Early Relapse Following ASCT for Patients with MM: Identification of Predictor Factors in the Era of Novel Agents

Abstract Introduction Auto-SCT, still remains as the standard therapy for patients with MM deemed to be eligible for this approach. Unfortunately, even when most patients will respond to auto-SCT, 10-20% of cases will progress within a year. Over the last few years, a dramatic improvement on clinical outcomes has been made by using novel agents in the treatment of MM. Based on the above mentioned, we aimed to assess the incidence of Early Relapse (ER) for patients undergoing auto-SCT treated with novel-agents induction combinations at our center and to explore possible predictor factors. Methods All consecutive patients who underwent single auto-SCT at Tom Baker Cancer Center (TBCC) from 01/2006 to March/2016 were evaluated. ER was defined as per recent publications (<12 months from auto-SCT). Two-sided Fisher exact test was used to test for differences between categorical variables. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. All statistical analyses were performed by using the SPSS 24.0 software. Results 232 consecutive patients with MM underwent single auto-SCT at our Institution over the defined period. Clinical characteristics are shown in Table 1. At the time of analysis, 172 patients are still alive and 112 have already progressed. Among these cases, 35 patients have relapsed in <12 months (ER) from auto-SCT (15.1%). 16 out of 35 patients with ER had HRC (high-risk cytogenetics) (45.7%). ER was seen in 25% of cases with HRC and 11% of patients with Standard Risk (SRC) (p=0.01). Patient with <VGPR at day-100 post-ASCT exhibited a shorther PFS (24 months vs 34 months, p=0.03) (Fig1b). Patients with <VGPR at day-100 post-ASCT were more likely to develop ER (31.5% vs 9%). (p=0.001) The use of lenalidomide maintenance or any consolidation strategy did not impact on the rate of ER (p=0.1 and 0.4, respectively). Neither the type of conditioning regimen nor the induction chemotherapy (p>0.5) was associated to a higher rate of ER. Median OS was shorter for the ER group (17.8 months) compared to an estimated 93 months for those patients relapsing >12 months. (p=0.0001) In conclusion, patients with ER after auto-SCT remain to be a challenge. Even with the advent of novel agents, patients with ER had poor outcomes. ER seems to be associated to HRC and low degree of response. Patients with these features should be considered for novel alternatives, aiming to achieve and sustain the deepest possible response. More biological insights on ER cases are needed to further improve survival outcomes. PFS according to level of response at day-100 post ASCT PFS according to level of response at day-100 post ASCT Figure 1 Overall survival according to the pattern of relapse Figure 1. Overall survival according to the pattern of relapse Disclosures Jimenez-Zepeda: Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene, Janssen, Amgen, Onyx: Honoraria. Neri:Celgene and Jannsen: Consultancy, Honoraria. Bahlis:Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

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Improved Survival of Patients with Myelofibrosis in the Last Decade

Blood ◽

10.1182/blood-2020-142578 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 50-51

Author(s):

Lucia Masarova ◽

Prithviraj Bose ◽

Naveen Pemmaraju ◽

Lingsha Zhou ◽

Sherry A. Pierce ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Research Funding ◽

Myeloproliferative Neoplasm ◽

Categorical Variables ◽

Rank Test ◽

Fisher Exact Test ◽

Grant Support ◽

Before And After

Introduction: The myeloproliferative neoplasm myelofibrosis (MF) is associated with reduced overall survival (OS) compared to the general population. In 2011, the JAK1/2 inhibitor ruxolitinib, was approved in the USA for the treatment of intermediate and high-risk MF. Long-term follow-up of patients in pivotal phase 3 studies showed survival benefit of ruxolitinib therapy. Objective: We sought to evaluate the outcome of patients with MF diagnosed before and after the year of 2010 to assess whether OS changed in the past decade in the era of ruxolitinib. Methods: We retrospectively reviewed the charts of 1346 patients with MF who presented to our institution in the last 25 years and compared clinical parameters and outcomes between those presented before and after the year of 2010 (before / after y. 2010). Newly diagnosed MF patients and patients within 12 months from diagnosis who were previously only treated with supportive therapy (danazol, growth-factors, steroids) were included. Cytogenetics (≥10 metaphases) was classified according to Gangat, JCO, 2011. Molecular analysis (≥ 28 genes) was performed only after y. 2010 by using next generation sequencing platform. Fisher exact test and χ2 were used for analysis of categorical variables. Overall survival (OS) was estimated using the Kaplan-Meier method and comparison was done by the log-rank test. Results: Among the 1346 patients, 806 (60%) patients were seen after y. 2010. Median age of all patients was 65 years (range, 20-94), 62% were males. Patient characteristics with comparison between groups are shown in Table 1. Patients after y. 2010 were older, with lower WBC and lower lactate dehydrogenase, but had more symptoms. The distribution of IPSS scores between groups were comparable at around 10% for low, 36% for intermediate-1, 20-25% for intermediate-2 and ~30% for high risk. Eighty-five and 80% of patients before and after y. 2010, respectively, received therapy for MF at our institution. Overall, 78 patients (37 after y. 2010) underwent stem cell transplantation. Among treated patients at our institution, 25% (n 117) and 37% (n 241) before and after y. 2010 received ruxolitinib during their follow-up. Ruxolitinib therapy was initiated with a median time of 2 months (range, 0.2-156) from presentation to our institution, longer in those before y. 2010 (11 vs 1 months in patients after y. 2010, respectively, p = 0.001) After a median follow-up of 30.4 months (range, 0.9-266); 659 (49%) of patients died. More deaths were noticed in those before y. 2010 (74% vs 32 %, respectively, p < 0.001); but these patients had also longer follow-up (37.5 months vs 25 months, p < 0.001). Eighty-five patients (10%) developed acute leukemia: 2 cases per 100 person-years per observation for both groups. Patients after y. 2010 had superior OS to those before y. 2010 with HR 0.7 (95% CI: 0.59-0.82), p < 0.001, Figure 1. Superior OS was observed in all patients after y. 2010 (vs before y. 2010) when stratified by IPSS score (higher equals for combination of int -2 and high, Figure 2), or age (cutoff of 65 years, Figure 3). Patients exposed to ruxolitinib had superior OS regardless of being diagnosed before or after y. 2010, with respective medians of 98 (95% CI: 78-118) and 91 (95% CI: 73-109) months (details to be presented at the conference). Conclusion: Our results demonstrate that survival of patients with MF has improved in the last decade. Survival has improved in younger and older patients as well as in those with more advanced disease (per IPSS risks). Many factors may have contributed to the observed improvement in outcome of MF patients, including new therapies, e.g. ruxolitinib, as well as improved supportive management and disease awareness. Disclosures Bose: Blueprint Medicines Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; NS Pharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding. Pemmaraju:Daiichi Sankyo: Research Funding; DAVA Oncology: Honoraria; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria; Incyte Corporation: Honoraria; MustangBio: Honoraria; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; SagerStrong Foundation: Other: Grant Support; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Affymetrix: Other: Grant Support, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Cellectis: Research Funding. Kantarjian:Novartis: Research Funding; Ariad: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Astex: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding. Verstovsek:CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; ItalPharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding.

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High-Risk Cytogenetics Multiple Myeloma: Impact of Consolidation and Maintenance

Blood ◽

10.1182/blood.v128.22.2271.2271 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2271-2271 ◽

Cited By ~ 3

Author(s):

Victor Jimenez-Zepeda ◽

Peter Duggan ◽

Paola Neri ◽

Jason Tay ◽

Fariborz Rashid-Kolvear ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Clinical Outcomes ◽

Research Funding ◽

Progression Free Survival ◽

Categorical Variables ◽

Rank Test ◽

Fisher Exact Test ◽

Free Survival ◽

The Impact

Abstract Introduction MM is a very heterogeneous disease for which several new treatments have become available over the past decade. With the advent of novel agents, the outcomes of this disease have improved dramatically. Unfortunately, High-risk myeloma (HRM) defined by the presence of del(17p), t(4;14), t(14;16), del13q by conventional karyotype and hypodiploidy, continues to exhibit poorer outcomes. Based on the above mentioned, we aimed to assess the clinical outcomes of patients with HRM treated at our center. Methods All consecutive HRM patients who underwent single auto-SCT at Tom Baker Cancer Center (TBCC) from 01/2004 to March/2016 were evaluated. HRM was defined by FISH and conventional karyotype when available. Two-sided Fisher exact test was used to test for differences between categorical variables. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. All statistical analyses were performed by using the SPSS 22.0 software. Results 73 consecutive patients with HRM underwent single auto-SCT at our Institution over the defined period. Clinical characteristics are shown in Table 1. Eighty-seven percent of patient received bortezomib-containing regimens as induction regimens. Day-100 response post-ASCT is seen in Table 1. Consolidation was given to 41.7% and maintenance to 79% of cases. At the time of analysis, 43 patients are still alive and 40 have already progressed. Median OS and PFS were 50.8 and 21.9 months, respectively for the whole group. Median OS was 50.4 months for the group receiving consolidation compared to 39 months for those without (p=0.1). In addition, median PFS was longer in the group treated with consolidation (NR, Estimate 25 months vs 13.5 months, p=0.02, Fig1a). Furthermore, OS and PFS were longer in the group receiving some form of maintenance compared to those without (56.3 and 22.5months vs 19.9 and 9 months, p=0.04 and 0.01, respectively) (Fig 1b and c). In conclusion, HRM is an aggressive form of myeloma where the OS and PFS are shorter than the standard risk MM. Consolidation and maintenance strategies seemed to increase both OS and PFS in our current report, but clinical outcomes are still poor. Novel strategies such as immune modulation,check-point inhibition, among others are needed to maximize the impact of the consolidation and maintenance phases in this group of patients. Progression-Free Survival and consolidation Progression-Free Survival and consolidation Figure 1 Overall survival and maintenance Figure 1. Overall survival and maintenance Figure 2 Progression-Free survival and maintenance Figure 2. Progression-Free survival and maintenance Disclosures Jimenez-Zepeda: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene, Janssen, Amgen, Onyx: Honoraria. Neri:Celgene and Jannsen: Consultancy, Honoraria. Bahlis:Amgen: Consultancy, Honoraria; BMS: Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau.

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Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to Bortezomib, Thalidomide and Dexamethasone (VTD) As Induction Therapy for the Treatment of Transplant Eligible Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4505.4505 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4505-4505 ◽

Cited By ~ 1

Author(s):

Victor Jimenez-Zepeda ◽

Nizar J. Bahlis ◽

Peter Duggan ◽

Rafael Alonso ◽

Juan José Lahuerta ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Treatment Regimen ◽

Research Funding ◽

Progression Free Survival ◽

Categorical Variables ◽

Rank Test ◽

Fisher Exact Test ◽

Similar Response ◽

Free Survival

Abstract Introduction: Cyclophosphamide, bortezomib and Dexamethasone (CyBorD) has become the standard frontline approach for the treatment of multiple myeloma (MM) in many centers across Canada. A recent study led by the IFM group showed that the triplet combination of bortezomib, thalidomide and dexamethasone is superior as an induction regimen compared to CyBorD for patients undergoing ASCT. Based on the above-mentioned, we aimed to compare the effect of CyBorD and VTD for the treatment of transplant eligible MM patients in 2 different centers from Canada and Spain. Patients and Methods: The primary objective was to assess ORR and ³VGPR rates after induction and at day-100 post-ASCT, as well as MRD assessed by flow cytometry. Two-sided Fisher exact test was used to test for differences between categorical variables. A p value of <0.05 was considered significant and survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Results: 101 patients have received CyBorD and 23 have received VTD. Clinical characteristics are shown in Table 1. At the time of analysis, 90 and 19 patients in the CyBorD and VTD are alive of which 25 and 9, respectively, have progressed. ORR and VGPR rates after a median of 4 cycles of induction were 94% and 56.4% for patients treated with CyBorD, and 91% and 78.2% for VTD, respectively (p=0.3 and 0.05). At day-100 post-ASCT, a ³VGPR rate of 84% and 94% was observed for the CyBorD and VTD groups, respectively (p=0.2). MRD negativity and CR rates were higher in the group receiving VTD (36.8% vs 27%, and 61% vs 38%, p=0.3 and 0.01). Furthermore, median OS and PFS did not differ among both groups (p=0.8 and 0.9, respectively) (Fig1a and Fig1b). In Conclusion: CyBorD and VTD appeared to be effective treatment options for transplant-eligible myeloma patients with similar response rates. Our study is in agreement with that reported by the IFM group, showing a higher rate of³VGPR after induction and day-100 post-ASCT in the VTD group. MRD negativity and CR rate appears also higher in the VTD group suggesting a higher degree of response by using animmunomodulatory drug and a proteasome inhibitor together. Overall Survival according to treatment regimen Overall Survival according to treatment regimen Figure 1 Progression-Free survival according to treatment regimen Figure 1. Progression-Free survival according to treatment regimen Disclosures Jimenez-Zepeda: Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene, Janssen, Amgen, Onyx: Honoraria. Bahlis:Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria. Neri:Celgene and Jannsen: Consultancy, Honoraria.

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Bortezomib-Containing Regimens (BCR) for the Treatment of Non-Transplant Eligible Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.1846.1846 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1846-1846

Author(s):

Victor H Jimenez-Zepeda ◽

Peter Duggan ◽

Paola Neri ◽

Nizar J Bahlis

Keyword(s):

Overall Survival ◽

Research Funding ◽

Clinical Characteristics ◽

Progression Free Survival ◽

Categorical Variables ◽

Rank Test ◽

Cancer Center ◽

Fisher Exact Test ◽

Free Survival ◽

The Impact

Abstract Introduction In patients not eligible for transplant due to age and/or co-morbidities, the selection of up-front therapy needs to balance efficacy and toxicity. Recently, regimens with bortezomib, a proteasome inhibitor proven to be efficacious in myeloma, have been reported. Based on these findings, we aimed to evaluate the impact of different bortezomib combinations for the treatment of non transplant-eligible MM. Methods All- consecutive patients treated with bortezomib-containing regimens (BCR) at Tom Baker Cancer Center (TBCC) from 01/2006 to June/2015 were evaluated. Definitions of response and progression were used according to the EBMT modified criteria and a category of very good partial response (VGPR) was added. Two-sided Fisher exact test was used to test for differences between categorical variables. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Results 113 consecutive patients with MM received BCR. Thirty-three patients were treated with cyclophosphamide, bortezomib and dexamethasone (CyBorD), 41 with bortezomib, melphalan and prednisone (VMP) and 39 with bortezomib and dexamethasone (VD). Clinical characteristics are shown in Table 1. At the time of analysis, 20, 17 and 18 patients in the CyBorD, VMP and VD groups are still alive and 14, 33 and 30 have already progressed, respectively. ORR and VGPR rates were 93.9%/75.7%, 80%/53% and 76%/48% (p=0.001) for patients treated with CyBorD, VMP and VD, respectively. Median OS was NR for CyBorD, compared to 41months and 37 months for VMP and VD patients (p=0.6). Median PFS was 16.7 months for CyBorD compared to 17.5 months and 11 months for VMP and VD (P=0.6), respectively. The rate of treatment discontinuation and median number of cycles were: 9%, 26% and 12.8% and 6, 7.5 and 4 cycles for CyBorD, VMP and VD patients, respectively. Patients were to receive 6-9 cycles of treatment and the regimen could be continued to a maximum of 2 years at the discretion of the treating hematologist based on tolerability and response. Nine patients (27%) in the CyBorD group and 17 (41.4%) and 4 (10%) in the VMP and VD group received maintenance treatment. Median OS and PFS was longer for the group receiving maintenance (62 months vs 32 months and 23 months vs 10 months, p=0.007). In conclusion, bortezomib containing regimens are efficacious in the treatment of non-transplant eligible MM. Patients receiving maintenance appeared to exhibit longer PFS and OS. Very elderly patients should be subjected to frailty and comorbidity indexes aiming to decrease toxicity and prolong survival. Table 1. Clinical Characteristics Characteristic CyBorD, n=33 VMP, n=41 VD, n=39 Age (median) 58 58 58 GenderMaleFemale 20 (60.6%)13 (39.4%) 22 (53.6%)19 (46.4%) 26 (66.6%)13 (33.4%) Hb (g/L) 107 110 103 Calcium (µmol/L) 2.4 2.35 2.31 Creatinine (µmol/L) 115.5 103 108 B2microglobulin (µmol/L) 4.1 3.42 5.9 Albumin (g/L) 31 31 30 Stage IStage IIStage III 6 (12.1%)14 (42.4%)13 (45.5%) 9 (21.9%)19 (46.3%)13 (31.8%) 4 (10.2%)16 (41%)18 (48.8%) LDH (IU/L) 185 179 174 BMPC (%) 31 30 33.5 Heavy chain:IgGIgAFLC onlyIgDIgMBiclonal 2247000 19148000 21107010 Light chain:KappaLambdaBiclonal 16170 29120 24150 High riskStandard risk 5 (15%) 28 6 (14.6%)35 8 (20%)31 Ab: BMPC: Bone marrow plasma cells. Figure 1. Overall survival for patients receiving CyBorD, VMP and VD Figure 1. Overall survival for patients receiving CyBorD, VMP and VD Figure 2. Progression-Free survival for patients receiving CyBorD, VMP and VD Figure 2. Progression-Free survival for patients receiving CyBorD, VMP and VD Figure 3. OS for patients receiving CyBorD, VMP and VD maintenance Figure 3. OS for patients receiving CyBorD, VMP and VD maintenance Disclosures Jimenez-Zepeda: Celgene: Honoraria; Amgen: Honoraria; J&J: Honoraria. Duggan:Jansen: Honoraria; Celgene: Honoraria. Neri:Celgene: Research Funding. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Early Relapse After Single ASCT For MM Patients Is a Major Predictor Of Survival In The Era Of Novel Agents

Blood ◽

10.1182/blood.v122.21.3396.3396 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3396-3396

Author(s):

Victor H Jimenez Zepeda ◽

Suzanne Trudel ◽

Donna E. Reece ◽

Christine I. Chen ◽

Rodger E. Tiedemann ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Induction Therapy ◽

Research Funding ◽

Novel Agents ◽

Cancer Center ◽

High Dose ◽

Prognostic Variables ◽

Early Relapse ◽

The Impact

Abstract Introduction The role of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in with the availability of effective novel agents. It has been shown that exposure to novel agents (NA) can improve the post-relapse survival (Venner CP, et al, 2011). However, the impact of early relapse (ER) after ASCT in the era of NA has not been fully defined. In this study, we aimed to assess the impact of ER after ASCT on overall survival (OS) for MM patients (pts) undergoing single ASCT who had received NA induction regimens Patient and Methods All consecutive pts with documented MM undergoing single ASCT at Princess Margaret Cancer Center from 01/02 to 09/12 who had novel induction therapy were evaluated. ER was defined as progression of myeloma within 12 months from the ASCT. The Cox proportional hazard model was used to perform multivariate analyses of possible prognostic variables for overall survival. A p value of <0.05 was considered statistically significant. Results The clinical and laboratory characteristics are of the 184 pts given induction therapy with NAs are listed in Table 1. The median age for this cohort of patients was 58 years (range 31-72). At day-100 post-ASCT, CR was achieved in 15.3% and VGPR in 57.1%. At the time of this analysis, 81% of pts are alive and 75 (40.7%) have already progressed. The median OS of the whole group was 93 months (95% CI, 70-116) (Fig.1a) and medianPFS was 25.43 months. Median time to relapse was 17.23 months (C I95%; 12-22). Early relapse was seen in 27/75 pts (36% of relapsed cases). Median OS was significantly shorter for the group of patients with ER (20 months, CI 95%; 15.56-24.51 versus 93 months, CI 95%; 75-111) (p=0.001) (Fig. 1b) Multivariate analysis showed the presence of ER as the major independent prognostic factor for OS; age > 60, B2M > 460 µmol/L, LDH > 350 IU/L, CRP > 20mg/L, albumin < 35g/L, and creatinine>200 µmol/L did not correlate with OS. In addition, FISH was available in only 78/184 cases. Only 1/27 pts in the ER group exhibited high-risk cytogenetics versus 0/48 in the non-ER group. In conclusion, not only the quality of response but also maintatenance of a deep response after ASCT, appear to be major prognostic variables in MM. Patients with ER post-ASCT should be biologically characterized to better understand the mechanisms of resistance associated with this particular entity and to develop new predictive models that can identify prospectively this myeloma subset. Also, patients with ER should be included in the definition of “high-risk” disease and priority candidates for the development of individualized therapeutic measures. Disclosures: Reece: Otsuka: Honoraria, Research Funding; BMS: Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Consultancy. Chen:Roche: Honoraria; Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Kukreti:Millennium Pharmaceuticals: Research Funding; Onyx: Research Funding.

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Risk of Metastatic Ovarian Involvement in Nongynecologic Malignancies

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e3182332cd1 ◽

2012 ◽

Vol 22 (1) ◽

pp. 3-8 ◽

Cited By ~ 4

Author(s):

Kidong Kim ◽

Soo Youn Cho ◽

Sang-Il Park ◽

Hye Jin Kang ◽

Beob-Jong Kim ◽

...

Keyword(s):

Overall Survival ◽

Malignant Tumors ◽

Rank Test ◽

Benign Tumors ◽

Binary Logistic Regression Analysis ◽

Fisher Exact Test ◽

Tumor Type ◽

Metastatic Tumors ◽

Number Of Patients ◽

Adnexal Tumors

ObjectiveThe objectives were to evaluate the risk of malignant adnexal tumors in women with nongynecologic malignancies and to identify variables associated with the risk of malignant adnexal tumors.MethodsThe eligibility criteria included the diagnosis of a nongynecologic malignancy and adnexal tumors, which were resected or subjected to biopsy at our institute between 1999 and 2010. The risk of malignant adnexal tumors was assessed by dividing the number of patients with metastatic tumors to the adnexa or primary adnexal cancers by the total number of patients. The association of clinicopathologic variables with the risk of malignant adnexal tumors was evaluated using the Fisher exact test and binary logistic regression analysis. In patients with metastatic tumors to the adnexa, the association of clinicopathologic variables with overall survival after adnexal surgery was examined using the log-rank test.ResultsIn 166 patients with adnexal tumors, 41 benign tumors, 113 metastatic tumors to the adnexa, and 12 primary adnexal cancers were diagnosed. Age older than 46 years, a tumor type associated with a high risk for malignant adnexal tumors, and bilateral tumors significantly increased the risk of malignant adnexal tumors. The overall survival of the patients with stomach cancer was significantly worse than the patients with colorectal or breast cancers.ConclusionOne hundred twenty-five of the 166 patients with nongynecologic malignancies who had adnexal tumors managed surgically were shown to have malignant tumors, and most of the tumors were metastatic from primary sites. The risk of malignant adnexal tumors was associated with age, nongynecologic malignancy, and bilaterality.

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236 Predictors of ICI renal toxicity: a pathological approach

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.236 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A252-A252

Author(s):

Ala Abudayyeh ◽

Liye Suo ◽

Heather Lin ◽

Omar Mamlouk ◽

Cassian Yee ◽

...

Keyword(s):

Overall Survival ◽

Renal Toxicity ◽

Checkpoint Inhibitors ◽

Interstitial Fibrosis ◽

Transplant Rejection ◽

Categorical Variables ◽

Rank Test ◽

Cancer Center ◽

Renal Response ◽

Md Anderson

BackgroundInflammatory response in unintended tissues and organs associated with the use of immune checkpoint inhibitors also known as immune related adverse events (irAEs) is a management challenge, and renal irAEs are associated with increased patient morbidity and mortality. The most common renal toxicity is acute interstitial nephritis (AIN), characterized by infiltration of renal tissue with immune cells, and may be analogous to kidney transplant rejection. Using both clinical variables and tissue findings we evaluated a large cohort of ICI cases to determine predictors of renal response and overall survival.MethodsWe retrospectively reviewed all patients treated with ICI (August 2007 to August 2020) at MD Anderson Cancer Center. A total of 38 patients with biopsy confirmed AIN and available tissue were identified. All slides were reviewed by two board certified renal pathologists and the severity of inflammation and chronicity was graded using transplant rejection BANFF criteria. Patients were categorized as renal responders if creatinine improved or returned to baseline after treatment and non-responders if it did not. Fisher’s exact tests for categorical variables and t-test/ANOVA or the counterparts of the non-parametric approaches (Wilcoxon rank-sum or Kruskal-Wallis) for continuous variables were used to compare patient‘s characteristics between groups. The distribution of overall survival (OS) was estimated by the Kaplan-Meier method. Log-rank test was performed to test the difference in survival between groups.ResultsBased on the detailed pathological findings, patients with increased interstitial fibrosis were less likely to have renal response with treatment compared to patients with less fibrosis, (p < 0.05). Inflammation, tubulitis, number of eosinophils and neutrophils had no impact on renal response. Patients with response within 3 months of AKI treatment had a superior OS in comparison to patients who responded late (12-month OS rate: 77% vs 27%, p < 0.05). Notably, patients who received concurrent ICI and achieved renal response within 3 months had the best OS while those who did not receive concurrent ICI nor achieved renal response had worst OS (12-month OS rate: 100% (renal response and concurrent ICI) vs 72% ( renal response with no concurrent ICI), vs 27% ( no renal response and nonconcurrent ICI) (p < 0.05).ConclusionsThis is the first analysis of ICI induced nephritis where a detailed pathological and clinical evaluation was performed to predict renal response. Our findings highlight the importance of early diagnosis and treatment of ICI-AIN while continuing concurrent ICI therapy.Ethics ApprovalThis retrospective study was approved by the institutional review board at The University of Texas MD Anderson Cancer Center, and the procedures followed were in accordance with the principles of the Declaration of Helsinki.

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Real-world comparison of abiraterone (A) versus enzalutamide (E) for first-line therapy of metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.133 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 133-133

Author(s):

Juan Rodrigo Briones Carvajal ◽

Mahdi Farzad Naimi ◽

Liying Zhang ◽

Urban Emmenegger

Keyword(s):

Overall Survival ◽

Median Time ◽

Real World ◽

Systemic Therapy ◽

Nonparametric Test ◽

Outcome Data ◽

Categorical Variables ◽

Fisher Exact Test ◽

Castration Resistant Prostate Cancer ◽

First Line

133 Background: Second generation androgen receptor signaling inhibitors such as A and E are commonly used first-line treatment options for mCRPC. While differences in the side effect profile of these agents are well documented, there are no predictive markers of response to A versus E, and there is a paucity of comparative outcome data. Methods: We conducted a retrospective exploratory analysis of 100 mCRPC patients (pts) treated at Odette Cancer Centre (Toronto, ON, Canada) between August 2012 and June 2020 with either A (n = 50) or E (n = 50). Pts undergoing first-line mCRPC therapy were randomly selected from a list of 327 A and 254 E patients. Following extraction of disease and pt characteristics, as well as outcome data, we applied the Wilcoxon rank-sum nonparametric test or the Fisher exact test for continuous or categorical variables, respectively, for between group comparisons. For time to event analyses, we created Kaplan-Meier (KM) curves with log-rank testing. Two-sided p-values < 0.05 were considered significant. Results: The A and E cohorts were comparable regarding diagnostic PSA, Gleason score categories, and treatments prior to presentation with mCRPC. The median time to CRPC in the A cohort was 23.3 (95%CI 15.6-29.9) months, compared to 24.1 (19.4-37.4) months in the E cohort (p = 0.942). At initiation of A or E therapy both the median (Q1,Q3) age (77(70,82) vs 76(69,81) years) and median Charlson Comorbidity Index (10(9,11) vs 10(9,11)) were similar (p = 0.469 and p = 0.736, respectively). The rate of diabetes was significantly lower in the A group (8% vs 38%; p < 0.001), but there were no significant differences in cardiovascular comorbidities. Pts starting A therapy had a higher rate of bone metastasis (92% vs 68%; p = 0.005); otherwise, the metastatic pattern did not differ. The median PSA at start of A was 46.75 (13.77,176.80), compared to 27.07 (8.64,136.20) in the E group (p = 0.218). Baseline ALP, hemoglobin and albumin were all comparable. Median follow-up was 13.7 (8.3,26.3) and 19.5 (9.8,34.0) months in the A and E groups (p = 0.091). 38% of A pts and 44% of E pts went on to further lines of systemic therapy upon progression (p = 0.685). The median time to next line of systemic therapy was 11.3 (95%CI 8.3-15.9) months for the A cohort and 12.7 (9.7-16.6) for the E cohort (p = 0.844). The actuarial median overall survival from KM estimations was 35.7 (20.4-52.5) months for the A group, and 34.0 (25.7-38.0) months for the E group. Conclusions: In men undergoing first-line A or E therapy for mCRPC, time to next line of systemic therapy and overall survival did not differ significantly, while baseline pt and disease characteristics were largely similar. A substantial number of pts do not receive ≥2 lines of therapy for mCRPC under real-world circumstances.

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Outcomes of Patients with Myelofibrosis and Favorable Karyotype

Blood ◽

10.1182/blood-2020-142650 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Daniel Rivera ◽

Srdan Verstovsek ◽

Prithviraj Bose ◽

Naveen Pemmaraju ◽

Lingsha Zhou ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Clinical Features ◽

Research Funding ◽

Chromosome 1 ◽

Categorical Variables ◽

Molecular Abnormalities ◽

Grant Support ◽

Single Deletion ◽

Deletion 20Q

Introduction Myelofibrosis (MF) is an aggressive myeloproliferative neoplasm negatively affecting patient's (pts) overall survival (OS). Several clinical and molecular factors, such as anemia, leukocytosis, thrombocytopenia, increased blasts, presence of unfavorable karyotype, or adverse molecular abnormalities (e.g., ASXL1, IDH1/2, SRSF2, EZH2), further worsen outcomes. Pts with favorable karyotype (e.g., diploid, single deletion 13q, or single deletion 20q), are assumed to have comparable and superior outcome, only affected by their clinical features and molecular background. We decided to evaluate how adverse clinical and molecular factors impact OS within this subset of patients. Methods We conducted a retrospective analysis on patients with favorable karyotype and newly diagnosed MF who presented to our institution within the last 20 years. Favorable karyotype was considered according to classification in DIPSS-Plus and MIPSS70v2.0 models. Prognostic models, IPSS, DIPSS, DIPSS-Plus and MIPSS70v.20 were calculated for patients as published. Molecular analysis was performed in some patients using at least 28-gene panel by next generation sequencing (NGS). Categorical variables were compared by Chi-squared test. Univariate analysis for association between variables and outcome was performed with Cox-regression analysis. Overall survival (OS) was estimated using Kaplan-Meier method and calculated from the time of presentation to our institution until the last follow-up or death. Results Among 1002 patients, 741 pts (74%) had diploid karyotype (DP); the remaining patients had single deletion 13q (del13q, n 33), single deletion 20q (n 97), single abnormality of chromosome 1, 9 or minus Y (n 131). Only pts with del13q had inferior OS to all other groups (42 vs ~ 62 months, p 0.001), and therefore we decided to further focus on pts with del13q and DP karyotype. Patients and disease characteristics are detailed in Tables 1 and 2. We did not observe any significant clinical differences between groups. Distribution by prognostic systems; IPSS, DIPSS, DIPSS-Plus and MIPSS10v2.0 is shown in Table 1. IPSS and DIPSS classified more patients with del13q into higher (combined intermediate 2 and high) risks. DIPSS-Plus and MIPSS70v2.0 showed similar distribution of patients into risks in both groups. Forty - two percent (n 87) and 36% (n 4) of patients with DP karyotype and del13q carried at least one high risk molecular mutation (HMR; such as ASXL1, IDH1/2, EZH2, U2AF1/SRSF2/SF3B1), respectively (Table 2). Whilst all applied clinical risk models (IPSS, DIPSS, DIPSS-Plus) appropriately discriminated distinct OS in pts with DP karyotype, only DIPSS-Plus was able to accurately predict distinct OS in those with del13q (Table 3). MIPSS70v2.0 (only patients with NGS panel) did not predict for distinct OS in DP or del13q pts (Table 3). Pts with DP karyotype had superior OS to those with del13q with median OS of 62 and 42 months, respectively (Figure 1), p < 0.001, HR 0.49, 95% CI 0.32-0.78. Although presence of HMR had negative impact on OS in both groups (Figure 2), pts with del13q with HRM had OS of only 15 months (vs 55 months in DP pts with HMR, p < 0.001). Conclusion Patients with MF and del13q appear to have inferior OS than those with diploid karyotype, despite similar clinical features. Impact of molecular abnormalities, especially presence of high-risk mutations, might be underestimated in this group and deserves further investigation. Ongoing research in our center is aimed to provide new evidence on the role of mutations for this karyotypically "favorable" subgroup. Disclosures Verstovsek: CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding. Bose:Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Celgene Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pemmaraju:Blueprint Medicines: Honoraria; SagerStrong Foundation: Other: Grant Support; Pacylex Pharmaceuticals: Consultancy; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; LFB Biotechnologies: Honoraria; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Roche Diagnostics: Honoraria; DAVA Oncology: Honoraria; Celgene: Honoraria; Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding.

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Genetics of Patients with F-Refractory CLL or Early Relapse After FC or FCR: Results From the CLL8 Trial of the GCLLSG

Blood ◽

10.1182/blood.v116.21.2427.2427 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2427-2427 ◽

Cited By ~ 8

Author(s):

Thorsten Zenz ◽

Raymonde Busch ◽

Anna Fink ◽

Dirk Winkler ◽

Kirsten Fischer ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Tp53 Mutation ◽

Genetic Profile ◽

Similar Distribution ◽

Line Treatment ◽

Poor Overall Survival ◽

Early Relapse ◽

Number Of Patients ◽

Travel Grant

Abstract Abstract 2427 Introduction: The introduction of chemo-immunotherapy (R-FC) has led to impressive improvement of response, PFS and remarkably overall survival in CLL. Irrespective of these improvements, the genetic markers remain important predictors of outcome. With increasing intensity of 1st line treatment, the proportion of patients with refractory disease is decreasing. At the same time the selective pressure on tumor cells increases. Relatively little is known about the genetic profile of risk groups as defined by the length of 1st remission. We therefore analysed the CLL8 cohort (FC vs. FCR in untreated and fit patients with CLL) to identify the genetic profile (before 1st line treatment) of patients either not responding to (refractory) or relapsing early after first line therapy. Methods and material: In order to characterize the genetic profile of refractory CLL and CLL with early relapse we formed 4 cohorts based on response and response duration after initial therapy. We selected F-refractory (no PR/CR or PR/CR < 6 months), patients with PFS 6−<12 months, 12−<24 months and ≥ 24 months for the analysis. Median follow-up was 37.7 months. Genetic characterization was performed in a central laboratory (Ulm). Data was available for IGHV (n=587), TP53 mutation (n=592), and FISH (n=581). Results: Based on the above definition 84/767 (11%) patients were F-refractory. Very short PFS was observed in 43/767 (5.6%)(6−<12 months) and 110/767 (14.3%)(12−<24 months). The overall survival (OS) of patients in the 4 categories was significantly different with median OS (from study entry) of 21.9 months (F-refractory patients), 21.2 months (PFS 6−<12 months), and 47.3 months (12−<24 months) compared to not reached in patients with a median PFS ≥24 months. When comparing the treatment arms, the overall number of patients with short remission was lower in the FCR arm (Table 1). As shown in Table 1, the incidence of 17p- and TP53 mutation is highest in the F-refractory group with similar distribution in both treatment arms (34.4% 17p-; 43.8% TP53). In the subgroup of patients with very short PFS (6−<12 months) the incidence of highest risk genetic aberrations was still high (17p- 28.1%; TP53 mutation 23.5%). In contrast the fraction of patients with these aberrations was very low (1.5 and 4.1% resp.) in the group of patients with long PFS (≥24 months). Conversely, the incidence of good risk genetics (e.g. 13q- single) increased with length of remission (Table 1). Similarly, the incidence of trisomy 12 was higher in patients with longer PFS (11.3% and 11.4% for PFS 12−<24 months)(Table 1). Conclusion: Early relapse (within 24 months) is associated with high risk genetics (TP53 mutation and 17p deletion). In addition to patients with F-refractory CLL, patients relapsing within 6–12 and 12–24 months after intense 1st line treatment have a poor overall survival. Decisions on 2nd line treatment options should integrate genetic characterisation and remission duration. Disclosures: Zenz: Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria. Fink: Roche: Travel grant. Fischer: Roche: Travel grant. Kneba: Roche: Honoraria, Research Funding. Boettcher: Roche: Research Funding. Mendila: Roche: Employment. Wenger: Roche: Employment. Hallek: Roche: Honoraria, Research Funding. Döhner: Roche: Research Funding. Stilgenbauer: Roche, Celgene, GSK, Boehringer, Genzyme: Honoraria, Research Funding.

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