Clinical and Genomic Factors Are Predictive of Response and Prognostic of Progression-Free Survival in Patients with Waldenström Macroglobulinemia Treated with Ibrutinib

Introduction: The Bruton tyrosine kinase inhibitor ibrutinib is the only FDA approved therapy for the treatment of symptomatic Waldenstrom macroglobulinemia (WM), and has been associated with high response rates and durable progression-free survival (PFS). Factors associated with depth of response and PFS duration are not well established. We performed a retrospective study aimed at identifying predictive and prognostic factors in WM patients treated with ibrutinib. Methods: We included consecutive patients with a diagnosis of WM treated with ibrutinib monotherapy evaluated at the Dana-Farber Cancer Institute since January 2012 through March 2019. Patients with Bing-Neel syndrome (WM involving the central nervous system) were excluded. Baseline clinical and laboratory characteristics were gathered. MYD88 and CXCR4 mutations were assessed using polymerase chain reaction assays and Sanger sequencing. Responses at 6 months were assessed using criteria from IWWM3. PFS was defined as the time from ibrutinib initiation until last follow-up, death or progression. Univariate and multivariate logistic regression models were fitted for partial response (PR) and very good partial response (VGPR) at 6 months, and Cox proportional-hazard regression models were fitted for PFS. Results: A total of 252 patients were included in our analysis. Selected baseline characteristics include: age ≥65 years (60%), hemoglobin <11.5 g/dl (68%), platelet count <100 K/uL (12%), albumin <3.5 g/dl (39%), b2-microglobulin ≥3 mg/l (70%), serum IgM level ≥7,000 mg/dl (6%), bone marrow involvement ≥60% (54%), previously untreated for WM (33%), time to ibrutinib <3 years (46%). MYD88 L265P and CXCR4 mutations were detected in 98% and 38% of patients, respectively. At 6 months, 71% of patients obtained PR, and 17% VGPR. Multivariate logistic regression analyses showed higher odds of PR at 6 months for hemoglobin <11.5 g/dl (78% vs. 56%; OR 2.8, 95% CI 1.1-6.9; p=0.03) and serum albumin <3.5 g/dl (90% vs. 66%; OR 3.2, 95% CI 1.0-10; p=0.045), while CXCR4 mutations associated with lower odds (44% vs. 82%; OR 0.15, 95% CI 0.06-0.37; p<0.001). Multivariate logistic regression analyses showed higher odds of VGPR at 6 months for b2-microglobulin ≥3 mg/l (21% vs. 3%; OR 3.3, 95% CI 1.1-10; p=0.04) and lower odds for serum IgM level ≥4,000 mg/dl (9% vs. 23%; OR 0.3, 95% CI 0.1-0.8; p=0.02). The median follow-up was 30 months, and the median PFS has not yet been reached. The 5-year PFS rate was 60% (95% CI 48-69%). In the multivariate Cox regression analysis, worse outcomes were seen with CXCR4 mutations (5-year PFS: 45% vs. 71%; HR 2.8, 95% CI 1.4-5.8; p=0.004) and serum albumin <3.5 g/dl (5-year PFS: 36% vs. 68%; HR 2.7, 95% CI 1.3-5.5; p=0.007). A novel PFS risk score was designed using CXCR4 mutational status and serum albumin (Figure), which divided patients into 3 distinct groups: low risk (no risk factors: 43%; 5-year PFS 81%), intermediate risk (1 risk factor: 46%; 5-year PFS 51%) and high risk (2 risk factors: 11%; median PFS 25 months). The PFS difference between groups was statistically significant (p<0.001). The PFS risk score showed consistent results when evaluating previously treated and untreated patients, as well as patients on and off clinical trials. Conclusion: Serum albumin and CXCR4 mutations emerge as important factors predictive of PR at 6 months and also prognostic of PFS in WM patients treated with ibrutinib. A novel PFS stratification tool that separates patients into 3 risk groups was established and would need further validation. Figure Disclosures Castillo: Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Hunter:Janssen: Consultancy. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.

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Ibrutinib Dose Reduction Does Not Affect Progression-Free Survival in Patients with Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-111626 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1598-1598

Author(s):

Jorge J. Castillo ◽

Joshua Gustine ◽

Andrew Keezer ◽

Kirsten Meid ◽

Toni Dubeau ◽

...

Keyword(s):

Dose Reduction ◽

Median Time ◽

Research Funding ◽

Regression Models ◽

Progression Free Survival ◽

Free Survival ◽

Waldenstrom Macroglobulinemia ◽

Major Response ◽

Dose Reductions

Abstract Introduction: Ibrutinib is an oral Bruton Tyrosine Kinase inhibitor, approved for the treatment of symptomatic Waldenstrom Macroglobulinemia (WM). MYD88 and CXCR4 mutations affect progression-free survival (PFS) in patients with WM. In some cases, ibrutinib dose reductions are needed for the management of toxicity. However, it remains unclear if ibrutinib dose reductions adversely affect PFS in WM patients. Methods: We evaluated 217 consecutive patients with the clinicopathological diagnosis of WM who were symptomatic and received treatment with ibrutinib. We analyzed relevant clinical features and their association with the risk of dose reduction, using logistic regression models, as well as PFS using Cox proportional-hazard regression models. Time to events was estimated using the Kaplan-Meier method. p<0.05 were considered statistically significant. Results: All 217 patients were initiated on ibrutinib monotherapy at the approved dose of 420 mg by mouth (PO) once daily (QD). At a median follow-up of 26 months (95% CI 22-31 months), 159 patients (73%) continued ibrutinib without dose-reduction, while 58 (27%) patients had a decrease in their ibrutinib dose. There was no difference in follow-up between those with and without dose reduction. Of the 58 patients that dose reduced, 45 (78%) were reduced to 280 mg daily; 12 patients (21%) were reduced to 140 mg daily, and 1 (2%) to 140 mg every other day. The median time to ibrutinib dose reduction from 420 mg PO QD to 280 mg PO QD was 155 days (95% CI 89-282 days), and median time to dose reduction from 280 mg PO QD to 140 mg PO QD was 55 days (95% CI 24-260 days). Reasons for ibrutinib dose reduction included cytopenia(s) (n=13; 24%), arrhythmia (n=9; 17%), musculoskeletal discomfort (n=8; 15%), constitutional symptoms (n=6; 11%), skin changes/rash (n=5; 9%), mouth sores (n=4; 7%), gastrointestinal symptoms (n=3; 6%), infections (n=3; 6%), bleeding (n=2; 4%) and transaminase elevation (n=1; 2%). Patients in whom ibrutinib dose reduction was needed were more likely to be older than 65 years (76% vs. 47%; p<0.001), had higher International Prognostic Scoring System for WM (IPSSWM) at ibrutinib initiation (IPSSWM 1, 2 and 3 were 19%, 23% and 58% vs. 24%, 39% and 37%, respectively; p=0.03), and were more likely to have attained a major response (93% v. 69%; p<0.001) than patients in whom ibrutinib dose was not reduced. There were no differences in baseline characteristics including sex, hemoglobin levels, platelet counts, beta-2-microglobulin levels, serum IgM levels, bone marrow involvement, previous treatment, MYD88 and CXCR4 mutational status and time from WM diagnosis to ibrutinib initiation between those with and without dose reduction. Regression analyses showed higher odds of dose reduction occurring in patients >65 years (OR 3.6, 95% CI 1.8-7.1; p<0.001) and those who had attained a major response (OR 6.0, 95% CI 2.1-17.5; p=0.001). The median PFS for the entire group was not reached, and the 3-year PFS rate was 76% (95% CI 68-83%). Factors associated with a worse PFS were platelet count <100 K/uL (HR 3.9, 95% CI 1.8-8.7; p=0.001) and CXCR4 mutations (HR 3.0, 95% CI 1.5-6.0; p=0.001). Expression of mutated MYD88 (HR 0.01, 95% CI 0.00-0.09; p<0.001) and attainment of major response (HR 0.23, 95% CI 0.12-0.43; p<0.001) were associated with a better PFS. Importantly, those who experienced a reduction in their ibrutinib dose showed no significant difference in PFS (HR 1.19, 95% CI 0.61-2.35; p=0.61; Figure 1A). There were no differences between patients who reduced to 280 mg PO QD (HR 1.0, 95% CI 0.5-2.2; p=0.99) or 140 mg PO QD (HR 1.9, 95% CI 0.7-5.5; p=0.22) versus those without dose reduction (Figure 1B). Conclusion: Ibrutinib dose reduction occurred in 27% of patients with WM, at a median time to dose reduction of 155 days. Patients older than 65 years and those with major responses were more likely to have a dose reduction. With a median follow-up time of 26 months, ibrutinib dose reduction did not significantly impact PFS. Figure 1. Figure 1. Disclosures Castillo: Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Genentech: Consultancy. Hunter:Pharmacyclics: Consultancy. Treon:Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding.

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Randomized Trial of Two Dosages of Rabbit Antithymocyte Globulin in Patients with Aplastic Anemia

Blood ◽

10.1182/blood-2018-99-111323 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3873-3873

Author(s):

Atsushi Narita ◽

Xiaofan Zhu ◽

Hideki Muramatsu ◽

Xiaojuan Chen ◽

Ye Guo ◽

...

Keyword(s):

Logistic Regression ◽

Regression Analysis ◽

Aplastic Anemia ◽

Research Funding ◽

Antithymocyte Globulin ◽

Clonal Evolution ◽

Multivariate Logistic Regression Analysis ◽

Multivariate Logistic Regression ◽

Free Survival

Abstract Introduction: In patients with severe aplastic anemia (SAA) who are not candidates for stem cell transplantation (SCT), immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CyA) is the treatment of choice. A randomized controlled trial demonstrated the inferiority of rabbit ATG compared with horse ATG for first-line treatment of SAA (Scheinberg et al. N Engl J Med 365:430-438, 2011). However, horse ATG remains unavailable in many countries outside the USA. In Asian countries, the recommended dose of rabbit ATG ranges from 2.5 to 3.5 mg/kg/day. Here we report the first prospective randomized multicenter study comparing two dosages of rabbit ATG in patients with SAA (www.umin.ac.jp UMIN000011134). Methods: Patients with SAA who required initial IST in Japan (n = 89), China (n = 85), and Korea (n= 48) were enrolled between May 2012 and October 2017. Randomization was 1:1 in blocks between the two dosages of rabbit ATGs. The IST regimen comprised rabbit ATG (thymoglobulin®, 2.5 or 3.5 mg/kg/day for 5 days), CyA (6 mg/kg/day for minimum 6 months), and methylprednisolone (2 mg/kg/day for 5 days) with subsequent tapering of the dose for 28 days. The dose of CyA was adjusted to maintain whole blood trough concentrations between 150 and 250 ng/mL. The primary endpoint was hematologic response at day 180. Secondary endpoints included frequency of Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD), hematologic response at day 360, relapse, and overall survival (OS). Results: In total, 222 patients (age 0.5-71.0 years) were randomized, with 112 patients receiving 2.5 mg/kg and 110 receiving 3.5 mg/kg of rabbit ATG. Patient characteristics were well matched between the two groups. Median follow-up duration for all patients was 742 days from first ATG infusion (range, 16-2165) and 887 days for those surviving till the end of the study (range, 32-1757). After 3 months, in the 2.5mg/kg of rabbit ATG group, 4 (4%) patients achieved a complete response (CR) and 35 (31%) a partial response (PR), for an overall response rate (ORR) of 35%. In the 3.5mg/kg of rabbit ATG group, 1 (1%) patient achieved a CR and 43 (39%) a PR, for an ORR of 40%. After 6 months, in the 2.5mg/kg of rabbit ATG group, 55 patients (49%) achieved an ORR including 7 (6%) who achieved a CR and 48 (43%) PR. In the 3.5mg/kg of rabbit ATG group, 53 patients (48%) achieved a response including CR in 9 patients (8%) and PR in 44 (40%). The response rates did not differ significantly between the two groups at 3 (P = 0.488) or 6 (P = 0.894) months. Multivariate logistic regression analysis identified disease severity [odds ratio (OR), 2.09; 95% confidence interval (CI), 1.18−3.67; P = 0·011] and interval between diagnosis and treatment (OR, 1.86; 95% CI, 1.07−3.22; P = 0.027) as independent predictors of response to IST at 6 months. Despite relatively short follow-up, relapse and clonal evolution occurred with similar frequencies between the two groups, with 4 relapse (among 55 responders) and 1 clonal evolution in the 2.5 mg/kg group and 4 relapse (among 53 responders) and no evolutions in the 3.5 mg/kg group. One patient in the 3.5 mg/kg group developed EBV-LPD at day 109 after IST. During follow-up, 22 (10%) patients died, all of whom showed no response to IST. The causes of death were infections (n = 13), hemorrhage (n = 4), SCT-related complications (n = 2), clonal evolution (n = 1), and unknown (n = 2). Transplantation free survival (TFS), failure free survival (FFS), and OS at three-year were similar between the two groups [TFS, 73% (95% CI, 63%−81%) vs. 71% (95% CI, 60%−80%); P = 0.991; FFS, 45% (95% CI, 35%−54%) vs. 45% (95% CI, 61%−84%); P = 0.909; OS, 85% (95% CI, 76%−91%) vs. 91% (95% CI, 82%−96%); P = 0.107]. Multivariate logistic regression analysis revealed that lack of response to IST was an independent predictor of OS (OR, 6.95; 95% CI, 1.76%−27.46%; P = 0.006). Conclusions: The current study revealed no differences in the efficacy and safety between 2.5 mg/kg and 3.5 mg/kg dose of rabbit ATG for patients with SAA. However, as the follow-up period was relatively short, longer surveillance is warranted to compare long-term complications and survival rates between the two groups in the follow up study. Disclosures Usuki: Daiichi Sankyo: Research Funding; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Novartis: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; SymBio Pharmaceuticals Limited.: Research Funding; Shire Japan: Research Funding; Sanofi K.K.: Research Funding; Pfizer Japan: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; GlaxoSmithKline K.K.: Research Funding; Celgene Corporation: Research Funding, Speakers Bureau; Boehringer-Ingelheim Japan: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau. Nakao:Novartis: Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

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Time to Progression Post-Induction Predicts Outcomes of Ixazomib Based Therapy for Relapsed/Refractory Myeloma: Real World Data from a Multi-Site Israeli Registry Study

Blood ◽

10.1182/blood-2018-99-114217 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1972-1972

Author(s):

Yael C Cohen ◽

Hila Magen ◽

Noa Lavi ◽

Moshe E. Gatt ◽

Evgeni Chubar ◽

...

Keyword(s):

Research Funding ◽

Overall Response Rate ◽

Target Organ Damage ◽

Progression Free Survival ◽

Organ Damage ◽

Real World Data ◽

Free Survival ◽

Grade 3 ◽

Indolent Disease

Abstract Introduction Ixazomib is an orally available proteasome inhibitor, shown to be safe and efficacious in combination with lenalidomide and dexamethasone (IRd regimen) in patients with relapsed and refractory multiple myeloma (RRMM) with 1-3 prior lines, demonstrating a progression free survival (PFS) benefit which was similar across cytogenetic risk groups (Tourmaline-MM1 phase 3 trial). A European real world data analysis of an IRd named patient program (NPP) outcomes in Greece (n=35), UK (n=46) and Check republic (n=57) showed similar favorable outcomes (Terpos et al, Blood 2017 130:3087). We aimed to analyze outcomes of ixazomib combinations among a multi-site cohort in the Israeli Myeloma registry. Overall response rate (ORR) was classified according to IMWG criteria. Primary endpoint was PFS, secondary endpoints included ORR, overall survival (OS), safety and tolerability. Patients A total of 78 patients across 7 sites, who received at least one cycle of ixazomib combination between June 2013 and June 2018 for treatment of RRMM were retrospectively included. Median age was 68 (range: 38-90). Male/Female ratio was 42/36. ISS (rISS) I/II/II was 30%/42%/27% (25%/54%/15%). Patient received between 1 and 7 prior lines of therapy, 66% received ixazomib in 2nd line, 18% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 86%) prior to IRd, 41% to IMiDs (thalidomide 28% lenalidomide 22% and pomalidomide 6%), and 35% had undergone autologous transplantation (ASCT). Induction treatment was mostly bortezomib based (85%), most frequently VCD (62%). FISH cytogenetics were available for 60 patients, 29 (48%) had high or intermediate risk aberrations (t(4:14) 12 pts, amp 1q21 12 pts, del17p 9 pts). Disease aggressiveness was classified by treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 27%, respectively. 60 (77%) of the 78 patients received ixazomib via a named patient program, the rest via national or private healthcare provider. Results Median time of follow up from first ixazomib dose was 22 months (range: 1-39 months), and 54 months from diagnosis of myeloma. Treatment is ongoing in 44 (56%) patients with a median duration of 19 months (range: 1-29). Among patients who discontinued treatment, the median duration was 9 months (1-31). Ixazomib was combined with lenalidomide, pomalidomide, and daratumumab in 69%, 9% and 4%, respectively. Overall response rate was 88% - CR 10%, VGPR 36%, PR 42%. Progression free survival was 78% and 54% at 12 and 24 months, respectively (fig1a). A worse PFS was found with physician assessment of aggressive vs indolent disease (14.5 vs 25.9 months, p=0.001), and with post induction progression free period (PFS1) ≤ 24 months vs. >24 months (23.9 vs 31.5 months, p=0.038) (fig 1b); age >=65 trended towards a worse PFS (p=0.058). Poor cytogenetic risk, prior exposure to bortezomib, prior auto transplant, and number of prior lines of therapy did not affect PFS or ORR. OS from first ixazomib administration was 90% and 81% at 12 and 24 months, respectively; median OS was not reached (fig1a). Any (grade 3-4) toxicity considered by investigator as related to ixazomib was reported in 70% (18% grade 3-4), including neutropenia 14% (6%), anemia 19% (6%), thrombocytopenia 17% (5%), nausea and vomiting 17% (1%), DVT/PE 4% (1%), neutropenic infection 0 (4%), peripheral neuropathy 14% (3%), diarrhea 14% (3%), rash 10% (4%), pneumonia 5% (3%). There were no ixazomib related deaths. Dose reduction or discontinuation due to toxicity occurred in 28% and 12%, respectively. Conclusion Our data shows ixazomib-based combinations are efficacious and safe regimens for patients with RRMM, achieving ORR of 88%, at 2nd as well as later lines of therapy, regardless to cytogenetic risk. Over a median follow up of almost 2-years, 54% remained progression free at 24 months. An ixazomib based regimen may be particularly attractive for patients who remain progression free for more than 24 months after a bortezomib induction and for patients with a more indolent disease phenotype. Disclosures Cohen: Neopharm Israel: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Medisson Israel: Consultancy, Honoraria, Research Funding. Tadmor:NOVARTIS: Consultancy; PFIEZER: Consultancy; ABBVIE: Consultancy; JNJ: Consultancy; ROCHE: Research Funding.

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MDR1 Gene Expression Predicts Response and Progression-Free Survival Of Ph+ CML Patients On Second-Line Nilotinib Therapy After Imatinib Failure - 4-Year Follow-Up

Blood ◽

10.1182/blood.v122.21.1494.1494 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1494-1494

Author(s):

Mridul Agrawal ◽

Benjamin Hanfstein ◽

Philipp Erben ◽

Dominik Wolf ◽

Thomas Ernst ◽

...

Keyword(s):

Gene Expression ◽

Research Funding ◽

Progression Free Survival ◽

Mdr1 Gene ◽

Imatinib Resistance ◽

Free Survival ◽

Mdr1 Gene Expression ◽

Mdr1 Expression

Abstract Introduction The activity of the drug efflux transporter protein MDR1 reduces the intracellular concentration of nilotinib and thereby impairs its efficacy. Nilotinib has been shown to be efficacious in imatinib-resistant patients. In the face of competing second-generation tyrosine-kinase inhibitors (TKI), early identification of favorable responders is crucially important. We have reported the unexpected positive prognostic impact of high MDR1 gene expression at time of imatinib resistance for subsequent 2nd line nilotinib treatment. Here, we present (i) a 48-month follow-up of our clinical data and (ii) additional functional analyses studied in an established in vitro, transposon-based vector system with stable siRNA mediated knockdown of MDR1. Aim We sought to assess (i) whether high MDR1 expression remains associated with improved cumulative rates of major molecular remission (MMR), complete cytogenetic remission (CCyR) and patients’ outcome (progression-free survival, PFS) after 48 months and (ii) the impact of MDR1 expression on nilotinib in vitro sensitivity. Methods (i) We analyzed 83 patients resistant to imatinib frontline treatment in chronic phase CML treated with nilotinib 400 mg bid within the CAMN107A2101 trial. MDR1 and BCR-ABL mRNA expression levels were determined by qRT-PCR using LightCycler™ technology, normalized against beta-glucuronidase (GUS) and standardized according to the international scale (IS). Log-rank tests were performed to compare PFS and the cumulative incidences (CI) of MMR and CCyR at 48 months. (ii) MDR1high overexpressing (K562-DoxH1) and MDR1low knockdown (K562-DoxMM) cell lines were used for in vitro testing (Rumpold et al., Exp Hematol 2005). Results (i) (a) At 24 and 48 months, patients with MDR1/GUS ratios ≥2.0 attained MMR in 39% and 41%, CCyR in 58% (at both time points), and PFS rates of 75% and 67%, whereas patients with initial MDR1/GUS ratios <2.0 had significantly worse response and PFS rates, i.e. MMR in 13% and 16% (p=0.014), CCyR in 35% and 39% (p=0.044), and PFS of 50% and 46% (p=0.032). (b) BCR-ABL tumor burden prior to nilotinib revealed a significant impact on molecular response rates. BCR-ABLIS <28% separated best concerning cumulative incidences of MMR by 24 and 48 months (41% vs 21% and 48% vs 21%, p=0.009). (c) Nilotinib in vitro sensitivity of BCR-ABL kinase domain mutations at time of imatinib resistance was associated with improved PFS under nilotinib therapy: patients without any mutation showed PFS rates of 71% and 63% at 24 and 48 months, whereas those with either sensitive mutations, intermediately sensitive mutations or mutations with unknown IC50attained PFS rates of 67% and 61%; patients with mutations resistant to nilotinib achieved PFS rates of 23% at both time points (p=0.01). (ii) Even though MDR1high K562 cells are less sensitive than MDR1low expressing cells, nilotinib (applying doses from 0.01 µM up to 0.5 µM) was still able to significantly impede proliferation of both MDR1high and MDR1low, whereas imatinib-mediated growth inhibition was only seen in MDR1low, but not in MDR1highcells. Conclusion (i) At the time of imatinib-resistance, a high MDR1 gene expression predicts favorable MMR, CCyR, and PFS on consecutive 2nd line nilotinib treatment. As shown earlier, single nucleotide polymorphisms (SNPs) within MDR1 (1236CT/TT and 2677GT/TT) were significantly associated with higher MDR1 expression. (Agrawal et al., ASH 2010) (ii) Our functional data support our clinical observation that nilotinib remains efficacious in MDR1 overexpressing cells, whereas even dose-escalated imatinib does not reverse resistance. High MDR1 gene expression might select patients whose mode of resistance is essentially determined by increased efflux activity of MDR1 and not by other pathways of resistance that cannot be overcome by nilotinib. Altogether, our data might be used for the clinical risk stratification in case of imatinib resistance before switching to nilotinib and are undergoing prospective validation within the ENEST1st study. Disclosures: Saussele: Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria. Purkayasatha:Novartis: Employment. Woodman:Novartis: Employment. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.

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Follow-up Analysis of Ixazomib, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in Routine Clinical Practice

Blood ◽

10.1182/blood-2021-148836 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2716-2716

Author(s):

Jiri Minarik ◽

Jakub Radocha ◽

Alexandra Jungova ◽

Jan Straub ◽

Tomas Jelinek ◽

...

Keyword(s):

Clinical Practice ◽

Research Funding ◽

Previous Analysis ◽

Progression Free Survival ◽

Routine Clinical Practice ◽

Toxicity Profile ◽

Advisory Committees ◽

Free Survival ◽

Significant Difference

Abstract Background: The addition of ixazomib to the doublet lenalidomide and dexamethasone (RD) in relapsed and refractory multiple myeloma (RRMM) has shown significant benefit in progression free survival (PFS) in the TOURMALINE-MM1 study. Several real-world data including our previous analysis confirmed that the combination IRD is feasible and with fair outcomes even outside the clinical trial. Here we report an updated analysis which is aimed at overall survival (OS) and the PFS2 interval which is defined as the time from the date of treatment initiation to the date of first documentation of progressive disease after initiation of further anti-myeloma treatment or death from any cause. Methods: We analyzed a cohort of 344 patients with RRMM, 127 being treated by IRD and 217 by RD combination. The group characteristics and study design are described elsewhere. 1 The median follow-up of the whole cohort was 28.5 months. The primary endpoint was OS, OS in patients with relapse 1-3, progression free survival (PFS), and PFS2. Secondary endpoints were response rates and toxicity profile. For statistical analysis we used Fisher's exact test or Mann-Whitney U test. Survival measures were assessed using the Kaplan-Meier methodology, and statistical significance was assessed using the log-rank test at a significance level of α = 0.05 (all tests two-sided). Results: The outcomes of OS in the whole cohort were already published before, with significantly longer median OS in the IRD vs RD cohort (mOS 36.6 months vs 26.0 months, p = 0.008).1 In the follow-up analysis, the medians were slightly improved, maintaining a significant difference (mOS 40.9 vs 27.1 months, p = 0.001). In patients treated within relapse 1-3, the results outcomes were even more pronounced (mOS 51.7 vs 27.8 months, p ˂ 0.001). The median PFS was also better in the IRD cohort (mPFS 17.5 vs 12.5 months, p = 0.013) but the results did not substantially differ from our previous analysis. The median PFS2 in the IRD vs RD cohort was significantly longer in the IRD cohort (mPFS2 29.8 vs 21.6 months, p = 0.016). The subsequent therapy included mostly pomalidomide (27.5% vs 30.8%), bortezomib (28.8% vs 28.2%) or thalidomide (10.0% vs 16.2%). Monoclonal antibodies (daratumumab, isatuximab) were more frequently used after IRD combination (21.3% vs 4.3%). The response rates in the IRD vs RD cohort were similar as in our primary analysis: overall response rate (ORR) 73.0% vs 66.8%, with significant difference in very good partial response and better (VGPR+) 38.1% vs 26.3%. The toxicity profile did not reveal any additional safety concerns. Majority of grade 3+ toxicities included hematological toxicity (anemia, neutropenia, thrombocytopenia) and infections, with similar distribution in the cohorts. Conclusion: The treatment of RRMM using the full oral IRD regimen in routine clinical practice is easy, safe and with significantly improved outcomes in comparison to RD doublet. Our follow-up analysis confirmed the impact on OS in patients in the whole cohort including relapse 1-3. The median PFS2 was also longer in the IRD cohort, possibly affected by more frequent use of monoclonal antibodies in the next treatment. With support of AZV 17-29343A, NV18-03-00500, MH CZ - DRO (FNOl, 00098892), IGA-LF-2021-001. 1) Minarik J, Pika T, Radocha J. et al. Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice. BMC Cancer 2021; 21: https://doi.org/10.1186/s12885-020-07732-1 Disclosures Minarik: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Hajek: Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Safety and Efficacy of Venetoclax-Based Treatment in Elderly CLL Patients: A Retrospective Study from the Filo Group

Blood ◽

10.1182/blood-2021-149640 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3747-3747

Author(s):

Charlotte Doublet ◽

Marie-Sarah Dilhuydy ◽

Emmanuelle Ferrant ◽

Pierre Feugier ◽

Alexandra Fayault ◽

...

Keyword(s):

Retrospective Study ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Oncology Nurses ◽

Advisory Committees ◽

Free Survival ◽

Daily Dose ◽

History Of

Abstract Median age at diagnosis of chronic lymphocytic leukemia is 72 years. However, only few patients over 80 years of age are included in clinical trials, even in those devoted to unfit patients. In order to evaluate both efficiency and safety of venetoclax in this category of patients, we conducted a multicentric retrospective study and collected data from 77 CLL patients from 19 FILO centers who started venetoclax after 80 years of age. Median age at venetoclax initiation was 86 years old (81-97). 63% of patients had a history of heart disease, 62% had renal failure (moderate 59% and severe 3%) and 29% had a history of severe infections. Despite their comorbidities and a CIRS greater than 6 in 70% of cases, their autonomy was preserved with a median performans status of 1 (0-4). In this comorbid geriatric population, pretherapeutic geriatric assessment was only performed in a single patient. The median number of prior therapies was 2 (0-6) with an exposure to a BCR inhibitor in 56% of cases. 11q and 17p deletion were found in 39% and 30% of cases respectively, 39% of patients had a complex karyotype and 30% harbored a TP53 mutation. However, in this real life population, these prognostic factors were only performed in half of patients. IGHV mutational status was only available in 11 patients, and 83% of them had unmutated IGHV. At the time of venetoclax initiation, the tumor lysis syndrome (TLS) risk was moderate in 57% of cases and high in 8% of cases. Venetoclax was administered as a single agent (42%) or in association with rituximab (58%). In total, half of the patients were hospitalized at each dose ramp-up, and only 3 patients were treated on outpatient basis. 82% of the cohort was able to reach the daily dose of 400mg. Half of the patients were included in a phone call monitoring program with oncology nurses to pre-emptively manage side effects and foster therapy adherence. The safety study reported 14% of TLS, with 2 discontinuations of treatment within the first month: one of which led to dialysis and the other to death. As in the previously published studies, 25% of patients had infectious complications, and grade 3 haematological and digestive toxicities were reported in 42% and 22% of cases, respectively. The reduction of the daily dose of venetoclax was necessary for 33%. Permanent discontinuation of venetoclax occurred in 40% of subjects, including 29% of early withdrawal (within the first 3 months). Main reasons for discontinuation were intolerance (21%), CLL progression (21%), death (21%) and scheduled treatment discontinuation (10%). The overall response rate was 86%, consisting of 49% of complete response (unconfirmed by bone marrow biopsy) and 37% of partial response. With a median follow-up of 21months, estimated progression free survival and overall survival were 29 and 38 months respectively. Prior exposure to a BCR inhibitor had no impact on progression free survival. To conclude, venetoclax has a manageable safety profile in elderly patients with comorbidities and can induce prolonged responses. Finally, if additional follow-up by oncology nurses seems to be more and more implemented, the pre-therapeutic onco-geriatric evaluation remains underexploited in this population. Disclosures Ferrant: AstraZeneca: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Other: Travel, Accommodations, Expenses. Feugier: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria. Laribi: AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; AbbVie: Other: Personal Fees, Research Funding; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding. Tchernonog: JANSSEN: Consultancy; ABBVIE: Consultancy; ASTRAZENECA: Consultancy. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

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An Oncology Simulation Model to Estimate 10-Year Progression-Free Survival and Stem Cell Transplantation for Frontline, Stage III or IV Classical Hodgkin Lymphoma Based on the 5-Year Update of the ECHELON-1 Trial: A United States Perspective

Blood ◽

10.1182/blood-2021-147308 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2440-2440

Author(s):

Tycel Phillips ◽

Kristen Migliaccio-Walle ◽

Kristina S. Yu ◽

Brian Bloudek ◽

Nicholas Liu ◽

...

Keyword(s):

Simulation Model ◽

Research Funding ◽

Progression Free Survival ◽

Stage Iii ◽

Publicly Traded ◽

Free Survival ◽

Annual Prevalence ◽

Number Of Patients ◽

Relapsed Disease

Abstract Objectives Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) is the most common frontline (1L) regimen for patients with stage III or IV classical Hodgkin lymphoma (cHL), but about 30% of patients with stage III or IV cHL have refractory or relapsed disease after ABVD treatment. Based on the 5-year update of the ECHELON-1 trial, patients on 1L brentuximab vedotin, doxorubicin, vinblastine and dacarbazine (A+AVD) continued to demonstrate a robust and durable progression-free survival (PFS) improvement vs ABVD with a 32% reduction in the risk of progression or death (HR=0.681, nominal P=0.002). Our objective was to estimate the future number of patients with cHL who are alive and progression-free over 10-years with 1L A+AVD, based on the 5-year follow-up results from ECHELON-1. Methods An oncology simulation model, from the United States perspective, was developed with a 1-month cycle length that estimates population-level outcomes based on annual prevalence of cHL, considering disease incidence, treatment patterns, PFS, and overall survival of commonly used treatment regimens for stage III or IV cHL. Incidence of cHL was derived from the 2019 Surveillance, Epidemiology, and End Results (SEER) Program, assuming 95% of HL is classical of which 41% is stage III or IV. To populate the base case model, treatment patterns following 1L use of ABVD (64.5%) and positron emission tomography (PET)-adapted therapy (35.5%) were varied over time and compared to A+AVD (24%). For every model cycle, patients who experienced disease progression on 1L therapy discontinued therapy and transitioned to second-line (salvage) therapy. The transition from second-line therapy to transplant is also included in the model based on patient eligibility. Model inputs were informed by 1) real-world treatment utilization; 2) treatment-specific clinical trial data, including ECHELON-1 with 5-year PFS rates of 75.3% for ABVD (95% CI: 70.0, 85.0) and 82.2% for A+AVD (95% CI: 71.7, 78.5); and 3) expert clinicians' opinions. Annual prevalence of patients living progression-free with cHL in the 1L setting with each prescribing scenario was estimated for 10 years (year 2031) with and without the availability of A+AVD. Results The annual number of newly diagnosed patients with stage III or IV cHL at 10 years in 2031 was estimated at 3,586. The number of patients alive and progression-free in the 1L setting was 19,494 without A+AVD and 19,660 with A+AVD (Δ+166, 0.85% increase) in 2031. Overall, for every 100 patients prescribed A+AVD, it was predicted that an additional 6.5 patients per year achieved at least 5 years PFS and 4.2 to 4.7 fewer patients per year required a stem cell transplant (SCT), based on the 70% to 80% of eligible patient proceeding to SCT, respectively. Conclusions The durable PFS improvement of A+AVD vs ABVD in the 5-year follow-up data from ECHELON-1 resulted in increasing the number of patients with stage III or IV cHL who remain progression free for greater than 10 years and reducing future SCTs, based on this oncology simulation model for cHL. The significant improvement in PFS observed in the 5-year ECHELON-1 trial may translate to fewer patients with cHL developing primary refractory or relapsed disease and reduce the need for additional therapies including SCT. Disclosures Phillips: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy. Migliaccio-Walle: Seagen, Inc: Consultancy. Yu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Bloudek: Seagen, Inc: Consultancy. Liu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Burke: Beigene: Consultancy, Speakers Bureau; Verastem: Consultancy; Kymera: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive Biotechnologies: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Roche/Genentech: Consultancy; Kura: Consultancy; Epizyme: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau; AbbVie: Consultancy.

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Autologous Haematopoietic Stem Cell Transplantation in Waldenström Macroglobulinemia: A Single-Centre 18-Year Experience

Blood ◽

10.1182/blood-2021-150637 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3548-3548

Author(s):

Suzanne O Arulogun ◽

Charalampia Kyriakou ◽

Jackie Horder ◽

Fiona Newrick ◽

Aisha S Patel ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Partial Response ◽

Research Funding ◽

Progression Free Survival ◽

Survival Outcomes ◽

Free Survival ◽

Depth Of Response ◽

Remission Status

Abstract BACKGROUND The role of autologous stem cell transplantation (ASCT) in Waldenström Macroglobulinaemia (WM) is not well established, largely due to the paucity of evidence. It remains unclear where ASCT should be placed in the sequence of treatment lines. The debate is stronger in the era of targeted therapies that can achieve prolonged progression free survival (PFS) intervals and expected treatment-free intervals of approximately 4 to 8 years. The goal of this real world analysis was to review response and survival outcomes, and relapse risk factors in WM patients who underwent ASCT in a single WM referral centre. METHODS A retrospective cohort analysis was undertaken of consecutive WM patients treated with ASCT at a single specialist centre between 2003 and 2020. Baseline demographic/biological data, number/types of prior therapies, and pre- and post-ASCT depth of response, were collected from patient records and the WMUK Rory Morrison Registry. The primary aims were to determine depth of response, overall survival (OS), progression free survival (PFS), transplant related mortality (TRM) and relapse-associated mortality. RESULTS A total of 32 patients received ASCT, with a median age at time of ASCT of 57 years (range 40-68 years) and median interval from diagnosis to ASCT of 2.3 years (range 0.5-16.8 years); 14 (43.7%) were male. Prior to ASCT, 11 patients (34%) had received one therapy, 11 patients had 2 lines of treatment (excluding mobilisation), and 10 patients (31%) had received 3 or more therapies. The disease status pre-ASCT was complete remission (CR)/very good partial response (VGPR) in 14 patients (43.7%) and partial response (PR) in 18 patients (56.2%). Conditioning therapy comprised LEAM (Lomustine, Etoposide, Cytarabine, Melphalan; 18 patients, 56.2%), BEAM (Carmustine substituted for Lomustine; 12 patients, 37.5%), or Melphalan only (2, 6.2%). All patients had successful engraftment. Median time from stem cell reinfusion to hospital discharge was 15.5 days (range 13-187 days) in the 24 patients for whom these data were available; 5/24 patients (21%) were discharged >25 days after stem cell reinfusion. Restaging at 100 days post-ASCT showed deepening of response by ASCT in 17 patients (53.1%). CR/VGPR was achieved by 26 patients (81.2%) and PR by 4 patients (12.5%). Two patients (6.2%) experienced disease progression before day 100 post-ASCT (both receiving ASCT in second remission/PR2). At a median follow up of 8.9 years (range 0.1-18 years), the estimated median PFS was 4.5 years (95% confidence interval [CI] 3.2-5.7 years), with estimated 2-year and 5-year PFS rates of 75% and 35.9%, respectively (Figure 1A). In this small cohort, there was no significant difference in PFS based on age, number of prior lines of treatment, pre-ASCT remission status (CR/VGPR vs PR) or post-ASCT response achieved. At time of analysis, 14/32 patients (43.7%) had died: TRM rate was 6.2% (2 patients died during inpatient admission of ASCT complications), 4 patients (12.5%) died of PD, and 1 patient died of unknown causes. Another 7 patients (21.9%) died of infective causes after the immediate post-ASCT period: the median time from ASCT to death among these patients was 5.5 years (range 0.8-10.8 years). Estimated median OS for the unstratified cohort was 10.8 years (95% CI 7.3-14.3 years), with estimated 2- and 5-year OS rates of 87.5% and 77.5%, respectively (Figure 1B). Overall survival did not differ significantly based on age at time of ASCT, number of therapy lines prior to ASCT, pre-ASCT remission status (CR/VGPR vs PR) or post-ASCT response achieved. One patient (3.1%) underwent ASCT after BTK inhibitor therapy, achieving deepening of response (PR to VGPR) with ASCT and progression free interval of 11 months. CONCLUSION ASCT is a feasible treatment option for patients with relapsed WM, producing deeper responses following salvage therapy and resulting in PFS intervals comparable to other currently available therapeutic options. With the benefit of a long follow up period, performing ASCT at later stages in the treatment course (i.e. following 3 or more prior therapy lines) did not appear to result in inferior survival outcomes; timing of ASCT should therefore be considered on an individual patient basis and in light of other available therapy options for relapsed disease. Figure 1 Figure 1. Disclosures Yong: Sanofi: Honoraria, Research Funding; GSK: Honoraria; Amgen: Honoraria; Autolus: Research Funding; BMS: Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Wechalekar: Amgen: Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy; Caelum Biosciences: Other: Clinical Trial Funding; Takeda: Honoraria; Celgene: Honoraria; Janssen: Consultancy. D'Sa: Sanofi: Honoraria; Janssen Cilag: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding.

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Combined Treatment of Bortezomib, Continuous Low-Dose Cyclophosphamide and Dexamethasone Followed By One Year of Maintenance Treatment for Refractory or Relapsed Multiple Myeloma Patients: A Prospective Phase II Study

Blood ◽

10.1182/blood.v124.21.4733.4733 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4733-4733

Author(s):

Esther GM Waal de ◽

Linda Munck de ◽

Gerhard Woolthuis ◽

Annet velden Van Der ◽

Yvonne Tromp ◽

...

Keyword(s):

Overall Survival ◽

Maintenance Therapy ◽

Research Funding ◽

Low Dose ◽

Progression Free Survival ◽

Free Survival ◽

First Relapse ◽

Grade 3 ◽

One Year

Abstract Introduction: Combination therapy for longer periods but at low dose, also called metronomic scheduling, might be an effective manner to treat patients with relapsing myeloma. In particular if the used agents attack the malignant clone in an alternative manner. Therefore we used the combination of bortezomib, dexametasone and daily low dose of oral cyclophosphamide as an induction regimen followed by one year of maintenance therapy consisting of bortezomib and cyclophosphamide. Methods: Relapsing myeloma patients, bortezomib naïve, were treated with three cycles of 1.3 mg/m2 bortezomib at day 1, 4, 8 and 11, cyclophosphamide 50 mg daily, and 20 mg dexamethasone at day 1, 2, 4, 5, 8, 9, 11 and 12 followed by three cycles of bortezomib 1.6 mg/m2 (day 1, 8, 15 and 2), cyclophosphamide (50 mg) daily and dexamethasone (20 mg) at day 1, 2, 8, 9, 15, 16, 22 and 23. Maintenance therapy consisting of bortezomib 1.3 mg/m2 every two weeks and daily dose of 50 mg cyclophosphamide for one year was applied to patients in partial or complete remission. Primary endpoints were toxicity during re-induction and maintenance therapy. Secondary endpoints were response to treatment and progression free and overall survival. Results: 59 patients with relapsing multiple myeloma were included of whom 69% were in first relapse (Table 1). The upfront treatment consisted mainly of thalidomide-based and vincristine-based chemotherapy and 40% of the patients have been treated with an autologous stem cell transplantation. All 6 cycles of induction chemotherapy could be given in 49% of the patients. Premature discontinuation before starting maintenance therapy was due to toxicity (31%), progressive disease (7%), death (7%) or other reasons (6%). Myelosuppression was the most common side effect with WHO grade 3-4 in 31% of the patients. Neuropathy grade 3-4 was observed in 16% of patients, partially due to the fact that bortezomib was given intravenously during the first 2 yrs of the protocol which included 76% of the patients. Maintenance therapy was started in 47% of the patients with a median duration of 7.3 months (range 0.36.-13.4). Grade 3-4 toxicity was observed in 25% of the patients including infections (n=3) and myelosuppression (n=3) which did not resulted in discontinuation of therapy. Median follow up time was 29 months with an overall response of 62%, and a very good partial response (VGPR), complete remission (CR) in 21% and 7% of the patients respectively. During the maintenance phase an improvement in responsiveness was observed in 25% of the patients. The CR rate increased with 9% to a total of 16%. VGPR rate was 20% and 16% of the patient had a PR. At end of the maintenance therapy 50% of patients started with maintenance had stable disease. The median progression free survival (PFS) was 17.2 months (range 0.13 – 43.5) as depicted in figure 1. and the median overall survival was 21.6 months (range 0.46-54.4, figure 2). During follow up 33 % of the patients died due to progression of MM. Conclusion: The present study demonstrates that combination therapy with bortezomib, continuous low dose cyclophosphamide and dexamethasone is an effective and manageable regimen. Adding a year of maintenance was feasible with limited side effects and an increase in CR rate. Table 1: patient characteristics Patients (%) Age, mean (min,max) 69 (46-86) Sex Male 56 Female 44 Relapse number First relapse 75 Second relapse 20 Third relapse 5 Performance status 0 65 1 29 2 5 M-protein heavy chain IgA 18 IgG 65 Light chain disease 18 Polyneuropathy No 61 Yes 39 Figure 1: Progression free survival Figure 1:. Progression free survival Figure 2: Overall survival Figure 2:. Overall survival Disclosures Waal de: Jansen Cilag: Research Funding. Munck de:Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. velden Van Der:Jansen Cilag: Research Funding. Tromp:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding. Vellenga:Jansen Cilag: Research Funding. Hovenga:Jansen Cilag: Research Funding.

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CALGB 100801 (Alliance): A Phase II Multi-Center NCI Cooperative Group Study of the Addition of Azacitidine (AZA) to Reduced-Intensity Conditioning (RIC) Allogeneic Transplantation for High Risk Myelodysplasia (MDS) and Older Patients with Acute Myeloid Leukemia (AML): Results of a “test dose” Strategy to Target Busulfan Exposure

Blood ◽

10.1182/blood.v124.21.543.543 ◽

2014 ◽

Vol 124 (21) ◽

pp. 543-543 ◽

Cited By ~ 4

Author(s):

Ravi Vij ◽

Vera Hars ◽

William Blum ◽

Tsiporah B. Shore ◽

Aaron P. Rapoport ◽

...

Keyword(s):

Surface Area ◽

Body Surface Area ◽

Body Surface ◽

Older Patients ◽

Research Funding ◽

Progression Free Survival ◽

Test Dose ◽

Validation Sample ◽

Free Survival

Abstract Relapse remains the major cause of death in older patients transplanted for AML in first complete remission (CR1) or for patients with advanced MDS at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with RIC when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (Bu) exposure, combined with the administration of AZA post transplantation would mitigate the risk of relapse while avoiding non-relapse mortality (NRM) and ultimately improve progression free survival (PFS). Here we report the results of a Bu test dose strategy targeting daily Bu exposure as determined by the area under the plasma concentration versus time curve (AUC). The primary endpoint of the study was two year progression free survival (PFS). An important secondary objective was to determine whether administration of a test dose of Bu with post test sampling would enable achievement of a daily target Bu AUC level of 4000 uM*min in at least 80% of the recipients. We used this strategy as part of a RIC regimen on a prospective multi-center phase II trial conducted by the Alliance (formerly Cancer and Leukemia Group B (CALGB)). Eligibility included patients with AML in CR1 aged 60-74 years inclusive, MDS with IPSS risk > Int-2 with less than 10% marrow blasts and age <75, availability of a well matched sibling or volunteer unrelated donor (VUD), and absence of significant end-organ damage prior to transplantation. The study completed accrual in 10/2013. 67 patients were registered, and 63 transplanted with 39 receiving grafts from VUDs and 23 from matched siblings. The donor type was not documented at the time of this abstract for one patient. The median age was 63 (44-74), 18 had AML and 45 had MDS. Ten centers enrolled at least one patient. All patients were conditioned with a uniform regimen consisting of fludarabine IV (days -7 to -3), busulfan IV (Bu) targeted to a daily AUC of 4000uM*min (Days -6 to -3) following administration of a 25mg/m2 test dose on one day between Days -14 to -9, and antithymocyte globulin (days -6, -5 and-4 (two doses for matched sibs and three for VUDs only). Body surface area was calculated using a corrected weight formula in overweight individuals (ideal weight + 25% of the difference between ideal and actual weight). Beginning day +42, all patients were planned to receive up to six monthly cycles of AZA at 32mg/m2 subcutaneously x 5days. The proportion of patients who actually received AZA and the median number of cycles received will be reported at the time of abstract presentation. 58 patients received a test dose of Bu and had target validation samples drawn on day -6, following the first dose. Test dose was infused over 45 minutes and blood samples were drawn at end of infusion and 1, 2, 4, and 6 hours after test dose completion. Bu target level validation samples were then obtained at the same time points following the Day-6 dose of Bu. The validation results are depicted in the table: Table Test dose AUC Body surface area (median) Targeted daily Bu dose received(mg/m2) (median; range) Median AUC achieved on validation sample(median,range) Median AUC/4000 927.5uM*min 1.9m2 107 (32-198) 4170uM*min (3284-6642) 1.043 90% of patients were within 20% of the target AUC (95% CI=0.79-0.96) based on the validation sample. Maximum non-hematologic CTCAE v4.0 toxicity was grade 3 in 28 (50%), grade 4 in 6 (11%), and grade 5 in 5 (9%) of the 56 patients with available adverse event data. There were ten deaths within the first 100 days after transplant; six of these were due to NRM. With a median follow up of 564 days, the estimated overall survival at 2 years was 39 %. In conclusion, the preliminary results of this prospective multi-center trial suggest a strategy of targeting busulfan exposure to an AUC of 4000uM*min based on a prior “test dose” is successful in the majority of patients without causing excessive non-hematologic toxicity even in older patients. Further follow up is necessary to determine whether this results in less relapse and improved PFS. Disclosures Vij: celgene: Honoraria, Research Funding. Off Label Use: Busulfan, fludarabine, thymoglobulin: conditioning for transplant Azacytidine: post allogeneic transplant. Blum:Celgene: Consultancy. Shea:CALGB/Alliance: CALGB Board of Directors Other. Devine:sanofi: Research Funding.

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