The Role of Serum Immunoglobulin Free Light Chain In Response and Progression In Waldenstrom Macroglobulinemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3095-3095
Author(s):  
Xavier Leleu ◽  
Wanling Xie ◽  
Meghan Rourke ◽  
Ranjit Banwait ◽  
Renee Leduc ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Response Rate ◽  
Early Response ◽  
Response To Therapy ◽  
Time To Progression ◽  
Therapy Initiation ◽  
M Spike

Abstract Abstract 3095 Introduction: Waldenstrom macroglobulinemia (WM) is a low grade B cell lymphoma characterized by the secretion of IgM protein in the serum. The IgM level lacks sensitivity due to its prolonged half-life. The serum free light chain (sFLC) assay has shown significant clinical application in plasma cell dyscrasias, specifically in multiple myeloma, and is used to monitor response to therapy. In this study, we sought to examine the role of sFLC in the response and progression of patients with WM. Methods: This study was performed using serum collected from a homogeneous cohort of patients diagnosed with WM and uniformly treated on a phase 2 trial using the combination of bortezomib with rituximab, previously untreated (N=26) or relapsed and or refractory to prior therapy (N=37). Patients eligible for this analysis must have measurable sFLC levels at baseline. A total of 48 patients were included. FLC response is defined as achievement of normal iFLC value or 50% decrease from baseline in the iFLC level during therapy and follow-up. Concordance between FLC and IgM response rate was evaluated using Kappa statistics. Correlation was evaluated using Spearman correlation coefficient. Time to progression was estimated using Kaplan-Meier methodology. We also did landmark analysis to compare overall response rate and time to progression by FLC or IgM response status at 2 months after therapy initiation; Fisher Exact test or Log-rank test were used. Results: The median iFLC value was 103.50mg/L (range 22.5–3540), the median kappa over lambda ratio was 13.45 (0.01-665), and the median serum IgM value by nephlometry was 3995 mg/dL (537-10,800). Overall, as per M spike response criteria, 29 (60%, 90% CI: 48%, 72%) patients responded, e.g. had partial response or better, and 19 patients failed to obtain response. Using serum IgM protein measurement by nephlometry during therapy and follow up post-therapy, 35 (73%, 90% CI: 60%, 83%) patients responded with a PR or better (>50% decrease), with 3 (6%) having normalization of their serum IgM. In comparison, iFLC response during treatment and follow up occurred in 38 (79%, 90% CI: 67%, 88%): with 2(4%) having normalization of value, 21(44%) having 50% reduction and 15(31%) having both. The time to iFLC response and IgM response among patients who achieved response by both criteria was calculated (N=33). The median time to iFLC response was 2.1 months (range 0.9–28.7months), while the median time to IgM response was 3.0 months (0.9-14.7) (p=0.07). The median time to progression per the protocol was 18.9 months (95% CI:10.5-NR). The Kappa concordance between iFLC 25% increase and M spike progression was 0.63 (95% CI: 0.41–0.84). This showed a better concordance compared to using the iFLC >50% definition (kappa=0.58, 95% CI: 0.35, 0.81), indicating that progression using iFLC>25% would be a better definition for patients with WM. The median time to progression by iFLC>25% increase was 13.7 months (95% CI:10.9-19.4) and the median time to IgM >25% increase was 14.6 months (95% CI: 9.5–19.1), showing a more rapid detection of progression by iFLC compared to M spike and IgM measurements. We next examined whether attaining a response using iFLC can be a predictor of overall response to therapy. Seventeen patients (35%) achieved an iFLC response at 2 months after therapy initiation. Patients with early iFLC response were more likely to have intermediate/high ISS-WM stage, elevated B2M or low Hemoglobin<11.5 gm/dL (p<0.05). Early iFLC response was related to overall IgM response during therapy and follow up (p=0.02). In multivariable models when adjusting for ISS stage, B2M or Hgb, there was no significant association between FLC early response and TTP either by protocol, FLC or IgM criteria. However, there was trend that early response was related to prolonged TTP especially when adjusting for hgb risk factors (HRs ranges from 0.63∼0.80, p>0.3 for various TTP endpoints. Conclusion: iFLC may be a useful marker of tumor measurement that correlates well with IgM and M spike measurements. The time to iFLC response was shorter by 1 month compared to IgM or M spike measurement. The median time to progression by iFLC was shorter by 1 month compared to IgM. There was a trend that early response was related to prolonged TTP when adjusting for other risk factors. Disclosures: Leleu: Celgene: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Chugai: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; LeoPharma: Consultancy, Honoraria.

Early Response Using Serum Immunoglobulin Free Light Chain (sFLC) Measurement Predicts Response to Therapy in Waldenstrom Macroglobulinemia (WM)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3755-3755
Author(s):  
Xavier Leleu ◽  
Aldo M. Roccaro ◽  
Renee Leduc ◽  
Stephanie Poulain ◽  
Anne-Sophie Moreau ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Light Chain ◽  
Overall Response Rate ◽  
Response Rate ◽  
Early Response ◽  
Free Light Chain ◽  
Response To Therapy ◽  
Overall Response ◽  
M Spike

Abstract Background. Measurement of serum M-spike is used to determine response to therapy and treatment free survival in Waldenstrom Macroglobulinemia (WM). However, there are many limitations to the use of IgM M-spike, and new sensitive markers are needed to determine early response or progression in these patients. We have previously shown that involved serum free light chain (sFLC) accurately diagnosed patients with WM, and correlated with markers of poor prognosis, specifically beta- 2 microglobulin (B2M). In this study, we sought to determine the role of levels of involved in the response to therapy in patients with WM treated on clinical trials, and compare it to the response observed using the traditional M-spike measurement. Methods. We prospectively studied involved sFLC in 61 WM patients enrolled on 2 clinical trials, at diagnosis (N=8) and with relapse/refractory disease (N=53). Patients were treated on one of two clinical trials: either perifosine (N=30; given 150mg oral daily) or combination of bortezomib and rituximab (N=30; given IV bortezomib 1.6mg/m2 at days 1, 8, 15 q 28 days × 6 cycles and rituxan 375 mg/m2 at days 1, 8, 15, 22 on cycles 1 and 4). Response was assessed after cycle 2, confirmed on 2 consecutive measurements, and included minor response (MR), partial response (PR) or complete remission (CR). Results. The baseline characteristics of the patients were as follows: the median age was 65 years (44–83), male/female ratio 2.38, serum B2M 3.0mg/L (1.00–7.30), hemoglobin 11.0g/dL (7.00–14.90), platelet count 216 ×109/mm3 (46–563), serum M-spike 2.24g/L (0.41–4.62), and involved sFLC 95.2mg/L (4.92–868). The WM International staging system (WM-ISS) showed that 28% of patients had low ISS, 31% intermediate, and 41% high ISS scores. The overall response rate for the entire cohort was 62.3%, assessed by M-spike measurement (MR=23, PR=13, nCR=2). The overall response rate using involved sFLC level was 72.1% (MR=14, PR=29, and CR=1), (p<0.001). We then investigated the role of sFLC in predicting early response to therapy in patients treated with bortezomib and rituximab. We studied the level of sFLC weekly for the first month of therapy. Interestingly, early measurement of sFLC in the first month of therapy significantly predicted response; 93% of the patients who obtained at least an MR within the first 3 weeks of therapy by sFLC demonstrated a response on further follow up using serum M-spike (p=0.024). Conclusion. In this study, we identified that involved sFLC is a new and reliable marker for monitoring response to therapy in WM disease, especially to determine early response in these patients.

Follow-Up Results of a Prospective, Multicenter, Open-Label Study of Oral Fludarabine Phosphate in Patients with Previously Untreated B-CLL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2128-2128
Author(s):  
Jean-Francois Rossi ◽  
A. Van Hoof ◽  
K. De Boeck ◽  
S. A. Johnson ◽  
D. Bron ◽  
...  
Keyword(s):  
Disease Progression ◽  
Median Time ◽  
Response Rate ◽  
Time To Progression ◽  
Open Label ◽  
Overall Response ◽  
Fludarabine Phosphate ◽  
Duration Of Response ◽  
Grade 3

Abstract The IV formulation of fludarabine phosphate is an effective treatment in patients with B-cell chronic lymphocytic leukemia (B-CLL), yielding overall response rates of 60% to 80%. An oral formulation of fludarabine phosphate has been developed. In a previously published multicenter, open-label, phase II clinical trial, 81 previously untreated B-CLL patients received 10-mg tablets of fludarabine phosphate (Fludara® oral) 40 mg/m2/day for 5 days, repeated every 4 weeks. The primary endpoint of the trial was response rate, and secondary endpoints included safety and quality of life assessments. Of 81 patients (mean age, 61.2 years; range, 30–75 years) with previously untreated B-CLL, 81.5% were classified as Binet stage B or C. The overall response rate (complete response [CR] + partial response [PR]) using National Cancer Institute (NCI) criteria was 80.2% (12.3% CR and 67.9% PR) and the median time to progression was 841 days (range, 28–1,146 days) (Rossi JF, et al. J Clin Oncol2004;22:1260–1267). The most frequently reported grade 3/4 adverse event was myelosuppression: WHO grade 3/4 hematologic toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). This analysis reports on the long-term follow-up of this cohort during the period from November 2001 to November 2004. Of the 74 patients eligible for the survival analysis, 61 were also assessed for duration of response using NCI criteria: 9 CR (14.8%) and 52 PR (82.2%). During the 3-year follow-up period, 22 (29.7%) patients did not progress. For those who progressed, median time to progression was 29.7 months, and median duration of response was 22.9 months. In 41 (80.4%) of these patients, an increase in circulating lymphocytes was reported as evidence of disease progression. In 23 patients (45.1%), an increase in the sum of the products of at least 2 lymph nodes and/or appearance of new palpable nodes was reported as evidence of disease progression. During the indicated follow-up period, 37 patients (50%) received subsequent treatment. Twelve patients (16.2%) died during the follow-up period: 7 patients (58.3%) due to disease progression, 3 patients (25.0%) due to adverse events, and 2 patients (16.7%) due to other causes. Results from this study suggest that oral fludarabine phosphate is clinically effective and well tolerated by patients with previously untreated B-CLL. Moreover, these data demonstrate that oral fludarabine phosphate achieves response rates and duration of response comparable to those achieved with first-line fludarabine phosphate IV therapy.

scholarly journals Characteristics and Outcome of Myelofibrosis Patients on Long-Term Ruxolitinib Therapy (≥3 years)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Lucia Masarova ◽  
Prithviraj Bose ◽  
Naveen Pemmaraju ◽  
Lingsha Zhou ◽  
Sherry A. Pierce ◽  
...  
Keyword(s):  
High Risk ◽  
Median Time ◽  
Median Duration ◽  
Research Funding ◽  
Response To Therapy ◽  
International Prognostic Scoring System ◽  
Duration Of Therapy ◽  
Grant Support

Introduction: The JAK1/2 inhibitor, ruxolitinib, was approved in the USA in 2011 for the treatment of patients with myelofibrosis (MF) with intermediate and high-risk IPSS score (International Prognostic Scoring System). In the approval phase 3 COMFORT 1 - 2 studies, about 50% patients were taking ruxolitinib for at least 3 years, respectively. Objective: We sought to evaluate the characteristics and outcome of MF patients on long-term ruxolitinib therapy (≥3 years) at our center. Methods: We retrospectively reviewed the charts of patients with MF who were treated with ruxolitinib for ≥3 years. Cytogenetic were classified into risks according to Gangat et all, JCO, 2011. Descriptive statistics were used for nominal and continues variables, captured at the time of ruxolitinib start. Duration of therapy and overall survival (OS) were estimated using the Kaplan-Meier method, from the start of ruxolitinib initiation until the last day of initial ruxolitinib therapy, the date of last follow-up or death, respectively. Response to therapy was according to IWG-MRT 2013 criteria. Results: Among 437 patients who initiated therapy with ruxolitinib at our center, 136 (31%) remained on therapy for ≥3 years and represent current cohort. Ninety-one patients (67%) were newly diagnosed; the remaining patients presented after a median of 28 months (range, 4-228) from MF diagnosis. Median time to initiate ruxolitinib from presentation to our center was 1 month (range, 0.3-123) for all patients. However, the time was longer for patients who presented &gt; 3 months from MF diagnosis (median of 11.5 months; range, 3.5-123). Patient's characteristics (n = 136) at the time of ruxolitinib initiation are summarized in Table 1. Median age was 67 years (range, 32-84), and 76 (56%) of patients were males. Half of the patients had high risk IPSS score, &gt; 80% had systemic symptoms or splenomegaly. Eighty six percent of patients had diploid or favorable karyotype. JAK2 mutation was detected in 87% of tested patients. Median duration of ruxolitinib therapy was 72 months (95% CI: 66-78). Over the median follow-up of 83 months (range, 36-174), 63 patients (46%) died. Currently, 48 (35%) patients are still on ruxolitinib; 88 discontinued therapy after a median time of 55 months (range, 47-63). By 5th and 7th year of therapy, out of 136 patients that were treated for at least 3 years, 35% and 65% percent of patients discontinued treatment. The reasons for discontinuation included allogeneic stem cell transplantation (SCT, n 5), cytopenia (n 6), progression of MF (n 38), progression to accelerate phase (n 2) or acute leukemia (n 7), patient's choice (n 11), and death (n 23: infection 4, cardiac 3, cancer 3, others 16). Overall, 101 patients (74%) achieved IWG-MRT response, represented in majority by clinical improvement (CI) in spleen (n 90, 84%) and CI in TSS (n 51, 71%), respectively. The remaining patients achieved clinical benefit not qualifying for overall IWG-MRT response. Median duration of IWG-MRT response was 55 months (95% CI: 48-63). Responses were ongoing in 29 patients (29% of initial responders) at the time of last follow-up. Median duration of therapy was 75 months (95% CI: 68-82) for responders vs 60 months (95% CI: 39-79) for non-responders, p = 0.74. Median OS from the start of ruxolitinib was 90 months (95% CI: 76-104), Figure 1. Median OS for patients who were on ruxolitinib for ≥5 years (n = 73) was 106 months (95% CI: 80-137). Univariate and multivariate analysis for factors associated with OS is shown in Table 2. After ruxolitinib discontinuation, 25 patients received subsequent treatment at our center: SCT in 6, another JAK inhibitor in 11, other investigational agents in 3, chemotherapy in 5 patients. Median OS from ruxolitinib discontinuation was 20 months (95% CI: 12-28). Conclusion: Our data with the longest follow-up of patients receiving ruxolitinib for ≥3 years confirm the long-term benefit of this therapy with a median OS approaching 8 years since ruxolitinib treatment initiation. Disclosures Bose: Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; NS Pharma: Research Funding. Pemmaraju:AbbVie: Honoraria, Research Funding; Incyte Corporation: Honoraria; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Celgene: Honoraria; Blueprint Medicines: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Jazz Pharma: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding. Verstovsek:Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding.

Hevylite, a Novel M-Component Based Biomarkers of Response to Therapy and Survival in Waldenstrom Macroglobulinemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2667-2667 ◽  
Author(s):  
Salomon Manier ◽  
Julie Lejeune ◽  
Lucile Musset ◽  
Eileen Boyle ◽  
Remy Dulery ◽  
...  
Keyword(s):  
Binding Site ◽  
Median Time ◽  
Research Funding ◽  
Response To Therapy ◽  
Female Ratio ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Reliable Marker ◽  
M Spike ◽  
The Impact

Abstract Abstract 2667 Background. Measurement of serum M-spike is used to determine response to therapy and treatment free survival in Waldenstrom Macroglobulinemia (WM), however, its resolution on serum protein electrophoresis (SPEP) can make accurate measurement difficult. The same applies to total IgM quantification by nephelometry (IgMneph) which inherently includes monoclonal and polyclonal immunoglobulins. IgM levels by either technique do not accurately reflect tumor load or prognosis in WM. There is a need to identify new markers that reflect disease burden and correlate with patients'outcome. Hevylite measures IgMkappa and IgMlambda, separately, and might provide true quantitative measurement of the IgM M-spike. We sought to determine whether Hevylite value can be used as a reliable marker for response to therapy in WM as compared to the M-spike measurement and to assess treatment free and overall survivals. Methods. The study was conducted in a series of 86 WM patients [71 at diagnosis and 15 at relapse], of whom 10 patients with WM were homogeneously treated at front line in the multicentric phase 3 trial, chlorambucil versus fludarabine that included WM. All serum samples were collected prior to treatment and were kept frozen since collection. Responses included partial response (PR) or better, confirmed at 2 consecutive values. Hevylite measurements were made at The Binding Site Ltd, Birmingham, UK. A normal range was produced from normal (blood donor) sera (n=120), median (and 95%ile ranges) were; IgMkappa 0.634g/L (0.29–1.82), IgMlambda 0.42g/L (0.17–0.94), IgMkappa/IgMlambda ratio 1.6 (0.95–2.3). For ease of comparison we have studied the clonal IgM hevylite, expressed as IgMi HL and the IgM hevylite ratios expressed as the involved monoclonal immunoglobulin/uninvolved polyclonal immunoglobulin (IgM HLR). Results. The median age was 66.7 years, Male/Female ratio was 1.77, and 51.2 % patients had WM-ISS score 3. The median (min-max) M-spike level was 20.6 g/L (3.2–90), IgMneph was 19.4 (2.4–87), the median IgM HLR ratio was 100 (2.59–2850) and the median IgMi HL level was 21.9 (1.94–126) g/L. The IgMi HL values correlated well with the M-spike (intra class correlation (icc) coefficient = 0.48 [0.31; 0.60]) shown on the Bland-Altman plot left panel, and with the IgM neph (icc = 0.74 [0.52; 0.86]), right panel of the attached figure. The IgM HLR also correlated to the M-spike (r=0.44, p<10−5) and the IgMneph (r=0.52, p<10−5), but on a lesser extent. The high IgMi HL level did not correlate to hemoglobin level, platelet count, beta-2 microglobulin and age, as for the IgM HLR in our study. The median IgMi HL did not vary significantly across ISS subgroups. The response rate was 60% at 14 months and 40% were stable (including minor disease) on the 10 WM homogeneously treated. The response rates and stable diseases were 40% and 60% using IgMneph, and 50% and 50% using IgMi HL, respectively. The concordance between IgMi HL with M-spike was quite good (k=0.61, p=0.13). The median time to response was similar across the 3 IgM techniques, 10.4 months as per protocol as compared to 12.9 months with IgMneph, and 11.8 months using IgMi HL. With a median follow-up of 45.7 months [40.7; 53.9], 50% of patients had a progression in the protocol, with a median time to progression (TTP) of 25.2 months. The progression rate was 66% using IgMi HL and 50% using IgMneph. The median TTP was similar with IgMi HL and IgMneph, 23.1 months and 13.8 months (p=NS), respectively. Similar results were observed with the median time to next treatment, 4.43 months, 10.9 months and 10.9 months, respectively (p=NS). Overall, 10 patients died, the median Overall Survival (OS) was not reached, the 5 year survival was 83.7% [73.6; 95.1]. The M-spike level by SPEP, as for the IgMi HL and IgMneph, did not predict for OS. Conclusion. Hevylite is a new and reliable marker for monitoring response to therapy and to accurately monitor progression in WM, although still under investigation. The preliminary data we and other have obtained encourage to further monitor the impact of this marker in larger studies, especially clinical trials, in WM. Hevylite might become the reference technique to monitor the IgM M-spike protein in years to come. Disclosures: Pietrantuono: The Bindint Site: Employment. Combat:The Binding Site: Employment. Harding:The Binding Site: Employment. Leleu:LeoPharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Research Funding; Amgen: Honoraria; Novartis: Research Funding.

scholarly journals A Single Institution Respective Study of Tyrosine Kinase Inhibitor Cessation in Patients with Chronic Phase CML in MMR

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5168-5168 ◽  
Author(s):  
James K. McCloskey ◽  
Jamie L. Koprivnikar ◽  
Stuart L. Goldberg ◽  
Themba L Nyirenda ◽  
Genique Stanislaus ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Chronic Phase ◽  
Response To Therapy ◽  
Myelogenous Leukemia ◽  
Categorical Variables ◽  
Treatment Variable ◽  
Durable Response ◽  
Significant Difference

Abstract Background: Imatinib revolutionized the treatment of chronic myelogenous leukemia (CML) demonstrating improved survival and durable response to treatment. Earlier and deeper response rates were observed with dasatinib and nilotinib in the front line setting compared to imatinib. Multiple clinical trials have revealed that carefully selected patients may safely discontinue TKI therapy. However, lifelong TKI therapy remains the standard of care outside of clinical trial. Methods: We reviewed the charts of patients with chronic phase CML treated with imatinib, dasatinib or nilotinib for chronic phase CML between January 2010 and April 2015 and identified 29 patients that had discontinued therapy. We collected data on their treatment history, response to therapy, and outcomes following TKI withdrawal. Results: At the time of TKI cessation all the patients had achieved an MMR (MR4) for at least 2 years. The median time in MMR prior to treatment withdrawal was 64 months. Twelve patients (41%) were treated with imatinib, 7 (24%) were treated with dasatinib, and 10 (35%) were treated with nilotinib. More than half of the patients had received prior treatment with an alternative TKI. At the time of data collection, 16 patients (55%) remained in MMR off therapy. The median time off treatment was 7 months (range: 3-24 months). The median time to loss of MMR was 5 months (range: 2-11 months). No significant difference was observed between TKI and time to loss of MMR (Table 1). Of those patients who lost MRR while off therapy, all achieved a second MMR upon resuming TKI therapy. Based on the average wholesale price, $3,149,576 was saved by cessation of TKI therapy during the observed period. The required follow up and PCR testing accounted for an additional cost of $84,200 for a net savings of $3,065,376. Conclusions: TKI therapy can be safely discontinued in patients with an MMR duration more than two years with close follow up. While this is a small retrospective study, the results are in keeping with those observed in larger trials. With the life expectancy of patients with chronic phase CML now approaching that of the healthy population, lifelong use of TKI has important implications for patients in terms of medical costs and quality of life. Table 1. Comparison of Patient Characteristics and Outcomes Off Treatment Variable Imatinib (n=12) Dastanib (n=7) Nilotinib (n=10) P-Value Age (years) Median (IQR) 55.5 (53.0 - 61.5) 68.0 (50.0 -72.0) 63.5 (51.0 - 72.0) 0.3811 Range 42.0 - 75.0 48.0 - 72.0 42.0 - 76.0 Gender Male n= 6 (50.0) n= 4 (57.1) n= 2 (20.0) 0.2266 Female n= 6 (50.0) n= 3 (42.9) n= 8 (80.0) Time on treatment prior to discontinuation Median (IQR) 98.0 (64.0- 110.5) 49.0 (39.0 - 69.0) 37.5 (27.0 - 60.0) 0.0016 Range 52.0 - 155.0 33.0 - 115.0 6.0 - 92.0 Time in MMR prior to stopping TKI Median (IQR) 52.5 (39.0 - 96.0) 37.0 (30.0 - 92.0) 71.0 (56.0 - 91.0) 0.6707 Minimum - Maximum 8.0 - 126.0 17.0 - 109.0 19.0 - 108.0 Time off treatment Median (IQR) 7.5 (3.0 - 12.0) 5.0 (2.0 - 9.0) 10.0 (6.0 - 12.0) 0.1599 Range 2.0 - 24.0 2.0 - 11.0 2.0 - 16.0 MMR status off treatment Remain in MMR N= 5 (41.7) N= 4 (57.1) N= 4 (40.0) 0.7970 Loss of MMR N= 7 (58.3) N= 3 (42.9) N= 6 (60.0) Time measured in months. Unless specified otherwise, data are presented as counts (percentages). Categorical variables were examined using Pearson's Chi-square test or Fisher's exact test, as appropriate. Continuous variables were examined using Kruskal-Wallis test or Proc mixed for one-way models, as appropriate. Any P<0.05 was considered statistically significant. Disclosures McCloskey: Novartis: Consultancy; Pfizer: Consultancy. Koprivnikar:Alexion: Consultancy. Goldberg:Novartis: Research Funding, Speakers Bureau; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Pfizer: Research Funding; BMS: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau. Howlett:Teva: Speakers Bureau.

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

Blood ◽  
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.

scholarly journals The Role of Low Dose Whole Body CT in the Detection of Progression of Patients with Smoldering Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Maria Gavriatopoulou ◽  
Andriani Boultadaki ◽  
Vassilis Koutoulidis ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Charis Bourgioti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Research Funding ◽  
Low Dose ◽  
Whole Body ◽  
Bone Lesions ◽  
Time To Progression ◽  
Symptomatic Disease ◽  
Time Points

Introduction: Multiple myeloma (MM) is the second most common haematological malignancy and is characterized by bone marrow infiltration of monoclonal plasma cells and end-organ involvement. Smoldering MM (SMM) is an intermediate clinical entity between MGUS and MM, with a risk of progression to symptomatic disease at 10% per year. Bone disease is the most frequent related symptom of MM, with approximately 90% of patients developing bone lesions throughout their disease course. Therefore, imaging plays a crucial role in diagnosis and management of these patients. Conventional radiography was traditionally considered as the standard of care, however the limited sensitivity in detecting osteolytic bone lesions has led to more advanced imaging modalities. Imaging also is of high importance to discriminate MM from smoldering disease, since the presence of bone lesions establishes the diagnosis of active disease and requires treatment initiation. Computed tomography (CT) was found to be the most sensitive modality in detecting small osteolytic bone lesions less than 5 mm. Ionizing radiation exposure was one of the main limitations of this technique. Technological advances have made possible low dose assessment of the entire skeleton with effective radiation doses comparable to those of a whole-body plain radiographic skeletal survey. Furthermore, the low dose CT is widely available and has a very short scan time. Therefore, whole-body low dose CT (WBLDCT) has been incorporated in the latest diagnostic criteria of the IMWG. The purpose of this study was to evaluate the role of WBLDCT in the early identification of patients with asymptomatic MM who progress with bone disease only and who require immediate antimyeloma treatment. Patients and Methods: Our study was approved by the local IRB and all patients provided informed consent. All patients diagnosed with SMM based on the 2003 International Myeloma Working Group (IMWG) definition of SMM were serially assessed with WBLDCT from July 2013 until March 2020 as part of our institutional workup. The assessments were performed at baseline, 1-year post diagnosis and every 1 year thereafter. The patients enrolled in the study were those who had at least 2 consecutive CT assessments at the above described time points. All WBLDCT exams were performed with a 16-detector CT scanner. The CTs were evaluated by two experienced radiologists, blinded to the clinical and laboratory data. RESULTS We prospectively evaluated 100 patients with SMM (median age at diagnosis 61 years, range 40-86 years, 52 female /48 male) who underwent WBLDCT at the above described time points. Median number of WBLDCTs exams performed was 2.5 (range 2-5). Totally, 31 patients progressed (either with CRAB criteria and/or at least one myeloma defining event). During a median follow up of 57 months 31 patients have progressed (with either CRAB criteria and/or at least one myeloma defininf event). Importantly, 10 of 31 patients progressed only with bone lesions that were identified on the scheduled WBLDCT as per protocol. Median time to progression from asymptomatic to symptomatic disease for all patients has not been reached, while median time for those who actually progressed was 22 months (95% CI:15,6-28,4). For the subgroup of patients who progressed with bone lesions only the median time was also 22 months (95%CI:3,4-40,6). Median time to progression was not statistically different between the two progressor subgroups. All patients were initiated with antimyeloma treatment immediately post evolution to symptomatic disease. PFS for all 31 patients at first line treatment was 52 months (95%CI:34,5-69,5) and median PFS for bone progressors has not yet been reached. Among the patients who progressed 29 were alive at the time of the analysis. The 2 deaths that occurred were one related (progressive disease) and one unrelated to multiple myeloma (cardiovascular event). Neither had progressed with isolated bone involvement. Conclusion: In conclusion, our strategy allowed early detection of bone lesions in 10% of our patients and these patients were immediately initiated with antimyeloma treatment to avoid further myeloma-related complications. Consecutive low-dose WBLDCT studies can identify early myeloma evolution to symptomatic disease and optimize the disease monitoring along with our therapeutic strategy. Disclosures Gavriatopoulou: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. Terpos:Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Medison: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria; Takeda: Honoraria.

scholarly journals Belumosudil for Chronic Graft-Versus-Host Disease (cGVHD) after 2 or More Prior Lines of Therapy: The Rockstar Study (KD025-213)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-46
Author(s):  
Corey Cutler ◽  
Stephanie J. Lee ◽  
Sally Arai ◽  
Marcello Rotta ◽  
Behyar Zoghi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Response Rate ◽  
Phase 2 ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Meaningful Improvement ◽  
Fund Research

Introduction: Belumosudil (KD025) is a novel oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor specifically designed for the treatment of cGVHD, an immune-mediated inflammatory and fibrotic disorder. In a previous dose-finding study (KD025-208, N=54), two-thirds of patients, including those with fibrotic and inflammatory manifestations, achieved a partial or complete response with belumosudil. Herein, we report on the top-line results (6 months after the last patient in) from the pivotal phase 2 trial (ROCKstar [KD025-213], N=132). Methods: This phase 2, open-label, randomized, multicenter study evaluated belumosudil 200 mg QD (n=66) and BID (n=66) in patients with cGVHD who received 2 to 5 prior lines of therapy (LOT). Treatment continued until clinically significant progression of cGVHD. The primary end point was overall response rate (ORR), defined per the 2014 National Institutes of Health Consensus Criteria. Additional end points included duration of response (DOR), Lee Symptom Scale (LSS) score, failure-free survival (FFS), corticosteroid (CS) dose reductions and overall survival. The study was powered such that the lower bound of the 95% confidence interval (CI) excludes 30%, with appropriate multiplicity adjustment. Results: At enrollment, the median age was 56 years, the median time from cGVHD diagnosis to enrollment was 29 months, 67% of patients had severe cGVHD, 52% had ≥4 organs involved, 72% had received ≥3 prior LOT (including ibrutinib [n=46] or ruxolitinib [n=38]) and 73% were refractory to their last LOT. The baseline characteristics of both arms were well balanced. With a median follow-up of 8 months, the ORR (95% CI) with belumosudil 200 mg QD and BID was 73% (60%-83%) and 74% (62%-84%), respectively (Table 1). In patients who previously received ruxolitinib (29%), the ORR with belumosudil 200 mg QD and BID was 65% (41%-85%) and 72% (47%-90%), respectively. In patients who previously received ibrutinib (35%), the ORR with belumosudil 200 mg QD and BID was 73% (50%-89%) and 71% (49%-87%), respectively. High ORRs were seen in all patient subgroups, regardless of length of time from diagnosis to treatment, including those with severe cGVHD, involvement of ≥4 organs and a refractory response to prior LOT (Figure 1). The response rate was similar across all affected organs. The median time to response was 4 weeks. Of responders, 49% have maintained response for ≥20 weeks. The median DOR has not yet been reached. Clinically meaningful improvement (≥7-point reduction) in LSS score on consecutive assessments was observed in 39% and 33% of patients in the QD and BID groups, respectively. Both responders (43%) and nonresponders (17%) experienced a clinically meaningful improvement in LSS score. FFS was 77% (69%-84%) at 6 months. CS and calcineurin inhibitor discontinuations were seen in 18% and 13% of patients, respectively. Belumosudil was well tolerated, with &gt;95% relative dose intensity in 83% of patients. Drug discontinuation occurred in 10% of patients due to possible drug-related adverse events (AEs), 3% due to progression of underlying disease and 12% due to progression of cGVHD. AEs were consistent with those expected in patients with cGVHD receiving CS and other immunosuppressants (Table 2). Common AEs included fatigue (32%), diarrhea (29%), nausea (26%), cough (24%), dyspnea (24%), upper respiratory tract infection (23%), peripheral edema (21%) and headache (20%). At least 1 serious AE occurred in 34% of patients. Twenty-three percent of patients had at least 1 liver-related investigation; the most common was increased gamma-glutamyltransferase (11%), and only 1 patient showed an increase in bilirubin. Eight patients died during the study; 5 due to AEs (1 possibly related to belumosudil) and 3 during long-term follow-up (&gt;28 days after last dose). There were no reports of cytomegalovirus reactivation or infection. Conclusion: Treatment with belumosudil at both doses resulted in high ORRs across key subgroups, meeting the primary end point of this pivotal randomized trial in cGVHD. Responses were durable and clinically meaningful, irrespective of patient and cGVHD characteristics, and were seen in patients who previously received ruxolitinib and ibrutinib. Belumosudil was well tolerated, with limited and manageable AEs. Further studies will evaluate its use earlier in disease management. The 12-month data analysis will be presented at ASH 2020. Disclosures Cutler: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Syndax: Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Ramakrishnan:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cigna: Honoraria. Eiznhamer:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Schueller:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Yang:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Green:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Aggarwal:Kadmon Corporation, LLC: Consultancy; Angiocrine Bioscience, Inc: Current Employment, Other: stock options. Blazar:BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Fate Therapeutics Inc.: Research Funding; Magenta Therapeutics: Consultancy; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. Jagasia:Ocugen: Other; Mallinckrodt: Research Funding; Janssen: Research Funding.

scholarly journals A Phase II Study of the Combination of Lenalidomide and Rituximab in Patients with Treatment-NaïVe and Relapsed Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4389-4389 ◽  
Author(s):  
Paolo Strati ◽  
Philip A Thompson ◽  
Michael Keating ◽  
Christina Hinojosa ◽  
Diana Rodriguez ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Response Duration ◽  
Response Assessment ◽  
Response To Therapy ◽  
Median Response ◽  
Treatment Naïve

Abstract Introduction. The combination of Lenalidomide (Len) and rituximab has been investigated in patients (pts) with treatment-naive (TN) and relapsed (R) CLL with an overall response rate (ORR) ranging between 66% and 85%. Fludarabine refractoriness and a median daily Len dose < 5 mg were the only factors predictive of a worse response to therapy in these reports. We, therefore, conducted a phase II study to evaluate how clinical and biological prognostic factors correlate with response. Methods. Pts were eligible for this study if they had treatment indications per IWCLL 2008 criteria, WHO PS ≤2 and adequate hepatic and renal function. Len was started on day 9 of cycle 1 at 10 mg orally and administered daily indefinitely. Rituximab, 375 mg/m2, was administered every 28 days for 12 cycles. Response was assessed at month 3, 6 and every 6 months thereafter. Pts in this study returned to our center at time of response assessment and were allowed to receive R infusion at their oncologist's office. The primary end point of this study was ORR. Results. One-hundred-twenty pts (61 TN and 59 R) were enrolled between 1/2012 and 11/2014; 83 (69%) pts received their R infusion locally. Baseline pts characteristics are shown in the Table. The median number of cycles administered was 16 [1-54] in TN and 20 [1-59] in R pts. Fifty-five TN and 53 R pts were evaluable for response. Twelve pts discontinued therapy before the first response assessment [toxicity (8), loss to follow-up (3), and death (1)]. ORR was 73% in TN and 64% in R pts, CR/CRi rate was 35% in TN and 28% in R pts. MRD eradication was achieved in 16% of TN and 2% of R pts. Median time to response was 11 [8-14] and 6 [5-7] months in TN and R pts. Median response duration (RD) has not been reached for TN pts and was 37 (29-45) months for R pts; 28% of TN and 62% of R pts have progressed. Characteristics predictive of higher ORR were: B2M ≤ 4 mg/L in TN pts (85% vs 55%, p=0.03); age < 65 (p=0.05), Rai 0-II (p=0.03), B2M < 4 (p=0.009) and eGFR > 60 mL/min in R pts; on MVA, only B2M maintained its association (84% vs 46%; OR 5, 95% CI 1.1-10; p=0.03). FISH and IGHV status did not predict ORR. Characteristics associated with longer RD were age ≤ 65 years (p=0.009) and non-complex karyotype (p=0.05) in TN pts; on MVA, only age maintained its association (not reached vs 33 months; HR 5; 95% CI 1-25.6; p=0.05); < 2 prior treatments was the only factor associated with RD in R pts (48 vs 20 months, p=0.03). Treatment-associated G 3-4 toxicities occurred in 28% of TN and 30% of R pts. Most common toxicities were: infections (10% of TN and 22% of R pts), thromboembolic complications (6%, both groups), skin rash (6% in TN pts only), and tumor flare reaction 6% (TN pts only). Forty-three (70%) TN and 50 (85%) R pts have discontinued treatment, median time to failure (TTF) was 22 [16-28] and 34 [25-43] months, respectively. Reasons for interruption were: progression in 13 (30%) TN and 25 (50%) R pts, toxicity in 25 (57%) TN and 20 (40%) R pts, pt/physician choice in 3 (7%) TN and 4 (8%) R pts, and other cancers in 2 (5%) TN and 1(2%) R pt. Factors predictive of a longer median TTF were eGFR ≥ 60 mL/min in TN pts (23 months vs 7 months, p=0.05) and early Rai stage in R pts (41 vs 36 months, p=0.04). At a median follow-up of 34 [1-53+] months, 4 (7%) TN and 14 (24%) R pts died, with a 4-year OS of 90% and 70%, respectively. Factors associated with shorter median OS were advanced Rai stage in TN pts (75% vs 100%, p=0.02), and > 2 prior treatments in R pts (on MVA; 50% vs 90% 4-years OS; HR 5.2; 95% CI 1.3-21; p=0.02). When comparing pts treated at our center to those receiving R infusion in the community, no significant differences in ORR, G3-4 toxicity rate or OS were observed. Conclusions. In our experience, the combination of Len and R is able to induce responses in 73% of TN and in 64% of R pts. Pts age <65 years, with a history of <2 prior treatments and with B2M <4 were more likely to respond and to have a longer response duration. No differences were seen based on pts' FISH abnormalities and IGHV status. Similar results in terms of efficacy and toxicity were observed in pts treated at our center or managed in close cooperation with local providers. With the expanding number of active treatment options for pts with CLL, the identification of clinical and biological factors predictive of response is becoming increasingly important. Table Table. Figure Figure. Disclosures Thompson: Pharmacyclics: Consultancy, Honoraria. Jain:Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Infinity: Research Funding; Genentech: Research Funding; Servier: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Incyte: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger:Pharmacyclics: Research Funding. Wierda:Gilead: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Novartis: Research Funding; Genentech: Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

scholarly journals Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2352-2352
Author(s):  
Tomas Jose Gonzalez-Lopez ◽  
Fernando Fernandez-Fuertes ◽  
Maria Cristina Pascual Izquierdo ◽  
Isabel Caparros ◽  
Silvia Bernat ◽  
...  
Keyword(s):  
Platelet Count ◽  
Median Time ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Previous Treatment ◽  
Complete Response ◽  
Platelet Response ◽  
Platelet Counts

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

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