Prognostic Parameters in Adults with Acute Lymphoblastic Leukemia at Second Complete Response

Abstract Background: Acute lymphoblastic leukemia (ALL) represents 20% of adult leukemias. With the optimization of doses and schedules of chemotherapy regimens, and incorporation of targeted agents into adult therapy, over 80% of adults with ALL attain a complete remission. However, the majority will ultimately relapse and the utility of prognostic criteria in predicting long-term survival at the time of 1st relapse has not been fully elucidated. We investigated the prognostic significance of neutrophil and platelet count recovery after salvage therapy in predicting long-term survival after second complete response [complete remission (CR), CR with incomplete platelet count recovery (CRp), or CR with incomplete neutrophil count recovery (CRi)] in adult patients (pts) with ALL. Methods: ALL pts at Cleveland Clinic, University of Washington, and Stanford treated during the yrs 1997-2015 were included. A total of 87 adult pts with ALL who achieved CR1 after induction treatment but subsequently relapsed and achieved second complete response with salvage therapy were analyzed. Pts refractory to salvage treatment and cases with isolated extramedullary relapse were excluded. Response to salvage treatment was assessed. CR was defined as <5% blasts with an absolute neutrophil count (ANC) of ≥1000/uL and platelets ≥100,000/uL; CRi: same as CR but ANC <1000/uL; CRp: same as CR but platelets <100,000/uL. Cases with both incomplete ANC and platelet recovery were categorized as CRi. Minimal residual disease (MRD) was assessed by ten-color flow cytometry and any abnormal blast population was considered MRD positive. Cytogenetic (CG) risk was ascribed by CALGB criteria. Results: Of 87 pts included, the median age was 37 yrs (range, 18-76) at diagnosis and 38 yrs (range, 20-73) at relapse. Fifty-five percent were males, 69% were Caucasian, 84% had B-ALL, and 23% had extramedullary involvement in addition to bone marrow involvement. Age, sex, race, immunophenotype and extramedullary involvement had no impact on overall survival (OS) or relapse-free survival (RFS) after first relapse. Sixty-eight percent of pts had available CG data at relapse, and of these, 39% had normal CG, while 37% were poor risk and 24% were grouped in "others". Of the poor risk pts, 68% were Ph+. CG risk at relapse had no impact on OS or RFS after first relapse. Relapse therapies included hyper-CVAD: 26%, high dose cytarabine: 17%; BFM-based regimens: 17%; inotuzumab: 13%; nelarabine: 8%; blinatumomab: 5%; and 14% of pts received other regimens. In addition, 70% of Ph+ pts received tyrosine kinase inhibitors in combination with salvage chemotherapy. Best response achieved was CR in 72%, CRp in 19%, and CRi in 9% of pts. Among 55 pts with MRD assessment following response to relapse therapy, 27% were MRD positive. The frequency of MRD positivity was significantly higher in pts with CRi (100%) as compared to CR (26%) and CRp (11%) (p=0.009). Pts with CRp or CRi after salvage treatment had worse OS compared to those with CR (p=0.006) (Figure 1A). Moreover, pts with CRi had worse RFS than those who attained CR or CRp (p=0.008) (Figure 1B). MRD positivity at the time of relapse response did not impact OS (p=0.48), but MRD negative pts had significantly better RFS than pts with MRD positivity (p<0.001) (Figure 1C). Sixty percent of pts received hematopoietic stem cell transplant (HCT) after salvage therapy in CR2, and 14% had HCT before relapse in CR1. Pts receiving HCT after salvage therapy had significantly longer OS (p<0.001) (Figure 1D) and RFS (p<0.001) (Figure 1E) than pts without HCT. Multivariable cox proportional hazard analysis included relapse treatment response (CR vs CRi vs CRp), MRD status at the time of relapse response, and HCT status, and demonstrated that MRD status at relapse response (p=0.002) and HCT (p<0.001) were independent predictors of RFS after first relapse. Type of salvage therapy response (CR vs CRi vs CRp) did not impact OS (p=0.17) or RFS (p=0.16) in multivariable analysis. Only HCT status was an independent predictor of better OS in multivariable analysis (p=0.006). Conclusion: In adult ALL pts who achieved CR2, CG risk at the time of relapse does not affect long-term survival. MRD positivity at the time of relapse response is an independent predictor of worse RFS, and it is associated with CRi. Ability to get to a successful HCT is the only independent predictor of longer RFS and OS at the time of CR2. Figure 1 Figure 1. Disclosures Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Carraway:Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Advani:Pfizer Inc.: Consultancy, Research Funding; Blinatumomab: Research Funding.

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Long-Term Follow up of a Comparison of Non-Myeloablative Allografting with Autografting for Newly Diagnosed Myeloma

Blood ◽

10.1182/blood.v116.21.525.525 ◽

2010 ◽

Vol 116 (21) ◽

pp. 525-525 ◽

Cited By ~ 1

Author(s):

Benedetto Bruno ◽

Barry Storer ◽

Francesca Patriarca ◽

Marcello Rotta ◽

Roberto Sorasio ◽

...

Keyword(s):

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

New Drugs ◽

High Dose ◽

Advisory Committees ◽

Term Survival ◽

High Dose Melphalan

Abstract Abstract 525 Background: Role and timing of allografting in myeloma are hotly debated. Before the introduction of new drugs, we carried out a trial where the treatment assignment was based only on the presence/absence of an HLA-identical sibling (Bruno et al, N Engl J Med 2007). Methods: Overall, 162/199 (81%) of patients with at least one sibling were HLA-typed. First-line treatments included induction with VAD-based regimens and a cytoreductive autograft, followed by a nonmyeloablative allograft (Tandem auto-allo) or a second melphalan-based autograft (Double-auto). We now report an update at a median follow up of 7.1 years. Results: Response rates [complete (CR) and partial remissions (PR)] at the time and after the non-myeloablative allograft and at the time and after the second autograft did not differ between the two cohorts: 76% and 86%, and 76% and 91% respectively (p=1 and p=0,54). However, CR rate was significantly higher after the non-myeloablative allograft than after the second autograft: 55% versus 26% (p=0,0026). At a median follow up of 7.1 years (range 2.5 – 10.7+), by intention-to-treat analysis, median overall survival (OS) and event free survival (EFS) were significantly longer in patients with HLA-identical siblings (No.80) as compared with those without (No.82): not reached vs. 4.25 years (HR 0.51, CI 95% 0.34–0.76, p=0.001) and 2.8 vs. 2.4 years (HR 0.62, CI 95% 0.44–0.87, p=0.005). By multivariate analysis, independent of age, gender, myeloma protein isotype, Durie&Salmon stage, and disease status at the first autograft; the presence of an HLA-identical sibling was significantly associated with longer OS (HR 0.5, CI 95% 0.3–0.8, p=0.001) and EFS (HR 0.63, CI 95% 0.4–0.9, p=0.01). At a median follow up of 7.3 (range 5.4 – 10.7+ years), median OS was not reached in the 58 patients who received a non-myeloablative allograft and 5.3 years in the 46 who received a second high-dose melphalan autograft (HR 0.55, CI 95% 0.32–0.94, p=0.02), whereas EFS was 39 months and 33 months (HR 0.62, CI 95% 0.40–0.96, p=0.02) respectively. Cumulative incidence of transplant related mortality was 11% and 2% at 2 years respectively. At median follow-ups of 7.3 years from diagnosis (range 5.4 – 10.4+) and 6.5 years from the allograft (range 4.2 – 9.4+), and 7.4 years from diagnosis (range 5.6 – 10.7+) and 6.2 years from the second autograft (range 4.7 – 9.1+), 30/58 (52%) and 37/46 (80%) patients, respectively, were treated for disease relapse/progression. Salvage therapies included bortezomib- or thalidomide-containing regimens in most patients of both cohorts. After 1–3 lines of therapy, 22/30 (73%) had a response, including 5 CR and 17 PR, in the tandem auto-allo group, whereas 21/37 (54%) had a response, including 4 CR and 16 PR after the second autograft. Of note, at a median follow up of 3.9 years from the start of the first salvage therapy, OS was not reached and was 1.7 years in patients who had relapsed/progressed after the allograft and the second high-dose melphalan (HR 0.44, CI 95% 0.24–0.82, p=0.01) respectively. Conclusions: In this study, allografting conferred a long term survival advantage over standard autografting. Salvage therapy was associated with longer OS perhaps due to a synergistic effect between new drugs and residual graft-vs.-myeloma effects. In prospective clinical trials, the combination of graft-vs.-myeloma effects with “new drugs” should be explored and may increase the cure rate of myeloma patients. Disclosures: Bringhen: Celgene: Honoraria; Janssen-Cilag: Honoraria. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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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 ◽

10.1182/blood.v128.22.4649.4649 ◽

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.

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

Blood ◽

10.1182/blood-2018-99-120314 ◽

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.

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

Blood ◽

10.1182/blood-2018-99-117802 ◽

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.

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Salvage Therapy with Obinutuzumab (GA101) Plus Chlorambucil (Clb) after Treatment Failure of Clb Alone in Patients with Chronic Lymphocytic Leukemia (CLL) and Comorbidities: Results of the CLL11 Study

Blood ◽

10.1182/blood.v124.21.3327.3327 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3327-3327 ◽

Cited By ~ 3

Author(s):

Valentin Goede ◽

Anja Engelke ◽

Kirsten Fischer ◽

Javier Lopez Jimenez ◽

Alexej Kuzmin ◽

...

Keyword(s):

Board Of Directors ◽

Active Treatment ◽

Salvage Therapy ◽

Research Funding ◽

Complete Response ◽

Initial Study ◽

Line Treatment ◽

Advisory Committees ◽

Comorbidity Burden ◽

Grade 3

Abstract Introduction: Chemoimmunotherapy with the glycoengineered type II anti-CD20 antibody obinutuzumab plus the alkylating drug chlorambucil (G-Clb regimen) has been investigated in the CLL11 study and demonstrated clinical benefit in patients with previously untreated CLL and comorbidities. Whether G-Clb is also an active treatment in patients with refractory CLL after frontline therapy with Clb alone has been explored in the subpopulation of CLL11 subjects treated with such salvage therapy. Methods: Thirty patients who received Clb alone as initial study treatment, but developed progressive CLL within up to 6 months after end of Clb treatment were offered G-Clb as optional salvage therapy. The dosing schedule for obinutuzumab was 100 mg intravenously on day 1, 900 mg on day 2, and 1000 mg on day 8 and 15 of cycle 1, and 1000 mg on day 1 of cycles 2-6. Clb was administered orally with 0.5 mg/kg body weight on day 1 and 15 of each 28-day cycle. Results: The median age in the crossover patient population (n=30) was 72 years. The comorbidity burden was high as assessed at study entry (median cumulative illness rating scale total score 8), and renal function was reduced (median calculated creatinine clearance 67 mL/min). Deletions of 11q and 17p were present in 12% and 20% of the patients, respectively; and 64% had unmutated IGHV genes. When crossing over to G-Clb, the majority (93%) had not responded to the initial study treatment with Clb while two patients had responded transiently to Clb with a partial remission, but had relapsed early (median time from start of Clb to crossover: 9.7 months). After crossover, all but one patient completed the 6 cycles of salvage therapy with G-Clb; one subject discontinued after the first infusion of obinutuzumab due to an infusion-related reaction (IRR). Grade 3 or 4 IRRs occurred in 17% of the patients. Grade 3 or 4 neutropenia, anemia, thrombocytopenia, and infection were reported in 33%, 7%, 10%, and 13% of the patients, respectively. Response rates at the end of crossover treatment with G-Clb are given in the table. Negativity for minimal residual disease in bone marrow and/or peripheral blood after crossover treatment was achieved in 23% of the patients. The median progression-free survival from start of crossover treatment was 17.2 months (95% CI 14.2; 22.4 months) (median observation time: 23 months). Conclusions: These results suggest that, besides its established role as frontline treatment of CLL, chemoimmunotherapy with G-Clb could be a safe and active treatment for patients with CLL refractory to prior chlorambucil chemotherapy. Table: Clinical response to G-Clb after failure of Clb alone n (%) Responders 26 (87) Complete response 2 (7) Complete response incomplete 1 (3) Partial response 23 (77) Non-Responders 4 (13) Stable disease 2 (7) Progressive disease 1 (3) Not evaluable* 1 (3) * Due to early treatment discontinuation after IRR Disclosures Goede: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other. Off Label Use: Obinutuzumab (GA101, Gazyva); approved for 1st line treatment of CLL; paper includes results / discussion of drug use in 2nd line treatment of CLL. Engelke:Roche: Travel grants Other. Langerak:Roche: Research Funding. Ritgen:Roche: Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding. Asikanius:Roche: Employment. Humphrey:Roche: Employment. Wenger:Genentech: Employment. Fingerle-Rowson:Roche: Employment. Hallek:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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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 ◽

10.1182/blood.v124.21.2287.2287 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2287-2287 ◽

Cited By ~ 4

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.

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Antibody-Interferon-Alpha Fusion Protein Therapy for the Treatment of B-Cell Non-Hodgkin Lymphoma: Enhanced ADCC, Inhibition of Proliferation, and In Vivo Eradication of CD20+ Human Lymphomas

Blood ◽

10.1182/blood.v126.23.2762.2762 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2762-2762 ◽

Cited By ~ 1

Author(s):

John M. Timmerman ◽

Kristopher K Steward ◽

Reiko E Yamada ◽

Patricia A Young ◽

Dena M. Minning ◽

...

Keyword(s):

Fusion Protein ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Term Survival ◽

Equity Ownership

Abstract Background: Interferon-alpha (IFNα) is a pleiotrophic cytokine with direct anti-tumor and immunostimulatory effects. Currently IFNα is approved for the treatment of multiple hematologic malignancies, including non-Hodgkin lymphoma (NHL). However, its clinical utility has been hindered by dose-limiting toxicitiy due to systemic activation of the interferon receptor. To overcome this limitation, we engineered anti-tumor antibody-IFNα fusion proteins to selectively increase delivery of IFN to the tumor site and reduce systemic toxicity. We previously reported that IGN002, an anti-CD20-IFNα fusion protein, exhibits enhanced complement-dependent cytotoxicity (CDC) compared to rituximab, and inhibits proliferation and induces apoptosis of human B-cell NHL (Yamada et al, ASCO 2013). We now extend these previous findings and show that IGN002 possesses enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effector function and superior in vivo anti-tumor activity against B-cell NHL, compared to rituximab. Methods: IGN002 was evaluated against a panel of human Burkitt and diffuse large B-cell lymphoma (DLBCL) cell lines. Proliferation was measured by [3 H]-thymidine incorporation, STAT1 activation by flow cytometry, ADCC by lactate dehydrogenase release using human PBMC effectors, and IFN bioactivity by encephalomyocarditis (EMC) viral protection assay. NHL xenografts were grown in SCID mice. Results: IGN002 more potently inhibited the growth of NHL cell lines expressing CD20 than rituximab or unfused IFNα. Intrinsic IFNα activity of IGN002 was reduced in viral protection and anti-proliferation assays using cells lacking CD20 expression. STAT1 activation by IGN002 was enhanced on cells expressing the target antigen, whereas a control antibody-IFNα fusion protein showed reduced STAT activation activity compared to unfused IFNα. Together, these results indicate that fusion of IFNα to the antibody results in reduced IFN effects on cells not bearing the tumor antigen target. IGN002 exhibited enhanced ADCC activity compared to rituximab against Daudi, Ramos, and Raji NHL cells in long-term (overnight incubation) assays, demonstrating both higher potency and higher maximal cytotoxicity. This result is possibly due to activation of the effector cell populations by the fused IFNα moiety, as IFN is known to activate both NK cells and monocytes. The in vivo anti-tumor efficacy of IGN002 was compared to rituximab and a control antibody-IFNα fusion protein against 10-day established Raji NHL xenografts. IGN002 was superior to both rituximab and the control fusion protein, achieving a longer median survival and higher long-term survival rate (p = 0.0015 and < 0.0001 vs. rituximab and control fusion protein, respectively). The in vivo anti-tumor efficacy of IGN002 was also compared to rituximab at three equimolar dose levels (5 mg/kg, 1 mg/kg, and 0.2 mg/kg antibody) against 10-day established Daudi NHL xenografts. IGN002 showed superior efficacy compared to rituximab at all doses (p < 0.001), achieving tumor eradication (100% long-term survival) in all mice treated at all three dose levels, whereas rituximab only delayed tumor progression. Conclusions: IGN002 demonstrated more robust direct anti-proliferative and antibody effector functions than rituximab against human NHL cells in vitro, and also showed the ability to eradicate established NHL xenografts in vivo. Against cells expressing the CD20 target antigen, IGN002 exhibited greater anti-proliferative potency than unfused IFNα. In contrast, the anti-proliferative and anti-viral potency of IGN002 was reduced against cells lacking CD20, compared to unfused IFNα. These findings support the hypothesis that tumor antigen-targeted IFN therapeutics may possess a broader therapeutic index than unfused IFNα, inhibiting tumor growth by multiple mechanisms while reducing systemic toxicity. These results support the further development of IGN002 for the treatment of B-cell NHL, and a first-in-human phase I clinical study will begin later this year in the United States. Disclosures Timmerman: Janssen: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Valor Biotherapeutics: Research Funding. Steward:ImmunGene, Inc.: Employment. Minning:Valor Biotherapeutics, LLC: Consultancy. Sachdev:ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gresser:ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Valor Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Khare:Valor Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Morrison:ImmunGene, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽

10.1182/blood-2018-99-117633 ◽

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.

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Depth of Response and Response Kinetics in the Icaria-MM Study of Isatuximab with Pomalidomide/Dexamethasone in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2019-129840 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3185-3185 ◽

Cited By ~ 1

Author(s):

Cyrille Hulin ◽

Paul G. Richardson ◽

Michel Attal ◽

Hugh J. Goodman ◽

Vadim A Doronin ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Residual Disease ◽

Response Rates ◽

Complete Response ◽

Advisory Committees ◽

Depth Of Response ◽

First Response

BACKGROUND: In multiple myeloma (MM), deep responses have been associated with improvements in progression-free survival (PFS) and overall survival (OS). Response kinetic data, including renal response times, which are highly important for patients with renal impairment, are infrequently reported. We analyzed the association between depth of response, including minimum residual disease (MRD) negativity, plus response kinetics and long-term outcomes, using data from the randomized, open-label, phase 3 ICARIA-MM study. ICARIA-MM evaluated the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory MM (RRMM) after ≥2 prior lines of therapy (NCT02990338). METHODS: All patients received standard doses of Pd and those randomized to the Isa-Pd group received 10 mg/kg IV on days 1, 8, 15, and 22 (cycle 1), and days 1 and 15 in subsequent 28-day cycles. Depth and kinetics of response were analyzed for each treatment group. MRD was assessed at 10-5 (tested by next-generation sequencing in patients with complete response [CR] / stringent CR [sCR]). Time to tumor response, time to renal response (CRenal; improvement in estimated glomerular filtration rate (eGFR), using the MDRD formula, from <50 mL/min/1.73m² at baseline to ≥60 mL/min/1.73m² at ≥1 post-baseline assessment), and time to sustained CRenal (a CRenal lasting ≥60 days) were recorded. No neutralization assay was used for patients with IgG kappa clonality. RESULTS: Overall, 307 patients were randomized to Isa-Pd (n=154) or Pd (n=153), of whom 33/142 (23.2%) and 24/145 (16.6%) patients had eGFR <50 mL/min/1.73m² at baseline. Patients had received a median of 3 prior lines of therapy (range 2-11) and 73.4% and 71.9% of patients in the Isa-Pd and Pd groups, respectively, were double refractory. Median PFS was 11.53 months with Isa-Pd and 6.47 months with Pd (hazard ratio [HR] 0.596; 95% confidence interval [CI] 0.436-0.814). Tumor responses on Isa-Pd were more frequent and deeper than on Pd. Overall response rates (ORR) were 60.4% vs 35.3% (odds ratio [OR] 2.80; 95% CI 1.72-4.56; p<0.0001); at least very good partial response rates (≥VGPR) were 31.8% vs 8.5% (OR 5.03; 95% CI 2.51-10.59; p<0.0001). As no isatuximab interference assay was performed, near-complete response rates (immunofixation remained positive) were reported: 15.6% vs 3.3% (OR 5.47; 95% CI 1.96-18.78; p=0.0002). MRD negativity rates in the ITT population were 5.2% vs 0%. Depth of response correlated with improved long-term outcomes in both arms (Figure). After a median follow-up of 11.6 months in the Isa-Pd arm, 100% of MRD-negative (MRD−) patients were progression free and alive. In the Isa-Pd arm, median PFS was longer with increased depth of response: MRD− patients, not reached (NR); ≥VGPR and MRD+, 15.21 months; partial response (PR), 11.53 months; less than PR, 3.29 months. This pattern was also observed for 1-year OS probabilities (100% > 92.9% > 82.4% > 46.4%, respectively). Tumor responses occurred faster with Isa-Pd than with Pd. Among patients who achieved a response of ≥PR (93 in the Isa-Pd arm and 54 in the Pd arm), the median time to first response was shorter for Isa-Pd (1.1 months) than for Pd (1.9 months). Among patients who achieved a response of ≥VGPR (49 and 13 in the Isa-Pd and Pd arms, respectively), the time to first VGPR or better response was similar at 2.9 months for Isa-Pd and 3.0 months for Pd. Renal responses occurred faster in patients on Isa-Pd than on Pd. A CRenal was observed in 23/32 (71.9%) patients in the Isa-Pd arm (median time to response 3.4 weeks) and in 8/21 (38.1%) of patients in the Pd arm (median time to response 7.3 weeks). A sustained CRenal was observed in 10/32 (31.3%) patients in the Isa-Pd arm (median time to first response 2.4 weeks) and in 4/21 (19.0%) patients in the Pd arm (median time to first response 4.8 weeks). CONCLUSION: In the heavily pretreated ICARIA population, Isa-Pd induced more frequent and faster tumor and renal responses than Pd. Depth of response, including MRD negativity, was improved with Isa-Pd and was clearly associated with better long-term survival outcomes. Figure. PFS (A) and OS (B) by best overall response and minimal residual disease for Isa-Pd Figure Disclosures Hulin: celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Richardson:Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: 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, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Spicka:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Le-Guennec:Sanofi: Employment. Campana:Sanofi: Employment. van de Velde:Sanofi: Employment. Beksac:Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Isatuximab is an investigational agent and has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the uses under investigation.

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Efficacy and Safety Profile of Long Term Exposure to Lenalidomide in Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v120.21.2964.2964 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2964-2964

Author(s):

Guillemette Fouquet ◽

Stéphanie Tardy ◽

Helene Demarquette ◽

Sarah Bonnet ◽

Julie Gay ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Safety Profile ◽

Research Funding ◽

Response Rate ◽

Advisory Committees ◽

Vte Prophylaxis ◽

First Relapse

Abstract Abstract 2964 Background. Lenalidomide is an oral IMiD®, immunomodulatory compound, approved for use in combination with dexamethasone (Len/Dex) in patients with RRMM who have received one prior therapy. Len/Dex is indicated until evidence of disease progression at the best-tolerated dose of both Len and Dex (Dimopoulos et al. Leukemia 2011). However, the tolerability profile of long term exposure to Len/Dex is not well described, and evidence that long term exposure to Len/Dex would improve on the response rate and survival has yet to be determined. We sought to determine the efficacy and safety profile of long term exposure to Len/Dex in RRMM pts in a multicentre study. Method. We retrospectively reviewed the medical records of 50 RRMM pts treated with Len/Dex and remaining on Len for ≥2 years with a special focus on pts receiving Len for ≥3 years. All pts included had complete follow up records. Results. The median (range min-max) age was 58 years (39–79) with 30% (n=15) > 65 years (elderly MM), the sex ratio M/F was 1.2, 49% (n=24) ISS 2 and 3, 12% (n=6) severe renal insufficiency (CrCl < 30mL/min), and 8% (n=4) adverse FISH [del17p and/or t(4;14)]. Overall, 25 pts (50%) had Len/Dex at first relapse, 19 pts (38%) at second relapse and 6 (9%) pts in subsequent relapses. Len/Dex was given at first relapse in 10 (66%) elderly patients. The median time from diagnosis to starting Len/Dex was 4.5 years (1–16) for overall cohort and 3 years (1–8) for elderly patients (p=0.05). 28 pts (56%) received Len/Dex for ≥3 years. The median duration on Len/Dex was 3 (2–7) years for the overall cohort, and was 4 (3;7) years for patients exposed to Len ≥3 years. Treatment duration was similar across age categories and across number of previous relapses. With a median follow up of 4 years, 19 patients had stopped Len/Dex. The response rate (ORR, ≥PR) was 96% (n=48), including 37 (74%) patients with ≥VGPR, similar across age categories. Interestingly, the ORR and ≥VGPR were similar irrespective of whether patients have stopped Len/Dex in our study. The ORR was also similar across number of previous relapses, but the ≥VGPR rate was lower in patients at third relapse and beyond, (50%; p=ns). The ORR and ≥VGPR rate was 93% and 77% in patients exposed to Len ≥3 years, similar to the whole cohort. The median time to first response and best response were 2 (1–5) months and 4.5 (2–9) months, respectively. Overall, 9 (18%) patients stopped treatment due to toxicity, 9 (18%) progression of MM, and 1 (0.5%) patient decision. With a median follow up of 4 years, the median (95%CI) TTP was not reached, the estimated 4-yr TTP was 51.5%. There was no imbalance in the incidence of toxicity based on age, number of previous relapses, and patients exposed to Len ≥3 years did not discontinue more often due to toxicity, 14% versus 19% for those receiving Len < 3 years. The hematological safety profile was similar across age categories, number of previous relapses, and patients exposed to Len ≥ 3 years; overall, 8 (16%) patients experienced grade 3–4 neutropenia, 6% thrombopenia, and 6% anemia. Ten (20%) patients experienced a thromboembolic event (VTE), all of them of venous type. Two patients had previous history of VTE, but none of them experienced VTE on Len/Dex, likely related to adequate VTE prophylaxis. The median time to first occurrence was 5 (1;28) months, although 4/10 occurred in patients with ≥3 years on Len. All VTE occurred while on VTE prophylaxis except for 1 patient, 5 on aspirin, 2 on prophylactic doses of LMWH, and 2 on VKA (target INR 2–3). The incidence rate of second primary malignancy (SPM) was 3 (6%) (larynx, lung, and MDS). The SPMs occurred at a median time of 4 years from start of Len, while Len was already stopped in 2/3 patients, the latter stopped len at time SPM was diagnosed. Interestingly, none of the patients with more than 3 years exposure on Len had SPM. Conclusions. The current study provides estimates of responses, TTP and safety in a series of MM pts with long-term exposure to Len-based regimen at relapse. 62% of patients remained on Len beyond 3 years reflecting the efficacy and good safety profile of Len in relapsed MM, irrespective of age and number of prior therapies. Furthermore, no excess of long term side effects, including SPM, was observed with a prolonged long follow-up in this study. Disclosures: Robinson: Celgene: Employment. Miljkovic:Celgene: Employment. Morel:Celgene: Employment. Boccacio:Celgene: Employment. Facon:millenium: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees. Hulin:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Leleu:Onyx: Honoraria, Speakers Bureau; Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau.

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