Analysis of Long-Term Survival in Multiple Myeloma Patients after First-Line Autologous Stem Cell Transplantation: Impact of Clinical Risk Factors and Duration of Response

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4649-4649
Author(s):  
Nicola Lehners ◽  
Natalia Becker ◽  
Axel Benner ◽  
Maria Pritsch ◽  
Elias Karl Mai ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Conditional Survival ◽  
First Line ◽  
Advisory Committees ◽  
Term Survival ◽  
Long Term Survival

Abstract Background: In the last decade, the introduction of novel agents into multiple myeloma (MM) therapy has significantly improved response rates and enabled long-term survival in a subset of patients. Yet, clinical characteristics of these long-term survivors as well as the exact impact of depth and sustainment of response still remain a matter of debate. Methods: MM patients treated at our center with high-dose melphalan supported by autologous stem cell transplantation (ASCT) as part of their first-line therapy between June 1992 and July 2014 were retrospectively analyzed. Response assessment was performed 100 days after ASCT according to EBMT criteria, since 2008 response according to IMWG criteria was also available. Overall survival (OS) and progression-free survival (PFS) were calculated from day of first ASCT. Additionally, landmark analyses regarding OS were performed at 1, 2, 3, and 5 years after ASCT. Impact of variables on PFS and OS were analyzed using multivariate Cox regression models. Furthermore, in order to assess evolution of prognosis over time, the conditional survival CS(t|s), which expresses the conditional probability of surviving further t years, was calculated as the ratio of two Kaplan-Meier estimates Ŝ(t) with . Results: 865 patients were included in this analysis, median age was 57.0 years (range 24-74), 509 were male. New agents based induction therapy was administered in 358 patients, 258 patients underwent tandem ASCT. Following ASCT, 386 patients received maintenance therapy, mainly with interferon or thalidomide. 75 patients proceeded to allogeneic transplantation and were censored at that time. Median PFS was 2.1 years, median OS was 6.4 years. Analysis of clinical influence factors revealed novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and achievement of complete response (CR) (p=0.01) to be significantly associated with prolonged PFS, while older age (p=0.01) and thrombocytes at diagnosis < 150/nl (p=0.02) were identified as risk factors; a negative trend was seen for ISS stage 3 (p=0.067). With regard to OS, novel agent based induction therapy (p<0.01), maintenance therapy (p<0.01) and duration of time to progression (p<0.01) showed a highly significant positive impact, older age (p<0.01) and renal insufficiency at diagnosis (p=0.048) exerted a negative influence. To assess the importance of duration of response, landmark analyses were performed at 1, 2, 3, and 5 years after ASCT evaluating OS of patients with sustained CR, sustained inferior responses (non-CR), lost CR and lost non-CR at these respective time points. Remarkably, sustainment of any response showed a highly significant impact on survival at each of these time points (p<0.01) with no discernable difference between sustained CR and sustained non-CR patients. Landmark analysis at 1 year is shown in Figure 1. Administration of maintenance therapy independently improved outcome (p<0.01). Conditional survival regarding the probability to survive further three years CS(3|s) was calculated starting from the time of first ASCT stratified for the different response cohorts (see Figure 2). No significant differences could be found between patients with complete and partial response. In contrast, patients with progressive disease (PD) at day 100 after ASCT had a much lower probability of surviving the following three years after ASCT compared to patients responding to ASCT. However, those patients with PD that did survive the first year after ASCT, achieved a similar conditional three-year survival to that of patients responding initially. Conclusions: In this large retrospective study, sustainment of response after first-line ASCT was revealed as a major impact factor for OS independent of the depth of response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions prolonging responses achieved after ASCT are essential to reach long-term survival. Figure 1 OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 1. OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 2 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 2. 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 3 Figure 3. Disclosures Hillengass: Amgen: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Amgen: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding.

scholarly journals Impact of Early Progression on Long Term Outcomes Among Myeloma Patients Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3302-3302
Author(s):  
Ajay K Nooka ◽  
Jonathan L Kaufman ◽  
Charise Gleason ◽  
Nisha Joseph ◽  
Craig C Hofmeister ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Term Survival ◽  
Risk Status ◽  
Early Progression

Abstract Background: The incorporation of modern day induction regimens, autotransplant and continuous maintenance has resulted in better long-term outcomes for myeloma patients. Experience and trials demonstrated that by prolonging 1st progression-free survival (PFS1) and pushing the relapse farther, we can gain the OS advantage (McCarthy et al NEJM 2012). Unfortunately, a subgroup of patients fail to exploit this advantage, either due to their disease biology or due to inadequate therapy and suffer early progression (inferior PFS1) that impacts their long term outcomes. First, we evaluated the predictors of early progression to highlight the modifiable factors that can prevent progression. Next, we quantified the impact of shorter PFS1 (<36 months) on the long-term survival (OS). Methods: Of the 1000 consecutive newly diagnosed myeloma patients treated with homogenous induction therapy (RVD) induction therapy per Richardson et al (Blood 2010) from July 2005 until August 2016, 230 patients progressed within the first 36 months while 96 patients progressed beyond the 36-month mark, at the time of analysis. Median follow up duration was 38 months. Demographic and outcomes data for the pts were collected from myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the pts is 60 years (range 29-78). 29% of the patients are above the age of 66. M/F 54%/46%; W/AA 60%/32%; ISS III 27% were other patient characteristics. Cytogenetic abnormalities of significance: t(11;14): 13.5%, t(4;14): 7.8%, t(14;16): 5% del 17p: 16%, complex cytogenetics: 29% and high-risk status was conferred to 44% of the patients. 83% of patients underwent an autotransplant and median time to transplant was 6 (2-50) months. 68% of patients received maintenance therapy. Response rates are summarized in Fig 1. The median PFS for early and non-early progressors were 32 months (95% confidence interval (CI), 30.293-33.707) and 101 months (95% CI, 77.14-124.86) months, respectively (P<0.001). The median overall survival (OS) for early progressors was 94 months, and non-early progressors was not reached. (Fig 2). Among the predictors of early relapse, presence of high-risk status, ISS stage 3, inability to achieve ≥VGPR after transplant, non-receipt of transplant and/or maintenance were independent predictors of early progression on the multivariate analysis as illustrated in Table 1. Conclusions: Even with the effective use of the 3-drug induction regimen, these functionally high-risk patients that are early progressors have truncated long term survival. Our analysis advocates for using transplant, deepening the responses with modern drugs such as monoclonal antibodies to achieve ≥VGPR after transplant and intense maintenance strategies to prevent relapse. Disclosures Nooka: Spectrum Pharmaceuticals: 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; Amgen: 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; GSK: 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; BMS: 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. Kaufman:Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Roche: Consultancy; Janssen: Consultancy; BMS: Consultancy. Hofmeister:Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; 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; Janssen: Membership on an entity's Board of Directors or advisory committees. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Lonial:Amgen: Research Funding.

scholarly journals Long-Term AL Amyloidosis Survivors Among Non-Selected Referral Population

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3226-3226
Author(s):  
Eli Muchtar ◽  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
David Dingli ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Survival Rates ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Term Survival ◽  
Long Term Survival ◽  
Long Term Survivors

Abstract Introduction: Prognosis of AL amyloidosis has improved in recent years; however for many patients prognosis remains poor. We aimed to define patient-, disease- and treatment characteristics which are associated with long-term survival. Method: A retrospective chart review of all patients with biopsy-proven systemic AL amyloidosis, who were seen within 90 days of the confirmed diagnosis. Long-term survival was defined as 5-year and 10-year survival from the time of diagnosis. For 5-year survival we selected patients seen between January 1, 2000 and December 31, 2012 (allowing a minimum of 5-year follow-up, n=1331) and for 10-year survival we screened patients seen between January 1, 2000 and December 31, 2007 (allowing a minimum of 10-year follow-up; n=779). Treatment allocation was defined as the first regimen given, irrespective of subsequent treatment modifications. Results: Of the screening population, 498 patients survived ≥5 years from diagnosis (37% of the 5-year screening cohort) and 168 patients survived 10 years or more (22% of the 10-year screening cohort). Five-year survivors and 10-year survivors as compared to their counterparts were (Table): younger, higher proportion of women, more likely to have single organ involvement, less heart/liver/nerve involvement and more kidney involvement. Long-term survivors also had lower bone marrow plasma cell percentage at the time of diagnosis and lower tumor burden measured by the difference between involved to uninvolved light chain (dFLC). Similarly, long-term survivors had lower Mayo stages and higher systolic blood pressure. No difference in light chain isotype was observed between long-term survivors to long term non-survivors. Long-term survivors were less likely to be seen within 30 days of diagnosis compared to their counterparts (52% among 5-year survivors vs 67% among 5-year non-survivor; P<0.001). FISH abnormalities (data available for 555/1331 patients, 42%) were comparable between groups with regard to t(11;14) (50% among 5-year survival compared to 50% among 5-year non-survivors; P=0.93) and 13q abnormalities (34% vs 36%, respectively; P=0.53). However, trisomies were less frequently encountered in the 5-year survivor group (20% vs 29%, respectively; P=0.01), and far less common among 10-year survivors (11% vs 26%, respectively; P=0.04). Autologous stem cell transplantation (ASCT) was more likely to be associated with long-term survival. Of all patients who underwent ASCT, 74% survived more than 5 years and 49% survived more than 10 years. In comparison, among the standard-intensity therapies, 5-year survival rates for melphalan-dexamethasone, bortezomib-based regimens, immunomodulatory drug-based regimens and single agent dexamethasone/ melphalan-prednisone were 29%, 28%, 30% and 10%, respectively. The corresponding 10-year survival rates were 15%, 20%, 20% and 5%, respectively. Conclusions: Long-term AL survivors have distinct favorable baseline characteristics (including those introduced by referral bias) and ASCT as their initial therapy. Identification of these patients, especially the Mayo 2004 stage III and the Mayo 2012 stage III-IV patients who unexpectedly survived 10 years, will allow for further study and insights. Disclosures Gertz: Teva: Consultancy; Prothena: Honoraria; Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Physicians Education Resource: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; janssen: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; annexon: Consultancy. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; AbbVie: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

scholarly journals Long-Term Survival in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL) Who Achieved Minimal Residual Disease (MRD) Response Following Anti-CD19 BiTE® Blinatumomab

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2287-2287 ◽  
Author(s):  
Gerhard Zugmaier ◽  
Nicola Goekbuget ◽  
Andreas Viardot ◽  
Matthias Stelljes ◽  
Svenja Neumann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Advisory Committees ◽  
Term Survival ◽  
Long Term Survival ◽  
Equity Ownership

Abstract Introduction: Relapsed/refractory (r/r) B-precursor ALL in adults has an unfavorable prognosis with a median overall survival of 4–8 months and a 5-year survival of <10%. Long-term follow-up data are presented from an exploratory phase 2 study with blinatumomab, an investigational bispecific T-cell engager (BiTE®) antibody construct that directs cytotoxic T-cells to CD19-expressing target cells (Topp MS et al. Blood 2012;120(21):670). Methods: The primary endpoint was hematologic complete remission (CR) or CR with partial hematologic recovery (CRh*) within 2 cycles of blinatumomab. Secondary endpoints included rate of minimal residual disease (MRD) response (defined as < 10-4), overall survival (OS), and relapse-free survival (RFS). Blinatumomab was administered by continuous intravenous infusion for 28 days followed by a 14-day treatment-free interval. Responding patients had the option to receive 3 additional cycles of treatment or to proceed to allogeneic hematopoietic stem cell transplantation (aHSCT). Results: 36 patients were treated; 25 (69%) responded, with 15 (42%) achieving CR and 10 (28%) CRh*. MRD response was achieved in 22 (88%) of these 25 patients with CR or CRh*. Thirteen patients with CR or CRh* proceeded to aHSCT after blinatumomab treatment. In addition, one patient with hypocellular bone marrow and MRD response after the first cycle underwent aHSCT. Follow-up for RFS is 22.4 months; median RFS is 8.8 months. Median follow-up for OS is 30.2 months; median OS is 12.9 months. Ten patients (28%) are alive at 29.7 months (Figure). We analyzed the characteristics of the 10 living long-term survivors, defined as OS of 2 years or longer, seven of whom were relapse-free. The age of these 10 patients at the time of first infusion ranged from 21 to 72 years; the blast count at screening ranged from 8% to 97% (median, 56%). Four of the 10 patients alive had received aHSCT prior to blinatumomab treatment. Of the six patients without a prior aHSCT, two were primary refractory; two had the first relapse within 12 months and two after 12 months post first diagnosis. In the 10 surviving patients blinatumomab treatment induced CR in seven patients, CRh* in two patients, and blast-free hypo-cellular bone marrow in one patient. All 10 surviving patients had an MRD response following blinatumomab treatment. The patient with hypocellular bone marrow received a transplant after the first cycle before potential recovery of blood counts qualifying for CR/CRh* could occur. Seven of the surviving patients underwent aHSCT after blinatumomab, including four patients who received a second aHSCT after they had already received an aHSCT prior to blinatumomab. One of the three patients who did not undergo aHSCT after CRh* had grade 4 cytokine release syndrome requiring resuscitation after 1 day of blinatumomab treatment and has remained in ongoing remission for 22 months without any further treatment aside from 5 cycles of blinatumomab. Another one of these three patients, who had a grade 3 neurologic event on day 2 of cycle 2, has remained in ongoing remission for 34 months without any further treatment aside from 5 cycles of blinatumomab. The third of these three patients had two CD19-positive relapses after CR following blinatumomab treatment. The patient was retreated with 3 cycles of blinatumomab, resulting twice in CR and MRD response. Two of the 10 surviving patients relapsed after blinatumomab and aHSCT; one patient with a CD 19-negative relapse achieved another hematologic remission by chemotherapy. Summary: These data show that patients with r/r ALL, who achieved MRD response and received subsequent aHSCT following blinatumomab immunotherapy may achieve long-term survival longer than 2 years. Studies with a larger sample size are warranted to confirm these data. Two patients with grade 3 or 4 toxicities showed long-term survival without aHSCT after blinatumomab. Figure Figure. Disclosures Zugmaier: Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Goekbuget:Amgen Inc.: Consultancy, Honoraria, Research Funding. Viardot:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Travel support Other; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel support, Travel support Other; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Travel support Other. Horst:Amgen Inc.: Honoraria, Research Funding. Brueggemann:Amgen Inc.: Consultancy, Research Funding. Holland:Amgen Inc.: Employment, Equity Ownership. Schmidt:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Mergen:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Bargou:Amgen Inc.: Consultancy, Honoraria. Topp:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Integration of Multiple Bioassays Using Machine Learning to Identify High-Risk CP-CML Patients Treated with Frontline Imatinib

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1728-1728
Author(s):  
Chung Hoow Kok ◽  
Sakrapee Paisitkriangkrai ◽  
David T Yeung ◽  
Liu Liu ◽  
Verity A Saunders ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Board Of Directors ◽  
Predictive Value ◽  
Research Funding ◽  
Molecular Response ◽  
Advisory Committees ◽  
Term Survival ◽  
Long Term Survival

Abstract Introduction. Imatinib has revolutionised the treatment of chronic phase-chronic myeloid leukemia (CP-CML), with up to 70% of patients (pts) achieving major molecular response (MMR, BCR-ABL1 < 0.1% IS). Achievement of MMR by 2 years (yrs) is associated with an excellent prospect of long term survival. Currently, three baseline prognostic scoring systems - the Sokal, Hasford (Euro) and EUTOS risk scores - have all been used to identify pts with a poor response and/or an adverse prognosis in CP-CML. Recently, the EUTOS long-term survival (ELTS) score is shown to have strong predictive power for overall survival in CML pts. We have previously reported bioassays that have significant value for predicting MMR. Combinations of these biomarkers, together with clinical risk score, may provide a better indicator of high risk pts at the time of diagnosis. Aim. To identify high-risk pts by combining selected predictive bioassay, determine whether the ELTS score is more discriminating, and determine whether it provides additional predictive value when combined with the biomarker score. Methods. Bioassays including CRKL IC50 imatinib (White, Blood, 2005), OCT-1 Activity (OA)(White, JCO, 2010), leves of 39 plasma cytokines (Nievergall, Leukemia, 2016), expression of 20 most prognostic gene by qPCR TLDA (Kok, ASH abstract, 2015), ABCB1 gene expression (Eadie, Leukemia, 2016), KIR2DL5B genotype (Yeung, Blood, 2015), BIM and ASXL1 polymorphisms (Marum, Blood advances, 2017) were used in this study. High-risk by biomarker score (HR) was defined as pts who did not achieve MMR by 2 yrs. 210 TIDEL-II pts (frontline imatinib with early switch to nilotinib for failure to meet optimal time-dependent molecular targets) were used in this study (Yeung, Blood, 2015). Only 201 pts had ELTS scores. The Recursive Partitioning and Regression Trees (rpart) algorithm was used to identify important bioassays in predicting high-risk pts. Fisher's-exact test was used for statistical analysis. Results. In the TIDEL-II cohort, there were 21 high ELTS and 180 low/intermediate ELTS pts. Pts with high ELTS had significantly lower rates of MMR by 2 yrs compared to those pts with low/intermediate ELTS (57% vs 81%, p=0.02). We constructed a predictive model using multiple different bioassays as variables to predict high-risk pts. The rpart based model used in this analysis yielded four variables (IGFBP2 gene expression, KIR2DL5B genotype, OA, and MCP-1 cytokine plasma level) as most important for predicting high-risk pts. The accuracy of the model was 84%. Pts predicted as high-risk (HR, n=27) had significantly lower MMR achievement rate compared to those predicted as low-risk (LR), (26% vs 86%, n=183, p<0.0001, OR:17.3). Importantly, pts with HR had significantly higher rate of blast-crisis progression (15%, n=4/27) compared to those with LR (1.6%, n=3/183, p=0.006, OR:10.4) and pts with high ELTS (5%, n=1/21). Interestingly, there were two categories of HR patient groups based on the model: 1) Patient with high IGFBP2 gene expression and low OA, and 2) pts with low IGFBP2, KIR2DL5B positive genotype and high MCP-1 cytokine level. When combined with ELTS, the bioassays model improved ELTS performance in predicting HR pts. For instance, within the low/intermediate ELTS pts group, our assays could futher distinguish HR pts with inferior MMR (n=20, 2 yrs MMR of 30%) versus LR pts (n=160, 2 yrs MMR 87%). Similarly, pts with high ELTS in combination with HR also had lower MMR rate (n=1/5, 20%) compared to pts with high ELTS in combination with LR (n=11/16, 69%, p=0.11, OR:8.8). Conclusion. We developed a combined bioassays model that is predictive of MMR failure and adverse clinical outcomes for pts who receive optimised frontline imatinib therapy. This model performs well even without adding clinical parameters. Our model has additional predictive value when used together with the ELTS score, and can distinuguish HR pts within the low/intermediate ELTS group, as well as LR patients within the high ELTS category. Further confirmation of the predictive performance of this model, using a large independent patient cohort is now indicated. We postulate that this bioassay-based model could be used, in combination with ELTS, for identifying HR pts who would benefit from intensified therapeutic approaches to obtain optimal clinical outcome. Disclosures Yeung: Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Specialised Therapeutics Australia: Honoraria. Yong:Celgene: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:BMS: Research Funding; Novartis: Honoraria, Research Funding. Hughes:Novartis: 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; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Long-Term Survival for Myeloma after Autologous Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Samer A. Srour ◽  
Qaiser Bashir ◽  
Denái R. Milton ◽  
Yago Nieto ◽  
Rohtesh S. Mehta ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Short Term ◽  
Advisory Committees ◽  
Term Survival ◽  
Long Term Survival ◽  
Grant Support ◽  
Term Survivor

Introduction: Multiple myeloma (MM) remains incurable with only a small proportion of patients surviving over 10 years (long-term survivors) from diagnosis. It has been more than 3 decades since the first autologous stem cell transplantation (ASCT) was performed for MM at our institution. In this study, we sought to determine baseline patient and disease characteristics that are associated with long-term survival after the ASCT. Methods: We included all consecutive patients who received their first ASCT between January 1988 and December 2015. The primary objective was to identify the variables associated with long-term overall survival (&gt;10 years). The control group were patients who survived less than 10 years from their diagnosis data (short-term survivors). Logistic regression models were used to evaluate the association between predictive factors and overall survival of &gt; 10 years. Results: Among 2176 patients who underwent their first ASCT during the study period, 1409 patients met the eligibility criteria. Overall, 392 (28%) patients were long-term survivors (&gt;10 years) and 1017 (72%) were short-term survivors (&lt;10 years). Table 1 shows baseline patient and disease characteristics. Only 24% and 42% of patients in the long-term and short-term survivor groups, respectively, received proteasome inhibitor-based induction therapies. Maintenance therapy was received by 49% and 45% in the short- and long-term survivor groups, respectively (p=0.19). The long-term survivor group was characterized by having higher percentage of patients younger than age 65 (86%) years, and having higher proportions of ISS Stage I (47%), standard-risk cytogenetics (96%), normal LDH (88%) and with serum creatinine &lt;2 mg/d (87%). With a median follow-up of 13 years (range, 10-30 years), the 15-year PFS and OS survival rates in the long-term survivors were 19% (95% CI: 14% - 23%) and 62% (95%: CI 56% - 68%) (Figure 1A). The cumulative incidence rates of relapse at 1, 3, and 5 years in the short-term survival group were 9%, 63%, and 82%, respectively, compared to 2%, 20%, and 40%, respectively, in the long-term survivor group (p&lt;0.001) (Figure 1B). All variables listed in Table 1 were assessed in univariate analysis. Seventy-six percent of patients were relapse-free at 24 months in the long-term survival group, compared to only 32% in the short-term survival group. On multivariable analysis, age, cytogenetic-risk status, race-ethnicity, and duration of remission after ASCT were significant predictors for surviving &gt; 10 years (Table 2). ISS Stage III (vs. Stage I: OR 0.45, 95% CI 0.19-1.09; p=0.08) showed a trend towards surviving ≤ 10 years. Conclusions: ASCT is associated with durable responses and prolonged survival in a subgroup of MM patients irrespective of type of induction therapy and/or use of maintenance therapy. Duration of remission after transplant is the strongest predictor for long-term survival. Age &lt;65 years, being African-American, and standard-risk cytogenetics were also associated with surviving more than 10 years. Disclosures Bashir: Acrotech: Research Funding; StemLine: Research Funding; Celgene: Research Funding; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; KITE: Other: Advisory Board. Nieto:Affimed: Consultancy, Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Secura Bio: Other: Grant Support. Mehta:CSL Behring: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Ciurea:Kiadis Pharma: Current equity holder in publicly-traded company, Research Funding. Popat:Bayer: Research Funding; Novartis: Research Funding. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Kebriaei:Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Jazz: Consultancy; Kite: Other: Served on advisory board; Amgen: Other: Research Support. Manasanch:GSK: Honoraria; Adaptive Biotechnologies: Honoraria; Merck: Research Funding; Quest Diagnostics: Research Funding; Takeda: Honoraria; BMS: Honoraria; Sanofi: Research Funding; Novartis: Research Funding; Sanofi: Honoraria; JW Pharma: Research Funding. Hosing:NKARTA Inc.: Consultancy. Patel:Janssen: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Oncopeptides: Consultancy; Precision Biosciences: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Lee:Regeneron: Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding. Shpall:Zelluna: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Orlowski:Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. Champlin:Omeros: Consultancy; Cytonus: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy; Genzyme: Speakers Bureau; Takeda: Patents & Royalties; DKMS America: Membership on an entity's Board of Directors or advisory committees. Qazilbash:Bioclinica: Consultancy; Amgen: Research Funding; Janssen: Research Funding; Angiocrine: Research Funding; Bioline: Research Funding.

Impact Of Response Duration and Maintenance Therapy After Autologous Stem Cell Transplantation On Long-Term Survival In Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3183-3183
Author(s):  
Nicola Lehners ◽  
Christiane Heiss ◽  
Soh-Yun Kim ◽  
Thomas Hielscher ◽  
Jens Hillengass ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Response Duration ◽  
Advisory Committees ◽  
Term Survival ◽  
Long Term Survival ◽  
Significant Difference

Abstract Background The introduction of novel agents has significantly improved response rates in multiple myeloma (MM) patients. The exact impact of quality and duration of response on long-term survival, however, remains controversial. Methods We retrospectively analyzed MM patients who underwent high-dose chemotherapy and autologous stem cell transplantation (ASCT) as first-line therapy at our center between June 1992 and February 2012. Treatment response was assessed according to IMWG criteria both immediately before and 100 days after ASCT. Overall survival (OS) was calculated from day 100 after first ASCT. In addition, in a landmark analysis OS was calculated starting from 3 years post first ASCT. Log-rank tests were used to assess the impact of response on OS. P-values < 0.05 were regarded as statistically significant. Results 1155 patients with symptomatic MM (683 males, 472 females) were evaluated for this analysis. Median age was 56 years (y) (range 24 to 74y). 751 received single, 404 tandem ASCT. Maintenance therapy with interferon, thalidomide, or bortezomib was administered after ASCT to 629 patients. 37 proceeded to allogeneic transplantation and were censored at that time. Median OS was 5.2y (range 4.8 to 5.8y). The achievement of complete response (CR) or near CR (nCR) before ASCT was associated with a superior OS of 7.0y, significantly longer than for those achieving either a partial response (PR) or very good PR (VGPR) (p < 0.01 and p = 0.04, resp.). Evaluating response on day 100 after ASCT, patients in CR/nCR continued to show superior OS in comparison to those in PR (p < 0.01). However, VGPR post-transplant had similar prognostic value to CR/nCR (p = 0.17). Interestingly, patients remaining in stable disease or minimal response after ASCT also had a favorable OS of 6.4y (range 4.8 to 9.7y), potentially indicating a distinct biological entity. To assess whether timing of response is of prognostic relevance, we compared outcome of patients reaching CR/nCR before ASCT with those of patients achieving CR/nCR only after ASCT. Early and late responders showed a similar OS (7.0y vs 6.4y, p = 0.2) with no significant difference between the two groups. For the 3-year landmark analysis 709 patients were evaluable. Remarkably, the depth of response before or after ASCT did not exert any significant effect on survival for those patients still alive 3y after ASCT (p = 0.8 and 0.3 resp.). However, the implementation of maintenance therapy after ASCT was associated with a strong survival benefit (OS 5.6 vs 2.9y, p < 0.01). To assess the importance of response duration, we compared the OS of patients with sustained CR/nCR at 3yrs after ASCT to patients in all other response groups (non-CR/nCR) and patients who had relapsed in the interval (lost CR/nCR and lost non-CR/nCR, respectively). Remarkably, OS was excellent for patients with sustained CR/nCR (10.2y) as well as with sustained non-CR/nCR (7.8y), with no significant difference between both groups. However, patients with lost CR/nCR or lost non-CR/nCR had an unfavorable OS of 2.4 and 2.7y, resp. (fig. 1). Combining the effects of sustained response and application of maintenance therapy showed a significant benefit for maintenance therapy in patients with both sustained and lost response without annihilating the clear difference in survival between the two latter groups (fig. 2). Conclusion In this large, retrospective single-center study, achievement of CR/nCR before and after ASCT was prognostic in regard to OS. Yet, for patients evaluable 3y after ASCT, no further significant influence of the quality of response achieved by ASCT was detectable. While patients with sustained CR/nCR as well as those with inferior yet sustained responses showed similar survival, both groups had a markedly better outcome than those patients losing a once obtained response. This effect was independently improved by the implementation of maintenance therapy, indicating that intervention to sustain achieved responses appears to be a key factor for long-term survival. Disclosures: Ho: Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genzyme: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4112-4112
Author(s):  
Charline Moulin ◽  
Romain Morizot ◽  
Thomas Remen ◽  
Hélène Augé ◽  
Florian Bouclet ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Intermediate Risk ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Long Term Survivors ◽  
First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Conditional Survival Analysis of 816 Multiple Myeloma (MM) Patients Constitutes a Different Way to Provide More Specifically Determined Prognosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2091-2091
Author(s):  
Maximilian Schinke ◽  
Inga Promny ◽  
Stefanie Hieke ◽  
Johannes M. Waldschmidt ◽  
Gabriele Ihorst ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Conditional Survival ◽  
Term Survival ◽  
Long Term Survival ◽  
Prediction Time ◽  
Risk Parameters ◽  
Over Time

Abstract Introduction: Disease monitoring based on genetics or other molecular markers obtained by noninvasive or minimally invasive methods will potentially allow the early detection of treatment response or disease progression in cancer patients. Investigations in order to identify prognostic factors, e.g. patient's baseline characteristics or molecular markers, contributing to long-term survival potentially provide important information for patients with multiple myeloma. Overall survival (OS) is not very informative for patients who already survived one or more years. To better characterize long-term survival respectively long-term survivors, conditional survival (CS) analyses are useful. Conditional survival (CS) describes probabilities of surviving t additional years given they survived s years and provides information, how prognosis evolves over time. We have demonstrated the use of CS in a large data set of multiple myeloma patients with long-term survival which is mandatory for the calculation of CS (Hieke,... Engelhardt, Schumacher. CCR 2015). Methods: We evaluated 816 consecutive multiple myeloma patients treated at our department from 1997 to 2011 with follow-up until the end of 2011. Patients' data were assessed via electronic medical record (EMR) retrieval within an innovative research data warehouse. Our platform, the University of Freiburg Translational Research Integrated Database Environment (U-RIDE), acquires and stores all patient data contained in the EMR at our hospital and provides immediate advanced text searching capacity. We assessed 21 variables including gender, age, stage and admission period. We calculated 5-years CS and stratified 5-years CS according to disease- and host-related risks. Component-wise likelihood-based boosting and variables selected by boosting were investigated in a multivariable Cox model. Results: The OS probabilities at 5- and 10- years were 50% and 25%, respectively. The 5-year CS probabilities remained almost constant over the years a patient had already survived after initial diagnosis (~50%). According to baseline variables, conditional survival estimates showed no gender differences. The estimated 5-year survival probabilities varied substantially, from 25% for patients ages 70 or older to 65% for patients younger than 60 years. Similarly, patients with D&S stage I have an estimated 5-year survival probability of about 75% compared with 40% for patients with D&S stages II and III. Significant risk factors via Cox proportional hazard model were D&S stage II+III, age >70 years, hemoglobin <10g/dl, ß2-MG ≥5.5mg/dl, LDH ≥200U/l. Renal impairment, low albumin and unfavorable cytogenetics increased the risk, but failed to reach significance. Cytogenetics, response, response duration and other risk parameters post treatment are currently included in our assessment. Of note, over the study period, admission of patients <60 years decreased from 60% to 34%, but increased for those ≥70 years from 10% to 35%, respectively, illustrating that not only young and fit, but also elderly patients are increasingly treated within large referral and university centers and that patient cohorts and risks do not remain constant over time. Conclusions: Conditional survival has attracted attention in recent years either in an absolute or relative form where the latter is based on a comparison with an age-adjusted normal population being highly relevant from a public health perspective. In its absolute form, conditional survival constitutes the quantity of major interest in a clinical context. We defined conditional survival by using the fact that the patient is alive at the prediction time s as the conditioning event. Alternatively, one could determine conditional survival, given that the patient is alive and progression-free or alive, but has progression at time s (Zamboni et al. JCO 2010). Analysis of the above and additional variables from diagnosis to prediction time s may refine conditional survival towards an even more specifically determined prognosis; follow-up response and risk parameters most likely further refining these CS analyses. Figure 1. Figure 1. Disclosures Wäsch: MSD: Research Funding; Janssen-Cilag: Research Funding; Comprehensiv Cancer Center Freiburg: Research Funding; German Cancer Aid: Research Funding.

Bortezomib in Combination with Dexamethasone and Pegylated Liposomal Doxorubicin (DoVeD) Breaks Plateau Responses Following Initial Induction Therapy in Multiple Myeloma: Results of a Phase II Pilot Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2311-2311
Author(s):  
Megan C. Manco ◽  
Tomer Mark ◽  
David S Jayabalan ◽  
Faiza Zafar ◽  
Roger Pearse ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Liposomal Doxorubicin ◽  
M Protein ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Disease Characteristics ◽  
Grade 3

Abstract Abstract 2311 Poster Board II-288 Improved quality of response to induction therapy has been shown to be associated with improved long-term outcomes, including prolonged progression-free (PFS), event-free, and overall survival (OS), in newly diagnosed multiple myeloma (MM) patients (pts). Induction regimens incorporating the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide have demonstrated high overall response rates (ORR), and substantial complete response (CR) and very good partial response (VGPR) rates in MM; however, while a large majority of pts respond, a proportion does not achieve ≥VGPR. Per the Norton–Simon hypothesis, the sequential, dose dense, use of agents or regimens that are not cross-resistant may improve the proportion of pts achieving CR or VGPR to induction therapy, and subsequently improve long-term outcomes. This phase II pilot study investigated the efficacy and safety of bortezomib + dexamethasone ± liposomal doxorubicin (DoVeD) in MM pts who had reached a response plateau (<25% change in M-protein level for three successive assessments) after achieving a partial response (PR) to initial induction with IMiD-containing therapy. All pts proceeded to high-dose therapy and stem cell transplantation. Pts received six 3-week cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, plus dexamethasone 40 mg on days 1–4, 8–11, and 15–18. Pts achieving <PR after two cycles or <CR after four cycles received liposomal doxorubicin 30 mg/m2 on day 4 for the remaining four or two cycles, respectively. Response to DoVeD was assessed relative to baseline prior to start of DoVeD therapy according to IMWG uniform response criteria. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 34 pts were enrolled; baseline demographics and disease characteristics are shown in the Table. Initial induction therapy comprised lenalidomide–dexamethasone in 22 pts, thalidomide–dexamethasone in 5 (followed by VAD in 1), thalidomide in 2, and thalidomide–lenalidomide–dexamethasone in 5. At data cut-off, 3 pts remained on DoVeD therapy and were not evaluated for response. The other 31 pts received a median of 6 cycles of DoVeD; liposomal doxorubicin was added in 22/31 (71%) pts, 11 after cycle 2 and 11 after cycle 4. Best responses to DoVeD were 5 (16%) stringent CR, 2 (6%) CR, 6 (19%) VGPR, and 12 (39%) PR, for a ≥VGPR rate of 42% and an ORR of 81%. Four (13%) pts achieved a minimal response, and 2 (6%) had disease progression. Median PFS was 1,210 days (95% CI: 387–1311) and 3-year PFS was 57% (95% CI: 27%–73%). Four pts died during the follow-up period. Median survival was not reached; 4-year OS was 83% (95% CI: 60%–94%). A Cox proportional hazards model controlling for age, sex, and ISS showed that only a ≥90% reduction in M-protein significantly correlated with reduction in disease progression (p=0.014). Among 33 pts who had completed one cycle of DoVeD and were thus evaluable for safety, all experienced at least one AE, including 23 (70%) who experienced at least one grade 3/4 AE. Hematologic grade 3/4 AEs during DoVeD therapy included 9/3% neutropenia and 9% grade 4 thrombocytopenia; non-hematologic AEs included fatigue, pneumonia, infection (9% each), diarrhea, constipation, irritability, hypotension (6% each), hand–foot syndrome, chest pain, and myopathy (3% each). In total, 23 (70%) pts experienced peripheral neuropathy, including 9 (27%) grade 2 and 3 (9%) grade 3 (no grade 4 PN). In conclusion, DoVeD therapy can result in further substantial reductions in tumor burden, including additional CRs and VGPRs, in MM pts whose response has reached a plateau following PR with prior IMiD-containing induction. The additional cytoreduction and increase in CR/VGPR rates achieved with this tandem approach, plus the potential associated improvement in long-term outcomes, suggest a possible paradigm shift for MM induction therapy in general. Table Patient baseline demographics and disease characteristics Characteristic* N=34 Age, years 60.5 (27-76) Male, n (%) 19 (56) B2-microglobulin, mg/L 2.1 (1.0-10.2) Albumin, g/dL 3.5 (2.0-4.3) Durie-Salmon Stage Ia / IIa / IIIa / IIIb, n 2 / 14 / 17 / 1 ISS Stage I / II / III, n 16 / 15 / 3 Abnormalities by FISH, n (%) del 13q14 13 (38) Trisomy 11 6 (18) Hyperdiploidy 5 (15) t(4;14) 4 (12) p53 3 (9) t(11;14) 2 (6) t(14;16) 2 (6) None 16 (47) * Median (range) shown unless stated Disclosures: Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zafar:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau. Crann:Milllennium: Membership on an entity's Board of Directors or advisory committees. Leonard:Milllennium: Consultancy; Johnson & Johnson: Consultancy. Coleman:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau; Immunomedics: Membership on an entity's Board of Directors or advisory committees. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding.

Pharmacodynamic Monitoring of the Efficacy of a Targeted Therapy with Midostaurin By Plasma Inhibitor Activity (PIA) Analysis in FLT3 -ITD Positive AML Patients within the AMLSG 16-10 Trial: A Study of the AML Study Group (AMLSG)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2585-2585 ◽  
Author(s):  
Frauke Theis ◽  
Peter Paschka ◽  
Daniela Weber ◽  
Verena I. Gaidzik ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Inhibitor Activity ◽  
Advisory Committees ◽  
Time Points

Abstract Background: Activating mutations in receptor tyrosine kinases like FLT3 (FLT3mut) lead to an aberrant signal transduction thereby causing an increased proliferation of hematopoietic cells. Internal tandem duplications (FLT3-ITD) or mutations in the tyrosine kinase domain (FLT3-TKD) occur in about 25% of younger adult patients (pts) with acute myeloid leukemia (AML), with FLT3 -ITD being associated with an unfavourable outcome. FLT3mut present an excellent target for small molecule tyrosine kinase inhibitors (TKI). The multi-targeted kinase inhibitor midostaurin (PKC412) is currently under investigation as a FLT3-inhibitor in combination with intensive chemotherapy. Monitoring of the efficacy of such a targeted therapy and correlation of the results with clinical outcome will be of major importance. The plasma inhibitor activity (PIA) assay allows the visualization of the level of dephosphorylation of the target under TKI therapy. Preliminary data suggest a correlation between the grade of dephosphorylation, as a marker for the activity of the TKI, and clinical outcome. Aims: To individually measure the level of FLT3 dephosphorylation by PIA analysis in a large cohort of FLT3-ITD AML pts treated within our AMLSG16-10 trial (NCT: NCT01477606) which combines midostaurin with intensive chemotherapy, and to correlate the results with clinical outcome. Methods: Plasma samples from pts (age 18-70 years) with newly diagnosed FLT3-ITD AML were obtained at different time points for PIA analysis. All pts were enrolled on the ongoing AMLSG 16-10 trial applying intensive therapy in combination with midostaurin (50mg twice a day). For consolidation therapy, pts proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT) as first priority; pts not eligible for alloHSCT were intended to receive 3 cycles of age-adapted high-dose cytarabine (HiDAC) in combination with midostaurin from day 6 onwards. In all pts one year of maintenance therapy with midostaurin was intended. PIA analyses were performed at defined time points (day 15 of induction, each consolidation cycle, at the end of each treatment cycle, every 3 months during maintenance therapy) as previously described (Levis MJ, et al. Blood 2006; 108:3477-83). Results: So far, PIA analyses were performed in 63 pts (median age, 51.6 years; range, 20-70 years) during (n=63) and after (n=73) first and second induction cycle, during (n=40) and after (n=53) consolidation therapy with HiDAC as well as during maintenance therapy (n=82). During and after induction therapy median levels of phosphorylated FLT3 (p-FLT3) were 46.6% (4.5-100%, <20% in 7.9%) and 39.4% (0.3-100%, <20% in 20.5%), respectively. Co-medication with azoles had no impact on p-FLT3 levels. In pts with a FLT3-ITD mutant to wildtype ratio above our recently defined cut-off value of 0.5, levels of p-FLT3 <20% were associated with a complete remission (CR)-rate of 100%, whereas in those pts with p-FLT3 levels ≥20%, 4 out of 22 pts (18%) had resistant disease. In contrast, response in pts with a mutant to wildtype ratio below 0.5 was independent of the p-FLT3 level. During and at the end of consolidation cycles as well as during maintenance therapy p-FLT3 levels in pts treated with midostaurin were 52% (14.8-100%, <20% in 5%), 63% (7.6-100%, <20% in 7.4%) and 60.2% (11.5-100%, <20% in 3.7%), respectively. In pts concomitantly treated with azoles levels of p-FLT3 were lower without reaching significance. 39 of 63 pts received alloHSCT in first CR; those pts with p-FLT3 levels <20% after induction therapy had an in trend better survival, whereas no impact of phosphorylation levels was evident in pts receiving chemotherapy alone. Conclusion: In our study of FLT3-ITD AML pts treated with midostaurin in combination with intensive chemotherapy we could show that the lowest levels of p-FLT3 were reached during and after induction therapy. In pts with a FLT3-ITD mutant to wildtype ratio >0.5, levels of p-FLT3 <20% during and after induction therapy were associated with a high CR-rate. When receiving alloHSCT these pts had an in trend better survival compared to those with p-FLT3 levels >20%. An update of the data will be presented at the meeting. Disclosures Salwender: Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Horst:Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Ingleheim: Research Funding; Boehringer: Research Funding; MSD: Research Funding; Gilead: Honoraria, Research Funding. Schlenk:Novartis: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Arog: Honoraria, Research Funding.

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