Lenalidomide As a Second-Line Therapy after Failure of Hypomethylating Agents in Patients with Myelodysplastic Syndrome

Abstract Background: There is no standard therapy after the failure of hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) without only providing supportive cares including transfusion or cytokine therapies when the patient is not eligible for allogeneic hematopoietic cell transplantation. Lenalidomide is the treatment of choice in case of MDS with 5q deletion. A study of lenalidomide for non-5q deletion MDS patients showed that transfusion independency rate was 26% which was relatively acceptable and suggested that lenalidomide could be used for non-5q deletion MDS patients. Method: We conducted the prospective phase II trial to evaluate the efficacy of lenalidomide for patients who failed to HMA (ClinicalTrials.gov Identifier: NCT01673308). Patients took lenalidomide 10mg daily for 3 weeks and rested for a week. New cycle began every 4 weeks. The primary objective was the objective response rate (ORR; CR+PR+marrow CR+HI). Unknown or not evaluable response were regarded as failure. The planed sample size was 29 (P0: 10%, P1: 30%, α-error:0.5, β-error:0.2) patients. The major inclusion criteria were adult MDS by WHO classification and they should be treatment failure after HMAs (azacitidine or decitabine) which were defined as either intolerant to HMAs or progressive disease after HMA. Results: Total 31 patients were included in this analysis. Among them, 1 patient didn't receive study drug at all. Male was 21 (67.7%) patients. Median age was 68 (range 40-82) years. Reasons for stopping HMA were no response in 10, progression in 14, adverse events in 3 and other causes in 4 patients. WHO classification was follows; RA in 4, RARS in 1, RCMD in 8, RAEB-1 in 4, RAEB-2 in 8, MDS with 5q deletion in 2 and not known in 4 patients. IPSS at study enrollment were low (n=4), INT-1 (n=12), INT-2 (n=9), high risk (n=3) and unknown (n=3) risk. Revised IPSS were very low (n=3), low (n=3), intermediate (n=5), poor (n=2), very poor (n=8) and unknown risk (n=3). Median cycles of lenalidomide was 3 (range 0-21). The responses after 4 cycles were CR in 5, PR in 2, SD in 5, failure in 12, unknown in 7 patients. The maximal responses were CR in 5, marrow CR in 1, PR in 4, HI-E in 1, SD in 5, failure in 14 patients. Best ORR was 11/31 (35.5%) patients, with 16/31 receiving clinical benefit (52%, inclusive of SD). The toxicity profile was tolerable except for hematological toxicities including neutropenia and thrombocytopenia. Among 2 patients with 5q deletion, 1 patient achieved CR but 1 patient failed. Median overall survival was 8.936 (95% CI 0.0-19.685) months which compares with a historical estimate in HMA failures of 4.3-5.6 months. Two patients received alloHCT after progression or failure to lenalidomide. Causes of death were infection (n=8) and bleeding (n=1). Patients who failed to benefit from lenalidomide showed significantly poorer survival when comparing with patients who achieved ORR or SD (median overall survival 2.990 vs. 17.774 months; p=0.010). Among 17 patients who had achieved ORR or SD, 6 patients didn't progress while 8 patients progressed and 3 patients were lost to follow up. Conclusion: Lenalidomide showed reasonable response and excellent overall survival after failure of HMA in adult MDS with tolerable toxicities. Therefore, lenalidomide can be a promising option after failure of HMA even in non-5q deletion MDS. Disclosures Kim: Alexion Pharmaceuticals: Research Funding; Celgene: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

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Survival and Time to Response with Frontline Hypomethylating Agents in AML

Blood ◽

10.1182/blood-2018-99-119463 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4035-4035

Author(s):

Jing Ai ◽

Danielle Boselli ◽

Lauren M. Bohannon ◽

Thomas G. Knight ◽

Brittany Ragon ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Rank Test ◽

Hypomethylating Agents ◽

Advisory Committees ◽

Curative Intent ◽

Npm1 Mutation ◽

Platelet Recovery

Abstract Background: The hypomethylating agents (HMAs) azacitidine and decitabine have been increasingly used in the frontline setting for elderly and/or unfit patients with acute myeloid leukemia (AML). While these therapies are oftentimes used in the palliative setting, HMAs have also been used with curative intent in some patients, as a bridge to allogeneic hematopoietic cell transplantation (HCT). It is well known that 4-6 cycles of HMA therapy can be necessary to achieve a response; however, it is still common in practice for treating physicians to stop HMAs earlier when a rapid response is not observed. Few studies have investigated time to response in the setting of frontline HMA treatment for AML. Methods: We retrospectively evaluated all patients who were initiated on frontline HMAs for AML at our institution from September 2013 to April 2018. HMAs were administered without dose reduction or treatment delays. Responses were evaluated and categorized as hematologic response (HR; defined by neutrophils > 1000/µL, platelets > 100k/µL, transfusion independence, and no peripheral blasts), complete remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), and no response. Patient, cytogenetic, and treatment characteristics were summarized and described. We evaluated patients exhibiting a response before receiving 4 cycles of HMA therapy ("early" responders) and compared these patients to those achieving a response after receiving at least 4 cycles of HMA ("late" responders). The Kaplan-Meier method estimated overall survival (OS). Odds of early response were estimated with logistic regression models. Results: During the study period, 137 patients received frontline HMAs. 122 (89.1%) patients received azacitidine, and 15 (10.9%) were treated with decitabine. Mean age at HMA start was 70.1 years (range 39.8-94.3). Most patients (62.8%) were male, and most (77.4%) were Caucasian. 21 (15.3%) patients were NCCN favorable-risk, 52 (38.0%) were intermediate-risk, and 64 (46.7%) were poor-risk. At first testing, 21.4% of the patients were positive for the FLT3/ITD mutation, 0.8% the FLT3/TKD mutation, and 21.4% the NPM1 mutation. Some patients received concomitant therapies along with the HMA; these included hydroxyurea, lenalidomide, and sorafenib. Median survival in the entire population was 11.6 (95% CI 8.3, 15.2) months. Overall response rate (ORR) was 60.6%. Among responders, 80.7% achieved HR as their first response; 19.3% were first noted to have marrow responses (1.2% CR, 4.8% CRp, and 13.3% CRi). Most patients did not undergo bone marrow evaluation to assess response. Among responding patients, 60.2% responded "early", whereas 39.8% responded "late". Median overall survival was 15.2 (9.3, 17.7) months in early responders, and 22.2 (11.7, 38.9) months in late responders. There was no difference in survival between the groups (p=0.108, log-rank test; Figure 1), although there was a trend toward improved survival in late responders. Nineteen patients underwent allogeneic HCT. Time to response was not associated with odds of receiving HCT (p=0.812). Conclusions: HMAs have a high ORR as frontline therapy in elderly and unfit AML patients. Among AML patients receiving frontline HMAs, later responders have equivalent survival to earlier responders. Physicians should consider exercising patience when treating AML patients with HMAs. These findings warrant validation in a larger, prospective study. Figure. Figure. Disclosures Avalos: Juno: Membership on an entity's Board of Directors or advisory committees. Grunwald:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Janssen: Research Funding; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medtronic: Equity Ownership.

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Selinexor, a First-in-Class XPO1 Inhibitor, Is Efficacious and Tolerable in Patients with Myelodysplastic Syndromes Refractory to Hypomethylating Agents

Blood ◽

10.1182/blood-2018-99-113840 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 233-233 ◽

Cited By ~ 3

Author(s):

Justin Taylor ◽

Morgan Coleman ◽

Kelsey Alvarez ◽

Janine Pichardo ◽

Filiz Sen ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Nuclear Export ◽

Research Funding ◽

Median Overall Survival ◽

Response Rate ◽

Response Duration ◽

Advisory Board ◽

Hypomethylating Agents ◽

Average Response

Abstract There is no standard therapy for patients with myelodysplastic syndromes (MDS) refractory to hypomethylating agents (HMA) and the median overall survival (OS) of HMA-refractory MDS patients with IPSS Intermediate-2/High-risk MDS is ~6 months. Here, we present data from a phase 2 clinical trial of selinexor, an oral, first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that inhibits XPO1, in patients with MDS refractory to HMAs. XPO1 is the major nuclear export protein responsible for shuttling many key cellular regulators out of the nucleus and is overexpressed in many cancers. Preclinical studies of selinexor have shown that inhibition of XPO1 causes nuclear retention of wildtype p53 and disruption of the NF-κB pathway, both relevant targets for MDS. Moreover, selinexor has shown promising responses in acute myeloid leukemia, multiple myeloma, and Non-Hodgkin lymphoma. We therefore set out to determine the safety and efficacy of selinexor in MDS, and to study potential molecular correlates of response to selinexor. Patients with MDS or MDS/MPN who were refractory to azacitidine or decitabine were included (defined as either progression after initial response or if no response after >6 cycles). The primary endpoint was overall response rate (ORR = CR + mCR + PR + HI) and secondary endpoints included safety, response duration, and OS. The starting dose was 35 mg/m2 PO twice-weekly in 28-day cycles. Bone marrow biopsies, bone marrow DNA and peripheral blood RNA were collected from serial samples and used for correlative analyses including next-generation targeted gene sequencing, RNA-seq, immunohistochemistry, and proteomics. A total of 25 patients were evaluable for safety and 19 were evaluable for response. Six patients were not evaluable for response based on unrelated death from concurrent illness (n=5) or withdrawal of consent (n=1) before completion of one cycle. The median age was 77 (range, 50-85) and the majority of pts were High- or Very High-risk by IPSS-R (72%) with >10% bone marrow blasts (70%). The ORR was 32% (all mCRs) with an average response duration of 6.8 months. An additional 42% of pts achieved stable disease (SD) for an average response duration of 6.4 months for all patients receiving clinical benefit (Figure A). The median overall survival was 9.7 months with a median follow-up of 2.1 years. Those with mCR or SD had greater survival than non-responders (Figure B). Grade 3 or 4 adverse events (AEs) in the first 3 pts (thrombocytopenia (n=3) and hyponatremia (n=1)) led to reduction of the dose to 60mg flat dose twice-weekly for 2 weeks followed by 1 week off, resulting in significantly improved tolerability. The most frequently occurring AE thereafter was grade 2 or 3 fatigue. All other AEs were manageable with routine supportive care. The presence of an SF3B1 hotspot mutation was significantly associated with response to selinexor (p=0.01; Figure C). No other single mutation had a significant association, although patients with mutated TP53 and those with >3 mutations were numerically higher in the non-responders but did not reach statistical significance. The mRNA levels of a number of transcripts from the NF-κB pathway and of Myc were decreased after treatment with selinexor in responders, albeit with some variability. The levels of XPO1 mRNA increased with treatment within 4 hours of the fist dose, indicative of XPO1 target engagement with selinexor (Figure D). Further analyses are underway to determine if splicing is differentially modulated in SF3B1 mutated patients. Immunohistochemistry and proteomics for protein alterations are also ongoing. These data indicate that selinexor is safe and tolerable in MDS when given at 60mg twice-weekly for 2 weeks with 1 week off with a 32% response rate. Responses appear to be enriched in patients with SF3B1 mutations and selinexor appears to affect pathways that may be activated downstream of mutant-SF3B1, such as NF-κB and Myc. Detailed correlative and pre-clinical analyses are ongoing and should provide further illumination of the biological relevance of these markers, which will be tested prospectively in future clinical trials. Further studies of selinexor combined with targeted agents that disrupt similar or complementary oncogenic pathways in MDS could further improve responses. Figure. Figure. Disclosures Rampal: Incyte: Honoraria, Research Funding; Stemline: Research Funding; Jazz: Consultancy, Honoraria; Constellation: Research Funding; Celgene: Honoraria. Park:Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Shire: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Stein:Agios: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy. Tallman:AbbVie: Research Funding; Cellerant: Research Funding; ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; BioSight: Other: Advisory board; AROG: Research Funding.

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Clinical Outcome of Hypomethylating Agents in Hypocellular MDS: Mayo Clinic Experience

Blood ◽

10.1182/blood.v126.23.5254.5254 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5254-5254

Author(s):

Sonia Cerquozzi ◽

Hassan B Alkhateeb ◽

Moritz Binder ◽

Darci Zblewski ◽

Shahrukh K Hashmi ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Median Time ◽

Cytogenetic Analysis ◽

Research Funding ◽

Median Overall Survival ◽

Progression Free Survival ◽

Hypomethylating Agents ◽

Free Survival ◽

Very High

Abstract Introduction: Hypocellular myelodysplastic syndrome (h-MDS) represents only a small portion of MDS, of which, the clinical significance and outcomes are not well understood. Both laboratory and clinical evidence suggests that h-MDS shares immune-mediated pathogenic mechanisms similar to acquired aplastic anemia. As a result, immunosuppressive therapy (IST) has been the mainstay treatment. Since h-MDS is poorly understood and reported response rates to IST vary, we retrospectively reviewed the outcome of our patients with hypocellular MDS and identified the effectiveness of alternative therapy using hypomethylating agents (HMA). Methods: AllMDS patients over a 13-year period (June 1997 to May 2010) were captured after an IRB approval was obtained. Patients' demographics, labs, bone marrow aspirates and biopsies as well as cytogenetic data were collected. We used the currently accepted age-adjusted criteria to define hypocellularity as ≤ 30% in patients <70 years old, and ≤20% in >70 years old. Only patients with available response data were included in the final analysis. Survival estimates were calculated using Kaplan-Meier curves. Results: We identified 65 (8%) h-MDS patients from a cohort of 827 adult MDS. Median age was 68 years (range, 20-90), with 69% males. The largest group of patients were RAEB-1 at 9 (14%) and RAEB-2 at 14 (22%) along with RCMD at 18 (28%) and 15 (23%) MDS-U, 2 (3%) MDS 5q, 4 (6%) RARS and 2 (3%) were considered atypical. Cytogenetic analysis was normal in 17 (26%) with 7 (11%) having trisomy 8, and 11 (16%) and 14 (22%) having abnormalities of chromosome 7 and 5, respectively. IPSS-R were very low, low, intermediate, high, and very high in 4%, 30%, 28%, 21% and 17%, respectively. Leukemic transformation (LT) occurred in 6 (9%). The 4 year overall survival and progression free survival was 35% and 34%, respectively. Median overall survival and progression free survival was 30.2 and 29.7 months, respectively. Nine out 65 h-MDS patients were treated with a HMA, azacitidine (4) or decitabine (5). The median age of patients was 71 years (range, 66-85) with 6 (66%) being males. The median cellularity of the diagnostic bone marrow was 15% with the majority of patients presenting with RAEB-1 (11%) and RAEB-2 (55%) classification and 2 (22%) cases of RCMD as well as 1 (11%) case of MDS with isolated 5q. Cytogenetic analysis was normal in 3 (33%). IPSS-R were low in 1 (11%), intermediate in 4 (44%), high in 1 (11%) and very high risk in 3 (33%). The median time to initiation of a HMA from diagnosis was 5 months with response assessed at a median of 4.2 months. Two patients had received prior therapy including lenalidomide (for MDS 5q) and one had 1 cycle of trial therapy. Two patients (22%) achieved a marrow complete remission at a median time of 2.95 months; with one case of relapse at 9.8 months using HMA. Three patients (33%) had LT at a median time of 7.9 months post initiation of HMA. Median overall survival of patients with LT was 20 days. A total of 4 (44%) patients remain alive with a leukemia free survival of 67% at 2 years. In comparing to h-MDS patients without HMA treatment versus HMA treated, median OS was 28.2 vs 50.9 months (p=0.41) and PFS was 28.1 vs 40.6 months (p=0.69), respectively. Conclusions: The results from our clinical experience confirm that hypocellular MDS is a rare variant and that it is distinct from normocellular/hypercellular MDS. Two thirds of h-MDS received HMA for the treatment of higher risk disease (RAEB1-2). HMA has some efficacy in h-MDS. Further studies are warranted to better understand the clinical significance and outcomes of hypocellular MDS. Disclosures Binder: American Society of Hematology: Research Funding. Al-Kali:Celgene: Research Funding.

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Final Phase I/II Results of Rigosertib (ON 01910.Na) Hematological Effects in Patients with Myelodysplastic Syndrome and Correlation with Overall Survival,

Blood ◽

10.1182/blood.v118.21.3822.3822 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3822-3822 ◽

Cited By ~ 2

Author(s):

Azra Raza ◽

Peter L. Greenberg ◽

Matthew J. Olnes ◽

Lewis R. Silverman ◽

Francois Wilhelm

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Myelodysplastic Syndrome ◽

Research Funding ◽

Who Classification ◽

Kinase Inhibitor ◽

Phase 1 ◽

Phase Iii ◽

Refractory Anemia ◽

Blast Response

Abstract Abstract 3822 Rigosertib is a multi-kinase inhibitor that selectively induces mitotic arrest leading to apoptosis in cancer cells and blasts, while being non-toxic to normal cells. We analyzed bone marrow (BM) response and overall survival (OS) in 60 patients (pts) with myelodysplastic syndrome (MDS), including 51 patients with refractory anemia and excess blasts (RAEB) and 9 patients with refractory cytopenia and multilineage dysplasia (RCMD) enrolled in 4 independent phase 1/2 clinical trials. These pts were treated with rigosertib administered as a continuous intravenous infusion (CIV) from 2 to 6 days weekly or every other week with BM response initially assessed per protocol by week 4 or 8 and every 8 weeks thereafter. Overall survival (OS) analyses were performed by the method of Kaplan-Meier. OS was related (p=0.04) to FAB/WHO classification (see Table 1) in all MDS pts. Eight pts had hematological improvements. OS was also related to IPSS scoring (p=0.02; Table 2) and to BM blastic response (Table 3; p=0.008) in the 51 RAEB-1,-2,-t pts and in a subset of 38 RAEB-1,-2,-t pts refractory or relapsing after treatment with hypomethylating agents (azacitidine/decitabine) (Table 4; p=0.001). A 49-week OS was found in 15 patients in this last group treated with 3-day rigosertib infusions (1800 mg/day) every other week. Rigosertib infusions were well tolerated without evidence of bone marrow myelotoxicity. These results and the predictive value of BM response to rigosertib for estimating OS survival have led to the initiation of a randomized Phase III survival trial of rigosertib 3-day CIV infusions vs best supportive care in RAEB -1, -2 and-t pts who failed or progressed after receiving hypomethylating agents.Table 1.Overall Survival by FAB/WHO Classification in 60 MDS ptsFAB/WHO ClassificationRCMDRAEB-1RAEB-2RAEB-tP valueN pts9172113Median OS (weeks)988235210.04Table 2.Overall Survival by IPSS Scoring in 51 RAEB-1, -2, -t ptsIPSS ScoringIntermediate-1Intermediate-2High RiskP valueN pts101427Median OS (weeks)Not Reached37280.02Table 3.Overall Survival by BM Blast Response in 51 RAEB-1, -2, -t ptsBM Blast Response≥ 50% Blast DecreaseStable BM ResponseProgressive DiseaseNot AssessedP valueN pts1620510Median OS (weeks)513715110.008Table 4.Overall Survival by BM Blast Response in 38 RAEB-1, -2, -t pts Refractory or Relapsing After Azacitidine/Decitabine TreatmentBM Blast Response≥ 50% Blast DecreaseStable BM ResponseProgressive DiseaseNot AssessedP valueN pts1312310Median OS (weeks)444915100.001 Disclosures: Raza: Onconova Therapeutics Inc: Research Funding. Greenberg:Onconova Therapeutics Inc: Research Funding. Olnes:Onconova Therapeutics Inc: Onconova Therapeutics Inc provided study drug. Silverman:Onconova Therapeutics Inc: Research Funding. Wilhelm:Onconova Therapeutics Inc: Employment, Equity Ownership.

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Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-134237 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-14

Author(s):

Alexander Coltoff ◽

Joseph G. Jurcic ◽

Peter Campbell ◽

Daniel J. Lee ◽

Mark L Heaney ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Median Overall Survival ◽

Residual Disease ◽

Institutional Research ◽

Negative Group ◽

Advisory Committees ◽

Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

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Up-Front Tandem High-Dose Chemotherapy Compared With Standard Chemotherapy With Doxorubicin and Paclitaxel in Metastatic Breast Cancer: Results of a Randomized Trial

Journal of Clinical Oncology ◽

10.1200/jco.2005.06.072 ◽

2005 ◽

Vol 23 (3) ◽

pp. 432-440 ◽

Cited By ~ 42

Author(s):

Peter Schmid ◽

Walter Schippinger ◽

Thorsten Nitsch ◽

Gerdt Huebner ◽

Volker Heilmann ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Metastatic Breast Cancer ◽

Combination Therapy ◽

Objective Response ◽

Metastatic Breast ◽

High Dose Chemotherapy ◽

Primary Objective ◽

High Dose ◽

Intent To Treat

Purpose The role of high-dose chemotherapy (HDCT) in metastatic breast cancer remains controversial. Trials with late intensification HDCT have failed to show an advantage in overall survival. This study was initiated to compare up-front tandem HDCT and standard combination therapy in patients with metastatic breast cancer. Patients and Methods Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. HDCT was repeated after 6 weeks. Patients were stratified by menopausal and hormone-receptor status. The primary objective was to compare complete response (CR) rates. Results A total of 93 patients were enrolled onto the trial. Intent-to-treat CR rates for patients randomized to HDCT and AT were 12.5% and 11.1%, respectively (P = .84). Objective response rates were 66.7% for patients in the high-dose group and 64.4% for patients in the AT arm (P = .82). In an intent-to-treat analysis, there were no significant differences between the two treatments in median time to progression (HDCT, 11.1 months; AT, 10.6 months; P = .67), duration of response (HDCT, 13.9 months; AT, 14.3 months; P = .98), and overall survival (HDCT, 26.9 months; AT, 23.4 months; P = .60). HDCT was associated with significantly more myelosuppression, infection, diarrhea, stomatitis, and nausea and vomiting, whereas patients treated with AT developed more neurotoxicity. Conclusion This trial failed to show a benefit for up-front tandem HDCT compared with standard combination therapy. HDCT was associated with more acute adverse effects.

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Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma: Preliminary Toxicity and Activity Data in Dogs

Cancers ◽

10.3390/cancers12051272 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1272 ◽

Cited By ~ 1

Author(s):

Laura Marconato ◽

Silvia Sabattini ◽

Giorgia Marisi ◽

Federica Rossi ◽

Vito Ferdinando Leone ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Safety Profile ◽

Median Overall Survival ◽

Response Rate ◽

Treatment Options ◽

Objective Response ◽

Metronomic Chemotherapy ◽

Time To Progression ◽

Activity Data

Unresectable nodular and diffuse hepatocellular carcinoma (HCC) have a poor prognosis with limited treatment options. Systemic traditional chemotherapy has been only rarely reported, with unsatisfactory results. The aim of this prospective, non-randomized, non-blinded, single center clinical trial was to investigate safety profile, objective response rate, time to progression and overall survival of sorafenib in comparison with metronomic chemotherapy (MC) consisting of thalidomide, piroxicam and cyclophosphamide in dogs with advanced, unresectable HCC. Between December 2011 and June 2017, 13 dogs were enrolled: seven received sorafenib, and six were treated with MC. Median time to progression was 363 days (95% CI, 191–535) in dogs treated with sorafenib versus 27 days (95% CI, 0–68) in dogs treated with MC (p = 0.044). Median overall survival was 361 days (95% CI, 0–909) in dogs receiving sorafenib, while 32 days (95% CI, 0–235) in those receiving MC (p = 0.079). Sorafenib seems to be a good candidate for the treatment of dogs with advanced HCC, due to a benefit in disease control and an acceptable safety profile, offering a good basis on which new randomized prospective clinical trials should be undertaken to compare the efficacy and drawback of sorafenib versus MC or traditional chemotherapy.

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Efficacy of Stereotactic Body Radiotherapy for Recurrent or Residual Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization

BioMed Research International ◽

10.1155/2018/5481909 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6

Author(s):

Erhua Yao ◽

Jinghong Chen ◽

Xiaofang Zhao ◽

Yinyan Zheng ◽

Xianheng Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Stereotactic Body Radiotherapy ◽

Palliative Treatment ◽

Median Overall Survival ◽

Transcatheter Arterial Chemoembolization ◽

Response Rate ◽

Objective Response ◽

Overall Survival Rate ◽

Arterial Chemoembolization

Aim. To evaluate the efficacy and toxicity of hypofractionated stereotactic body radiotherapy (SBRT) for patients with recurrent or residual hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). Methods. Between June 2008 and July 2015, thirty-three patients with HCC were treated by SBRT. There were 63 lesions in 33 patients. A total dose of 39–45 Gy/3–5 fractions was delivered to the 70–80% isodose line. Results. Objective response rate (CR + PR) was 84.8% at 6 months. The overall survival rate was 87.9%, 75.8%, 57.6%, and 45.5% at 6, 12, 18, and 24 months, respectively. Median overall survival was 19 months. At 3 months, AFP decreased by more than 75% in 51.5% of patients (17/33). Overall survival was significantly different (P<0.001) between the group of patients for whom AFP decreased more than 75% and the group for whom AFP decreased by less than 75%. The AFP-negative rate was 48.5% (16/33) after 6 months. Eight patients (24.2%) had grade 1-2 transient fatigue, and 11 patients (33.3%) had grade 1-2 gastrointestinal reactions within 1 month. Conclusion. SBRT is a promising noninvasive and palliative treatment with acceptable toxicity for recurrent or residual HCC after TACE.

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Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia In Patients up to Age 75: Comparison of Survival In Patients with An Available Donor Compared to Patients without a Donor

Blood ◽

10.1182/blood.v116.21.2381.2381 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2381-2381

Author(s):

Teresa Field ◽

Janelle Perkins ◽

Taiga Nishihori ◽

Joseph Pidala ◽

Hugo F. Fernandez ◽

...

Keyword(s):

Overall Survival ◽

Survival Analysis ◽

Myelodysplastic Syndrome ◽

Cell Transplantation ◽

Research Funding ◽

Chronic Myelomonocytic Leukemia ◽

No Donor ◽

Hematopoietic Stem ◽

Myelomonocytic Leukemia

Abstract Abstract 2381 Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment strategy for patients with Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML). Recent reduction of the transplant related toxicity has permitted the expansion of empiric age limitations for HCT up to 75 years. There has been limited comparative data on HCT focusing on donor availability in patients with MDS/CMML. Between January 2004 and September 2009, a total of 255 new patients (NP) with a diagnosis of MDS or CMML were evaluated for HCT at Moffitt Cancer Center. This report describes the outcomes of these patients with emphasis on donor availability. Donor Search Results: Of the 255 NP, 58 did not undergo a donor search. Reasons for not proceeding were as follows: Medicare declined coverage due to age >65 (18), waiting as have low risk disease (15), patient declined (6), patient seen as second opinion only (7) and patient was not eligible for HCT (12). These patients were not included in the survival analysis. Of the 197 patients who had a donor search initiated, a sibling (SIB) matched unrelated (MUD) or single HLA antigen/allele mismatch (mMUD) unrelated adult donor was found in 173 patients. A suitable adult donor was not identified in the remaining 24 patients. To mitigate bias due to factors giving a survival advantage to patients who were stable enough to survive the donor and proceed to HCT, the survival analysis included only those patients alive 90 days after the donor search was initiated. We have been able to identify donors within this time frame for 99% of the patients who ever found one, although time to transplant is longer. At the 90 days landmark, there were 164 patient in the Donor cohort, and 19 patients in the No Donor cohort. Donor Cohort: The median age was 56.6 yrs (18.5 – 73.5). Ninety-seven patients (59%) were older than 55 yrs and 26 (16%) were above 65 yrs. At the time of the transplant consult, IPSS risk was Low (10), Int-1 (44), Int-2 (48), High (25), AML (21), CMML (13), or not evaluable (NE) (3). Donors included SIB (60), MUD (75) and mMUD (29). Median follow-up of surviving patients is 27.7months (7.2 – 70.7). No Donor Cohort: Median age was 57.4 yrs (32.6 – 68.1) with 12 patients (63%) older than 55 yrs and 3 (16%) patients older than 65 years of age. IPSS at initiation of the donor search was Int-1 (5), Int-2 (6), High (5), AML (1) and CMML (2). Median follow-up is 9.2 months (1.4 – 61.5). Of the 19 patients with no donor, 3 patients received an umbilical cord blood HCT elsewhere and were analyzed by intent to treat. Outcomes: Patients with a donor had significantly improved overall survival from time of donor search vs. patients with no donor (P=0.007) with 2 year OS of 48% vs. 23%, respectively. Median survival for the donor group was 22.2 months [95% CI 14.7 – 35.7] vs. 10.1 months for those without a donor [95% CI 2.3 – 14.7]. Transplant: Of the 164 patients with a donor, 121 (74%) patients received the planned allogenic transplants. The 2-year overall survival (OS) after transplantation is similar for SIB (51%), MUD (39%) or mMUD (68%) transplant recipients (P=0.4), and also similar by age below or above 55 years (P=0.7). These data demonstrate that most patients with MDS or CMML can have a suitable donor identified and proceed to HCT. Overall survival is significantly improved for those patients who have a suitable sibling or unrelated donor. Disclosures: Lancet: Eisai: Consultancy; Celgene: Honoraria. Alsina: Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. List: Celgene: Research Funding.

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Frontline Therapy for Older Patients (pts) with Acute Myeloid Leukemia (AML): Clofarabine Plus Low-Dose Cytarabine Induction Followed by Prolonged Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine

Blood ◽

10.1182/blood.v116.21.336.336 ◽

2010 ◽

Vol 116 (21) ◽

pp. 336-336 ◽

Cited By ~ 5

Author(s):

Stefan Faderl ◽

Farhad Ravandi ◽

Guillermo Garcia-Manero ◽

Xuelin Huang ◽

Elias Jabbour ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Median Overall Survival ◽

Low Dose ◽

Response Rates ◽

Newly Diagnosed ◽

Secondary Aml ◽

Prolonged Consolidation ◽

Low Dose Cytarabine

Abstract Abstract 336 Standard therapy (e.g. “3+7”) of newly diagnosed older pts (≥ 60 yrs) with AML is characterized by low response rates, short response durations, and substantial toxicities. New approaches are therefore actively explored in clinical trials. Clofarabine is a second generation deoxyadenosine nucleoside analogue with activity in older pts with frontline AML and presence of unfavorable prognostic factors. In our experience, the combination of clofarabine with low-dose cytarabine achieved higher response rates at no increase of toxicity compared with clofarabine alone (Faderl S et al. Blood 2008). Based on the initial experience, we have designed a combination of lower-dose clofarabine plus low-dose cytarabine induction followed by a prolonged consolidation of these drugs alternating with decitabine to improve survival and maintain the high response rates from the earlier study. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during courses 1–2, 6–8, 12–14 alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3–5, 9–11, and 15–17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Fifty-nine pts have been accrued with a median age of 70 yrs (range 60–81), of whom 17 pts (29%) were ≥ 75 yrs. Eleven pts (19%) had a PS of 2. Seven pts (12%) had a WBC of > 20,000/mcl at diagnosis. Thirty pts (51%) had abnormal cytogenetics. Molecular profile: FLT3/ITD 5 pts (9%), FLT3/D835 2 (4), NPM1 6 (13), Ras 2 (4). Thirteen pts (22%) had prior MDS (4 pts prior azacitidine; 2 pts prior lenalidomide) and 17 pts (29%) had secondary AML (Hx of prior chemo and/or XRT). Of 57 pts evaluable for response, 35 (61%) achieved CR and 4 (7%) CRp for an ORR of 68%. Six pts (11%) required more than one course to response. The ORR for pts with diploid vs abnormal cytogenetics was 79% vs 57%; for pts with prior MDS 46% vs 82% for pts with neither MDS nor secondary AML. All 7 pts with a FLT3 mutation responded. With a median follow up of 11.6 months (1.1-20.2+), 16 pts relapsed. Responses (CR) are ongoing in 19 pts. Median CR duration is 14.1 mos (1.8-16.4). Six pts (10%) died on study. Only one pt suffered an early death ≤ 28 days from induction (C1D26). Deaths were due to myelosuppression-associated infectious complications. Median overall survival for all 59 pts was 18.1 mos (0.8-20.2+). Median overall survival for responding patients has not been reached. The median number of consolidation cycles received by pts in CR/CRp was 4 (0-14). Fifteen of these pts have so far received at least 6 consolidation cycles. Most toxicities were ≤ grade 2 and included rash (64%), nausea (61%), transaminase elevations (58%), bilirubinemia (51%), diarrhea (32%), mucositis, creatinine evelations, and headache (12% each). Among toxicities > grade 2, transaminase elevations (14%) and bilirubinemia (5%) were most frequent. One pt (65 yr old female) experienced renal failure and pulmonary edema shortly following start of the induction. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression in responders was rare. In summary, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in pts ≥ age 60 with previously untreated AML. Longer follow up and comparisons with conventional therapy will help establish whether or not this combination also has a survival advantage. Disclosures: Faderl: Genzyme: Honoraria, Research Funding; Eisai: Research Funding. Off Label Use: clofarabine and decitabine in AML. Kantarjian:Genzyme: Research Funding; Eisai: Research Funding.

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