Complete Hematologic Response Rate Research Articles

Analysis of the efficacy and influencing factors of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia in the chronic phase and accelerated phase

目的分析二代酪氨酸激酶抑制剂（TKI）尼洛替尼和达沙替尼作为二三线药物治疗慢性髓性白血病（CML）慢性期（CP）和加速期（AP）患者的治疗反应和预后，以及相关影响因素。方法回顾性分析2008年1月至2018年11月北京大学人民医院收治的一二线TKI治疗失败并接受尼洛替尼或达沙替尼作为二三线治疗的CML-CP和AP患者资料。结果共收集183例尼洛替尼和达沙替尼作为二线治疗和43例尼洛替尼和达沙替尼作为三线治疗的CML-CP或AP患者。二线TKI治疗患者中，中位随访21（1~135）个月，完全血液学反应（CHR）率为80.4%，完全细胞遗传学反应（CCyR）率为56.3%，主要分子学反应（MMR）率为38.3%，3年疾病无进展生存（PFS）和总生存(OS)率分别为78.7%和93.1%。二线TKI治疗中，Sokal积分为高危、女性、一线TKI治疗期间获得最佳反应<CHR、诊断CML距转换二线TKI治疗时间≥18个月、二线TKI治疗前为AP/血液学耐药、二线TKI治疗前未检测出BCR-ABL特殊突变、二线治疗中发生≥3级血液学不良反应是获得细胞遗传学或分子学反应或PFS的不利影响因素。三线TKI治疗患者中，中位随访6（3~129）个月，CHR率为95.7%，CCyR率为29.3%，MMR率为18.6%，2年PFS和OS率分别为66.8%和93.8%。三线TKI治疗中，诊断距一线TKI治疗时间≥6个月、二线TKI治疗期间未获得细胞遗传学反应、诊断距三线TKI治疗时间≥60个月或转换治疗前疾病分期为AP患者获得治疗反应的比例显著降低或预后不良。结论尼洛替尼和达沙替尼作为二三线药物可以有效治疗TKI耐药的CML-CP和AP患者，前次TKI治疗期间获得的最佳反应、换药前疾病分期和本次TKI治疗中是否发生≥3级血液学不良反应等因素影响治疗结果。

Clinical efficacy and safety of imatinib treatment in children and adolescents with chronic myeloid leukemia

Chronic myeloid leukemia (CML) is relatively rare in childhood and few studies have reported the clinical use of imatinib (IM) in pediatric CML. In this study, we evaluated the efficacy and tolerability of IM in children and adolescents with CML.We investigated 21 patients under 18 years of age with newly diagnosed CML and treated with IM in Children's Hospital of Chongqing Medical University between May 2014 and February 2018. The disease was staged according to the European LeukemiaNet criteria and the IM dose was determined based on the disease stage. Cumulative responses and survival probabilities were estimated according to the Kaplan–Meier method.The estimated complete hematologic response rate of chronic phase-chronic myeloid leukemia (CML-CP) was 89.5% at 3 months. The complete cytogenetic response rates increased with time, reaching 47.4%, 73.7%, and 80.3% at 6, 12, and 24 months, respectively. The cumulative major molecular response rates were 42.1% and 76.3% at 12 and 24 months, respectively. With a median follow-up time of 33.8 months (range, 3.2–61.7 months), the estimated 2-year overall survival (OS) rate for CML was 95.2% (95% confidence interval [CI], 70.7%–99.3%). None of the CML-CP patients progressed to the accelerated phase or had a blast crisis. The 2-year OS and progression-free survival rates for the CML-CP cohort were both 100%, while the estimated 2-year event-free survival rate was 68% (95% CI, 42.1%–84.2%). None of the patients in this group had treatment-related deaths or IM discontinuation due to drug toxicities, and only 1 patient had a grade III–IV nonhematologic adverse event. Overall, anemia was the most common adverse effect and 42.9% of patients had a decrease in bone mineral density.IM was effective and the adverse effects were well-tolerated throughout the follow-up period in Chinese CML patients under 18 years of age.

The efficacy and safety of bortezomib-based chemotherapy for immunoglobulin light chain amyloidosis: A systematic review and meta-analysis

BackgroundThe role of bortezomib in the treatment of immunoglobulin light chain (AL) amyloidosis is not well defined. We performed this meta-analysis to evaluate the efficacy and safety of bortezomib-based regimens in patients with AL amyloidosis who are not eligible for or refuse autologous stem cell transplantation. MethodsA systematic search of Medline, Embase, and the Cochrane Library was conducted to identify related studies. ResultsTwenty-four studies with 1238 patients were included. The pooled overall response rate (ORR) and complete hematological response rate (CHR) were 0.72 (95% CI, 0.67–0.77) and 0.35 (95% CI, 0.30–0.40), respectively. Bortezomib significantly improved the outcome of ORR compared to other regimens (RR 1.28, 95% CI, 1.04–1.57, P = .02). Similar results were observed in CHR (RR 1.90, 95% CI, 1.45–2.50, P < .001) and cardiac response (RR 2.03, 95% CI, 1.31–3.13, P = .002), but not in overall survival (HR 0.82, 95% CI, 0.62–1.09, P = .17). In addition, once-weekly bortezomib was associated with improved overall survival compared with twice-weekly bortezomib (HR 0.52, 95% CI, 0.27–0.99, P = .05). Peripheral neuropathy was the most widely reported adverse event. Incorporation of bortezomib into the standard melphalan + dexamethasone setting showed a trend of increased serious adverse events, though this was not statistically significant (RR 1.29, 95% CI, 0.95–1.75, P = .10). ConclusionsCurrent evidence indicates that bortezomib-based regimens might be effective and safe therapies for patients with AL amyloidosis. There is a great need to conduct more well-designed randomized controlled trials to provide high-quality evidence.

PS1457 MAINTENANCE OF RESPONSE IN LONG‐TERM TREATMENT WITH ROPEGINTERFERON ALFA‐2B (BESREMI®) VS. HYDROXYUREA IN POLYCYTHEMIA VERA PATIENTS (PROUD/CONTINUATION‐PV PHASE III TRIALS)

Background:Ropeginterferon alfa‐2b (Besremi®; ropegIFN) is a novel mono‐pegylated IFNα with an improved application schedule of only every 2–4 weeks. It is the first IFNα with an EU marketing authorization in any of the MPNs and is indicated as first‐line monotherapy in high‐risk PV patients without symptomatic splenomegaly.Aims:Here, we present the first randomized long‐term head‐to‐head comparison between ropegIFN and Hydroxyurea (HU) regarding maintenance of response. As the time in hematologic response may be relevant for the risk for thrombosis, it was the aim of the present analysis to compare durations of hematologic response of ropegIFN with HU treated patients in this randomized study.Methods:254 PV patients (WHO2008 criteria) received ropegIFNor HU in the PROUD‐PV Study for 12 months. Thereafter, 89.6% (ropegIFN)and 68.5% (HU) treated patients continued treatment in the CONTINUATION‐PV Study. Complete hematological response (CHR) was assessed according to ELN criteria, and maintenance was defined as no change of response status from first time when response was achieved. The tight schedule of assessment visits in these trials ranging from every two weeks in the first year to every 3 months in the third year, allowed for an estimation of cumulative days in response: “days in response” were defined as percentage per overall days on study. Additional efficacy measures, molecular response/disease modification and safety/tolerability have been presented previously (Gisslinger et al., ASH 2018).Results:During 3 years of treatment, CHR was achieved and maintained continuously in 38.9% of patients in the ropegIFN but only 14.5% in the control treatment arm (p &lt; 0.05). In line with this finding, duration of CHR was significantly longer in the ropegIFN treatment arm, and the risk to lose response was significantly higher in the control treatment arm (p &lt; 0.0001). The first quartile of response duration in the ropegIFN alfa‐2b and control treatment arm was 15.3 months and 6 months, respectively. During the 3rdyear, when both treatment arms had achieved stable response levels, maintenance rates of CHR were 70.5% and 46.1%, respectively for ropegIFN treated vs. patients in the control arm (RR: 1.55 [95% CI: 1.19 to 2.02]; p &lt; 0.01).In the ropegIFN arm, days in response increased every year from 27.4% in the 1st, to 59.2% in the 2ndand to 75.1% in the 3rdyear. In contrast, patients in the control arm showed quicker onset of response resulting in 44.2% of the days in response during the 1st year, followed by a stabilization at 51.3% during the 2ndand by a slight decrease to 50.2% of the days in response during the 3rdyear of treatment.Summary/Conclusion:The long‐term results focusing on maintenance of CHR in PV patients, showed a clear benefit of ropegIFN (Besremi®) over control (i.e. HU) in (1) achieving significant higher maintenance rates of CHR over the course of treatment, (2) showing a significant lower risk of losing CHR, and (3) presenting significant higher numbers of days in response during each subsequent treatment year vs. a decrease in the control arm. As CHR can be considered as surrogate for risk of thrombosis, these data suggest that RopegIFN is not only the best candidate for disease modification but may in the long run also be an optimal treatment modality for managing risk of thrombosis.

High-Dose Melphalan and Stem Cell Transplantation in Patients on Dialysis Due to Immunoglobulin Light-Chain Amyloidosis and Monoclonal Immunoglobulin Deposition Disease

The kidney is the most common organ affected by immunoglobulin light-chain (AL) amyloidosis and monoclonal immunoglobulin deposition disease (MIDD), often leading to end-stage renal disease (ESRD). High-dose melphalan and stem cell transplantation (HDM/SCT) is effective for selected patients with AL amyloidosis, with high rates of complete hematologic response and potential for improved organ dysfunction. Data on tolerability and response to HDM/SCT in patients with ESRD due to AL amyloidosis and MIDD are limited. We analyzed data on toxicity, efficacy, and hematologic and renal response of HDM/SCT in 32 patients with AL amyloidosis and 4 patients with MIDD who were dialysis-dependent for ESRD treated at Boston Medical Center between 1994 and 2016. The most common grade 3/4 nonhematologic toxicities were infections (75%), metabolic abnormalities (56%), mucositis (42%), constitutional symptoms (39%), pulmonary complications (39%), and diarrhea (28%). Treatment related mortality (defined as death within 100 days of SCT) occurred in 8% (3 of 36). A complete hematologic response was achieved in 70% of evaluable patients (19 of 27) at 1 year after HDM/SCT. In the entire cohort, median overall survival (OS) after HDM/SCT was 5.8 years; median OS was 1 year for those who did not achieve a complete hematologic response and 8 years for those who did achieve a complete hematologic response. Twelve patients (33%) underwent kidney transplantation after successful treatment with HDM/SCT at a median of 2.4 years after SCT. HDM/SCT is safe and effective in inducing hematologic complete responses and prolonging survival in patients with ESRD from AL amyloidosis and MIDD. Achievement of a durable hematologic response can make these patients possible candidates for renal transplantation.

Comparative Study of Clinico-hematological Features, Molecular Spectrum and Response to Imatinib in Chronic Myelogenous Leukemia Patients: Pediatric and Adolescent Versus Adults.

Chronic myelogenous leukemia (CML) is a rare disease in children, accounting for approximately 3% of leukemias in children and adolescents, with an annual incidence of 1 case per million children in western countries. This study was conducted, at PGIMER, Chandigarh. Ninety eight patients, 48 in children and adolescents group, and 50 in adult group were included in the study. Their hematological profiles along with the bone marrow findings were analyzed. The diagnosis of CML was confirmed by cytogenetics and/or molecular analysis. The complete hematological response (CHR) was analyzed at 3months and cytogentic response (CgR) at 12months after starting imatinib therapy. Compared to adults, pediatric and adolescent patients were more symptomatic at presentation (93.5 vs. 75%). Among symptomatic patients, massive splenomegaly (>10cm), higher total leucocyte and platelet counts were seen more frequently in pediatric patients. The most common transcript in both groups was e14a2. The distribution of pediatric and adolescent cases in Sokal, Hasford and EUTOS score, showed only statistically significant difference for low risk Sokal group, which had more patients in pediatric group. Compared to adults, pediatric and adolescent patients had similar CHR rate (91.3 vs. 92%), but showed lesser major CgR rate (90.9 vs. 95.5%) however, this was not statistically significant.

Prognostic Value of Clonal Evolution at the Time of Diagnosis in Patients with Chronic Myeloid Leukemia Treated with Frontline Tyrosine Kinase Inhibitors

Introduction:Additional cytogenetic clonal evolution (CE) is a known risk factor for a poor prognosis in chronic myeloid leukemia (CML). However, its prognostic significance in the setting of new tyrosine kinase inhibitor (TKI) remains unclear. We sought to analyze the baseline characteristics and clinical outcome in chronic phase (CP) CML pts with or without CE treated on frontline TKI clinical trials in a single institution.Methods:Patients (pts) with Ph-positive CML in CP with or without CE at the time of diagnosis receiving initial therapy with imatinib 400 mg/d, imatinib 800 mg/d, dasatinib 100 mg/d, nilotinib 800 mg/d or ponatinib 30 or 45 mg/d in consecutive or parallel clinical trials at a single institution were analyzed. Overall survival (OS), transformation free survival (TFS), event free survival (EFS), failure free survival (FFS) were analyzed from the start of therapy by Kaplan-Meier method. Clonal evolution (CE) was defined by the presence of any cytogenetic abnormality other than a single Ph, variant Ph chromosome or loss of Y chromosome. Also we analyzed CML pts with CE with regard 'major route' abnormalities vs other. The major route abnormalities includes trisomy 8 (+8), trisomy 19 (+19), isochromosome 17q10 (i17q) and additional Ph chromosome.Results:A total of 603 pts were analyzed including 579 pts in CP without CE and 24 pts with CE. Pts in CP without CE received initial therapy with imatinib-400 (n=70), imatinib-800 (n=200), dasatinib (n=138), nilotinib (n=122), or ponatinib (n=49), and pts with CE received imatinib-400 (n=2), imatinib-800 (n=7), dasatinib (n=10), nilotinib (n=4), and ponatinib (n=1). Pts with CP were usually older, female and have a higher WBC (P < 0.001). There was a statistically significant higher Complete cytogenetic response (CCyR) at 6 mo in pts without CE (P = 0.012), however the cumulative and 3-month rates of complete hematologic response (CHR), and the cumulative rates of CCyR and MMR were not different (Table). Similarly, the rates of MR4.0 and MR4.5 were similar for the two groups. At 5 years, the presence of additional cytogenetic findings at diagnosis does not seem to affect the rate of transformation, failure-free, event-free and overall survival. Acknowledging the small sample size for subset analysis, response rates and survival outcomes were comparable in CP with CE irrespective of whether chromosomal abnormalities were ’major route’ or other (n=12 in each arm).Conclusion:Additional cytogenetic CE at the time of diagnosis among patients with CML in CP is associated with a similar favorable outcome as those without CE when treated with TKI. The type of additional CE (major route vs other) does not seem to impact outcome. Patients with CML-CP with CE at the time of diagnosis can thus be treated with TKI as all other pts with CP with no need for consideration for SCT unless there is clear evidence of failure. DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. DiNardo:Abbvie: Research Funding; Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding. Daver:Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Efficacy and safety of tyrosine kinase inhibitor in treating elderly patients with chronic myeloid leukemia during chronic phrase

Objective To evaluate the efficacy and safety of tyrosine kinase inhibitors (TKI) in treating the elderly patients with chronic myeloid leukemia (CML) during chronic phrase. Methods From January 2015 to January 2016, a total of 52 cases of chronic phrase CML patients who received TKI treatment, over 60-year-old and were treated at Department of Hematology, West China Hospital were included in this study. Thirty-three cases of them chose imatinib (IM) as the first-line treatment regimen and 2 cases of them chose nilotinib (NIL) as the first-line treatment regimen, while the other 17 cases were treated with interferon before IM. The therapeutic response, overall survival (OS), event-free survival (EFS), comorbidity and drug-related adverse reactions of all the patients were analyzed by retrospective method, in order to summarize the efficacy and safety of TKI in the treatment of CML in elderly patients. Results ① The rates of cumulative complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and major molecular response (MMR) were 100.0% (52/52), 82.7 % (43/52), 80.8 % (42/52) and 71.2 % (37/52), respectively. The rates of OS of 1-year, 5-year and 10-year were 100.0%, 95.1% and 75.3%, respectively, while the rates of EFS of 1-year, 5-year and 10-year were 92.3%, 73.3% and 51.4%, respectively. ② Twenty-five patients had comorbidities. The scores of Charlson comorbidity index (CCI) of these 52 patients were all less than 2 scores. There were no significant differences in the incidence of cumulative CCyR, MCyR, MMR, grade Ⅲ hematologic and non-hematologic adverse reactions between 32 patients with CCI score=0 and 20 patients with CCI score>0 (χ2=0.948, 0.525, 0.021, 0.288, 0.021; P>0.05). ③ In 50 patients who received treatment of IM, the incidence rates of Ⅲ-Ⅳ grade neutropenia, thrombocytopenia and anemia were 16.0 % (8/50), 28.0% (14/50) and 18.0% (9/50), respectively. While 14 patients occurred Ⅲ-Ⅳ grade non-hematologic adverse reactions, with the incidence rate of 28.0% (14/50). Due to intolerance of IM, 5 cases (10.0%, 5/50) of the patients received the second-line TKI treatment. Conclusions TKI is an effective and safe treatment for the elderly patients who have chronic phrase CML. Mild comorbidities have no influence on the therapy. Key words: Leukemia, myelogenous, chronic, BCR-ABL positive; Tyrosine kinase inhibitor; Aged; Drug-related side effects and adverse reactions; Comorbidity

Predictive and Prognostic Implications of Variant Philadelphia Translocations in CML: Experience From a Tertiary Oncology Center in Southern India.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by Philadelphia (Ph) chromosome with classical t(9;22)(q34;q11) seen in up to 90% of cases. However 5% to 10% of patients who present with variant Ph translocations (vPh) have been an area of research for their significance in predicting response to various therapies including tyrosine kinase inhibitors as well as prognosticating survival outcomes for many years involving varied patient populations, with conflicting results. We retrospectively analyzed our data from January 2002 to December 2014. Patients with vPh in chronic phase of CML (CML-CP) were analyzed with respect to their demographic parameters, response to imatinib therapy, and survival and their data were compared with data of patients with classical Ph translocation (cPh). Of 615 patients diagnosed with CML-CP, 72 patients (11.7%) showed vPh. Most common chromosomes involved in these translocations were 14 (13.9%), 11 (12.5%), 19 (9.7%), and 7 (8.3%). Rates of complete hematological response, complete cytogenetic response, and major molecular response were not statistically different between the groups. At 5 years, event-free survival, failure-free survival, progression-free survival, and overall survival were 60% versus 67.9%, 62.7% versus 69.7%, 84.7% versus 92.1%, and 87.5% versus 92.4%, respectively, in vPh and cPh. The differences in survival were statistically not significant. To our knowledge, this is the largest series of variant translocations in CML-CP, pertaining to the Indian population. Our data suggest that the presence of vPh in CML has no significant effect in predicting response to imatinib as well as in prognosticating survival.

Dasatinib treatment based on BCR- ABL mutation detection in imatinib- resistant patients with chronic myeloid leukemia

目的探讨在BCR-ABL突变检测指导下选用达沙替尼治疗伊马替尼耐药慢性髓性白血病（CML）患者的有效性。方法83例伊马替尼耐药和39例伊马替尼与尼洛替尼均耐药的CML患者，持续口服达沙替尼，其中慢性期（CP) 55例，加速期（AP) 21例，急变期（BP) 46例。达沙替尼治疗前，经BCR-ABL突变筛查，除外具有对达沙替尼高度耐药突变类型（T315I/A、F317L/V/C和V299L）的患者。定期监测血液学、细胞遗传学和分子学反应，评估疾病进展和生存情况。当发生达沙替尼治疗失败时检测BCR-ABL突变。结果CP患者中，完全血液学反应（CHR）率为92.7%，完全细胞遗传学反应（CCyR）率为53.7%，主要分子学反应（MMR）率为29.6%，MR4.5率为14.8%，4年疾病无进展生存（PFS）率和总生存（OS）率分别为84.4％和89.5%。AP患者中，血液学反应（HR）率和CCyR率分别为81.0％和35.0%，3年PFS率和OS率分别为56.1％和59.3%。BP患者中，HR率和CCyR率分别为63.0%和21.4%，1年PFS率和OS率分别为43.6％和61.8%。达沙替尼作为二线和三线酪氨酸激酶抑制剂时，治疗反应相似。当发生达沙替尼治疗失败时，75例患者中37例（48.7%）检出新突变，T315I最为多见（59.5%）。达沙替尼治疗前存在突变的患者与无突变患者相比，治疗反应、PFS和OS差异均无统计学意义，但当出现达沙替尼耐药时，发生新突变的可能性显著增高（65.7％对34.1%，P=0.006）。结论达沙替尼可以有效治疗伊马替尼耐药或伊马替尼与尼洛替尼均耐药的CML各期患者，CP和AP患者疗效持久。达沙替尼治疗前BCR-ABL突变筛查及治疗中突变监测非常重要。

Imatinib Mesylate Reduces Bone Marrow Fibrosis and Overwhelms the Adverse Prognostic Impact of Reticulin Formation in Patients with Chronic Myeloid Leukemia

Introduction: Imatinib mesylate (IM) is the first tyrosine kinase inhibitor (TKI) licensed for the treatment of chronic myeloid leukemia (CML). Severe bone marrow fibrosis (BMF) has been reported in excess of 40% of the patients with CML at diagnosis. Before TKIs became available, BMF which emerged at diagnosis and/or in the late periods of the disease was defined to be a poor prognostic factor, and it contributed significantly to morbidity and mortality from 10% to 30% in patients with CML. The relationship between BMF and both disease progression and prognosis has been the subject of re-evaluation after the introduction of IM therapy. In patients with CML, it has not been clearly demonstrated yet, whether IM improves the poor prognostic effect of fibrosis, and prevents the new BMF development or not.Aim: The purpose of this study was to evaluate the effects of IM therapy on BMF formation, and the prognostic significance of BMF in patients with CML.Material and Methods: One hundred and thirty-five CML patients were enrolled in the study. Patients' demographics, Sokal risk scores, molecular and cytogenetic responses and follow-up periods were noted from the patients' files retrospectively. All pre- and post-IM bone marrow biopsy samples, which were stained with hematoxylin and eosin, were re-evaluated for the current analysis. Grading of BMF was according to the European consensus decisions, graded as 0-III. The term "last bone marrow biopsy" (LBMB) is referred to a biopsy, which was performed at 18th months or later on during IM treatment.Results: The median age was 44 years (range, 18-92 years), and 78 patients (58%) were male. One hundred and twenty-eight patients (95%) were in chronic phase [CP], 4 patients (3%) were in accelerated phase [AP], and 3 patients (2%) were in blast crisis [BC] at the time of IM initiation. Out of 128 CML-CP patients, one hundred and twenty patients (93%) were in early CP, whereas 8 (7%) were in late CP. The percentage of low, intermediate, and high Sokal risk scores were 35%, 43%, and 22%, respectively. Before IM was initiated, thirty-one patients had received previous treatment modalities (hydroxyurea (HU) in twenty-one, and 10 patients had received interferon plus HU. he median duration of IM treatment was 45 months (range, 2-106 months). The rates of complete hematological response (CHR) at 3rd month, complete cytogenetic response (CCyR) at 12th month, and major molecular response (MMR) at 18th month were 92.4%, 71.6%, and 67.6%, respectively. BMF before the initiation of IM therapy was grade 0 in 52 patients (39%), grade I in 39 patients (29%), grade II in 28 patients (21%), and grade III in 16 patients (12%). There was a positive correlation between the Sokal risk scores and the grades of BMF at diagnosis (r:0.313, p <0.01), and as the Sokal risk scores increase, the grades of BMF also increase and the difference was significant (p =0.025). Also the spleen size significantly differ according to the grade of BMF, and the patients with a higher grade of BMF also had a larger spleen (p <0.001). The control bone marrow biopsies at the 12th month of IM were available in one hundred and four patients, and 70 (67%) of them have grade 0, 26 (25%) of them have grade I, 7 (7%) of them have grade II, and 1 (1%) of them has grade III BMF. After 12 months of IM treatment, the grades of BMF have significantly decreased when compared to the pre-treatment values (p =0.001), and BMF grades in LBMB has shown to be significantly decreased when compared to the pre-treatment values (p <0.001) (Table 1 and Figures 1&2). There was no significant difference regarding the grades of BMF, between the biopsy at 12th months and LBMB (p =0.703).The CCyR rates at 12th month did not differ according to the pre-imatinib BMF grades (p =0.127). There was no significant difference between patients with or without CCyR at 12 months of IM regarding grades of BMF (p =0.785). The MMR rates at 18 months did not differ according to pre-treatment grades of BMF (p =0.112). There was no significantly difference in overall survival rates between initial BMF mild (grade 0-I) and severe (grade II-III) groups (p =0.278).Conclusion: IM can reduce BMF after a long period of follow-up, independently from the molecular and cytogenetic responses. The BMF grades at diagnosis does not have a negative impact on the response to IM treatment. Therefore, the adverse prognostic impact of the marrow fibrosis among CML patients seems to disappear in the era of the TKIs. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia Accelerates Count Recovery and Increases Response Rates

Immunosuppressive treatment (IST) with horse antithymocyte globulin (hATG) and cyclosporine (CsA) for severe aplastic anemia (SAA) has a 60-65% rate of overall hematologic response (OR) and approximately 10% complete response (CR). These rates have remained stable over the last three decades despite efforts to improve upon this regimen (Scheinberg Blood 2012). Eltrombopag (EPAG), an oral thrombopoietin receptor agonist has activity in refractory SAA producing hematologic responses, the majority multilineage, in about 40% of patients when administered as a single agent (Olnes NEJM 2012; Desmond Blood 2014). We conducted an investigator-initiated, phase II, single-center trial to test the efficacy of adding EPAG to h-ATG/CsA (clinicaltrials.gov, NCT01623167), using a triple cohort design to optimize the regimen.Eighty-eight patients with treatment-naive SAA have been enrolled from July 2012 to October 2015. All received standard h-ATG and CsA. EPAG was administered at 150 mg daily to three consecutive cohorts: in the first (n=30) and second (n=31) cohorts, EPAG was introduced after hATG, from day 14 until 6 months (cohort 1) or 3 months (cohort 2), due to initial concern of hepatotoxicity. In the third cohort, EPAG was concurrent with hATG on day 1 and continued for 6 months (n=27). As analysis of our previous IST trials suggested that CR correlates with better survival and less evolution to MDS/AML, the primary endpoint in the current protocol was CR at 6 months.Baseline enrollment characteristics were similar across cohorts: median age was 31 years (range 3 – 82; 20% were <18 years old), 26% had very severe disease (ANC<200/uL), and 34% had PNH clones >1%. EPAG was well tolerated when combined with CsA and hATG; 2 patients discontinued EPAG for severe cutaneous reactions, and 6 patients withdrew before 6 months due to refractoriness (n=4) or evolution to MDS (n=2). OR and CR were higher at 3 months and 6 months for all cohorts compared to historic rates (Table): OR at 6 months was 80%, 87% and 92%, respectively for the three cohorts; CR at 6 months was 33%, 26%, and 54%, respectively. For all patients evaluable to date, OR at 3 and 6 months of 80% and 85% and CR rates of 28 and 34% were higher when compared to our historical rates (p<0.001 for both 3 and 6 months).Improvements in blood counts among partial responders were robust by 3 months in all cohorts: median ANC 1790/ul; hemoglobin 10 gm/dL; and platelets 60,500/ul. For patients with very severe neutropenia (ANC<200/ul) the median time to ANC >500/uL was 47 days for all cohorts (n=23), and 35 days for cohort 3 (n=7). Among responders, median time to transfusion-independence for platelets was 32 days and for red cells 42 days. Serial BM biopsies showed improved cellularity in 80% without increased fibrosis. Median increase from baseline in BM CD34+ cells, as measured by flow cytometry, was 17-fold and 4-fold at 3 months for cohorts 1 and 2 respectively (p<0.001). Pharmacokinetics at 3 months showed a trend toward higher drug bioavailability with older age and female sex. Previously established baseline predictors for response such as telomere length, reticulocyte count, lymphocyte count, paroxysmal nocturnal hemoglobinuria, were not predictive of outcome. Twelve patients underwent hematopoietic stem cell transplantation (HSCT) due to relapse (n=3), refractoriness (n=6) or evolution to MDS (n=3). Death occurred in 3 subjects.At median follow up 15 months (range 1 – 42 m), cytogenetic abnormalities have occurred in 7 patients: 4 monosomy or partial deletion of chromosome 7, 1 complex (t(3;3)(q21;q26), -7), 1 deletion 13q that later normalized, and 1 subject with trisomy 6 and trisomy 15 in 2 metaphases. We sequenced 54 candidate genes, recurrently mutated in MDS/AML: somatic mutations were not identified in 4 of 7 subjects prior to treatment or at the time of cytogenetic evolution. Clonal evolution to MDS occurred at a similar frequency compared to our historic experience with standard IST.Addition of EPAG to IST markedly increases overall and complete hematologic response rates in treatment-naive SAA. These results suggest that immediate institution of EPAG with IST may salvage and expand residual hematopoietic stem cells in aplastic anemia, accelerating the rate and quality of hematopoietic recovery. Rapid blood count improvement and reduced transfusion burden support early use of EPAG for patients with newly diagnosed severe aplastic anemia. [Display omitted] Disclosures:Townsley:Novartis: Research Funding ; GSK: Research Funding. Off Label Use: Eltrombopag (Promacta) is not FDA approved for treatment naive aplastic anemia. Dumitriu:Novartis: Research Funding ; GSK: Research Funding. Winkler:GSK: Research Funding ; Novartis: Research Funding. Larochelle:Novartis: Research Funding ; GSK: Research Funding. Dunbar:Novartis: Research Funding ; GSK: Research Funding. Young:Novartis: Research Funding ; GSK: Research Funding.

Clinical presentation and treatment responses in IgM-related AL amyloidosis

Amyloid light-chain (AL) amyloidosis is a multi-organ disease due to deposition of misfolded monoclonal immunoglobulin light chains. IgM AL amyloidosis is a rare variant, about 6% of AL amyloidosis cases, and more data are needed for treatment guidance. In IgM AL amyloidosis, the clonal cell of origin may be a plasma or lymphoplasmacytic cell, and treatments targeting each are employed. We describe presenting clinical and laboratory features of 95 patients with IgM AL amyloidosis treated at Boston University Amyloidosis Center from 1996 to 2012. The median diagnosis age was 66 years (range: 38–89) with 56% males. Organ involvement rates were: kidney (51%); heart (40%); lymph nodes (25%) and gastrointestinal tract (17%). Treatment responses were analyzed for 46 patients seen after 2003. Five treatment regimens were assigned by bone marrow pathology and patient-specific factors. Overall hematologic response rates and very good partial or complete hematologic response rates, respectively, were: high-dose melphalan/stem cell transplant (HDM/SCT) 100%;80%, Bortezomib 82%;27%, Rituximab 80%;27%, immunomodulatory agents (IMids) 75%;0%, and standard dose alkylating agents (Melphalan or cyclophosphamide) 63%;19%. Overall, 5-year survival rates were significantly higher in patients with a hematological response: 79.2 ± 8.5% versus 41 ± 14.9% in non-responders, which is more favorable than typically expected in AL amyloidosis.

Clinical Efficacy of Dasatinib, Nilotinib and Imatinib in Newly Diagnosed Patients with Chronic-Phase Chronic Myeloid Leukemia: A Three-year Retrospective Analysis

To evaluate efficacy and safety of second-generation tyrosine kinase inhibitors (TKI) dasatinib, nilotinib and imatinib in treatment of newly diagnosed patients with chronic-phase chronic myeloid leukemia (CML). The clinical data and follow-up results of 163 patients with chronic-phase chronic myeloid lenkemia(CP-CML) who were treated in our hospital during the nearly 3 years were analysed retrospectively, among 163 patients 47 received dasatinib, 43 received nilotinib and 73 received imatinib. The efficacy, disease progression and safety were evaluated. After treatment for 3 months, the rate of complete hematologic response(CHR) in three treatment groups were 77%, 79% and 67%, respectivily, CHR at 12 months in three treatment groups were 92%, 91% and 90%, respectively. By 3 months, the rates of complete cytogenetic response(CCyR) with dasatinib and nilotinib were higher than that with imatinib (55%, 53% vs 33%)(P<0.05 for both comparisons), CCyR at 12 months in three treatment groups were 86%, 88% vs 69% (P<0.05 for both comparisons). The rates of major molecular response(MMR) for dasatinib (11%) and nilotinib (9%) by 3 months were significantly higher than that for imatinib (1%) (P<0.05 for both comparisons), MMR at 12 months in three treatment groups were 49%, 50% and 28%, respectively (P<0.05 for both comparison). Progression to the accelerated or blast phase of CML occurred in 2 (4%) patients received dasatinib, 2 (5%) received nilotinib and 6 (8%) received imatinib. The safety profiles of these 3 second-generation TKI treatments were similar. Both dasatinib and nilotinib induced strikingly higher and faster rates of complete cytogenetic response and major molecular response, with a statistically significant difference from imatinib.

Long Term Efficacy and Tolerance of Pegylated Interferon Alpha Therapy for Patients with High Risk Essential Thrombocythemia: An Observational Study of the French Intergroup of Myeloproliferative Disorders (FIM)

Background: Therapeutic guidelines in essential thrombocytemia (ET) are based on established criteria, ie. age more than 60 years, history of thrombosis, platelets more than 1000-1500 ×109/L and to lesser degree cardio-vascular risk factors. Hydroxyurea and anagrelide are the most commonly used cytoreductive therapy for high risk ET. Despite a proven activity in Ph negative myeloproliferative disorders, generalized use and efficacy of Interferon-alpha (IFN-α) have been hampered by frequent side effects. Nonetheless it is a non leukemogenic therapeutic option for younger patients (pts) and during pregnancy. Two phase II trials using Pegylated (Peg) forms of IFN-α in pts with polycythemia vera (PV) or high risk ET have provided interesting results: i) an improved toxicity profile generally associated with a rapid hematolologic response, ii) a molecular response described in a subset of JAK2V617F positive PV or ET pts treated with PegIFN-α.Aim: To estimate the rationale of PegIFN-α therapy selection in high risk ET patients, efficacy and tolerance.Methods:Cases of high risk ET patients, who started PegIFN-α therapy between 2006 and 2011, were reported by centres of the French Intergroup of Myeloproliferative disorders and included in an observational study. We collected information regarding history of MPN, treatment, hematologic response at different timepoints, toxicities related to PegIFN-α, thrombo-hemorrhagic events and hematologic progression. The current analysis was performed on 103 consecutive pts.Results: Median follow-up from ET diagnosis was 9 years (3-27). 74% of pts were female, median age was 37 years (range 16-67). Previous vascular event was observed in 36% of cases and JAK2V617F mutation was detected in 52% of pts. .Median time from diagnosis to PegIFN-α was 40 months (1-255). PegIFN-α was administered after hydroxyurea and anagrelide in second or third line (56% and 27% respectively). No prior therapy has been used for 16% of pts. Reasons for starting PegIFN-α were lack of hematologic response (21%), toxicity to prior therapies (17%), pregnancy (15%), or medical decision for younger pts (47%). Pts received either PegIFNα-2a (n=91) or PegIFNα-2b (n=12), based on physician decision.According to the 2009 European LeukemiaNet criteria and with a median exposure to PegIFN-α of 29 months (1-92), 81% of pts achieved a complete hematologic response (CHR). Cumulative incidence of CHR were 58 % (95% CI: 49-68), 73% (95% CI: 65-81) and 80% (95% CI: 71-87) at 6, 12 and 24 months respectively.By analysing the response according to JAK2 status, cumulative incidence of CHR was better for the JAK2V617F positive subgroup (p=0.0183, overall). At 36 months estimated CHR rates were 89% (95% CI: 79-95) and 70% (95% CI: 57-82) for JAK2VF positive vs negative subgroup respectively. Median exposure to PegIFN-α was 29 months in both groups.At last follow-up, with a median of 42 months since PegIFN-α initiation, 53% of the pts were still treated with PegIFN-α. Among them, 76% have maintained a CHR. Reasons for discontinuation of PegIFN-α (47% of pts) were consecutive to PegIFN-α toxicity (59%), -mainly chronic moderate non hematologic toxicity-, or hematologic responses were considered insufficient in16%. In addition, PegIFN-α has been stopped in a subset of pts who achieved a durable stable CHR.In Conclusion, This study provides results of PegIFN-α therapy in a cohort of high risk ET pts not included in clinical trials. In this selected population of young pts, a durable efficacy of therapy was observed in half of patients. Characteristics of hematologic response according to molecular status will be presented. These results support the PegIFN-α as an alternative therapy to hydroxyurea and anagrelide in high risk ET, and warrant its investigation in further prospective randomized studies. DisclosuresRoy:Merck: Peg-Interferon provided for academic clinical trial in CML Other. Off Label Use: Peg-Interferon in essential thrombocythemia. Gyan:Roche: Research Funding. Nicolini:BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kiladjian:Roche: Peg-Interferon provided for academic clinical trial in PV Other.

IMATINIB IN CHRONIC MYELOID LEUKEMIA: AN OVERVIEW

Imatinib was the first signal transduction inhibitor (STI), used in a clinical setting. It prevents a BCR-ABL protein from exerting its role in the oncogenic pathway in chronic myeloid leukemia (CML). Imatinib directly inhibits the constitutive tyrosine kinase activity. Imatinib binds to BCR-ABL kinase domain by preventing the transfer of a phosphate group to tyrosine on the protein substrate and the subsequent activation of phosphorylated protein. As the result, the transmission of proliferative signals to the nucleus is blocked and leukemic cell apoptosis is induced. The FDA has approved imatinib as first-line treatment for newly diagnosed CML in December 2002 following an International Randomized Study (IRIS), initiated in June 2000, comparing imatinib at a single daily dose 400 mg to IFN alpha plus cytarabine in newly diagnosed patients with CML in CP. Results from this study show the outstanding effectiveness of imatinib and its superiority with respect to the rates of complete hematological response (CHR), major and complete cytogenetic response (MCyR, CCyR). Patients randomized to imatinib arm at 8 – year data cut off continue to have a durable hematologic and cytogenetic responses, low progression rates to AP or BC, and remarkable survival outcomes. An overall survival (OS) rate is 85% for patients receiving imatinib (93% when only CML-related deaths and those prior to stem cell transplantation are considered). The results have been confirmed in the last years by several groups. According these cumulative results the rates of CCyR achieved after one year of therapy with imatinib at standard dose ranged from 49% to 77%, and the proportion of patients who achieved major molecular response (MMR) after one year ranged between 18% and 58%. Discontinuation of imatinib has been also tried in patients in MMR, a molecular relapse occurs in about one third of patients, generally within 6 months from imatinib cessation.

Incidence, Clinical Characteristics, and Prognostic Significance Of Chromosome 3q Abnormalities In Patients With CML Blast Phase

Abnormalities involving the long arm of chromosome 3 (3q) have been associated with aberrant expression of the EVI1 oncoprotein and portend adverse prognosis in myeloid malignancies. Chromosome 3 abnormalities are relatively common in CML blast phase and may also be associated with treatment resistance and an unfavorable outcome. We sought to further characterize the frequency, clinical characteristics, and outcomes associated with 3q abnormalities in cases of CML in blastic phase (BP).We retrospectively reviewed cases of CML BP seen at our institution between 2000 and 2012 and analyzed their clinico-pathologic characteristics, response to therapy, and outcome. We then compared patients with BP and chromosome 3q abnormality (3q-POS) to patients with BP but without involvement of chromosome 3q (3q-NEG). A total of 320 patients with CML BP were analyzed. Among those, 38 pts (12%) had abnormalities of chromosome 3q. Abnormalities involving 3q were represented as follows: t(3;21) in 33%; inv(3), 24%; del 3q, 12%; t(3;4), 6%; t(3;7), 6%; t(3;8), 6%; t(3;6;7), 3%; t(3;11), 3%; t(2;3), 3%; and 3q+ in 3%. The characteristics of the two cohorts: 3q-POS vs. 3q-NEG are outlined in Table 1. The clinical characteristics were similar between the 2 cohorts. However, there were trends for older age and higher peripheral blast percentage in patients with 3q-POS. A similar percentage of pts received chemotherapy, stem cell transplant (SCT), and tyrosine kinase inhibitor (TKI, alone or combined with chemotherapy) among the 2 groups as their initial therapy for BP. Likewise, there was no significant difference in the percentage of pts eventually going for SCT. Patients with BP and 3q-POS had a significantly lower rate of complete hematologic response (CR, 22% vs. 45%), complete cytogenetic response (CCyR, 0% vs. 24%), and a higher rate of resistance (74% vs. 45%) to their first BP therapy compared to those with 3q-NEG. This translated into a trend towards lower median overall survival (OS) (7.5 vs. 9.9m, p=0.157) in pts with 3q-POS. Figure 1.Table 1Patient CharacteristicsChrom Abnl involving 3q (3q-POS)All other Blast Phase (3q-NEG)p-valueNumber of Patients (%)38 (12)282 (88)Median age (range)56 (29-79)52 (17-81)0.102Sex Male, N (%)23 (61)174 (62)0.849Median WBC (range)30.2 (0.5-347.0)25.7 (0.5-768.0)0.738Median Periph blast % (range)35 (0-95)30 (0-96)0.095Median BM blast % (range)38 (6-96)40 (0-99)0.457Median Platelets (range)146 (6-1009)80 (2-2750)0.248BCR-ABL transcript, N (%)b2a29 (47)60 (42)0.138b3a24 (21)55 (39)both4 (21)24 (17)other2 (11)3 (2)Median number of previous TKIs1 (0-4)1 (0-3)0.49Extramedullary disease (yes, N (%))7 (26)52 (25)0.92Therapy for BP, N (%)Chemo8 (32)56 (28)0.166SCT0 (0)2 (1)TKI13 (52)69 (34)TKI+Chemo4 (16)74 (37)Response to 1st BP Rx, N (%)CR5 (22)77 (45)0.029*Died1 (4)19 (11)Refractory17 (74)77 (45)Rate of CCyR after 1st BP Rx, N (%)0(0)42(24)0.008*Median OS in months7.59.90.157Pts going to transplant, N (%)6 (16)38 (13)0.697Median Months from Dx to BP (range)25.2 (0-173)35.8 (0-1240)0.378 [Display omitted] Chromosome 3q abnormalities are not uncommon in patients with CML BP and may occur with numerous translocation partners. The presence of 3q abnormalities is associated with resistance to therapy for BP and portends an unfavorable outcome. Understanding the role of EVI1 in the biology of these diseases will be important in developing more effective therapies to improve outcome. Disclosures:No relevant conflicts of interest to declare.

Treatment Response and Predictors of Response Among Patients with Chronic Myeloid Leukemia: A Retrospective Medical Record Review

AbstractAbstract 4450 Objective:To assess treatment responses and predictors of response among patients with chronic myeloid leukemia (CML) in Australia, Canada, and South Korea. Methods:Oncologists and hematologists abstracted data from medical records of patients diagnosed with CML between 1/1/2005 and 9/30/2010 via a web-based data collection tool. Patients included were at least 18 years old; had chronic phase, Philadelphia chromosome and/or BCR-ABL positive CML at the time of diagnosis; received imatinib as first-line therapy; and were not enrolled in a clinical trial between the date of CML diagnosis and the end of available chart data. A subset of patients received second- and/or third-line therapy with dasatinib or nilotinib. We assessed rates of complete hematological response (CHR), complete cytogenetic response (CCyR), and complete or major molecular response (MMR) at 3, 6, 12, and 18 months. Multivariable logistic regression models were fitted to assess predictors of response (CHR, CCyR, and MMR) to 1stline therapy with imatinib. The independent and control variables incorporated into the models were age, gender, employment status, Charlson comorbidity index (CCI) score, time to initiation of therapy, imatinib dose at treatment initiation, and presence of treatment-related side effects. Follow-up was truncated if the patient had a change in dose. Only those still in chronic phase at the time of imatinib initiation who had non-missing data on the variables of interest (n=387) were included in the regression analyses. Results:Ninety-three physicians (31 in Australia, 28 in Canada, and 34 in S. Korea) provided data on 609 patients (203 in Australia, 199 in Canada, and 207 in S. Korea). The average patient age was 57 years, and 59% of the patients were male. At 3 months after imatinib initiation, CHR was attained by 67%, 83%, and 86% of patients in Australia, S. Korea, and Canada respectively. Over 85% of all patients maintained CHR at 6, 12, and 18 months. Cytogenetics were not commonly evaluated at 3 and 6 months in the three countries studied. At month 12, 48% of patients achieved CCyR (42% in Australia and Canada, 60% in S. Korea), and a similar proportion of patients had CCyR at 18 months. Overall, MMR was achieved by 59% of patients at month 12, increasing to 70% at month 18. Multivariable regressions showed that receipt of previous treatment (odds ratio [OR]=1.88, 95% CI=1.08–3.25; reference [ref]: no previous treatment), and low Sokal score (OR=2.04, 95% CI=1.13–3.69; ref: intermediate) were associated with a greater likelihood of CHR at 3 months while initial dose > 400mg (OR=0.37 95% CI=0.13–1.03; ref: initial dose <= 400 mg), CCI score of 2 or higher (OR=0.23, 95% CI=0.11–0.51; ref: CCI score 0), and presence of treatment-related side effects (OR=0.41, 95% CI=0.18–0.95; ref: no side effects) predicted a lower likelihood of CHR at 3 months. High Sokal score (OR=0.39, 95% CI=0.18–0.87; ref: intermediate) was found to be associated with a lower likelihood of achieving CCyR at 12 months while the presence of treatment-related side effects (OR=1.86, 95% CI=1.04 – 3.33; ref: no side effects) was found to be associated with a higher probability of achieving CCyR at 12 months. Low Sokal score (OR=1.85, 95% CI=1.10–3.10; ref: intermediate) was the only significant prognostic indicator that was associated with a greater likelihood of MMR at 18 months while age >65 years was the only significant adverse prognostic indicator of MMR by 18 months (OR=0.42, 95% CI=0.20–0.86; ref: age 45–65). Conclusions:The favorable prognostic indicators of response among patients with chronic phase CML included previous treatment, low Sokal score, lower initial imatinib dose (< 400 mg), and no comorbidities. Better understanding of predictors of response may enable physicians to better tailor therapy to optimize patient outcomes. Disclosures:Whiteley:Pfizer Inc: Employment, Equity Ownership. Mitra:Pfizer Inc: Research Funding. Iyer:Pfizer Inc: Employment. Candrilli:Pfizer Inc: Research Funding. Kaye:Pfizer Inc: Research Funding.

Associations Between Baseline Mutation Status and Response to Treatment with Omacetaxine Mepesuccinate in Heavily Pretreated Patients with Chronic Myeloid Leukemia

AbstractAbstract 4433 BackgroundSubcutaneous omacetaxine mepesuccinate (“omacetaxine”) is an investigational, first-in-class cephalotaxine and is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells by blocking the initial step of protein translation at the level of the ribosome. Omacetaxine has shown clinical activity and adequate tolerability in two phase 2, open-label, international, multicenter studies in patients with chronic myeloid leukemia (CML). Patients with a history of the T315I mutation who failed prior imatinib were enrolled in the first study (CML202). Patients were enrolled in the second study (CML203) if they had resistance or intolerance to ≥2 tyrosine kinase inhibitors (TKIs). Point mutations occur frequently in CML patients who develop resistance to imatinib. This is a post hoc analysis of responses to omacetaxine in patients with any phase CML by mutational status. MethodsData from patients with CML in chronic phase (CP), accelerated phase (AP), or blast phase (BP) were included from the two phase 2 studies. Omacetaxine 1.25 mg/m2was administered subcutaneously twice daily for 14 consecutive days every 28 days for induction and the same dosage for 7 days every 28 days as maintenance. An exploratory analysis was conducted to elucidate associations between mutation status and complete hematologic response (CHR) or major cytogenetic response (MCyR) following omacetaxine treatment. ResultsAmong CP, AP, and BP patients, grade 3/4 hematologic toxicities were thrombocytopenia (in 89/105, 43/49, and 43/44 patients, respectively), neutropenia (86/106, 35/49, 36/44), leukopenia (76/106, 30/49, 29/44), and anemia (66/107, 39/49, 36/44). Common grade 3/4 nonhematologic adverse events included fatigue (5/108, 5/51, and 2/44 patients, respectively) and pneumonia (3/108, 4/51, and 2/44). Seventy-six deaths occurred during long-term follow-up (33, 24, 19); 8 were treatment-related (5, 2, 1), most commonly due to sepsis (n=3).The pooled baseline mutational analysis included 203 CML patients (108 CP, 51 AP, and 44 BP). Unknown mutations were noted in 24%, 25%, and 32% of CP, AP and BP patients, respectively. Mutations were identified in 52%, 51%, and 52% while no mutation status was recorded for 24%, 25%, and 16% of CP, AP, and BP patients, respectively. T315I was the most frequently identified mutation (Table), occurring in 36%, 24%, and 39% of patients, respectively. Multiple mutations, which include individual mutations listed separately, were detected in 12% CP, 14% AP, and 7% BP patients.Among patients with CP or AP CML, CHR rate was high in the presence of the T315I mutation. MCyR rates for CP patients were similar for patients with or without mutations but appeared to be relatively lower among patients with multiple mutations. Among AP patients, MCyR only occurred in those without mutations. ConclusionsPoint mutations, particularly T315I, were common in this heavily treated population of CML patients although T315I may be overrepresented due to CML202 inclusion criteria. Efficacy of omacetaxine, as measured by rates of CHR and MCyR, appeared to be largely independent of the presence or absence of point mutations. However, interpretation of these results is limited by small sample sizes in many of the groups.Support: Teva Pharmaceutical Industries Ltd.TableResponse Rates by Mutation and CML PhasePoint Mutations, n Responders/n with Mutation (%)CP (n=108)AP (n=51)BP (n=44)CHRMCyRCHRMCyRCHRMCyRNo mutation17/26 (65)5/26 (19)4/13 (31)2/13 (15)0/70/7Unknown status18/26 (69)6/26 (23)4/12 (33)0/122/14 (14)0/14Any mutation44/56 (79)13/56 (23)7/26 (27)0/261/23 (4)0/23T315I32/39 (82)10/39 (26)5/12 (42)0/120/170/17F317I/L3/5 (60)0/50/30/30/20/2G250E1/3 (33)0/32/5 (40)0/50/00/0V299L2/3 (67)1/3 (33)1/2 (50)0/20/00/0F359V/C4/6 (67)3/6 (50)0/00/00/10/1Multiple mutations (including those above)8/13 (62)2/13 (15)2/7 (29)0/70/30/3 Disclosures:Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Nicolini:BMS: Research Funding, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Teva: Speakers Bureau. Wetzler:BMS: Research Funding; Teva: Membership on an entity’s Board of Directors or advisory committees. Akard:Celgene: Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Eisai: Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Ariad: Research Funding; Teva: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Baccarani:Teva: Research Funding. Kantarjian:ChemGenex (Teva): Research Funding. Craig:Teva: Consultancy. Cortes:Chemgenex (Teva): Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Deciphera: Research Funding.

Long-Term Outcomes of Patients with Systemic Light Chain Amyloidosis (AL) Treated At Diagnosis with Risk-Adapted Stem Cell Transplant and Consolidation with Novel Agents.

AbstractAbstract 3150▪▪This icon denotes a clinically relevant abstract Background:AL is a plasma cell dyscrasia characterized by the pathologic production of monoclonal light chains which misfold, deposit in various organs, including the heart, and can cause early death. High dose melphalan with stem cell transplant (SCT) results in high hematologic response rates and is a standard treatment for eligible patients. Achieving a complete hematologic response (CR) to SCT results in extended event-free and overall survival (OS), up to 8 and 13 years respectively in one large series. (Blood 2011; 118:4346) We have studied the addition of novel agents as consolidation following risk-adapted SCT (RA-SCT) in order to improve hematologic response (HR) rates and therefore outcomes. (Br J Haem 2007;139:224; Amyloid 2010;17:80a) In this report we examine the long-term outcomes of patients who received initial therapy with RA-SCT followed by consolidation for hematologic response less than CR (HR < CR). Methods:We performed a retrospective study to assess the HR rates, incidence of hematologic progression and overall survival (OS) of AL patients enrolled at diagnosis on two consecutive phase II trials using RA-SCT with consolidation for HR < CR (NCT01527032 and NCT00458822). OS was calculated from date of transplant to date of death or last follow up. Median event free survival (EFS) and OS were estimated by the method of Kaplan Meier. Cumulative incidence function was used to estimate the incidence of progression and death. Results:Between 2002 and 2011, 83 patients were enrolled and underwent RA-SCT on these trials and, following RA-SCT, those with HR < CR received consolidation with thalidomide and dexamethasone (TD) in the first and bortezomib and dexamethasone (BD) in the second trial. Thirty-six patients had cardiac involvement (43%) and all patients had free light chain measurements employed to score hematologic response and progression using consensus criteria (Am J Hematol 2005;79:319; Blood 2010;116:1364a). The frequency of CR following SCT was 24% and increased to 48% with post-SCT consolidation. The CR rates increased at 1 year compared to 3 months post-SCT from 21% to 36% with TD and from 28% to 62% with BD. With a median follow up of 5.1 years, the EFS is 4.5 years (95% CI: 2.6 to not reached) and the OS of all patients has not been reached (Figure 1). Sixteen patients died prior to hematologic progression and 26 patients have progressed with a cumulative incidence of hematologic progression of 8%, 18%, and 29% at 1, 2 and 3 years, respectively (Figure 2). Thirty-one percent (8/26) of relapsed patients have not required second-line therapy while among those who have, 78% (14/18) have responded including 44% (8/18) with CR. The median OS following hematologic progression was 5 years (95% CI: 2.6–5.8). Conclusions:Half of the AL patients on initial therapy trials employing RA-SCT and consolidation for HR < CR achieved CR with 36% of pts on the TD and 62% on the BD consolidation trial in CR at 1 year post-SCT respectively. At 3 years post-SCT the cumulative incidence of relapse was 29% and a third of relapsed patients did not require therapy, likely due to the very sensitive serum free light chain assay that detects low level hematologic progression in the absence of organ progression. Almost 80% of patients requiring second-line therapy responded, over half with CR, and median OS after relapse was 5 years. These results indicate that initial therapy with RA-SCT and consolidation is an effective initial treatment strategy for patients with AL in the era of novel agents. With over 5 years of follow up the median OS has not been reached. [Display omitted] [Display omitted] Disclosures:Comenzo:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.