Influence of Renal Impairment and Genetic Risk Factors on Response to Induction Therapy in the HD4 and MM5 Trials of the GMMG

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4777-4777
Author(s):  
Christof Scheid ◽  
Thomas Hielscher ◽  
Uta Bertsch ◽  
Christina Kunz ◽  
Hans Salwender ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Renal Impairment ◽  
Board Of Directors ◽  
Genetic Risk ◽  
Research Funding ◽  
Response Rates ◽  
Genetic Risk Factors ◽  
Advisory Committees ◽  
Prospective Trials

Abstract Background: In the HOVON65/GMMG HD4 trial in patients with newly diagnosed multiple myeloma we have previously shown that patients with renal impairment (RI) (creatinine > 2 mg/dl) have higher response rates and better survival when receiving bortezomib both in the induction and maintenance therapy before and after high-dose chemotherapy (HDT) (Scheid et al. Haematologica 2014). In addition patients with RI showed a higher prevalence of genetic high-risk features such as del17p or t(4;14). The aim of this analysis was to further elucidate the interaction between renal and genetic risk factors in well defined homogeneously treated myeloma patients. Methods: For this study we selected 2 cohorts of patients entered into 2 consecutive prospective trials with centralised FISH-assessement on CD138-selected bone marrow cells. The first cohort (1) comprises 395 patients from the HOVON65/GMMG HD4 trial having been treated in the German centers and the second cohort (2) consisted in the 601 patients (intention-to-treat population) from the recently closed GMMG MM5 trial. Patients lacking FISH results were excluded from the analysis, which was the case for 53 (13.4%) patients in cohort 1 and 43 (7.2%) patients in cohort 2. In cohort 1 induction treatment was vincristine or bortezomib + doxorubicin and dexamethason followed by tandem HDT followed by bortezomib or thalidomide maintenance. Cohort 2 received doxorubicin or cyclophosphamide + bortezomib and dexamethason as induction followed by 1- 2 HDT and consolidation and maintenance with lenalidomide. Results: In cohort 1 38 (10%) had RI and del 17p was found in 12/33 (36.4%) evaluable patients compared to 24/302 (7.9%) patients without RI (p<0.001). t(4;14) was present in 11/33 (33.3%) patients with RI and 38/304 (12.5%) without RI (p=0.005). Gain of 1q21 (> 2 copies) was present in 14/33 (42.4%) patients with RI and 92/298 (30.9%) without RI (n.s.). In cohort 2 68/601 (11.3%) had RI and 7/63 (11.1%) had del17p compared to 56/495 (11.3%) patients without RI (n.s.) while 29/63 (46%) patients with RI had t(4;14) versus 265/495 (53.5%) without RI (n.s.). Gain1q21 (>2 copies) was found in 36/63 (57.1%) with RI versus 209/495 (42.2%) without RI (p=0.025). In cohort 1 the response rate with at least VGPR after induction was low with and without RI in the VAD arm (15 vs 7.1 %) and reduced in patients with RI in the PAD arm compared to those without RI (22.2 vs 37.9%). This trend was not found in cohort 2: Patients with RI had VGPR or better in 42.4% in the PAD and 52.9% in the VCD arm, compared to 33.5% and 33.1% without RI respectively. Del17p and t(4;14) which were more frequent in patients with RI in cohort 1 did not have a negative impact on response rates after induction. Similarly gain1q was more frequent among patients in cohort 2 with RI but did not impact on response to induction. Conclusions: We analysed the effect of RI and genetic risk factors on the response to induction therapy in two different patient cohorts from two consecutive prospective trials. High-risk genetic features where found more frequently in patients with RI, but the pattern was entirely different between cohort 1 and 2 and they did not seem to influence response rates after induction. Our results confirm that bortezomib-based induction regimens achieve high response rates in myeloma patients with RI similar to those in patients without RI, independent of the presence of genetic risk factors. Disclosures Scheid: Janssen: Honoraria; Celgene: Honoraria. Salwender:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Binding site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Mai:Janssen: Travel support Other. Hose:Novartis: Research Funding. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

scholarly journals Identifying Ultra-High Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3192-3192 ◽  
Author(s):  
Theresia Akhlaghi ◽  
Even H Rustad ◽  
Venkata D Yellapantula ◽  
Neha Korde ◽  
Sham Mailankody ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Ultra High Risk ◽  
Risk Of Progression ◽  
Equity Ownership ◽  
M Spike ◽  
Risk Biomarkers

Abstract Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage to active multiple myeloma (MM), comprised by a heterogenous group of patients with varying rates of progression. While the overall yearly progression rate is 10% the first 5 years, some patients progress at a considerably higher rate. A study from the Mayo Clinic showed that in a subset of 21 patients defined by ≥60% monoclonal bone marrow plasma cells (BMPC), 95% progressed within 2 years. It was subsequently concluded by the International Myeloma Working Group (IMWG) that patients with biomarkers predictive of a 2-year progression rate at 80%, and a median time to progression at 12 months were at ultra-high risk of progression and should be considered to have MM requiring treatment despite being asymptomatic. In 2014, ultra-high risk biomarkers were incorporated in the definition of MM, including BMPC ≥60%, free light chain (FLC) ratio ≥100 and ≥2 focal lesions on magnetic resonance imaging (MRI). While the updated myeloma definition changed the diagnosis of some patients with ultra-high risk SMM to MM, there remain patients classified as SMM progressing at a very high rate. In the present study, we aimed at further identifying ultra-high risk biomarkers predictive of a high rate of progression to active MM. Methods Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2017 were identified and included in the study. Diagnosis of SMM and progression to MM requiring therapy was defined according to the IMWG criteria at the time of diagnosis. Baseline patient and disease characteristics were collected at date of diagnosis with SMM, including pathology reports, laboratory results and imaging data. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Optimal cut-off values for continuous variables were assessed with receiver operating characteristics (ROC) curve. Patients who had not progressed by the end of study or were lost to follow up were censored at the date of last visit. Univariate Cox regression was used to estimate risk factors for TTP with hazard ratios (HR) and 95% confidence intervals (CI). Significant univariate risk factors were selected for multivariate Cox regression. Results A total of 444 patients were included in the study. Median follow-up time was 78 months. During the study period, 215 (48%) patients progressed to active MM, with a median TTP of 72 months. Cut-off points for BMPC, M-spike, and FLC ratio were determined with ROC curves to be 20%, 2 g/dL, and 18, respectively, for predicting high risk of progression. The following factors were associated with significantly increased risk of progression to active MM: BMPC >20%, M-spike >2g/dL, FLC ratio >18, immunoparesis with depression of 1 and 2 uninvolved immunoglobulins respectively, elevated lactate dehydrogenase, elevated beta-2-microglobulin, and low albumin (Table 1). In the multivariate model, BMPC >20% (HR 2.5, 95% CI 1.6-3.9), M-spike >2g/dL (HR 3.2, CI 1.9-5.5), FLC ratio >18 (HR 1.8, CI 1.1-3.0), albumin <3.5 g/dL (HR 3.9, CI 1.5-10.0), and immunoparesis with 2 uninvolved immunoglobulins (HR 2.3, CI 1.2-4.3), predicted a decreased TTP (Table 1). A total of 12 patients had 4 or 5 of the risk factors from the multivariate model, 8 of these did not meet the 2014 IMWG criteria for MM. These patients had a significantly shorter TTP than patients with less than 4 risk factors (median TTP 11 vs 74 months, p<0.0001, Figure 1). At 16 months, 82% of these patients had progressed, and within 2 years, 91% of the patients progressed. Only one patient remained progression free after 2 years, progressing at 31 months. Of patients with less than 4 risk factors, 19% progressed within the first 2 years. Conclusion In addition to baseline BMPC >20%, M-spike >2g/dL, FLC-ratio >18, we found that albumin <3.5g/dL and immunoparesis of both uninvolved immunoglobulins at the time of diagnosis with SMM were highly predictive of a decreased TTP to MM requiring therapy. These biomarkers are readily available and routinely assessed in clinic. Patients with 4 or 5 of these risk factors represent a new ultra-high risk group that progress to active disease within 2 years, further expanding on the definition of ultra-high risk SMM. In accordance with the rationale on ultra-high risk biomarkers as criteria established by the IMWG in 2014, such patients should be considered to have MM requiring therapy. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Lesokhin:Squibb: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Mezzi:Amgen: Employment, Equity Ownership. Khurana:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Werther:Amgen: Employment, Equity Ownership. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding.

scholarly journals EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4569-4569 ◽  
Author(s):  
Frits van Rhee ◽  
Sharmilan Thanendrarajan ◽  
Carolina D. Schinke ◽  
Jeffery R. Sawyer ◽  
Adam Rosenthal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Early Results ◽  
Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

scholarly journals Risk Factors Associated with Survival Outcome in Patients with Chronic Myeloid Leukaemia in Accelerated Phase Treated with Tyrosine Kinase Inhibitors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1222-1222
Author(s):  
Kee Yon, Lionel See ◽  
Kok Chong Bernard Yap ◽  
Dong-Wook Kim ◽  
Hein Than ◽  
Yeow-Tee Goh
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
P Value ◽  
Survival Curves ◽  
Advisory Committees ◽  
Kaplan Meier

Abstract Chronic Myeloid Leukaemia (CML) is a triphasic disease which typically presents in chronic phase with risk of progression to more aggressive phases in a certain proportion of patients. Accelerated Phase (AP), as described in the pre-Tyrosine Kinase Inhibitor (TKI) era by Kantarjian et al in 1988, is an intermediate stage with a poor median overall survival (OS) of ≤18 months without haematopoietic stem cell transplantation (HSCT). Since TKI therapy has revolutionized CML treatment, a significantly improved OS has been seen in most CML patients, including those in AP. Not all CML-AP patients require HSCT upfront nowadays and many are able to achieve major molecular remission (MMR) and favourable OS on TKI therapy. However, updated classifications of CML-AP by the World Health Organization (WHO) and European LeukemiaNet (ELN) do not reflect these significant advances in the TKI era. There is a need to re-evaluate the CML-AP classification that will have an impact on treatment decisions for CML-AP patients. In this study, we explored the association between various haematological parameters at diagnosis and the probabilities of OS and progression-free survival (PFS) of CML-AP patients on TKI therapy. Overall Survival (OS) and Progression-Free Survival (PFS) trends of 75 newly diagnosed CML-AP patients treated with frontline TKIs between 2000 to 2013 from Singapore General Hospital and Seoul St. Mary's Hospital in South Korea were retrospectively analysed with regards to demographic and haematological parameters, such as cell counts from serum and bone marrow at diagnosis, using cox proportional hazards analysis. Survival was also compared using log-rank test with Bonferroni corrections between CML-AP patients and 227 CML Chronic Phase (CML-CP) high-risk Sokal and 34 Blast Crisis (CML-BC) patients on TKI-based therapy. OS was defined as duration from diagnosis of CML-AP to death from any reason. PFS was defined as duration from disease diagnosis to the first occurrence of progression or death due to CML. As a whole, CML-AP patients treated with frontline TKI had survival that paralleled CML-CP high-risk Sokal patients (p-value = 0.694 for OS, p-value = 0.258 for PFS). Most of the death and progression occurred less than 3 years of starting TKI therapy (69.2% for OS, 84.6% for PFS). Multivariable analysis in CML-AP patients showed that male gender, bone marrow (BM) blasts ≥10% and clonal chromosomal abnormalities (CCAs) at diagnosis were associated with poor OS (Hazard Ratio (HR) 18.53, p-value = 0.013; HR 1.16, p-value = 0.010; HR 5.05, p-value = 0.044, respectively) and poor PFS (HR 12.96, p-value = 0.021; HR 1.17, p-value = 0.007; HR 8.84.05, p-value = 0.008, respectively). CML-AP patients with all 3 of these risk factors experienced the worst OS compared to those with 1 or zero risk factors (p-value <0.001). Patients with all 3 risk factors also had the poorest PFS compared to those with 2, 1 and zero risk factors (p-value = 0.022, <0.001, <0.001 respectively; figure 1). CML-AP Patients with 2 risk factors or less, had OS and PFS probabilities comparable to CML-CP patients with high-risk Sokal score (p-value = 0.082 for OS, p-value= 0.813 for PFS, figure 2 and 3 respectively). However, CML-AP patients with all 3 risk factors showed inferior OS and PFS probabilities similar to CML-BC patients (p-value = 0.799 for OS, p-value = 0.624 for PFS; figure 2 and 3 respectively). Our findings suggested that CML-AP was a heterogeneous group with varying survival probabilities on TKI therapy. Male gender, BM blasts ≥10% and CCAs at diagnosis were risk factors shown to be predictive of survival probabilities, and identified a high-risk sub-group among CML-AP patients with inferior OS and PFS rates similar to CML-BC patients. Aggressive chemotherapeutic strategies including HSCT should be warranted in these patients. However, TKI therapy alone with close molecular surveillance may be a reasonable option for optimally responding low-risk CML-AP patients who are not eligible for HSCT. Figure 1. Kaplan-Meier survival curves for PFS according to stratification of the number of risk factors present in CML-AP patients. Figure 1. Kaplan-Meier survival curves for PFS according to stratification of the number of risk factors present in CML-AP patients. Figure 2. Kaplan-Meier survival curves for OS according to phases of CML with AP patients separated by number of risk factors present. Figure 2. Kaplan-Meier survival curves for OS according to phases of CML with AP patients separated by number of risk factors present. Figure 3. Kaplan-Meier survival curves for PFS according to phases of CML with AP patients separated by number of risk factors present. Figure 3. Kaplan-Meier survival curves for PFS according to phases of CML with AP patients separated by number of risk factors present. Disclosures Kim: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Goh:BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Honoraria; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Phase II Study with R-FND Followed by 90-Y Ibritumomab Tiuxetan Radioimmunotherapy and Rituximab Maintenance for Untreated High-Risk Follicular Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 99-99
Author(s):  
Nathan H. Fowler ◽  
Sattva S. Neelapu ◽  
Michelle A. Fanale ◽  
Maria A. Rodriguez ◽  
Barbara Pro ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rates ◽  
Stage Iii ◽  
Ibritumomab Tiuxetan ◽  
Advisory Committees ◽  
Rituximab Maintenance

Abstract Abstract 99 Background: Follicular lymphoma (FL) patients (pts) with high-risk features using the FL International Prognostic Index (FLIPI) have an expected 5-year survival of approximately 50% with conventional chemotherapy. The incorporation of anti-CD20 monoclonal antibody therapy has improved results in this poor risk subgroup. (Buske, Blood 2006;108:1504) We have previously demonstrated that R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone) is an effective regimen for indolent lymphoma, capable of inducing molecular remissions. (McLaughlin, ASCO 2003;102:564). Both extended dosing of rituximab following induction, and consolidation of first remission with 90-Y ibritumomab tiuxetan radioimmnotherapy (RIT) can improve complete response rates and progression free survival (PFS) rates for patients with advanced FL. (Morschhauser, JCO 2008;32:5156; Salles, Lancet 2011;377:42) This is the first report of a chemoimmunotherapy approach followed by both RIT consolidation and rituximab maintenance. Methods: Untreated patients with FL (grade 1–3), with high risk disease (FLIPI score ≥ 3) who had adequate hematologic function and extensive stage (III/IV) disease were eligible for study entry. Patients received rituximab (375mg/m2 days 1 and 8 of cycle 1, and day 1 of subsequent cycles) fludarabine (25mg/m2 days 1–3), mitoxantrone (10mg/m2 day 1), and dexamethasone (20mg days 1–5) for four 28 day cycles. RIT was given 12–16 weeks following R-FND pending hematologic recovery. Six weeks following RIT, patients received rituximab 375mg/m2 every two months for one year. The primary objective of the study was to determine the PFS rates based on 1999 International Working Group criteria. The secondary objectives included assessing the safety and tolerance of RIT and maintenance rituximab after R-FND, assessing the CR and overall response rates, and determining the overall survival following treatment. Results: Forty nine patients were enrolled and 47 received treatment between October 2004 and April 2009. Forty-six patients were eligible for efficacy analysis. The median age was 61 (37–78), 80% had bone marrow involvement, and all had stage III/IV disease. Twenty four (51%) patients had bulky disease (>5cm) and 42 (91%) had elevated β2M. Thirty six patients completed all planned courses of treatment. Eight patients did not receive RIT, two due to neutropenia after R-FND. One patient had progressive disease while on treatment. Following R-FND, the complete (CR + CRu) and partial response rates were 87% and 13%. With RIT consolidation, the CR rate increased to 91%. At a median follow up of 50 months, the projected five year overall survival and PFS rates were 93% and 74%. Toxicity was mainly hematologic. Grade ≥ 3 neutropenia and thrombocytopenia occurred in 57% and 35% of patients respectively. Thirty seven patients required growth factors and 17 patients required transfusions. The median time to hematologic recovery following RIT was 10 weeks. The most common non-hematologic adverse events (≥Gr 3) were fatigue (17%), dypsnea (13%), and myalgia (11%). There were 3 cases of myelodysplasia (MDS), one in a patient who did not receive RIT. Conclusions: The combination of R-FND followed by RIT intensification and rituximab maintenance results in OS and PFS outcomes that are better than traditional combinations in this high risk population. Given the potential for serious toxicity (eg. MDS) seen in this trial and other intensive treatment strategies, this approach may be most appropriate in high-risk FLIPI patients whose outlook with standard therapy is poor. Acknowledgments: This study was sponsored by Genentech and Spectrum. Disclosures: Fowler: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Younes:Genentech, SBIO, Seattle Genetics, Syndax, Sanofi-Aventis: Honoraria, Research Funding.

scholarly journals Genetic Alterations at Diagnosis Predict Outcome of AML Patients Age 60 or Older Undergoing Allogeneic Transplantation in First Remission

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 48-48 ◽  
Author(s):  
H. Moses Murdock ◽  
Haesook T. Kim ◽  
Bryan Hambley ◽  
Pankit Vachhani ◽  
Nathan Denlinger ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Genetic Risk ◽  
Research Funding ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Advisory Committees ◽  
Genetic Characteristics ◽  
The Impact ◽  
Advisory Role

Background: Older age is associated with inferior outcomes after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML). High risk genetic characteristics are common among older patients and linked to poor outcomes in the non-transplant setting. An enhanced understanding of genetic risk may thus provide a basis for improving transplant outcomes in these patients. We evaluated the impact of leukemia genetic characteristics at diagnosis on HSCT outcomes in a multi-center cohort of AML patients age 60 or older receiving HSCT in first complete remission (CR1). Methods: We performed targeted sequencing of 112 genes on diagnostic leukemia samples from 257 patients with AML age 60 or older who received allogeneic HSCT in CR1 at 5 US transplant centers. Median age at diagnosis and HSCT were 65 (range 59-76) and 66 (range 60-76), respectively. 31% had clinically defined secondary AML, 11% had therapy-related AML, and 23% had adverse cytogenetics by 2017 ELN classification. Most (84%) were treated with anthracycline-based induction chemotherapy, while 16% received non-intensive induction. Conditioning was either reduced-intensity or non-myeloablative in 94% of patients. Median follow-up for survivors was 3.7 years; 3-year overall survival (OS) and leukemia-free survival (LFS) were 48% and 44%, respectively. Results: All patients had recurrent genetic alterations at the time of diagnosis, including 251 (98%) with gene mutations and 6 with only cytogenetic abnormalities. The most frequent gene mutations were DNMT3A (25%), NPM1 (23%), FLT3-ITD (22%), ASXL1 (21%), TET2 (21%), RUNX1 (20%), and SRSF2 (18%). Secondary-type mutations associated with antecedent MDS occurred in 42%, and 10% had TP53 mutations. As expected, secondary-type and TP53 mutations were associated with clinically-defined secondary AML (p&lt;0.001), need for reinduction (p=0.03), and CR with incomplete count recovery (p= 0.03). Despite the older age at leukemia diagnosis, putative germline pathogenic variants were identified in 22 (8.6%) patients, including 17 (6.6%) with DDX41 mutations (13/17 with somatic mutation of the second allele), and 5 with TERT or TERC variants not found in population databases. We evaluated the impact of gene mutations on LFS using univariable and multivariable Cox models and developed a hierarchical model of 3 molecular genetic risk groups according to the hazard ratios (Fig 1A): (1) patients with TP53 mutation or JAK2 mutation or FLT3-ITD/NPM1-WT (high risk), (2) patients without high risk mutations who have DNMT3A or GATA2 or DDX41 mutations (low risk) (3) patients without high- or low-risk mutations (intermediate risk), with 3-year LFS of 8%, 65%, and 47% (p&lt;0.001), respectively. Next, we combined molecular genetic and cytogenetic risk to derive a final genetic model comprised of 4 groups with distinct 3-year LFS (69%, 50%, 27%, and 0%) (Fig 1B). Poor LFS in the very high-risk group was due almost entirely to relapse (3-year relapse rate &gt; 90%), but was driven by a combination of relapse and non-relapse mortality in the intermediate and high-risk groups (Fig 2). Conclusion: Genetic characteristics at diagnosis are highly associated with OS and LFS in AML patients age 60 or older who undergo allogeneic transplantation in CR1. We identify patients with low genetic risk and remarkably good outcomes who may be candidates for strategies aimed at reducing toxicity, and those with very high-risk genetics who have limited benefit from current transplant approaches. Among intermediate and high-risk patients, the impact of disease genetics on LFS is mostly due to relapse, suggesting that a model incorporating measurement of residual disease in CR1 and after transplantation could enable a more dynamic estimation of risk. Disclosures Perales: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Koreth:Equillium: Consultancy; Amgen: Consultancy; Cugene: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Jazz: Consultancy; Cugene: Consultancy. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding.

scholarly journals Connect MM®—the Multiple Myeloma (MM) Disease Registry: Interim Analysis of Overall Survival and Outcomes in Patients with High-Risk Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2106-2106 ◽  
Author(s):  
Jatin J. Shah ◽  
Rafat Abonour ◽  
Brian G M Durie ◽  
Jayesh Mehta ◽  
Mohit Narang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
African American ◽  
High Risk ◽  
Board Of Directors ◽  
Interim Analysis ◽  
Research Funding ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
High Risk Disease

Abstract Background: MM treatment (Tx) advances have greatly improved clinical outcomes for patients (pts). A recent study demonstrated improved survival in MM through the past decade attributable to the impact of initial therapy with lenalidomide, bortezomib, and thalidomide. The greatest impact was observed in older pts (Kumar, et al. Leukemia, 2014). Connect MM, the first and largest prospective, observational, US-based, multicenter registry was designed to characterize pts, Tx patterns, and outcomes in newly diagnosed MM (NDMM). Methods: This ongoing registry was initiated in September 2009. Eligible pts with NDMM (diagnosis must have occurred within 2 mos of study entry) were enrolled at 234 US sites. Data were collected at baseline and each subsequent quarter using an electronic case report form. The initial enrollment includes all pts who had provided informed consent as of November 1, 2012 (N = 1493). The data cutoff for this analysis was Dec 10, 2013. A total of 1444 pts were treated and were included in overall survival (OS) analyses. Survival was examined for all treated pts adjusting for pt and Tx characteristics including age, autologous stem cell transplant (ASCT) status, gender, race, disease risk factors (International Myeloma Working Group [IMWG] high risk vs. non-high risk), and therapy received (triplet vs. non-triplet) among others. Triplet therapy was defined as any combination of 3 or more drugs during the first Tx regimen. OS was estimated using Kaplan-Meier methods and comparisons across groups were assessed used the log-rank test. Results: At the time of data cutoff, 1493 pts were enrolled with 1444 having received Tx. Of the treated pts 253 pts (18%) had IMWG high-risk disease and 108 pts (7%) had del(17p) at baseline. Median age was 67 y (range, 24-94 y), 57.2% were male, and 81.9% were white. Median follow-up was 29 mos (0-49.4 mos). The median OS for all treated pts was 44.4 mos. When assessed by age group, OS was significantly different (log-rank P < .0001) with a median of 47.6 mos for pts aged < 65 y (n = 632), 45.0 mos for those aged 65 to < 75 y (n = 443), and 33.7 mos for those aged ≥ 75 y (n = 369). OS was significantly longer for pts with ASCT vs. no ASCT (P < .0001), but not different by gender (P = .962) or race (Caucasian vs. African American vs. other; P = .250). Three-year OS probabilities by subgroup are listed in Table 1. When considering risk factors, IMWG risk was borderline significant (high vs. non-high; P = .106), and presence of del(17p) by cytogenetics and FISH was associated with significantly shortened OS (P = .005; Figure 1A). Interestingly, use of triplet therapy vs. non-triplet therapy was associated with significantly prolonged OS regardless of IMWG risk (non-high: P < .0001; high: P = .003; Figure 1B). However, no improvement was noted for triplet vs. non-triplet therapy in pts with del(17p). By multivariate analysis, the significant (P < .05) factors impacting OS were age (in 10-yr increments), International Staging System (ISS) disease stage, ECOG performance status, history of diabetes, anemia, renal function, and platelet count. Conclusions: This interim analysis based on initially treated pts demonstrated that age, ISS stage, and co-morbidities impact OS irrespective of IMWG cytogenetic risk. Triplet Tx was associated with significantly longer OS in pts regardless of IMWG risk status. This is the largest prospective pt cohort with high-risk disease including del(17p). Pts with high-risk disease did not have significantly lower OS vs. pts without high-risk features. Pts with del(17p) (p53 deletion) continue to have shorter OS approaching 3 y and increased survival with use of triplet therapy. Table 1. Kaplan-Meier Estimated 3-Y OS Probability Patients 3-y OS Probability (%) (95% CI) All (N = 1444) 62.6 (59.5-65.8) < 65 y (n = 632) 69.8 (65.2-74.3) 65 to < 75 y (n = 443) 65.0 (59.4-70.6) ≥ 75 y (n = 369) 47.2 (40.7-53.8) Gender Male (n = 831) 62.1 (57.9-66.3) Female (n = 613) 63.4 (58.7-68.2) Race Caucasian (n = 1191) 61.8 (58.3-65.3) African American (n = 183) 64.4 (55.4-73.5) Other (n = 27) 77.6 (57.3-98.0) ASCT Yes (n = 494) 77.1 (72.5-81.7) No (n = 950) 54.2 (50.0-58.3) Triplet therapy Yes (n = 778) 69.3 (65.3-73.3) No (n = 666) 54.8 (49.9-59.6) IMWG risk High (n = 253) 59.0 (51.6-66.4) Standard (n = 566) 66.3 (61.4-71.2) Low (n = 86) 75.7 (63.6-87.8) del(17p) Present (n = 108) 52.7 (41.8-63.6) Absent (n = 1336) 63.4 (60.1-66.7) Figure 1 Figure 1. Disclosures Shah: Celgene Corp: Consultancy, Research Funding. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Durie:Celgene Corp: Export Board Committee Other, Membership on an entity's Board of Directors or advisory committees; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Rifkin:Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy.

scholarly journals Trial in Progress: A Multicentre, Parallel Arm, Open-Label Trial of Frontline R-CHOP/Polatuzumab Vedotin-RCHP and Glofitamab in Younger Patients with Higher Risk Diffuse Large B Cell Lymphoma (COALITION)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3571-3571
Author(s):  
Adrian Minson ◽  
Nada Hamad ◽  
Costas K. Yannakou ◽  
Shu Min Wong ◽  
Jason P Butler ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Line Treatment ◽  
Front Line ◽  
Advisory Committees

Abstract Background: R-CHOP remains a standard frontline treatment for patients with DLBCL and high-grade B-cell lymphoma (HGBL). A significant proportion of patients will have refractory disease or subsequently relapse, particularly those with high-risk features such as an elevated IPI score or rearrangements of MYC and BCL2 and/or BCL6 (double/triple hit (DH/TH)). This population remains in need of improved induction treatments that can reduce the requirement for subsequent therapies which are associated with significant toxicities and diminishing response rates. Rationale: Glofitamab is a novel full-length bispecific antibody with a unique 2:1 configuration (two CD20 binding domains and one CD3 binding domain). In combination with a single pre-dose of obinutuzumab, glofitamab has demonstrated &gt;70% complete remission in aggressive B-cell lymphoma at the recommended target dose in a phase 1 trial (Carlo-Stella, EHA 2021). Pre-clinical studies suggest that glofitamab's activity is retained in the presence of concomitant cytotoxic and CD20 antibody therapies, making it an attractive agent for combination with R-CHOP-like induction. Polatuzumab vedotin (pola) is an antibody-drug conjugate approved for R/R DLBCL in combination with BR, and is currently in evaluation for the front-line treatment of DLBCL in combination with RCHP in a randomised trial. The safety and preliminary efficacy of glofitamab in combination with R-CHOP, or pola-RCHP as a front-line treatment for high risk DLBCL is being evaluated. Study Design and Methods: This is a parallel-arm phase Ib/II trial. Treatment consists of an initial cycle of R-CHOP, followed by 5 cycles of combination induction treatment and 2 cycles of consolidation glofitamab monotherapy. Key inclusion criteria are: age 18-65 years, a diagnosis of DLBCL or HBGL, high-risk features (IPI ≥3 or NCCN-IPI ≥4 or presence of DH/TH), treatment naïve or after 1 cycle of R-CHOP, ECOG 0-3. The primary endpoint is the safety of the combination and secondary endpoints include complete response rates at interim and end of treatment FDG-PET assessments by Lugano criteria, progression free survival and overall survival. Correlative studies assessing baseline immunologic profiles, tumour phenotype and potential resistance mechanisms are planned. Approximately 40 patients will be treated in each arm across 12-14 Australian sites. The trial commenced recruitment in July 2021 (NCT04914741). The ability to recruit prior to either cycle 1 or cycle 2 allows seamless cross-referral from non-trial sites. Figure 1 Figure 1. Disclosures Minson: Hoffman La Roche: Research Funding; Novartis: Research Funding. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Seymour: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: 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, Research Funding; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Takeda: Research Funding; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Phase 2 Study Of Bendamustine, Bortezomib (Velcade) and Prednisone (BVP) For Newly Diagnosed Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2155-2155 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Albert Oriol ◽  
Laura Rosiñol ◽  
Felipe de Arriba ◽  
Jesús Martín ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Stem Cell Collection ◽  
Poor Mobilizers

Abstract Background Bortezomib-based combinations, including alkylating agents (VMP or CyBorD) or immunomodulatory drugs (VTD or RVD) have been established as regimens widely used in newly diagnosed MM patients. Bendamustine is a bifunctional alkylating agent effective in relapsed and/or refractory MM patients, and approved in Europe in combination with prednisone for elderly newly diagnosed MM. Since bendamustine may be more efficient than other alkylators, an attractive possibility would be to explore it in combination with bortezomib and prednisone (BVP) in newly diagnosed MM patients both transplant and non transplant candidates. Patients and Methods 60 newly diagnosed MM patients were included in the trial. The first cycle consisted on bendamustine at 90 mg/m2 given IV on days 1 and 4, in combination with bortezomib at 1,3 mg/m2 given IV on days 1, 4, 8, 11, 22, 25, 29 and 32 and prednisone at 60 mg/m2 given PO on days 1 to 4. In the following cycles, bendamustine was given on days 1 and 8, and bortezomib on days 1, 8, 15 and 22 (weekly schedule), and prednisone as it was previously described. Patients younger than 65 years proceeded to peripheral blood stem cell collection (PBSC) using growth factors alone after 4 cycles; HDT-ASCT was performed after 6 cycles. Patients older than 65 years received up to nine 28-day cycles. Results Between May 2011 and July 2012 enrollment was completed (60 pts). Median age was 61 years (range 38-82; 18 pts ≥65), 67% had ISS stage II/III, and 67% had unfavorable cytogenetics: t(4;14), t(14;16), del 17p or 1q gains by FISH. After a median of 6 cycles (2-9), 75% of patients achieved at least PR, including 16% of sCR, 9% CR and 28% of VGPR. Although the differences were not statistically significant, there was a trend to higher CR rate in the group of patients <65 years (31%) compared with elderly patients (11%). No differences were observed in overall response rates and CR rates in patients with standard and high risk cytogenetic abnormalities. Forty patients proceeded to stem cell collection after a median of 4 cycles of BVP. Upon using G-CSF alone, 14 pts (35%) failed to collect a minimun of 2 x 106 CD34+ cells/Kg. An ammendment was done and plerixafor was recomended for poor mobilizers (peripheral CD34 cell count inferior to 10/μL on day 4); all patients but 2 achieved, with G-CSF plus plerixafor, the minimum of CD34+ cells required to proceed to ASCT. These 2 patients successfully collected CD34+ cells using chemotherapy plus G-CSF and plerixafor. Of the 31 patients who received HDT-ASCT, sCR and CR rate before transplant was 18% and 13%, respectively, upgrading up to 39% of sCR and 13% CR after transplant. 7 pts (22%) achieved immunophenotypic CR. After a median f/u of 12 months (5-25), 8 pts have progressed, resulting in a 15-m TTP of 85%. Concerning OS, 89% of patients remained alive at 15 months. None of patients achieving sCR and CR have progressed and all of them are alive at 15 months. Regarding cytogenetic abnormalities, although there were not significant differences, one patient progressed in standard risk group and five in the high risk subgroup resulting in a 15 m-TTP of 93% vs 85%. No significant differences have been observed in terms of 15 m-OS between standard and high risk cytogenetic subgroup (100% vs 92%, respectively). As far as toxicity is concerned, hematologic toxicities included: G3/4 anemia (11%), neutropenia (23%), and thrombocytopenia (14%). The most common G3/4 non-hematologic toxicities were: asthenia (10%), infections (9%), and peripheral neuropathy (4%). Conclusions In patients candidates to HDT-ASCT, response rates obtained before and after transplant are comparable to other three drug bortezomib-based combinations, such as VTD or CyBorD. However, growth factors alone for stem cell collection after four BVP cycles as induction resulted in a 35% of poor mobilizers who were rescued with plerixafor. In the elderly population, although the number of patients included was small, BVP seems not superior to VMP in response rates. Disclosures: Mateos: Janssen, Mundipharma: Honoraria. Off Label Use: bendamustine plus bortezomib and prednisone is not an approved combination for first line of therapy. Oriol:Celgene: Consultancy. Ocio:Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding. Alegre:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Bladé:Janssen, Mundipharma: Honoraria. San Miguel:Janssen, Mundipharma: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Efficacy of Induction Thearapy with Lenalidomide, Bortezomib, and Dexamethasone (RVD) in 1000 Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3294-3294 ◽  
Author(s):  
Nisha Joseph ◽  
Vikas A. Gupta ◽  
Craig C Hofmeister ◽  
Charise Gleason ◽  
Leonard Heffner ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Risk Patients ◽  
Standard Risk

Abstract Background : Lenalidomide, bortezomib and dexamethasone (RVD) has been shown to be a well-tolerated and efficacious induction regimen in newly diagnosed myeloma patients. Two large randomized phase III trials show an overall response rate (ORR) >95% (Durie et al, Attal et al) supporting this combination regimen. We have conducted a retrospective analysis utilizing our institutional data of 1000 patients treated with RVD induction therapy at the Winship Cancer Institute of Emory University. Methods: 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 61 years (range 16-83). Other notable patient characteristics include: M/F 54.3%/45.6%; W/AA 56.4%/34%; ISS I and II/III 54%/17%; Isotype IgG/IgA/FLC 59.1%/19%/15.8%; standard risk/high risk 72%/28%. High risk disease was defined as the presence of t(4;14), t(14;16), del(17p), and/or complex karyotype. A total of 835 patients (83.5%) underwent autologous stem cell transplant (ASCT) upfront after attaining at least a partial response with induction therapy, and 165 patients (16.5%) were offered deferred transplant. Among the patients that opted for deferred transplant, 56 of these patients (33.9%) underwent ASCT at first relapse with a median time to transplant of 30 months (3-96). 755 (75.5%) of patients received risk-stratified maintenance therapy following transplant. Evaluation of responses to induction therapy for the entire cohort show an ORR 97.3% with ≥VGPR of 68% post-induction therapy. Response rates 100 days post-transplant show an ORR 98% with 30.7% of patients achieving a sCR. Response rates are summarized in table 1. Median PFS was 63 months for the entire cohort, and 72 months for standard risk patients (61.75-82.25) versus 37 months for the high-risk patients (30.84-43.16), p<0.001. Median OS has not been reached at median of 38 months follow up (Figure 1). Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction. These results illustrate both the activity of this induction regimen with impressive response rates and long-term outcomes in both standard and high risk patients. Disclosures Hofmeister: Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Janssen: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals High Incidence of Venous Thromboembolism in Patients with Chronic Graft-Versus-Host Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-46
Author(s):  
Najla El Jurdi ◽  
Heba Elhusseini ◽  
Todd E. DeFor ◽  
Grigori Okoev ◽  
Aleksandr Lazaryan ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Advisory Committees ◽  
High Incidence ◽  
Independent Association ◽  
Very High ◽  
Fund Research

Background: Limited studies report a wide range of venous thromboembolism (VTE) incidence among allogeneic hematopoietic cell transplant (alloHCT) recipients. Chronic GVHD (cGVHD) is an immune mediated complication after alloHCT associated with vascular endothelial damage and prolonged systemic inflammation. We hypothesized that patients developing cGVHD are a subgroup at particularly high risk for VTE. Aims: To assess VTE incidence, sites of involvement, and risk factors in patients with cGVHD and to examine the impact of VTE on clinical outcomes after alloHCT. Methods: We performed a retrospective cohort study of all 145 patients who developed cGVHD after a matched sibling (MSD) and umbilical cord blood (UCB) donor alloHCT from 2010 to 2018. VTE was defined as a new confirmed event by imaging at any time after cGVHD diagnosis. VTE sites were categorized as upper extremity (UE), lower extremity (LE) deep vein thrombosis (DVT) or pulmonary embolus (PE). We assessed the cumulative incidence of VTE treating non-VTE mortality as a competing risk. Multivariate regression was used to evaluate the independent association of risk factors with the incidence of VTE using predefined factors in our model including gender, age, DRI, cGVHD severity, days to cGVHD from transplant and platelet level. We accounted for multiple events of VTE using PWP regression. Cox and Fine and Gray regressions were used to evaluate the independent association of time-dependent VTE on overall survival (OS) and non-relapse mortality (NRM), respectively using propensity scoring to control for confounding.. Results: Median age at time of cGVHD diagnosis was 52 years (range 19-74). 104 (72%) patients received MSD and 41 (28%) UCB alloHCT. Of the 145 patients with cGVHD, 32 (22%) developed either 1 or 2 VTE events and 14 (10%) developed 2 VTE events. The first VTE events were PE (n=6, 19%), and DVT (n=26, 81%; n=17 LE, n= 8 UE and n=5 catheter related UE DVT); one patient developed an IVC thrombus. The second VTE events were PE (n=2, 14%), and DVT (n=12, 86%; n=5 LE, n= 7 UE and n=4 catheter related UE DVT). Most patients were on corticosteroids at the first (n=28, 88%) and second (n=10, 71%) VTE with a median dose of (0.3 and 0.2 mg/kg/day, respectively) ± additional immunosuppression therapies. The cumulative incidence of VTE through 5 years post cGVHD diagnosis was estimated at 22% (95% CI: 15-29%) with median time from cGVHD diagnosis to VTE of 234 days (IQR 85-599). Median time to the development of LE DVT or PE was shorter than UE DVT (107 vs 450 days, respectively). Incidence was higher in males (24% vs 18%), and was not significantly different by age (&lt; or ≥50), BMI (&lt; or ≥30), HCT- comorbidity index, donor type, conditioning regimen and GVHD prophylaxis. Cumulative incidence was higher (50%) in patients with high/very high risk DRI compared to 19% in those with low and intermediate risk DRI. VTE incidence was highest in patients with de novo cGVHD (25%) compared to quiescent (20%) and progressive type (17%). Cumulative incidence was 9%, 17% and 38% in those with mild, moderate and severe GVHD respectively. Patients with lung, gastrointestinal, genitourinary and liver cGVHD had a higher incidence of VTE. Patients developing cGVHD &gt;6 months from HCT had a higher incidence of VTE (24% vs 19%). In multivariate analysis, high/very high risk DRI was associated with higher risk of VTE (HR 2.5; 95% CI; 1.2-5.3) (Figure 2). VTE was not associated with a significantly higher 2-year NRM (HR 1.2; 95% CI; 0.4-3.6) or 5 year OS (HR 1.4; 95% CI; 0.7-3.0). Conclusion: Patients who develop cGVHD after alloHCT have a high incidence VTE. Identifying a subgroup at a particularly high risk for VTE could inform thromboprophylaxis and other supportive care strategies for prevention of such events. Disclosures Bachanova: Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Blazar:Tmunity: Other: Co-founder; Magenta Therapeutics: Consultancy; KidsFirst Fund: Research Funding; Fate Therapeutics Inc.: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeuetic: Consultancy; BlueRock Therapeutics: Research Funding. Brunstein:Astex: Research Funding; AlloVir: Other: Advisory board; Magenta: Research Funding; Gamida: Research Funding. Holtan:CSL Behring: Other: Clinical trial data adjudication; BMS: Consultancy; Generon: Consultancy; Incyte: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Gangaraju:Sanofi Genzyme, Consultant for Cold Agglutinin Disease: Consultancy. MacMillan:Talaris Therapeutics, Inc: Consultancy; Angiocrine Biosciences, Inc.: Consultancy; Equillium, Inc.: Consultancy; Fate Therapeutics, Inc.: Consultancy; Mesoblast: Consultancy. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Arora:Pharmacyclics: Research Funding; Fate Therapeutics: Consultancy; Kadmon: Research Funding; Syndax: Research Funding.

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