding. O'Donnell:Genzyme: Consultancy; Eisai: Consultancy; Celgene: Consultancy. Allen:Antisoma: Research Funding. Powell:Antisoma: Research Funding. Stone:Celgene: Consultancy, Speakers Bureau; Merck: Consultancy; Genzyme: Consultancy; Eisai: Consultancy. Bennett:Antisoma: Consultancy. Lundberg:Antisoma: Employment. Capizzi:Antisoma: Consultancy. Rizzieri:Antisoma: Research Funding.

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Final Results of Phase I/II Trial of the Oral mTOR Inhibitor Everolimus (RAD001) in Combination with Bortezomib and Rituximab (RVR) in Relapsed or Refractory Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood.v124.21.3081.3081 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3081-3081 ◽

Cited By ~ 2

Author(s):

Irene M. Ghobrial ◽

Robert Allyn Redd ◽

Jeffrey Matous ◽

Philippe Armand ◽

Erica N Boswell ◽

...

Keyword(s):

Maintenance Therapy ◽

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Advisory Board ◽

Advisory Committees

Abstract Background: Waldenstrom Macroglobulinemia is a distinct lymphoplasmacytic lymphoma. Several clinical trials have shown high rates of response in patients with relapsed WM using bortezomib and rituximab combinations. In addition, the TORC1 inhibitor everolimus has previously shown a high response rate of 70% in this patient population. In this trial, we aimed to examine the safety and activity of the combination of everolimus with bortezomib and rituximab (RVR) and to determine whether a deep response can be achieved with a triple combination of targeted therapeutic agents in WM. Methods: The phase I portion of the study evaluated the maximum tolerated dose of everolimus, rituximab combination or RVR combination, while the phase II portion evaluated the depth of responses to the RVR combination. Patients were eligible for this trial if they had relapsed or refractory WM. There was no limit on the number of prior therapies. Patients were required to be ≥18 years old and have measurable and symptomatic disease. For the phase I, patients were assigned to a dose level in the order of study entry. In the dose-escalation scheme, everolimus was given at 5 or 10 mg PO with rituximab, or with bortezomib at 1.3 or 1.6 mg/m2 and rituximab. Rituximab was given at a fixed dose of 375 mg/m2 IV. In the phase II, patients received everolimus 10 mg flat dose PO daily, Bortezomib IV 1.6mg/m2 weekly on days 1, 8, 15 q 28 days and rituximab IV 375 mg/ m2 weekly on days 1, 8, 15 22 q 28 days on cycles 1 and 4 only. Treatment was daily and 4 weeks (28 days) was considered one cycle. Patients received a total of 6 cycles followed by maintenance therapy with everolimus 10 mg PO daily until progression. Dexamethasone was not permitted. Patients were assessed every cycle while on combination therapy, and every 3 months while on maintenance therapy. Patients with stable disease (SD) or responding disease could continue therapy until progression. Results: From April 2010 to July 2013, a total of 46 patients were enrolled on this trial; of these, 23 patients were in the phase I study and 23 patients in the phase II study. The median number of prior treatments was 2 (range 1-9) Prior therapies received included bortezomib-based therapy (26, 56%) and rituximab (45, 98%). Median treatment duration was 10 months (range, 3 weeks to 41 months) for all patients. There were no DLTs observed and no deaths occurred on this study. The most common toxicities in all patients on study were fatigue (29 patients, 63%); anemia and leukopenia (each in 24 patients, 52%); neutropenia (22, 48%); diarrhea (20, 43%); and neuropathy, pneumonitis/pulmonary infiltrates (each in 19 patients, 41%). The overall response rate (ORR) which includes patients with minor response (MR) or better in the phase II study (N=23) was 91% (95% CI, 72-99%) with 1 CR, 1 VGPR, 16 PR, and 3 MR. When all 36 patients on the phase I and phase II studies who received full dose of RVR were combined, the ORR was 89% (95% CI 74 – 97%), with 2 CR, 3 VGPR, 21 PR, and 6 MR. Conclusions: The RVR regimen is safe and well tolerated. RVR led to an overall response rate of 89% with PR or better achieved in 72% making this a highly effective regimen even in patients previously treated with bortezomib and/or rituximab. This study represents one of the first combination efforts of novel agents targeting the PI3K signaling pathway with a proteasome inhibitor. Disclosures Ghobrial: Sanofi: Research Funding; Noxxon: Research Funding; BMS: Advisory board, Advisory board Other, Research Funding; Onyx: Advisory board Other; Millennium: 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. Off Label Use: Bortezomib and everolimus are not approved for WM. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Anderson:Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy.

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Phase II Study on Bortezomib (BTZ) in Multiple Relapsed or Refractory Pediatric Acute Lymphoblastic Leukemia (rALL): High Response Rate with a Modestly Intensive Regimen Including BTZ, Not Related to Pharmacokinetics

Blood ◽

10.1182/blood.v126.23.2501.2501 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2501-2501

Author(s):

Gertjan J.L. Kaspers ◽

Denise Niewerth ◽

Bram Wilhelm ◽

Satianand Ramnarain ◽

Hans Berkhof ◽

...

Keyword(s):

Clinical Research ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Response Rate ◽

Phase Ii Study ◽

Interindividual Variation ◽

Research Support ◽

Off Label ◽

Blast Count

Abstract BTZ is a proteasome inhibitor and could improve the poor prognosis of rALL (Messinger 2012). We developed a European phase II study in pediatric rALL, in which patients were randomised for 'early' or 'late' BTZ, in compliance with the Declaration of Helsinki. BTZ was given as iv push for 4 doses at 1.3 mg/m2/dose, in group 'early' on days 1, 4, 8 and 11 and in group 'late' on days 8, 11, 15 and 18. All patients also received DXM (10 mg/m2/day in 3 doses for 2 weeks) and VCR (1.5 mg/m2/dose (maximum 2 mg) as 1-hour infusion on days 8 and 15), plus intrathecal methotrexate (i.t. MTX, dose age-adjusted) on day 1. Cycles could be repeated in case of a good response. The number of 12 patients in each group provides a power of 80% to detect a statistically significantly lower absolute number of circulating leukemic blasts on day 8 of treatment in patients exposed to 'BTZ early' as compared to patients not yet exposed to BTZ ('BTZ late') of at least 30% (2-sided test, alpha <0.05). Between October 2010 and September 2014, 29 patients with information on response and/or toxicity after cycle 1 enrolled, 17 boys and 12 girls, median 9.7 years of age (range, 1 - 17.5). Most had second or subsequent rALL (n=16). The primary endpoint, day 8 absolute blast count, was evaluable in 26 patients (n=2 not eligible for the primary endpoint in retrospect, n=1 no material received), and was not different between 'BTZ early' (n=13) and 'BTZ late' (n=13). Absolute blast count had decreased at day 8 in both 'BTZ early' (p =0.017) and 'BTZ late' (p =0.046) compared to day 1 blast count, but to the same extent (median 85-86% decrease). Regarding response after cycle 1, 25 patients were evaluable (n=2 discontinued treatment due to toxicity, n=2 no material received). Nine patients (36%) achieved a complete remission with incomplete blood count recovery (CRi), 6 (24%) a partial remission (PR), and 10 had a treatment failure (TF), for a total response rate of 60%. There was no relation between remission status and the administration of BTZ being early or late (p =0.7). There was no association between response and disease status, although numbers were small (p =0.8). Four patients with a relapse after allo-SCT achieved CRi, as well as 5 patients with a second or subsequent relapse. Grade 3 or 4 hematological toxicities were thrombopenia (n=29), leukopenia (n=23), neutropenia (n=25), and anemia (n=21). Most common grade 2-4 neurotoxicities were pain (n=9) and peripheral neuropathy (PN) (n=5). Thirteen patients received a second cycle, when one patient developed grade 2 PN and one patient with PN advanced from grade 2 to 3. There was remarkable intra- and inter-individual variability in peak plasma concentrations 15 min after the first administration of BTZ, ranging from 0.7 to 715 ug/L (median 12 ug/L, excluding 2 outliers above limit of quantification (2500 ug/L)). The area-under the plasma concentration curve (AUC) had a 25-fold interindividual variation: median 0.27 ug.h/L (range 0.07 - 1.77). Mean clearance in plasma was 1.1 L/h, with a interindividual variability of 95%. Median bone marrow concentrations of BTZ were 49 ug/kg (range: 1.6 - 106 ug/kg). In most patients, no BTZ was detected in the CSF, with a lower detection limit of 0.05 ng/ml. In 9 patients BTZ was detected at 0.07 - 5.2 ug/L. No correlation between AUC and concentration in CSF was found (r2 = 0.11). The 50% inhibitory concentration (IC50) of 20S activity in plasma was 10.7 ug/L. Plasma pharmacokinetic and pharmacodynamic parameters did not correlate with response to treatment. In conclusion, BTZ in combination with VCR and DXM and i.t. MTX is effective in a significant subset of pediatric rALL, with 60% of patients achieving PR or CRi. Because administration of BTZ early or late showed similar early treatment responses, randomized studies with more patients are necessary to determine the additive value of BTZ to conventional chemotherapy. Repetitive cycles could be given in several children without undue toxicity. In view of the observed toxicity, it might be wise to give these patients subcutaneous BTZ or novel proteasome inhibitors. BTZ does not or hardly penetrate the cerebrospinal fluid. This research is financially supported by the Dutch Foundation Children Cancer-free (clinical research support) and by Janssen Pharmaceuticals (clinical research support and free drug). Disclosures Kaspers: Janssen-Cilag: Research Funding. Off Label Use: Bortezomib off-label for pediatric ALL. Zwaan:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding.

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A Phase II Study of the Efficacy and Tolerance of Azacytidine (AZA) in Steroid Dependent/Refractory Systemic Autoimmune and Inflammatory Disorders (SAID) Associated with MDS or CMML (GFM- AZA-SAID -trial)

Blood ◽

10.1182/blood-2021-150904 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3697-3697

Author(s):

Arsène Mékinian ◽

Lin-Pierre Zhao ◽

Kristell Desseaux ◽

Rose Rose ◽

Laurent Pascal ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Phase Ii Study ◽

Immunosuppressive Treatment ◽

Joint Involvement ◽

Significant Prognostic Factor ◽

Hematological Response ◽

Steroid Dependent ◽

Significant Difference

Abstract Background: Systemic autoimmune and inflammatory diseases (SAIDs) occur in 10-15% of MDS or CMML patients. They are often severe, difficult to treat and steroid resistant/dependent disorders. In a retrospective report of 22 patients with steroid-dependent MDS/CMML associated SAID, we observed promising results with azacytidine (AZA) on the SAID component (Fraison et al, Leuk Res, 2016). In this prospective French nationwide trial, we aimed at confirming this effect prospectively. Patients and Methods: This open-label, single-arm multicenter, phase II study included MDS/CMML patients with IPSS/CPSS int 2 or high, or lower IPSS/CPSS but with significant cytopenias, especially ESA resistant anemia (or, for CMML, proliferative features) and SAID with steroid dependence and/or resistance. The primary endpoint was response rate (RR, including CR and PR) of SAID after 6 cycles of AZA. Secondary endpoints included RRof SAID after 3 cycles of AZA, response of MDS, time to MDS progression (including to AML), overall survival (OS) and safety. AZA was used at 75 mg/m²/d x 7 days, every 4 weeks for a minimum of 6 cycles (unless overt disease progression occurred before). At the onset of AZA, prednisone (PRED) was administered at 1 mg/kg during 1 month and then decreased progressively over 6 months. Results: 30 patients were included between July 2017 and June 2020 , 29 of whom received AZA and were considered evaluable: median age 72 [range 68-78], 69% males; WHO: MDS ML (n=11; 41%), CMML (n=11, 41%), MDS-RS (n=2, 7%), EB-1 (n=1) and EB-2 (n=1), unclassified (n=3); IPSS-R : good (n=15, 54%), very good (n=3; 11%, each), intermediate (n=7; 25%) and very poor profile (n=3; 11%) (all CMML had WBC <13G/l and could be classified by IPSS-R). SAIDs features included non-infectious fever (n=5; 17%), skin lesions (n=14; 48%), joint involvement (n=18; 68%), chondritis (n=6; 21%) and peripheral nervous system impairment (n=3; 10%). 11 (38%) /28 tested patients had UBA1 mutation (VEXAS syndrome), while inin the remaining cases SAID was vasculitis (n=5), rheumatic disease (n=6), neutrophilic dermatosis (n=2) and others (n=5). 19 patients (65.5%, IC95% [45.7.82.1]) obtained a SAID response after 6 cycles (including 8 CR and 11 PR), while 17 (58.6% (IC95% [38.9; 76.5]) patients achieved an IWG 2006 hematological response (7 CR, 9 SD with HI and 1 marrow CR). All the 13 patients who received 12 cycles of AZA achieved SAID CR or PR at 12 months, and 10 of them had a hematological response (6 CR, 1PR, 2 HI, 1 marrow CR). The SAID response rate at 12 month was at 72.4% (IC95% : [51.3;85.6]). SAIDs complete/partial response occurred in 3/9 (33%) UBAI-positive versus 8/19 (42%) non-mutated cases. No significant prognostic factor of SAID response after 6 cycles, including sex, age, WHO classification, IPSS-R, UBA1 and TET-2 mutation status was found. With a median follow-up of 18.5 months [11.8; 24.3], 9 (31%) patients had died, with a 1-year OS of 82.3% (IC95% [69.4; 97.7]. At least one SAE occurred in 23 patients, with a median of 2 events/patient [1.5; 5.5]. Death was due to infection (n=5, two of them in patients with good IPSS-R, but severe steroid dependent SAID), MDS progression (n=2), or unrelated causes (n=2). Conclusion We confirmed prospectively an effect of AZA on the autoimmune/inflammatory component in two thirds of MDS/CMML patients with steroid dependent / refractory concomitant systemic autoimmune/inflammatory disease. No significant difference in AZA response was noted between UBA1 mutated and unmutated MDS patients. The adverse events and mortality rates, often from infectious origin, appear to be those expected in such an MDS population, potentially worsened by the associated SAID and background of immunosuppressive treatment (especially steroids) Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Ades: ABBVIE: Honoraria; TAKEDA: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

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