Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma Overcomes Negative Prognostic Impact of Adverse Cytogenetics and Prior Resistance to Lenalidomide and Bortezomib

Abstract Background: Pomalidomide is a distinct IMiD¨ immunomodulatory agent with activity in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide (LEN) treatment. We have previously reported that the addition of clarithromycin enhances the anti-myeloma activity of pomalidomide+dexamethasone (Pom/Dex) in the treatment of RRMM (Mark et al, ASH 2012). We now report on the clinical benefit of ClaPd with regard to the presence of the negative prognostic features of adverse cytogenetics and prior resistance to novel agents. Methods: One hundred twenty patients (pts) with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPd. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included LEN. ClaPd is clarithromycin 500 mg twice daily, pomalidomide 4mg for days 1-21, and dexamethasone 40 mg on days 1,8,15,22 of a 28-day cycle. All subjects had thromboprophylaxis with 81 mg aspirin daily. Disease response evaluation was performed monthly with serum and urine protein electrophoresis, immunofixation, and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Cytogenetic testing was performed on CD138-selected cells. Treatment was continued as tolerated by the patient until disease progression. Results: One hundred seventeen pts had completed at least 1 cycle of ClaPd and were eligible for disease response analysis at data cut-off. All pts were included in the survival analysis. Median time on study was 7.2 months (range 0.3-55.8). Patients had undergone a median of 5 (range 3-15) prior lines of therapy. High risk cytogenetics were present in 72 patients (64%, n =113) as per IMWG definition. The proportion of patients who were refractory to LEN, refractory to bortezomib (BORT), and double (LEN+BORT) refractory were 84%, 78%, and 68%, respectively. The median number of ClaPd cycles was 8 (range 1-56). Median progression-free survival (PFS) and duration of response for the entire cohort was 7.7 and 9.3 months. Overall response rate for the overall, LEN-refractory, BORT-refractory, and double-refractory cohorts did not differ significantly, Table 1. Median PFS for high vs low-risk cytogenetic groups did not differ significantly: 7.7 vs 8.3 months (P = 0.5038); however, subjects with del17p (n=27) had significantly shorter PFS at 3.73 vs 8.67 months (P = 0.0036). The presence of t(4;14) (n= 11), t(14;16) (n = 7), gain 1q (n = 46) in the absence of concurrent del 17p had no significant impact on PFS. Median PFS was not affected by LEN-refractory, BORT-refractory, or double-refractory MM status at 7.7 (P = .5193), 6.5 (P = 0.2618), and 5.8 months (P = 0.2163) respectively. Median overall survival (OS) for the group was 19.3 months (CI 14.2, 26.7). Loss of 17p was associated with significantly shorter survival at 13.2 vs 25 months (P = .0008). Other adverse cytogenetic factors did not affect OS. Median OS was not affected by LEN-refractory, BORT-refractory, or double-refractory MM status at 19.2 (P = .9355), 16.8 (P = 0.5983), and 16.8 months (P = 0.3893) respectively. Conclusions: ClaPd is a highly effective and tolerable regimen for heavily treated RRMM that has progressed after prior treatments. Response rates are higher and survival outcomes are longer than expected from prior reports of Pom/Dex activity in similar populations. The presence of double refractory disease did not significantly impact clinical outcomes. Known adverse cytogenetic factors did not affect observed PFS and OS with the exception of del 17p leading to approximately 50% decrease in PFS and OS. This 17p OS result is consistent with previously reported data by Leleu (2015, OS = 12 months); however for ClaPD, t(4;14) had no impact while Leleu 2015 reported decrease in OS to 9.2 months with Pom/Dex. This finding may be due to sampling error due to the relatively low % of pts with t(4;14) (10%) in our study as opposed to the 64% in the Leleu report. Table 1. Best Response (IMWG Criteria) n (%) Overall (N = 117) Lenalidomide-refractory (n = 101) Bortezomib-refractory (n = 94) Double-Refractory (N = 81) ORR (>= PR) 70 (60) 59 (58) 52 (55) 44 (54) CBR (>= MR) 78 (67) 66 (65) 83 (88) 51 (61) sCR 6 (5) 6 (6) 5 (5) 5 (6) CR 1 (1) 1 (1) 1 (1) 1 (1) VGPR 20 (17) 15 (15) 14 (15) 9 (11) PR 43 (37) 37 (37) 32 (34) 29 (36) MR 8 (7) 7 (7) 7 (9) 7 (9) SD 29 (25) 23 (23) 24 (26) 20 (25) PD 10 (9) 10 (10) 8 (9) 8 (10) Disclosures Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Off label use of clarithromycin in combination with pomalidomide for treatment of relapsed myeloma. . Rossi:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Pearse:Celegen: Consultancy. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Perry:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Huang:Celgene: Research Funding. Chen-Kiang:Celgene: Consultancy. Niesvizky:Celgene: Consultancy, Speakers Bureau.

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Prognostic Impact of CD20 and CD25 Expression in Patients with Philadelphia-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL).

Blood ◽

10.1182/blood.v114.22.984.984 ◽

2009 ◽

Vol 114 (22) ◽

pp. 984-984 ◽

Cited By ~ 1

Author(s):

Fabio P.S. Santos ◽

Susan O'Brien ◽

Deborah A. Thomas ◽

Jorge Cortes ◽

Stefan Faderl ◽

...

Keyword(s):

Research Funding ◽

Adult Patients ◽

Lower Percentage ◽

Prognostic Impact ◽

Off Label Use ◽

Conventional Chemotherapy ◽

Off Label ◽

Cd25 Expression ◽

Significant Difference ◽

Label Use

Abstract Abstract 984 Poster Board I-6 Background: The Ph chromosome is the most common cytogenetic abnormality in adult patients with ALL and is associated with a higher risk of relapse and death. With the introduction of tyrosine kinase inhibitors (TKI; imatinib, dasatinib), the treatment of patients with Ph+ ALL has evolved. Regimens combining conventional chemotherapy with TKI have lead to significant improvements in the outcome of these patients. However, there is still a high incidence of relapse, and the determination of prognostic factors in these patients might lead to the development of risk-adapted therapy. CD20 is a cell surface marker expressed in 40% of adult patients with ALL, and it is associated with worse survival (Thomas D et al, Blood 2009; 113: 6330-6337). CD25 is the a-chain of the IL-2 receptor and has been reported to be associated with adverse outcomes in Ph+ ALL (Paietta E et al, Blood 2008; 112:Abstract 1500). Aims: To determine the prognostic impact of CD20 and CD25 expression in patients with Ph+ ALL. Methods: We retrospectively reviewed data of patients with Ph+ ALL treated at our institution with conventional chemotherapeutic protocols (Hyper-CVAD) alone or combined with TKI (Hyper-CVAD + imatinib and Hyper-CVAD + dasatinib). None of the patients received therapy with Rituximab. CD20 and CD25 expression were assessed by flow cytometry, and the cut-off for positivity was 20%. Survival was estimated by Kaplan-Meier method and compared by log-rank test. Results: We analyzed 126 patients with Ph+-ALL treated at our institution from November, 1992, until February, 2009. Patients received Hyper-CVAD alone (N=44), Hyper-CVAD + Imatinib (N=47) and Hyper-CVAD + Dasatinib (N=35). Median age of the whole cohort was 49 years (range 16-84). CD20 was positive in 69 of 124 (57%) evaluable patients. CD25 was positive in 63 of 112 (56%) evaluable patients. Patients that were CD20-positive had a higher incidence of peripheral lymphadenopathy (21% vs. 7%, p=0.04). Patients that were CD25-positive had lower lactate dehydrogenase (LDH) levels (median 1006 IU/L vs. 1433 IU/L; p=0.01), lower percentage of bone marrow blasts (median 86% vs. 90%, p=0.02), higher platelet counts (median 50×109/L vs. 32×109/L, p=0.01) and a higher incidence of CNS disease at diagnosis (21% vs. 4%, p=0.01). The complete response rate of the whole cohort was 91%. There was no impact of CD20 or CD25 positivity on disease-free survival (DFS) and overall survival (OS) of patients treated with Hyper-CVAD alone. In patients treated with Hyper-CVAD + dasatinib, CD20 positivity was associated with improved DFS (Figure 1) (median – not reached [NR] vs. 48 weeks [wks], p=0.01) and OS (median NR vs. 65 wks, p=0.06). Patients treated with Hyper-CVAD + imatinib who were CD20-positive had better DFS (median 91 vs. 57 wks, p=0.77) and OS (median 118 vs. 73 wks, p=0.98), but this did not reach statistical significance. There was a trend for worse survival in patients treated with Hyper-CVAD + dasatinib that were CD25 positive, but without a statistically significant difference (median DFS 55 wks vs. NR, p=0.10; median OS 85 wks vs. NR, p=0.11). We repeated the analysis combining Hyper-CVAD + dasatinib and Hyper-CVAD + imatinib (Hyper-CVAD + TKI). There was no significant difference in DFS and OS by CD20 expression (median DFS 130 wks vs. 53 wks, p=0.11; median OS 124 wks vs. 74 wks, p=0.11) or CD25 expression (median DFS 63 wks vs. 86 wks, p=0.33; median OS 100 wks vs. 117 wks, p=0.39). Conclusion: In patients with Ph+-ALL treated with regimens combining conventional chemotherapy and TKI, expression of CD20 may be associated with better survival outcomes. CD25 did not influence survival in our patients. More studies are needed to better determine the prognostic value of these markers and implement risk-adapted strategies treatment. Disclosures: Off Label Use: Off label use of imatinib and dasatinib in combination with cytotoxic chemotherapy. Cortes:Novartis: Research Funding; Bristol Myers Squibb: Research Funding. Kantarjian:Novartis: Research Funding; Bristol Myers Squibb: Research Funding.

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Gemcitabine, Busulfan and Melphalan (GemBuMel) Is a New High-Dose Chemotherapy (HDC) Regimen with High Activity In Refractory Hodgkin's Lymphoma (HL) Patients Receiving An Autologous Stem-Cell Transplant (ASCT): A Contemporaneous Comparison with BEAM and Busulfan/Melphalan (BuMel)

Blood ◽

10.1182/blood.v116.21.690.690 ◽

2010 ◽

Vol 116 (21) ◽

pp. 690-690 ◽

Cited By ~ 2

Author(s):

Yago Nieto ◽

Paolo Anderlini ◽

Uday Popat ◽

Ping Liu ◽

Borje S Andersson ◽

...

Keyword(s):

Research Funding ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Fixed Dose ◽

High Dose ◽

Cell Transplant ◽

Off Label Use ◽

Prognostic Features ◽

Off Label ◽

Label Use

Abstract Abstract 690 Background: BEAM is considered standard HDC for primary refractory or relapsed HL. However, pts with refractory HL have <30% chance of long-term event-free survival (EFS), underscoring the need for more active HDC regimens. Methods: We developed a new HDC regimen of gemcitabine (Gem), busulfan (Bu) and melphalan (Mel) (GemBuMel) exploiting their synergy. Bu was given as 4 daily doses on days −8 to −5 targeting an AUC of 4,000/d. Mel was given at 60 mg/m2/d on d-3 and d-2. Gem was infused over 3 hours at a fixed dose rate of 10 mg/m2/min (total dose 1875 mg/m2) on days −8 and −3 immediately preceding Bu and Mel, respectively. We compared the subset of refractory HL pts enrolled in this trial with all other refractory HL pts treated at MDACC with HDC during the same time period, who were eligible for the GemBuMel trial but either received BEAM off protocol or were enrolled in a separate trial of BuMel. All of these pts met ≥1 of the following criteria of refractory disease: primary induction failure (PIF) (defined as less than PR to 1st line chemotherapy), CR1 <6 mo, >1 relapse or progressive disease (PD) at HDC. Pts with relapsed but not refractory HL were not included in this analysis. Results: We analyzed 115 pts treated in one of the following three cohorts: 1) GemBuMel (N=51) since 01/07, median follow-up: 10 (2-43) mo; 2) BEAM (N=26) since 01/07, median f/u: 13 (3-56) mo; 3) BuMel (N=38) since 04/05, median f/u: 36 (17-56) mo. The GemBuMel cohort had significantly higher % PIF, median # prior relapses, % PET + tumors at HDC and % PD at HDC, with all other demographic and clinical features comparable (Table 1). There were no treatment-related deaths in any cohort. GemBuMel pts had improved EFS (Fig. 1) and OS (Fig. 2). GemBuMel was superior in patients with either PET- or PET+ tumors at HDC (Table 2). Cox proportional hazards regression models identified the use of a regimen other than GemBuMel (HR 2.38, P=0.02 for EFS; HR 8.25, P=0.009 for OS), >1 prior relapse (HR 2.91, P=0.006 for EFS) and B symptoms (HR 6.57, P=0.009 for OS) as independent adverse outcome predictors. Conclusions: Despite its worse prognostic features, the cohort of refractory HL pts treated with GemBuMel showed superior outcome to contemporaneous patients receiving BEAM or BuMel. A randomized trial of GemBuMel v BEAM is warranted. Disclosures: Off Label Use: Off-label use of gemcitabine for Hodgkin's lymphoma. Popat:Otsuka: Research Funding. Andersson:Otsuka: Consultancy. Champlin:Otsuka: Research Funding.

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Off‐label use of Letrozole in Chinese Short Pubertal Boys: Effectiveness, Safety, and Exposure‐Response Analysis

British Journal of Clinical Pharmacology ◽

10.1111/bcp.14775 ◽

2021 ◽

Author(s):

Yuan Xu ◽

Yan‐Hong Zhang ◽

Qiu‐Ping Zhang ◽

Qian‐Qian Zhao ◽

Xiao‐Fu Cao ◽

...

Keyword(s):

Response Analysis ◽

Off Label Use ◽

Off Label ◽

Exposure Response ◽

Pubertal Boys ◽

Label Use

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Immunomodulation of Both Donors and Recipients with Atorvastatin As a Strategy for the Prevention of Acute Graft-Versus-Host Disease (aGVHD): Results of Two Parallel Prospective Trials in Recipients of Matched Sibling Allogeneic Hematopoietic Cell Transplantation (alloHCT)

Blood ◽

10.1182/blood.v120.21.1942.1942 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1942-1942

Author(s):

Mehdi Hamadani ◽

Michael Craig ◽

Scot Remick ◽

Laura Gibson ◽

William Petros ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Fungal Infections ◽

Chronic Gvhd ◽

Off Label Use ◽

Phase Ii Trials ◽

Off Label ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Label Use

Abstract Abstract 1942 Introduction: Acute GVHD is a leading cause of morbidity and mortality following alloHCT. Atorvastatin (a statin drug) is a potent immunomodulatory agent capable of suppressing T cell–dependent immune responses that holds promise as a novel and safe agent for the prophylaxis of aGVHD. In murine models atorvastatin administration to both donor and recipient mice (compared to prophylaxis in either donors or recipients alone), prevented aGVHD by inhibiting donor T-cell proliferation, inducing T-helper 2 polarization, and by inhibiting recipient antigen presenting cell function (Zeiser et al. Blood, 2007). Several retrospective studies also suggest statins as potential prophylactic agents for aGVHD. Methods: We report here the results of two parallel, ongoing, prospective, phase II trials (NCT01175148 & NCT01491958) evaluating the safety and efficacy of a ‘two-pronged’ strategy of atorvastatin administration as aGVHD prophylaxis, to both adult (age ≥18yrs) donors and recipients of matched sibling alloHCT. The approach was identical in both protocols. Subjects with a history of atorvastatin allergy/intolerance were not eligible. As GVHD prophylaxis, atorvastatin at 40mg/day orally was administered to sibling donors, starting 14–28 days before the anticipated 1st day of stem cell collection. In alloHCT recipients GVHD prophylaxis consisted of atorvastatin (40mg/day) administered from day -14 to day +180 (or until stopping immunosuppression, toxicity, development of grade [Gr] II-IV aGVHD, or severe chronic GVHD [cGVHD]). In addition all recipients received standard GVHD prophylaxis with tacrolimus and methotrexate. Ex vivo CD34+ cell selection or in vivo T-cell depletion was not permitted. Primary outcomes were rate of Gr II-IV aGVHD at day +100 and safety of atorvastatin administration to alloHCT donor/recipient pairs. Both trials tested the null hypothesis H0: p≥35%, vs. the alternate H1: p≤15%, where p is probability of Gr II-IV aGVHD at day 100. Secondary outcomes included rates of late-onset aGVHD, cGVHD, relapse, progression-free survival (PFS), and overall survival (OS). Results: Between September 2010 and June 2012, 34 donor/recipient pairs were enrolled at WVU (n=24) and OSU (n=10). Median donor age was 50.5 yrs (range 24–69). Median duration of atorvastatin prophylaxis in donors was 15 days (range 7–26). No atorvastatin related Gr 3–4 toxicities were seen in the healthy donors. Table 1 shows baseline patient (pt) characteristics. At transplantation 16 pts (47%) had high-risk disease, 12 (35%) were chemorefractory, 11 (32%) had HCT-CI of ≥3, 14 (41%) were female to male allografts, and 12 (35%) pts had ABO mismatched transplants. Median follow up of survivors is 158 days (range 31 – 658). Atorvastatin was well tolerated with no Gr 2–4 adverse events. All pts engrafted. The median time to ANC ≥500/μL was 18 days (range 5–25) and to platelets ≥20k/μL was 15 days (range 11–51). The median day 100 chimerism was 85.5% (55–100%) for T-cells and 100% (26–100%) for myeloid cells. Respective numbers at day 180 are 99.5% and 100%. Among 34 evaluable pts, the cumulative incidences (CI) of Gr II-IV and Gr III–IV aGVHD at day 100 were 6.0 ± 4.2% and 0% respectively. Respective CI rates at day 180 are 16.7 ± 8.3% and 10.2 ± 7%. CI of mild/moderate and severe cGVHD at 1 year are 15.8 ± 8.9% and 18.3 ± 10.2%, respectively. Infectious complications were infrequent, with no fungal infections or EBV reactivations and few CMV reactivations (n=3). Non-relapse mortality was 0% at day 100 and 4.5% at day 180. CI of relapse at day 180 was 27.6 ± 9.2%. One year PFS and OS estimates are 54% and 66%, respectively. Conclusions: A two-pronged immunomodulatory strategy of atorvastatin administration to alloHCT donors/recipients appears to be a feasible, safe and potentially effective modality for aGVHD prophylaxis. Final results of NCT01175148 & updated results of NCT01491958 will be presented at the meeting. Disclosures: Hamadani: Celgene Corp: Speakers Bureau; American Cancer Society 116837-IRG-09-061-01: Research Funding; ASBMT & Millennium New Investigator Award: Research Funding; Conquer Cancer Foundation of ASCO: Research Funding. Off Label Use: Off Label use of atorvastatin for GVHD prophylaxis. Efebera:(NIA) K12 CA1333250: Research Funding; Leukemia and Lymphoma Society: Research Funding.

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Low Dose Azacitidine (AZA) Reduces the Incidence of Chronic Graft-Versus-Host Disease (cGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Blood ◽

10.1182/blood.v120.21.742.742 ◽

2012 ◽

Vol 120 (21) ◽

pp. 742-742 ◽

Cited By ~ 1

Author(s):

Marcos de Lima ◽

Simrit Parmar ◽

Julianne J Chen ◽

Sergio A Giralt ◽

Gabriela Rondon ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Research Funding ◽

Low Dose ◽

Control Group ◽

Cell Transplant ◽

Off Label Use ◽

Landmark Analysis ◽

Off Label ◽

Label Use

Abstract Abstract 742 AZA has immunomodulatory properties that may affect donor lymphocytes favorably, potentially leading to less GVHD after HSCT. We have been investigating low-dose AZA (32 mg/m2 daily for 5 days) to prevent AML/MDS relapse after HSCT. Interestingly, in our dose finding phase I study (Cancer, 2010) there was a suggestion of less cGVHD with longer AZA treatments. We then hypothesized that this approach leads to less cGVHD, and performed a comparison of patients that received AZA to prevent relapse versus historic controls that did not receive the drug. Major objective of this analysis is to determine the cumulative incidence of cGVHD with versus without AZA. Methods. Patients received AZA based on high risk of relapse disease, starting at a median of 45 days from transplant (range, 17–149). AZA effect on aGVHD was not studied since the drug was started after most cases of aGVHD had already occurred or/and had resolved or improved. Patients with active acute GVHD (aGVHD) were not eligible to receive AZA. Median dose was 32 mg/m2 (range, 8–40). Median number of AZA cycles was 3 (range, 1–54), and median time on AZA for patients that received >3 cycles (n=37) was 144 days (range, 93–1329). Using a computer algorithm, we randomly selected from our departmental database a control group consisting of patients who had received HSCT within the same time period, and had similar GVHD prophylaxis, stem cell source, and comparable low risk of grade II-IV aGVHD (Table). Two hundred and thirty patients were identified fulfilling these criteria. The rate of cGVHD was compared between the AZA group (grouped as 1–3 cycles and >3 cycles) and the control group, in a landmark analysis starting at 6 months after HSCT. Leukemia relapse or death in remission before cGVHD onset were considered as competing risks in this analysis. Results. Median follow-up was 25 months (range, 1–99) in the AZA group, and 31 months (range, 1.5–117) in the control group. 29, 24, and 115 patients in the >3 AZA cycles, 1–3 AZA cycles, and the control group were evaluable for the 6-month landmark analysis, respectively. The numbers of patients developing cGVHD and the HR at 2 years in this analysis were as follows: 53 of 115 controls (reference group), 11 of 24 patients who received 1–3 AZA cycles (HR at 2 years, 0.9; P=NS), and 6 of 29 patients who received >3 AZA cycles (HR at 2 years, 0.4; 95% confidence interval (CI), 0.1–0.8; P=0.02) developed cGVHD. Similarly, in a landmark analysis, the cumulative incidence of cGVHD was significantly lower in the subgroup that received >3 AZA cycles (figure). Conclusion. Low-dose AZA appears to reduce the likelihood of developing cGVHD. We are investigating if this effect is associated with preservation or improvement of the graft-versus-leukemia effect in an ongoing, randomized study. Disclosures: de Lima: Celgene: Research Funding. Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML. garcia Manero:celgene: Research Funding.

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Randomized Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab with or without Concurrent Avastin for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v124.21.4673.4673 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4673-4673

Author(s):

Tait D. Shanafelt ◽

Betsy R. LaPlant ◽

Timothy G Call ◽

Daniel Nikcevich ◽

Jose F. Leis ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Response Evaluation ◽

Off Label Use ◽

Advisory Committees ◽

Free Survival ◽

Off Label ◽

Grade 3 ◽

Label Use

Abstract BACKGROUND: Although chemoimmunotherapy (CIT) has improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 40-50% of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. Interactions with nurturing environments can enhance CLL B-cell resistance to apoptosis. These interactions include cytokine mediated prosurvival signals by angiogenic molecules, such as VEGF and bFGF that nurture CLL B-cells in an autocrine fashion and promote CLL cell survival partly through up regulation of anti-apoptotic proteins. These findings provide a strong rationale for testing anti-VEGF therapy in combination with a purine nucleoside analogue CIT regimen for upfront treatment. We conducted a randomized phase 2 CIT trial using pentostatin, cyclophosphamide, and rituximab with (PCR-B) or without (PCR) bevacizumab (B), an anti-VEGF monoclonal anti-body. METHODS: Eligible patients were previously untreated and had CLL in need of treatment by NCI-WG criteria (Blood 111:5446). Patients were randomized using a dynamic allocation procedure stratifying for stage (0-II vs. III-IV) and FISH (17p or 11q deletion vs. other) to receive either 6 cycles of rituximab (100 mg on day 1 of cycle 1; 375 mg/m2on day 2 of cycle 1 and day 1 of cycles 2-6) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) (PCR) administered every 21 days. Patients in the PCR-B cohort also received bevacizumab 15mg/kg on day 1 of cycles 1-5 and days 1, 22, & 43 of cycle 6. All patients underwent complete response evaluation 3 months after day 1 of cycle 6 (or last cycle of treatment for those completing < 6 cycles). MRD was assessed using 6-color flow cytometry (Leukemia 21:956) at the completion of treatment. RESULTS: 68 patients were enrolled through the Mayo Clinic Cancer Research Consortium between 1/2009 and 1/2013. Three patients were excluded from analysis: 1 patient canceled prior to treatment, 1 was dosed incorrectly, and 1 was ineligible due to immunophenotyping inconsistent with CLL. Median age of eligible patients was 63 years (range 43-81) and 43 (66%) were men. With respect to disease stage, 3 (5%), 38 (58%), and 24 (37%) had low, intermediate and high Rai stage disease. Eleven (17%) patients had deletion 17p or 11q & 29 (45%) had unmutated IGHV. No statistically significant differences were observed in these variables by treatment arm. All 65 evaluable patients have completed active treatment, with 54 (83.1%) completing the intended 6 cycles (PCR group 27/32 [84.4%] and PCR-B 27/33 [81.8%]). Hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 10 (31.3%) patients on PCR and 12 (36.4%) on PCR-B (p=0.79). Non-hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 9 (28.1%) patients on PCR and 18 (54.4%) on PCR-B (p=0.04). The most common such events were hypertension (PCR: 3.1% vs. PCR-B: 21.2%), proteinuria (0% vs. 6.1%) and creatinine increase (3.1% vs. 6.1%). Across both arms, 64/65 (98.5%) patients achieved a response including 31/32 (96.9%) treated with PCR and 33/33 (100%) treated with PCR-B (p=0.49). CR/CRi was achieved in 10/32 (31.3%) patients treated with PCR & 18/33 (54.5%) treated with PCR-B (p=0.08). Of the 28 who achieved a CR/CRi, MRD analysis was completed on 26, of whom 12 (46%) were MRD negative. With respect to treatment arm, 5/32 (16%) patients on PCR and 7/33 (21%) on PCR-B achieved an MRD negative CR. Median time to retreatment for all 65 patients was 44.8 (95% CI: 34.6 – NA) months. Median overall survival has not yet been reached. With current follow-up no differences between treatment-free survival (p=0.38), progression-free survival (p=0.23), or overall survival (p=0.45) are observed by treatment arm. Plasma levels of angiogenic cytokines VEGF, bFGF, thrombospondin (TSP) and the chemokines CCL3 and CCL4 were measured prior to treatment and at the time of the post treatment response evaluation. Correlations of these cytokines with clinical outcome will be presented. CONCLUSION: The addition of bevacizumab to purine analogue-based CIT was generally well-tolerated and may increase complete remission rates in patients with CLL. No clear improvement in treatment free survival has been observed to date. Disclosures Shanafelt: Hospiria: Research Funding; Pharmacyclics/Jannsen: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; glaxoSmithKline: Research Funding; Genetech: Research Funding; Polyphenon E Int'l: Research Funding. Off Label Use: Off label use of pentostatin for treatment of CLL. Off label use of bevacizumab for treatment of CLL. . Kay:Genetech: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

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Subcutaneous Alemtuzumab Combined with Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allo-SCT In CLL with 17p- or Refractory to Fludarabine – Interim Analysis of the CLL2O Trial of the GCLLSG and FCGCLL/MW

Blood ◽

10.1182/blood.v116.21.920.920 ◽

2010 ◽

Vol 116 (21) ◽

pp. 920-920 ◽

Cited By ~ 12

Author(s):

Stephan Stilgenbauer ◽

Florence Cymbalista ◽

Véronique Leblond ◽

Alain Delmer ◽

Thorsten Zenz ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Remission Rate ◽

High Dose ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Oral Dexamethasone ◽

Label Use

Abstract Abstract 920 CLL refractory to purine analogues (e.g. fludarabine, F) or with 17p- is associated with very poor prognosis. Alemtuzumab is active in F-refractory CLL, and has proven efficacy in patients (pts) with 17p-. However, outcome of F-refractory CLL is still poor in terms of remission rate and duration of remission. The multinational, multicenter CLL2O trial aims at achieving a higher remission rate by adding high-dose dexamethasone to alemtuzumab, and prolongation of remission duration and survival by alemtuzumab maintenance or allogeneic stem-cell transplantation (allo-SCT). Pts with CLL refractory (no PR/CR or PR/CR < 6 months) to F-based (e.g. FR, FC, FCR) or similar chemotherapy (i.e. pentostatin, cladribine, bendamustine), or exhibiting 17p- (untreated or at relapse) were eligible if they had “active disease”. Treatment was with subcutaneous alemtuzumab 30 mg weekly × 3 for 28 days, combined with oral dexamethasone 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or alemtuzumab maintenance with 30mg weekly every 14 days for up to 2 years (yrs). Decision for one of the two consolidation options was at discretion of patient and physician. From January 2008 to July 2010, 80 pts were enrolled at 22 centers and 79 were eligible; F-refractory (n=31), 17p- without prior therapy (n=31), and 17p- in relapse (n=17). Median age was 65 yrs in the F-refractory (range 38–76) and 17p- 1st-line group (36-76), and 60 yrs for the 17p- relapse group (54-73) with male predominance (F-refractory 74%, 17p- 1st-line 71%, 17p- relapse 82%). In the 17p- 1st-line and relapse groups, 52% and 50% were stage Binet C and exhibit reduced performance status (ECOG 1–2), compared to 81% Binet C and 60% ECOG 1–2 for the F-refractory cohort. Pretreated pts had received a median of 2 prior lines (F-refractory 1–6; 17p- relapse 1–5), and 5 pts had received prior SCT. In the F-refractory group, 16% of pts had 11q- and 52% had 17p-. IGHV was unmutated in 64% of 17p- groups and 72% in the F-refractory group. The median levels of ß2-MG / TK were 4.35 / 35.40 in the 17p- groups and 4.12 / 22.65 in the F-refractory group. Treatment data are currently available for 50 pts who completed induction therapy; F-refractory (n=19),17p- 1st-line (n=22), 17p- relapse (n=9). Full treatment duration (12 weeks) could be achieved in 47% F-refractory, 67% 17p- relapsed and 82% 17p- 1st-line pts. In the latter cohort, early stop of therapy was mainly correlated with CR, while in the F-refractory cohort with disease progression (n=2) and infections (n=5, 4 with no documented response). Response rates (ORR / CR) were 47% / 0% in the F-refractory cohort, 78% / 0% in the 17p- relapsed, and 100% / 23% in the 17p- 1st-line cohorts (as compared to this, ORR / CR was 71.4% / 4.8% with FCR in the 17p- 1st-line group of CLL8). Adverse events during treatment were mostly grade 1/2 apart from hematotoxicity. Grade 3/4 non-CMV infection occurred in 35% of F-refractory, 12% of 17p- relapsed, and 16% of 17p- 1st-line pts. CMV reactivation was observed in 32 % of the 17p- 1st-line pts, and less for the pretreated groups (F-refractory 16%, 17p- relapsed 18%). All CMV episodes were successfully treated, and there was no CMV-related death. Among 18 pts documented to receive alemtuzumab maintenance treatment, so far 3 SAEs have been reported: ITP (n=1, twice in the same pt), and fever / diarrhea / thyroiditis (n=1). At a median follow-up of 41.9 weeks (maintenance 54.7 weeks, allo-SCT 29 weeks), there were 7 (37%) deaths in the in the F-refractory cohort, 2 due to disease progression, and 5 due to infection. For the 17p- relapsed group, 3 progressions and 3 deaths were reported, with one case in each treatment option (SCT/maintenance), and one pt in salvage therapy. In the 17p- 1st-line cohort, 4 progressions occurred, 2 pts died, both in maintenance therapy. At 12 months, estimated overall survival was 54%, 66% and 100% in the F-refractory, 17p- relapse, and 17p- 1st-line cohorts, respectively. Accrual is currently ongoing with a target enrolment of 122 pts and updated results will be presented at the meeting. Disclosures: Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Off Label Use: off-label use of diagnostic tests and therapeutic agents. Leblond:ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria. Choquet:ROCHE : Consultancy. Hallek:Roche: Honoraria, Research Funding. Döhner:Pfizer: Research Funding.

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Improved Outcome with ATRA-Arsenic Trioxide Compared to ATRA-Chemotherapy in Non-High Risk Acute Promyelocytic Leukemia – Updated Results of the Italian-German APL0406 Trial on the Extended Final Series

Blood ◽

10.1182/blood.v124.21.12.12 ◽

2014 ◽

Vol 124 (21) ◽

pp. 12-12 ◽

Cited By ~ 3

Author(s):

Uwe Platzbecker ◽

Giuseppe Avvisati ◽

Gerhard Ehninger ◽

Laura Cicconi ◽

Christian Thiede ◽

...

Keyword(s):

High Risk ◽

Arsenic Trioxide ◽

Research Funding ◽

Primary Study ◽

Intermediate Risk ◽

Off Label Use ◽

Front Line ◽

Off Label ◽

Label Use ◽

Line Management

Abstract Background: We recently showed that the combination of ATRA and arsenic trioxide (ATO) is at least not inferior and possibly superior to standard ATRA and chemotherapy (CHT) in the front-line management of low/intermediate risk APL (Italian-German APL 0406 trial; Lo-Coco et al., NEJM 2013). We report herein on the extended and final series of 276 patients (162 were in the previous report) with the last case being enrolled into the study in January 2013. Methods: The APL0406 study was a prospective, open-label, randomized intergroup trial conducted by the Italian GIMEMA and the German SAL and AMLSG study groups. Eligible patients were adults aged 18-<71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10x109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally developed by the MD Anderson Cancer Center group, or the Italian AIDA2000 protocol (Estey et al., Blood 2006 and Lo-Coco et al., Blood 2010). Patients in the ATRA-ATO arm received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in the ATRA-CHT arm received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based consolidation together with ATRA and low dose CHT and ATRA for maintenance. The primary study objective was EFS at 2 years. Results: A total of 254 patients were evaluable for response to induction. CR was achieved in 122/122 (100%) in the ATRA-ATO versus 128/132 (97%) in the ATRA-CHT arm (P=0.12). Four patients died during induction in the ATRA-CHT arm. After a median follow-up of 36 months (range 1-75 months), the 2-year EFS was 98% and 84.9% in the ATRA-ATO and ATRA-CHT groups respectively (P= 0.0002), The 2-year cumulative incidence of relapse (CIR) rate was 1.1% and 9.4%, respectively (P=0.005) and, finally, the 2-year overall survival (OS) rate was 99.1% vs. 94.4% (P=0.01) for ATRA-ATO vs ATRA-CHT, respectively. Conclusions: The data on this extended cohort demonstrate a significantly augmented survival benefit coupled to a higher antileukemic efficacy provided by ATRA-ATO as compared to ATRA-CHT, in low/intermediate risk APL. These results further support ATRA-ATO as the new standard of care in this clinical setting. Figure 1 Figure 1. Disclosures Platzbecker: Teva: Honoraria. Off Label Use: Presentation includes off-label use of arsenic trioxide (ATO) in front-line management of APL. ATO is currently approved in treatment of relapsed APL in the US and Europe. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Lübbert:Cephalon / TEVA: Travel support Other. Link:TEVA: Consultancy, Speakers Bureau. Radsak:Celgene: Research Funding. Döhner:TEVA: Research Funding. Schlenk:TEVA: Research Funding, Speakers Bureau. Lo-Coco:TEVA: Honoraria; Lundbeck: Honoraria.

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Updated Results of a Phase 1/2a, Dose Escalation Study of Pvx-410 Multi-Peptide Cancer Vaccine in Patients with Smoldering Multiple Myeloma (SMM)

Blood ◽

10.1182/blood.v126.23.4246.4246 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4246-4246 ◽

Cited By ~ 2

Author(s):

Ajay K. Nooka ◽

Michael Wang ◽

Andrew J. Yee ◽

Sheeba K. Thomas ◽

Elizabeth K. O'Donnell ◽

...

Keyword(s):

Multiple Myeloma ◽

Immune Response ◽

Board Of Directors ◽

Research Funding ◽

Post Treatment ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Label Use

Methods: As reported previously, PVX-410 Multi-Peptide Vaccine (OncoPep, Inc.) is being developed for the treatment of SMM. PVX-410 consists of 4 human leukocyte antigen-A2 (HLA-A2), synthetic 9-mer peptides from unique regions of 3 multiple myeloma (MM)-associated antigens (XBP1 US184-192; XBP1 SP367-375; CD138260-268; and CS1239-247) emulsified in Montanide® ISA-720 VG (Seppic). Adults with SMM at high risk of progression to active MM and were HLA-A2-positive were eligible. The primary objective of this study was to determine the tolerability of PVX-410, initially as monotherapy. Immune response and change in M protein and free light chain ratio (FLC) were also assessed. PVX-410 alone was safe and immunogenic in the initial 12 patients treated, with all 12 having positive immune response to at least 1peptide, as determined by interferon-gamma enzyme-linked immunosorbent spot (Elispot) and tetramer assays. Given its immunomodulatory properties, it was hypothesized that co-administration of lenalidomide (len; Celgene Corporation) would enhance the T cell-mediated immune response induced by PVX-410. Accordingly, the tolerability, immunogenicity, and anti-MM activity of PVX-410+len was then investigated. Results in the PVX-410 alone cohort were previously reported. In the PVX-410+len cohort, patients received a dose of PVX-410, 0.8mg (0.2mg/peptide / 0.8mg total dose) subcutaneously plus 0.5 mL (1mg) Hiltonol® (poly-ICLC; Oncovir, Inc.) intramuscularly every 2 weeks for a total of 6 doses with 3 standard cycles of len (25 mg orally) on Days 1-21 every 28 days, without dexamethasone. Patients are followed for 12months post-treatment. Blood samples for immune response evaluation are collected at Week 0 (Baseline; pre-dose), 2, 4, and 8 during treatment and at Months 1, 3, 6, 9, and 12 post-treatment. Disease response is assessed at the same time points, except Weeks 0 and 2, using International Myeloma Working Group and modified European Group for Blood and Bone Marrow Transplant criteria. Results: Overall, 22 patients have been enrolled, with ages ranging from 39 to 82 years. Ten patients were enrolled in the PVX-410+len cohort, with 9 evaluable for response. All 10 patients received at least 1 cycle of len; 8 received all 3 cycles; 1 received 1 cycle before discontinuing due to a deviation; and 1 completed 2 cycles as of the cutoff date. One patient had 7 of 21 planned doses held due to neutropenia related to lenalidomide, but resumed the next cycle at a reduced dose (from 25 mg to 20 mg). Immunogenicity data with PVX-410+len and PVX-410 alone, as determined via intracellular cytokine staining and tetramer analysis, will be presented. With PVX-410 alone, 5 patients, 2 of 3 with the low-dose of 0.4 mg (0.1mg/peptide) and 3 of 9 at the target-dose (0.2 mg/peptide), experienced progression to active disease within 9 months post-treatment, and 7 had stable disease (SD) at the last follow up visit in the 12 month follow up period. With PVX-410+len, 5 patients have experienced partial or minimal responses and 3 have experienced SD. Durability of response is assessed through the 12-month study period; 1 patient has progressed to active myeloma during this time. PVX-410 was well-tolerated alone and with len. Most adverse events (AEs) have been ≤Grade 2 and non-serious. AEs seen more frequently with PVX-410+len versus PVX-410 alone are expected with len and include hematologic abnormalities (neutropenia, anemia, thrombocytopenia), gastrointestinal disorders (nausea, diarrhea, constipation), skin and cutaneous disorders (rash, pruritus), and myalgia. There was 1serious AE in the combination cohort (pneumonia), considered possibly related to len and unrelated to PVX-410. Conclusions: Six doses of PVX-410 were well tolerated in 22 patients with SMM. Additional AEs seen with PVX-410+len versus PVX-410 alone were expected with the addition of len to the treatment regimen. An immune response to the vaccine was seen in all patients treated with PVX-410 alone and is expected to be enhanced with PVX-410+len; these data will be presented. Based on the promising findings to date, an evaluation of PVX-410 in combination with an antibody to the programmed cell-death-1-ligand complex (PD1/PDL1) is planned to begin in 2015. Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy; Onyx Pharmaceuticals: Consultancy. Off Label Use: Off label use of lenalidomide. Wang:Janssen: Honoraria; Pharmacyclics, Janssen, Celgene, Oncopep, Kite, Juno: Research Funding. Thomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. O'Donnell:Millennium: Consultancy. Shah:Millenium: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Kaufman:Milleniumm, Celgene, Novartis, Onyx, Spectrum: Consultancy. Lonial:Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Raje:Takeda: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy; Amgen: Consultancy; Onyx: Consultancy; AstraZeneca: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding.

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Significance of Blast CD33 Expression for Effect of Gemtuzumab Ozogamicin at Different Doses in Adult Acute Myeloid Leukemia: Results from the UK NCRI AML16/17 Trials

Blood ◽

10.1182/blood.v126.23.320.320 ◽

2015 ◽

Vol 126 (23) ◽

pp. 320-320

Author(s):

Khan Naeem ◽

Robert K. Hills ◽

Paul Virgo ◽

Stephen Couzens ◽

Nithiya Clark ◽

...

Keyword(s):

Univariate Analysis ◽

Gemtuzumab Ozogamicin ◽

Prognostic Impact ◽

Off Label Use ◽

Fluorescent Intensity ◽

Expression Levels ◽

Off Label ◽

The Uk ◽

The Impact ◽

Label Use

Abstract On behalf of the UK NCRI AML Working Group CD33 was the first target for antibody directed therapy in any cancer with further CD33-directed strategies, including bispecific or chimeric antigen receptors, in development in AML. Our previous meta-analysis results with the first anti-CD33 antibody conjugate Gemtuzumab Ozogamicin (GO) demonstrated the importance of appropriately defining patient subgroups (e.g. by cytogenetics) that may most benefit from this therapy and as such provides a paradigm for other antibody-directed agents. However in adult AML there is limited data on whether CD33 expression levels (for total blasts and any 'immature' CD34+CD38- blasts) contribute to GO response, taking into account the differences of blast CD33 levels associated with specific genetic abnormalities and that CD33 expression level may potentially be a prognostic factor as suggested by the pediatric AML COG study. We evaluated the impact of blast CD33 expression levels on prognosis and GO response in adult AML by central standardised flow cytometric analysis of diagnostic samples from 1364 non-APML patients from the UK NCRI AML16 (older patients, n=334, CD33 expression data not an entry requirement) and AML17 (younger patients, n=1030) trials. Both trials included a GO randomisation (AML16 GO vs not, AML17 3mg vs 6mg vs not first induction); in AML17 all CBF AMLs received GO. CD33 mean fluorescent intensity was quantified for overall blast population (blast CD33 MFI) and CD34+CD38- subset (potentially enriched for leukemic stem cells) (CD33 MFI of CD34+CD38-). Percentage CD33negative blasts of WBC (%CD33neg) was also calculated. Patients were divided into quartiles 1-4 (Q1-4) based on increasing values for each of these parameters. Prevalence of CBF AML (n=152, AML17 only) was inversely associated with high blast CD33 MFI (43% Q1-2, 5% Q4 p<.0001) but MFI levels were also lower for adverse cytogenetics (n=235) (prevalence of non-CBF AML, 55% Q1-2, 10% Q4 p<.0001). Both FLT3 ITD (n=213) and NPM1c (n=322) mutations were more likely to have high (Q3-4) blast CD33 MFI levels even when compared to other intermediate cytogenetic patients (71% of FLT3 ITD in Q3-4 p<.0001; 79% of NPM1c in Q3-4, p<.0001; 40% of non-mutated intermediate in Q3-4). FLT3 ITD and NPM1c were also associated with a low %CD33neg (Q1, <6.5%); FLT3 ITD 37%, NPM1c 43% vs intermediate 20%, CBFs 11%, adverse 16%. In univariate analysis of all patients, higher blast CD33 MFI levels predicted significantly better 5 year OS from entry (Q4 43%, Q2 or 3 36%, Q1 28%, p=0.009): significance was not maintained in analyses adjusted for cytogenetics, FLT3 ITD+, NPM1c, plusage, WBC, performance status, and trial protocol (AML16 vs AML17), although there was an improved CR/CRi (OR 0.81 (0.67-0.97), P=0.02). 321 non-CBF AML patients in our cohort were randomised to GO vs no GO. There was no evidence that CD33 expression levels or percentage of CD33negative blasts or detectable CD33negative CD34+CD38- blasts affected the overall outcome benefit from GO (p=NS for all interactions). There was also no evidence of an interaction between GO treatment and the positive prognostic impact of high CD33. Blast CD33 parameters did not significantly alter outcome in CBF AMLs (all received GO) suggesting that other biological factors are important for CBF GO sensitivity. Interestingly, despite overall lower blast CD33 levels of CBF AMLs, only 1.4% of these had a detectable CD33neg CD34+CD38- immature population of >0.35% of WBC (mean +2SD normal range of CD34+CD38-) compared to 19% of intermediates and 17% of adverse. This might contribute to the effectiveness of GO (and potentially other CD33-directed therapies) in CBF AMLs since clearance of potential LSCs in the CD34+CD38- subset would not be limited by low CD33 expression. For the 270 patients in the AML17 GO dose randomisation, relapse risk was improved by the higher 6mg/m2 dose for patients with a low blast CD33 MFI (Q1) (OR 0.54 (0.26-1.10); p=0.03 for trend) with no increase in 60-day mortality (P=0.4) (Figure). Conclusion Although genetic subgroups have distinct profiles of blast CD33 expression (including low CD33 in both CBF and adverse risk) CD33 levels are not an independent predictor of OS or benefit from GO by adjusted analyses in adult AML. However a higher dose of GO may be more effective at preventing relapse in AMLs with lower blast CD33 expression. These results may be relevant to future CD33-directed strategies. Figure 1. Figure 1. Disclosures Off Label Use: Off Label Use: Gemtuzumab Ozogamicin, an antibody-drug conjugate used to treat AML. Russell:Therakos: Other: shares.

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