Efficacy and Safety of Selinexor for Acute Myeloid Leukemia: A Systematic Review

Introduction: Selinexor, an exportin 1(XPO1) inhibitor has demonstrated anti-leukemia activity as a single agent, as well as in combination regimens for the treatment of acute myeloid leukemia (AML). This systematic review aims to explore the efficacy and safety of selinexor based regimens for the treatment of AML. Methods: A systematic literature search was conducted using PubMed, Embase, Cochrane library, ClinicalTrials.gov, ASCO, and ASH meeting websites. The initial databases yielded 698 articles (last updated search until July 20, 2020). After excluding review articles, duplicates, and non-relevant articles, we included data from eight clinical trials (Table 1 and Table 2). Results: Among a total of 286 patients, 259 were evaluated. Selinexor was given as monotherapy to 81 patients and as combination regimens to 178 patients. The total newly diagnosed (ND) AML patients were 48 and relapsed refractory (RR) AML patients were 238. Garzon et al. did a phase I dose-escalation trial (n=81) with selinexor as a single agent in ND-AML and RR-AML patients with a median of three prior lines of therapy. The overall response rate (ORR) was 14%. The median overall survival (OS) was 2.7 months and median progression-free survival (PFS) was 1.7 months. 15% of the patients discontinued the treatment temporarily due to adverse events (AEs). Bhatnagar et al. (n=25) studied selinexor with decitabine, in phase I clinical trial, in ND and RR-AML patients. The ORR was 40% with higher ORR in ND-AML (80%) compared to RR-AML (30%). At a median follow-up of 21.8 months, the median PFS was 5.9 months (95% CI: 2.4-8.7) and median OS was also 5.9 months (95% CI: 3.9-10.4). The PFS was longer for patients who responded to therapy (11.8 months) as compared to those who did not respond to therapy (4.4 months). In phase I/II trial by Daver et al. (n=14) with selinexor and sorafenib in RR-AML patients, the composite complete remission including CR, CR with incomplete blood count recovery (Cri), and CR with incomplete platelet recovery (CRp) was 35.7%. The event-free survival was 1.8 months (0.4-5.0) in FLT3-ITD Inhibitor failure cohort vs 2.1 months (0.7-2.1) in FLT3-ITD inhibitor naive cohort. A single-arm phase I study with selinexor, cytarabine, and daunorubicin was performed testing ND-AML patients by Sweet et al., (n=19). It showed an ORR of 53% and a median OS of 10.3 months (95% CI: 3.74-NR). The early death rate (death ≤ 60 days) was 4.8%. The phase I dose-escalation trial by Weng et al. (n=28) in ND and RR-AML patients with selinexor+cytarabine+mitoxantrone had a better response rate. The ORR was 64% with a higher ORR in ND-AML (87%) compared to RR-AML (38%). The phase I trial by Alexander et al. (n=18) with selinexor+ cytarabine+ fludarabine on RR-AML patients achieved an ORR of 60 % and CR of 33.3%. Fielder et al. (n=38) did a phase II clinical trial on RR-AML patients with selinexor+ cytarabine + idarubicin with 40 mg/m2 selinexor in one cohort (C1) and flat 60 mg dose of selinexor in the second cohort (C2). In C1 37% of patients and C2 40% of patients had previous stem cell transplantation (SCT). The ORR was almost the same in both cohorts, with 55 % in C1 vs 54.5% in C2. The phase I/II trial on RR-AML patients by Abboud et al. (n=40) with selinexor+ cladribine+cytarabine+filgrastim had a total of CR and CRi in 45% of patients with a median overall survival of 7.8 months (95%CI: 5.7-14.1) and median event-free survival of 6.1 months (95% CI: 4.5 - 7.8 months). The main hematological adverse events were pancytopenia and non-hematological adverse events were hypophosphatemia, hyponatremia, gastrointestinal disturbances, and fatigue (Table 2). Conclusion: Selinexor in combination regimens showed superior response rates compared to selinexor alone for the treatment of AML patients. The response rates were better in selinexor based three and four-drug regimens. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

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Efficacy and Safety of Gemtuzumab-Based Regimens in Patients with CD33-Positive Refractory Leukemia.

Blood ◽

10.1182/blood.v110.11.4358.4358 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4358-4358

Author(s):

Suijing Wu ◽

Xin Du ◽

Wei Lin ◽

Jianyu Weng ◽

Jianjun Zhang ◽

...

Keyword(s):

Stem Cells ◽

Overall Survival ◽

Survival Time ◽

Myeloid Leukemia ◽

Median Overall Survival ◽

Response Rate ◽

Single Agent ◽

Efficacy And Safety ◽

Blast Phase ◽

Median Overall Survival Time

Abstract Patients with relapsed or refractory leukemia have less chances of obtaining remission than patients with newly diagnosed.It is reported that more than 80% of acute myeloid leukemia(AML) patients have myeloid blast cells that express the CD33 surface antigen. This antigen also is present on the leukemic stem cells at least some patients with chronic myeloid leukemia(CML)and acute lymphoblastic leukemia(ALL). It is absent from normal hematopoietic stem cells and nonhematopoietic cells and tissues. Gemtuzumab is a humanized anti-CD33 antibody conjugated to calicheamicin, a potent anti tumor antibiotic derived from a bacterium. It is conditionally approved in the US for treatment of CD33+ AML in first relapse in patients over 60 years[Sievers et al.Journal of Clinical Oncology,2001]. Here we evaluate the efficacy and safety of Gemtuzumab -based regimens. The study population comprise 11 patients with CD33-positive refractory leukemia (determined as CD33-antigen expression in over 50% of leukemic blasts by bone marrow aspirates and immunophenotyping), including two with myeloid blast phase of CML, one with refractory ALL, two relapsed after Auto-stem cell transplantation(Auto-SCT). The median age was 47 years. Four cases who were over 60 years or after Auto-SCT treated with single agent. The other seven cases treated with mylotarg and cytotoxic agents, including mylotarg plus idarubine (MI); Gemtuzumab plus fludarabine, cytarabine, CsA(MFAC); or plus mitoxantrone, Ara-C (MMA).The overall response rate was 54% (6/11), with 36%(4/11) patients obtaining complete remission (CR) and 18% (2/11) achieving CRp.The median overall survival time after treatment was 4.8 months, and the median overall survival time after CR was 8.2 months.Two patients with myeloid blast phase of CML achieved CR with BCR/ABL(−), the survival time after CR was 5+months and 20+months respectively, but failed in second relapse. One patient received Allo-SCT after CR with refractory ALL is still alive at present (21months) with disease free. The median time to ANC recovery of 0.5×109/L was 15 days.The common adverse events was myelosuppression (100% Grade 4 neutropenia and thrombocytopenia).Significant non-hematologic toxicitics included infection(96%), infusion-related chills and fever (55%).Although hepatic dysfunction and mucositis were observed,they were generally infrequent and not severe(Grade 1–2).Six patients (55%) developed Hepatic veno-occlusive disease(VOD), four of them were either over 60 years old or received Auto-SCT before although they received only single agent mylotarg therapy, but it was transient and no one died from it. In conclusion, patients with CD33-positive refractory leukemia, Gemtuzumab -based regimens have a comparable response rate and offer a more favorable toxicity profile, expecially for the patients with myeloid blast phase of CML. It is also effective for the patient with refractory ALL. In the treatment, we should pay attention to the hepatic condition of ones who are over 60 years old or after stem cell transplantation, attemps to avoid and treat VOD are warranted. Above all, When patients with refractory leukemia got remission, allogenic-SCT should be done as soon as possible

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Results of a Prospective Randomised Open Label Phase III Study Comparing Rituximab Plus Mitoxantrone, Chlorambucile, Prednisolone Chemotherapy (R-MCP) Versus MCP Alone in Untreated Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) and Mantle-Cell-Lymphoma (MCL).

Blood ◽

10.1182/blood.v104.11.584.584 ◽

2004 ◽

Vol 104 (11) ◽

pp. 584-584 ◽

Cited By ~ 45

Author(s):

Michael Herold ◽

Rita Pasold ◽

Stefanie Srock ◽

Sabine Neser ◽

Dietger Niederwieser ◽

...

Keyword(s):

Follicular Lymphoma ◽

Response Rate ◽

Single Agent ◽

Complete Response ◽

Phase Iii ◽

Published Data ◽

Event Free Survival ◽

Serious Adverse Events ◽

Free Survival ◽

Phase Ii Studies

Abstract Rituximab proved to be effective in relapsed and refractory indolent NHL as a single agent and generated impressive results in phase II studies in combination with chemotherapy. In a prospective randomized trial we compared the efficacy and toxicity of rituximab (375 mg/m² d 1) plus MCP-chemotherapy ( mitoxantrone 8 mg/m² d 3 + 4, chlorambucile 3 x 3 mg/m² d 3 – 7, prednisolone 25 mg/m² d 3 – 7 ) given every 28 days for a total of 8 cycles versus MCP (d 1 – 5) x 8 cycles alone in advanced indolent NHL and MCL. Efficacy endpoints included overall and complete response rates, event free survival, progression free survival, overall survival and toxicity. For response assessment classical definitions have been used. Between 10/98 and 09/03 we randomized 358 patients (pts) with advanced stage follicular lymphoma (FL) (grade 1 + 2), lymphoplasmacytic lymphoma and MCL to either R-MCP or MCP. The study arms are well balanced for all demographic factors. 201/358 pts (56%) had FL. Both regimens were well tolerated with a low incidence of serious adverse events. The overall response rate (RR) and the complete response rate (CR) for all pts was 85,5% and 42% in the R-MCP arm versus 65,5% and 20% in the MCP arm (p<0,0001). Results were even more impressive in the subgroup of FL pts (n=201) with an overall RR of 92,4% and a CR rate of 49,5% for R-MCP versus 75% and 25% for MCP alone respectively (p<0,0001). In the overall group event free survival (EFS) was significantly prolonged for pts receiving R-MCP vs MCP alone (p<0,001). Median EFS for MCP was 19 months, at this time point EFS for R-MCP was 73%. In FL pts the median EFS for MCP is 19 months too and EFS was 86% for R-MCP at this point. 2-year EFS for all pts was 69% for R-MCP versus 44% for MCP; for FL pts the respective 2-year EFS was 83% for R-MCP and 43% for MCP (p’s<0,0001) (Kaplan Maier estimates). These results compare favourably with the recntly published data of immunochemotherapy for treatment of NHL or MCL. The results from our study confirm the superiority of a combination of rituximab and chemotherapy in the first- line treatment of indolent NHL, primarily follicular lymphoma. The CR rates achieved with the R-MCP regimen are impressive, especially since stricter response criteria were used. In summary we conclude, that the addition of rituximab to MCP chemotherapy improves significantly the outcome of pts with indiolent NHL and MCL.

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Apatinib, a novel VEGFR-2 tyrosine kinase inhibitor, for relapsed and refractory nasopharyngeal carcinoma: data from an open-label, single-arm, exploratory study

Investigational New Drugs ◽

10.1007/s10637-020-00925-2 ◽

2020 ◽

Vol 38 (6) ◽

pp. 1847-1853

Author(s):

Ling Li ◽

Fei Kong ◽

Lei Zhang ◽

Xin Li ◽

Xiaorui Fu ◽

...

Keyword(s):

Overall Survival ◽

Nasopharyngeal Carcinoma ◽

Adverse Events ◽

Overall Response Rate ◽

Response Rate ◽

Kinase Inhibitor ◽

Progression Free Survival ◽

Efficacy And Safety ◽

Open Label ◽

Free Survival

Summary Purpose Apatinib, a new tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has shown promising efficacy against several solid cancers, but evidence of its efficacy against relapsed and refractory nasopharyngeal carcinoma is limited. We investigated the efficacy and safety of apatinib for relapsed and refractory nasopharyngeal carcinoma in an open-label, single-arm, phase II clinical trial. Fifty-one patients with relapsed and refractory nasopharyngeal carcinoma in the First Affiliated Hospital, Zhengzhou University, who met the inclusion criteria were enrolled in the study. All patients received apatinib at an initial dose of 500 mg daily (1 cycle = 28 days). The primary and secondary endpoints were overall response rate, progression-free survival, and overall survival. We evaluated treatment effects and recorded apatinib-related adverse events by performing regular follow-ups and workup. The overall response rate (complete and partial responses) was 31.37% (16/51). The median overall survival and progression-free survival were 16 (95% CI, 9.32–22.68) and 9 months (95% CI, 5.24–12.76), respectively. Most patients tolerated treatment-related adverse events of grades 1 and 2; hypertension (29, 56.86%), proteinuria (25, 49.02%), and hand–foot syndrome (27, 52.94%) were the most common adverse events. There were no treatment-related deaths. Apatinib showed good efficacy and safety in patients with relapsed and refractory NPC.

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A Phase I Study of Lenalidomide and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.2318.2318 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2318-2318

Author(s):

Elizabeth A. Griffiths ◽

William Brady ◽

Wei Tan ◽

Carlos E Vigil ◽

James E. Thompson ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase I Study ◽

Response Rate ◽

Single Agent ◽

Grade 3 ◽

Acute Myeloid ◽

Intermediate Dose

Abstract Background: Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Although cytarabine arabinoside (AraC) is the most active drug, constituting the backbone of a majority of r/r regimens, the benchmark response to therapy remains a dismal 17 to 20% (Burnett, Wetzler et al. JCO, 2011.). The immunomodulatory drug lenalidomide (Len), is approved by the Food and Drug Administration for multiple myeloma and myelodysplasia and has demonstrated activity as a single agent in AML at doses as high as 50 mg for 21 days (d) of a 28 d cycle (Blum et al, JCO, 2010.). Based upon this activity profile we developed a phase I study to evaluate the safety and tolerability of Len in combination with AraC in patients with r/r AML. Methods: Eligible patients were older than 18 years(y), had r/r AML with an Eastern Cooperative Oncology Group performance status better than 2 and adequate renal and hepatic function. Patients were excluded for active CNS disease, uncontrolled infections, congestive heart failure, adrenal insufficiency, anti-cancer therapy within 14 d of enrollment, or prior exposure to Len. All enrolled patients had to practice appropriate contraception. Patients received AraC 1.5 g/m2/d over 3 hours on d 1-5 of a 28 day cycle, with a plan for standard 3+3 Len dose escalation. Initial patients received Len 25 mg on d 6-10 (n= 3), subsequent patients received doses between 25 and 10 mg (dose de-escalation) on d 6-26 with 2 d of rest prior to the next cycle. Following induction, patients who had residual AML (>5%) could receive a second identical course of therapy, provided they demonstrated an improvement in blast percentage relative to baseline. Patients who achieved CR received maintenance with Len 10 mg/d continuously. A 12 patient expanded cohort was enrolled at the maximum tolerated dose (MTD) to assess efficacy. Responses were assessed by International Working Group Criteria for AML (Cheson B et al. JCO, 2003.). Patient Characteristics: Fifty-one patients were consented and 45 were treated on study, 32 of these were evaluable for response, all patients were evaluated for toxicity. Approximately half the patients were female (20/45). The median age was 66 y (range 33-82) and median WBC 2.42x109/L (range 0.18-63.15). Four patients (8%) had an antecedent hematological disorder. By European LeukemiaNet criteria 2 patients (4%) had favorable risk disease, 8 (18%) were Int-1, 12(27%) were Int-2 and 11 (24%) were adverse risk; 12(27%) patients were not evaluable by ELN due to lack of karyotype or molecular data from diagnosis. Twelve patients had primary refractory AML. Results: The MTD for Len given on d 6-26 in combination with AraC at 1.5 g/m2/d x 5 d was 10 mg. Dose de-escalation from the starting dose of 25 mg on this schedule was required due to excess toxicity. The most commonly observed non-hematologic drug related adverse events seen on the study (all < grade 2 unless indicated) were nausea, increased liver function tests (>grade 3), rash (grade >3), hypokalemia (> grade 3) and fatigue. At the 25 mg dose level the dose limiting toxicity was rash, while patients enrolled at the 15 mg dose level experienced dose limiting elevation in LFTs, fatigue and bleeding. Five patients achieved a CR (16%), 5 demonstrated CRi (16%) and there were 3 hematological improvements (HI) for an overall response rate (CR+Cri+HI) of 41% (13/32). The median overall survival (OS) (95% confidence interval) for patients treated on study was 5.8 (2.5, 10.6) months and disease free survival was 3.4 (2.3, 6.2) months. Conclusions: Although prior interesting data support the activity of single agent high dose Len in r/r AML, our single institute phase I study of intermediate dose AraC followed by Len was associated with marked skin and other toxicities at the Len 25 mg dose level, precluding dose escalation to the historically more active 50 mg dose. The CR rate in this study was not dissimilar to previously reported responses with single agent or combination AraC based regimens. Issues of dose and schedule for this combination may have had a significant impact on the potential benefit for these two drugs in combination. Nevertheless, the overall low CR rate from this study does not suggest any superiority for this combination in comparison with the historical single agent response rate for intermediate dose AraC in r/r AML. Disclosures Griffiths: Celgene, Incyte and Alexion: Honoraria; Astex Pharmaceuticals: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Other. Wetzler:MedPace: Consultancy; Bristol Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Plexus: Consultancy; Celgene: Research Funding.

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CD52 Is Expressed in Childhood Acute Myeloid Leukemia and May Be a Target for Alemtuzumab.

Blood ◽

10.1182/blood.v110.11.4316.4316 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4316-4316

Author(s):

Matthew K. Wegmann ◽

James Berger ◽

Bruce Bostrom ◽

Yoav H. Messinger

Keyword(s):

Acute Myeloid Leukemia ◽

Down Syndrome ◽

Myeloid Leukemia ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Low Risk ◽

Event Free Survival ◽

Platelet Recovery ◽

Free Survival ◽

Acute Myeloid

Abstract Event free survival in children with Acute Myeloid Leukemia (AML) remains low at approximately 50%, and more effective therapy is urgently needed. Alemtuzumab is an anti-CD52 humanized antibody with activity in Chronic Lymphocytic Leukemia. In adults with AML, CD52 was expressed in 36% of patients. Alemtuzumab treatment in relapsed adult AML patients resulted in complete response without platelet recovery (CRp) in 2/9 (22%), reduction of marrow blasts in 1/9 (11%) and reduction of peripheral blasts in 5/9 (56%) (Cancer, 2006;106:2645–51). The expression of CD52 has not been reported in childhood AML. AML (excluding M3) was diagnosed in 48 children at our institution from February 2002 to February 2007. The flow cytometric expression of CD52 antigens was studied in 41 pediatric patients at diagnosis: 20 girls and 21 boys and median age 5.1 years (range 0–18). CD52 expression ≥ 20% of leukemic blasts was considered positive. Of the 41 AML patients, 19 (46%) were positive and 22 (54%) were negative for CD52. In the CD52 positive patients the median expression was 72% (range 22%–99%), and intensity was moderate to dim. Expression by cytogenetic risk groups is demonstrated in Table 1: Cytogenetic Risk Group Low Risk: t(8;21) or Inv(16)/t(16;16) Intermediate Risk High Risk: −7 or -5/5q- Down Syndrome CD52 positive 7 9 2 1 CD52 negative 2 13 3 4 More low-risk patients were CD52 positive than negative, but the reverse was true for patients with Down syndrome. Age, gender, FAB subtype or presenting white blood cell count did not correlate with CD52 expression. Event free survival and overall survival were similar in CD52 positive and negative patients. In summary, CD52 is expressed in almost half of children with AML. The activity of single agent Alemtuzumab in adults with AML suggests that this agent should be evaluated to treat CD52-positive pediatric AML patients in combination with chemotherapy.

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Restrospective Multicenter Study Evaluating Efficacy and Safety of Dasatinib and Nilotinib in Patients with Imatinib-Resistant or –intolerant Chronic Myeloid Leukemia in Chronic Phase: Korean CML Working Party

Blood ◽

10.1182/blood.v120.21.1691.1691 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1691-1691

Author(s):

Jeong-Ok Lee ◽

Inho Kim ◽

Joo-Seop Chung ◽

Yeo-Kyeoung Kim ◽

Ho-Young Yhim ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Molecular Response ◽

Efficacy And Safety ◽

Event Free Survival ◽

Free Survival ◽

Imatinib Resistant

Abstract Abstract 1691 Dasatinib and nilotinib have been founded to be effective and well-tolerated in patients who develop resistance or intolerance to imatinib. Not enough data are currently available to recommend one over the other as the preferred second-line therapy based on efficacy data. Therefore we planned a multicenter retrospective study to analyze the efficacy and safety of dasatinib and nilotinib in patients with imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. In this Korean multicenter study, 126 patients imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase were treated with dasatinib (n=76) or nilotinib (n=50) The purpose of this study was to compare rates of cytogenetic and molecular response rate, event-free survival (EFS), progression-free survival (PFS) and overall survival (OS), and toxicities of nilotinib and dasatinib treatment of imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. PFS was defined as the time from the start of treatment to the earliest date of any of following event: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), progression to accelerated phase (AP) or blastic phase (BP), discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy. Event was defined by any one of the following: loss of CHR, loss of MCyR, progression to AP or BP, discontinuation due to treatment failure as assessed by the clinician, treatment discontinuation due to toxicity, and death from any cause on therapy. For dasatinib and nilotinib group, median ages (51 years old vs. 53), median durations of CML (23.7 months vs. 19.8 ) before receiving dasatinib or nilotinib and duration of prior imatinib treatment (21.7 months vs 17.7) were comparable. Nilotinib group had a higher proportion of intermediate and high sokal scores at the time of diagnosis than dasatinib group (41.5 vs 29.3% (high), 41.5% vs 32.5%(intermediate), 17.1% vs 37.9(low), p= 0.04). After median follow-up durations of 20.2 months of dasatinib group and 25.3 months of nilotinib group, the rates of major molecular response were 50.0% for dasatinib group and 59.6% for nilotinib group (p=NS) and the rates of MCyR (complete and partial cytogenetic response) were 78.4% for dasatinib group and 74.5% for nilotinib group (p=NS). The estimated EFS at 24 months was 67% and 48% in dasatinib and nilotinib group, respectively. (p<0.05). The estimated PFS at 24 months was 85% and 56% in dasatinib and nilotinib group, respectively. (p<0.05) Overall survival rates were comparable in both treatment groups (24-months OS; dasatinib 91%, nilotinib 94%; p=0.65). Both were generally well tolerated. Hematologic toxicities were more frequent among patients receiving dasatinib. 10 patients (13%) had pleural effusion in dasatinib; 9 events were grade 1 or 2. Elevated liver enzyme were more frequent among patients receiving dasatinib. In conclusion, In this study population, nilotinib and dasatinib showed similar cytogenetic and molecular response rates and survival. Toxicity profiles of two drugs were different and both drugs showed tolerable toxicities. In terms of event-free survival and progression-free survival, dasatinib was superior to nilotinib, but caution is warranted in interpretation because baseline characteristics including hematologic and cytogenetic response at the time of start with dasatinib and nilotinib and sokal scores at the time of diagnosis were different. Disclosures: No relevant conflicts of interest to declare.

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A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome

Blood ◽

10.1182/blood-2007-11-124602 ◽

2008 ◽

Vol 112 (5) ◽

pp. 1638-1645 ◽

Cited By ~ 166

Author(s):

Stefan Faderl ◽

Farhad Ravandi ◽

Xuelin Huang ◽

Guillermo Garcia-Manero ◽

Alessandra Ferrajoli ◽

...

Keyword(s):

Older Patients ◽

Myeloid Leukemia ◽

Low Dose ◽

Response Rate ◽

Randomized Study ◽

Event Free Survival ◽

Front Line ◽

Free Survival ◽

Low Dose Cytarabine

AbstractWe previously reported the feasibility of clofarabine and cytarabine combinations in AML. Questions remain as to (1) the therapeutic advantage of this combination and (2) the role of lower doses of clofarabine and cytarabine in older patients. We have conducted an adaptively randomized study of lower-dose clofarabine with or without low-dose cytarabine in previously untreated patients with AML aged 60 years and older. Patients received 30 mg/m2 clofarabine intravenously daily for 5 days with or without 20 mg/m2 cytarabine subcutaneously daily for 14 days as induction. Consolidation consisted of 3 days of clofarabine with or without 7 days of cytarabine. Seventy patients were enrolled. The median age was 71 years (range, 60-83 years). Sixteen patients received clofarabine and 54 the combination. Overall, 56% achieved complete remission (CR). CR rate was significantly higher with the combination (63% vs 31%; P = .025). Induction mortality was 19% with the combination versus 31% with clofarabine alone (P = .276). The combination showed better event-free survival (7.1 months vs 1.7 months; P = .04), but not overall survival (11.4 months vs 5.8 months; P = .1). Clofarabine plus low-dose cytarabine has a higher response rate than clofarabine alone with comparable toxicity. This trial is registered at www.clinicaltrials.gov as no. NCT00088218.

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Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14)

Journal of Clinical Oncology ◽

10.1200/jco.21.00443 ◽

2021 ◽

pp. JCO.21.00443

Author(s):

Nizar J. Bahlis ◽

Rachid Baz ◽

Simon J. Harrison ◽

Hang Quach ◽

Shir-Jing Ho ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Phase I ◽

Phase I Study ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Grade 3

PURPOSE Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS This phase I study ( NCT03314181 ) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

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Comparable Efficacy and Safety of Chinese Generic Imatinib and Branded Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia: A Retrospective Study

Blood ◽

10.1182/blood-2019-130081 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2940-2940 ◽

Cited By ~ 1

Author(s):

Xuelin Dou ◽

Yazhen Qin ◽

Yueyun Lai ◽

Hongxia Shi ◽

Xiaojun Huang ◽

...

Keyword(s):

Adverse Events ◽

Myeloid Leukemia ◽

Multivariate Analyses ◽

Education Level ◽

Comparable Efficacy ◽

Molecular Response ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Free Survival ◽

Significant Difference

Objectives To compare the efficacy and safety of Chinese generic imatinib with branded imatinib in adults with newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP). Methods Data of adults with newly diagnosed CML-CP receiving Chinese generic imatinib (Xinwei®, Hansoh, China; Genike®, Chiatai Tianqing, China) or branded imatinib (Glivec®, Novartis, Basel, Switzerland) between October 2013 and August 2018, during which both of the agents were commercially available in China, were retrospectively reviewed. Propensity score matching (PSM) case-control study was performed. Assessment of cytogenetic and molecular responses, failure-free survival (FFS), progression-free survival (PFS), and overall survival (OS) was according to European LeukemiaNet recommendation. Assessment of adverse events was according to Common Terminology Criteria for Adverse Events version 4.03. Cox regression model was used to identify independent factors associated with the responses and outcomes. Results In total, 442 adults receiving Chinese generic imatinib (n=236) or Glivec® (n=206) at an initial dose of 400mg once daily were included. 273 (61.6%) patients were male. Median age was 41 years (range, 18-83 years). Higher white blood cell (WBC) counts (P=0.019), rural household registration (P<0.001), lower education level (P<0.001), and divorced or widowed status (P=0.009) were more common in the Chinese generic imatinib cohort than those in the branded imatinib cohort. There was no significant difference in gender, age, Sokal risk, hemoglobin (HGB) level and basophile percentage in peripheral blood at diagnosis between the 2 cohorts. With the median follow-up of 30 months (range, 3-62 months) and 34 months (range, 3-67 months) in the generic and branded cohorts, respectively, there was no significant difference on the 4-year probabilities of achieving complete cytogenetic response (CCyR, 97% vs. 97.2%, P=0.851), major molecular response (MMR, 87.8% vs. 90.1%, P=0.131), molecular response 4.0 (MR4.0, 55.0% vs. 68.3%, P=0.169), molecular response 4.5 (MR4.5, 32.8% vs. 39.2%, P=0.191) as well as the 4-year probabilities of FFS (77.4% vs.81.1%, P=0.363), PFS (94.4% vs. 95.9%, P=0.480) and OS (95.8% vs. 98.3%, P=0.086) between the Chinese generic imatinib and Glivec cohorts. Multivariate analyses showed the type of drug was not associated with the cytogenetic and molecular responses and outcomes. However, male gender, education level, Sokal risk, WBC counts, HGB level and basophile percentage in peripheral blood at diagnosis were significantly associated with the responses or outcomes (Table 1). There was no significant difference on hematologic (P=0.923) and non-hematologic (P=0.655) adverse events between the 2 cohorts. After the PSM adjustment for gender, age, household registration, education level, marriage status, Sokal risk, WBC count and HGB level, 150 pairs of case-control patients with comparable baseline characteristics were re-analyzed. Similarly, multivariate analyses confirmed that Chinese generic or branded imatinib used as the front-line therapy was not associated with either responses or outcomes. Conclusions Socio-demographics might influenced patients' choice of the type of TKI used. Chinese generic imatinib and Glivec® as frontline therapy had comparable efficacy and safety in CML-CP patients. Disclosures No relevant conflicts of interest to declare.

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A Prospective Randomized Phase I/II Study of Lenalidomide, Melphalan, Prednisone and Thalidomide (RMPT) for Relapsed/Refractory Multiple Myeloma Patients.

Blood ◽

10.1182/blood.v114.22.2864.2864 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2864-2864 ◽

Cited By ~ 2

Author(s):

Federica Cavallo ◽

Alessandra Larocca ◽

Maria Teresa Petrucci ◽

Vincenzo Federico ◽

Antonietta Pia Falcone ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Adverse Events ◽

Phase I ◽

Response Rate ◽

Oral Prednisone ◽

Hematologic Toxicity ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Grade 3

Abstract Abstract 2864 Poster Board II-840 Background. New drug associations may improve patients outcome in relapsed/refractory multiple myeloma (MM). In newly diagnosed MM patients the addition of lenalidomide or thalidomide or bortezomib, to the standard oral melphalan and prednisone combination significantly increased response rate and event-free survival, showing synergistic effects. Aims. This is a multicenter, randomized, open label phase I/II trial designed to evaluate the safety/efficacy profile of the salvage treatment, Lenalidomide, Melphalan, Prednisone and Thalidomide (RMPT) in patients with relapsed/refractory myeloma. Methods. Oral lenalidomide was administered at 10 mg/day on days 1-21, in combination with oral melphalan at 0.18 mg/kg on days 1–4 and oral prednisone at 2 mg/kg on days 1–4. Thalidomide was administered at 50 mg/day (Arm A) or 100 mg/day (Arm B) on days 1-28. Each course was repeated every 28 days for a total of 6 courses. Maintenance therapy included Lenalidomide alone at 10 mg/day on days 1-21. Aspirin 100 mg/day was given as a prophylaxis for thrombosis. Results. Forthy-four patients with relapsed/refractory MM were enrolled in the study between May 2007 and March 2008, including 22 patients in arm A and 22 patients in arm B. After a median of 5 cycles 75% of patients achieved at least a partial response (PR), including 20% very good partial response (VGPR) and 14% near or complete response (nCR or CR). Among patients who received thalidomide 100 mg, the PR rate was 82% (including 23% VGPR and 23% CR/nCR). Higher response rate was observed among patients who received RMPT in first relapse. The 1-year-progression-free survival was 51,5% and the 1-year survival from study entry was 72%. Hematologic toxicity was the most frequent adverse event. Grade 3-4 hematologic adverse events included: neutropenia (68%), thrombocytopenia (36%) and anemia (32%). Grade 3-4 non hematologic adverse events included: infections (22,7%), neurological toxicity (4,5%) and fatigue (6,8%). No grade 3-4 thromboembolic events were reported. Conclusion. This is the first trial exploring the association of two immunomodulatory drugs, Thalidomide and Lenalidomide. RMPT is an active regimen in patients with relapsed/refractory MM. Toxicities were manageable and the incidence of neutrotoxcities was low. Updated results will be presented at the time of the meeting. Disclosures: Cavallo: CELGENE: Honoraria. Petrucci:CELGENE: Honoraria. Canepa:CELGENE: Honoraria. Boccadoro:CELGENE: CONSULTANCY, ADVISORY COMMITTEES, Research Funding. Palumbo:CELGENE: Honoraria.

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