Myelodysplastic Syndrome Patients Obtaining a Cytogenetic Response to Outpatient Decitabine Experience Improved Hematological Responses and Longer Survival: Additional Analyses From the ADOPT Trial.

Abstract Abstract 3817 Poster Board III-753 Background The multi-center ADOPT trial (J Clin Oncol 2009; 27:3942) demonstrated that decitabine (Dacogen), a cytidine analog with hypomethylating and direct cytotoxic properties, when administered to MDS patients with IPSS '0.5 on an outpatient schedule of 20 mg/m2 IV infusion 5 days per month resulted in an overall improvement rate of 51%, including 32% complete responses (CR+mCR), using the International Working Group 2006 criteria. The impact of obtaining a cytogenetic response to decitabine therapy on subsequent hematological parameters or survival is the focus of this analysis. Study Design/Methods 99 patients with de novo or secondary MDS were enrolled on the ADOPT trial. 49 patients had abnormal cytogenetics at baseline. 33 patients underwent at least one successful post-treatment karyotypic analysis and were therefore evaluable for cytogenetic response. Data analysis utilized student t-tests and comparisons of proportions. Results 17/33 evaluable patients (52%) achieved a cytogenetic response, with 11 complete responses and 6 partial responses (i.e., >50% reduction in abnormal metaphases). Responses were noted among patients in all IPSS cytogenetic risk categories: low risk cytogenetics 3/3 (100%), intermediate risk cytogenetic 5/8 (62%), and high risk cytogenetic (43%). Cytogenetic responses by abnormality included: -Y (3/3), del 5q (1/7) 1, del 20q (1/2), complex (6/14), chromosome 7 abnormalities (6/14), +8 (5/6), and others (3/7). Baseline characteristics were similar among cytogenetic responders and non-responders: mean age 72.2 vs 68.6 years (p=0.30), males 94 vs 63% (p=0.07), secondary MDS 24 vs 13% (p=0.72), high risk IPSS 35 vs 63% (p=0.21), int-2+high risk IPSS 59 vs 85% (p=0.20), blasts <10% 59 vs 31% (p=0.21), red cell transfusion dependent 41 vs 69% (p=0.21) and platelet transfusion dependent 6 vs 19% (p=0.54). The median time to cytogenetic response was 2.3 months, coinciding with the first post-treatment marrow sampling timing. Of the 17 cytogenetic responders, 13 (76%) had a clinical hematological responses (10 CR and 3 mCR) which was significantly higher (p=0.003) than the 3 of 16 evaluable patients (18%) not experiencing a cytogenetic response. Among cytogenetic responders the duration of the hematological response (451 days, 95% CI 143, NE) also was greater than the duration of hematological response among cytogenetic non-responders (219 days, 95% CI 184, NE). 71% (12/17) of cytogenetic responders were red cell transfusion independent on study by IWG criteria compared to 44% (7/16) non-cytogenetic responders (p=0.22). Significantly more cytogenetic responders achieved prolonged red cell transfusion independence lasting at least 24 weeks (10/17; 59%) compared to cytogenetic non-responders (3/16; 19%) (p=0.04). 88% (15/17) of cytogenetic responders were platelet transfusion independent during the study compared to 75% (12/16) non-cytogenetic responders (p=0.61). Higher rates of prolonged platelet transfusion independence lasting at least 24 weeks were achieved among 82% (14/17) cytogenetic responders versus only 38% (6/16) cytogenetic non-responders (p=0.03). Achieving a cytogenetic response correlated with improved survival. Cytogenetic responders had a median survival of 627 days (95% CI 420,760) versus 318 days (95% CI 265, 447) for cytogenetic non-responders. Conclusions Outpatient administration of decitabine (20mg/m2 IV 5 days per month) resulted in cytogenetic responses in 52% of patients with MDS with baseline cytogenetic abnormalities, with a median time to response of 2.3 months. Patients achieving a cytogenetic response had higher rates of hematological responses, longer durations of transfusion independence, and a doubling of projected survival. This analysis suggests that a deeper early response documented by cytogenetics with decitabine correlates with improved long term outcomes, and supports early cytogenetic testing to predict hematological response. Disclosures: Goldberg: Eisai, Inc.: Research Funding.

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Lenalidomide reexposure After Short Interruption In Del(5q) MDS Patients at Relapse of Transfusion Dependence

Blood ◽

10.1182/blood.v116.21.2923.2923 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2923-2923 ◽

Cited By ~ 1

Author(s):

Robert Marek Radkowski ◽

Sabine Haase ◽

Brigitte Schlegelberger ◽

Gudrun Goehring ◽

Stefanie Banisch ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Median Time ◽

Chromosomal Abnormality ◽

Myeloid Leukemia ◽

Red Cell ◽

Transfusion Independence ◽

Free Interval ◽

Red Cell Transfusion ◽

Time To Relapse ◽

Acute Myeloid

Abstract Abstract 2923 Introduction: Lenalidomide is effective in myelodysplastic syndroms (MDS) in patients with del(5q) chromosomal abnormality (List et al 2006). However, relapse of transfusion dependence occurs consistently and therapeutic measures at that moment are scarce. We report on our experience to achieve a second remission of transfusion dependence using lenalidomide after a variable period of lenalidomide treatment interruption. Methods: 5 patients with a del(5q) chromosomal abnormality (low- and intermediate-1-risk MDS according to IPSS) were treated within clinical trials, all transfusion-dependent with a median age of 67 years and with female prevalence. Mean MDS duration before start of lenalidomide therapy was 4.2 years. Patients were treated with doses of oral lenalidomide ranging from 5 mg every other day to 10 mg for 28 days of every 28 days cycle. All patients had a response to the initial lenalidomide treatment and achieved transfusion independence. All 5 patients relapsed and became red cell transfusion dependent, again. Median time to relapse was 24.2 months (13-55 months).The therapy was stopped and after a therapy-free interval of 7.2 months (2-13 months) we resumed lenalidomide therapy. The patients were treated with the initial lenalidomide dose. Results: 3 of 5 patients (60%) became transfusion independent, again. The median increase in hemoglobin from baseline to the maximum hemoglobin achieved was 4.4 g/dl. Patients are followed up and all of them are currently in ongoing transfusion independence with a median time of 16.3 months (11, 15, 23 months, respectively). The other two patients stayed transfusion dependent and lenalidomide was interrupted after 3 and 4 months, respectively. Both later progressed to higher MDS subtypes or acute myeloid leukemia. Responses seemed to be independent on age, time to relapse, interval to retreatment or doses of lenalidomide. Discussion: In low/int-1 IPSS del(5q) patients relapsing with red cell transfusion dependence during lenalidomide treatment, current algorithms recommend discontinuation of the drug. Our results suggest efficacy of lenalidomide in a significant portion of the patients when they are rechallenged with a standard dose after a therapy-free interval of 2 to 6 months. Second remissions might be as long lasting as, or exceeding, the initial one. We are unable to define predictive factors for second responses. Lack of further response may be an ominous prognostic sign and, in our experience, heralded progression to higher risk MDS subtypes or acute myeloid leukemia after a short time. Disclosures: Giagounidis: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Impact of Imatinib Dose Escalation in Chronic Myeloid Leukemia Patients in Chronic Phase with Sub-Optimal Response or Failure with Imatinib 400 Mg.

Blood ◽

10.1182/blood.v114.22.3289.3289 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3289-3289

Author(s):

Katia BB Pagnano ◽

Marcia T Delamain ◽

Eliana C.M. Miranda ◽

Vagner O Duarte ◽

Brunna Eulálio Alves ◽

...

Keyword(s):

Median Time ◽

Dose Escalation ◽

Conflicts Of Interest ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Dose Increase ◽

Free Survival ◽

Optimal Response ◽

Hematological Response

Abstract Abstract 3289 Poster Board III-1 Imatinib dose escalation has been used in sub-optimal response and therapeutic failure to imatinib in conventional doses. The aim of this study was to evaluate the efficacy of imatinib dose increase in CML patients in CP who did not achieve the best response to imatinib 400 mg QID. Patients and methods: All CML patients in CP treated in our institution with imatinib 400mg between March 2002 and December 2008 were evaluated. Imatinib was escalated to 600–800mg in cases with sub-optimal response or failure, according to Leukemia Net or IRIS Trial criteria. All survival curves were calculated from date of dose increase: overall survival (OS) until death or last follow-up, event free survival (EFS) until loss of complete hematological response (CHR) or major cytogenetic response (MCyR), progression to accelerated phase (AP) or blast crisis (BC) or death from any cause. Transformation free survival (TFS) was calculated from dose increase until progression to AP, BC or death. Results: 137 patients in CP were treated with imatinib 400 mg. Dose was escalated in 55 (40%) patients due to loss or failure to achieve CRH (13 = 24%); progression to BC (2 = 3.5%); no CCR (11 = 20%); loss of RCC (5 = 9%); CCR without major molecular response (MMR) after 18 months of imatinib (24 = 43.5%). Males: 37, females 18 cases. Median age: 44 (16–74) years. Twenty-eight patients (49%) were treated with imatinib as first line therapy and 51% had used IFN previously. Median time between diagnosis and imatinib start was 4.5 (0–94) months. Responses: 94% achieved CHR; 58% CCR and 34% MMR. After dose increase, 31 (56%) responded: 58% of the patients with previous sub-optimal molecular response achieved MMR. Among those who benefited from dose increase, only 3 cases lost the response: one with hematological resistance and two with cytogenetic resistance (2 lost CCR and one CHR). Seven out of 16 patients who increased dose due to cytogenetic failure (loss of response, failure and sub-optimal response) achieved response: one had partial cytogenetic response (PCyR) and 6 CCR. Five patients with hematological failure presented response: CHR (2), CCR (1), PCyR (1) and MMR (1). Patients with BC (2 cases) did not respond to dose escalation. TFS was 89% and 67% in 2 and 5 years, respectively. EFS was 71% and 64% in 2 and 5 years respectively. When stratified by the type of failure, EFS was 100%, 49% and 34% in the group with molecular sub-optimal response with median time of 22 (4–41) months, cytogenetic 17 (1.2–42) and hematological failure 7.7 (0.2–57), respectively (P<0.03). Conclusions: imatinib dose escalation was successful in molecular sub-optimal response. However, the patients who do not achieve MMR might be candidates to second line treatment. Patients who did not achieve cytogenetic or hematological response did worse with imatinib dose escalation. Disclosures: No relevant conflicts of interest to declare.

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Survival, Prognostic Factors, and Rates of Leukemic Transformation in a Multicenter Study of 303 Untreated Patients with MDS and Del(5q).

Blood ◽

10.1182/blood.v114.22.945.945 ◽

2009 ◽

Vol 114 (22) ◽

pp. 945-945 ◽

Cited By ~ 3

Author(s):

Ulrich Germing ◽

Michael Lauseker ◽

Barbara Hildebrandt ◽

Argiris Symeonidis ◽

Jaroslav Cermak ◽

...

Keyword(s):

High Risk ◽

Median Survival ◽

Research Funding ◽

Risk Group ◽

Competing Risk ◽

Refractory Anemia ◽

Red Cell ◽

Kaplan Meier ◽

Red Cell Transfusion

Abstract Abstract 945 In 2001, the WHO defined the category MDS with del(5q) due to unique cytogenetic, morphologic, hematologic, clinical, prognostic and therapeutic features. The survival of these patients, as well as patients with refractory cytopenia with unilineage dysplasia (RCUD) and refractory anemia with ring sideroblasts is favorable in comparison to other MDS types. Data on disease progression to a more advanced MDS category or to acute leukemia (AML) are sparse and have not been examined in detail. In order to address this issue we collated data of all patients with MDS and del(5q) characterized by low or intermediate-1 IPSS risk score that had been included into various collaborating MDS registries. Patients were followed from diagnosis and data on cell counts, transfusion dependency, and MDS progression were documented. No patients received treatment other than best supportive care. The status of 62 patients was censored at the time of the initiation of Lenalidomide therapy. AML progression was defined as >20% marrow blasts. Estimates of survival probability were calculated with the Kaplan-Meier method. The cumulative incidence of progression to AML was calculated both with the Kaplan-Meier method and with the competing risk method where “death without progression to AML” is considered as competing event, not as censoring. For both events the cumulative incidences are estimated simultaneously. This method has the advantage that it takes into account that there is a difference between end of follow-up and death. Depending on the number of competing events, the curves are lower than those calculated with the Kaplan-Meier estimator. We identified 303 patients, median age at diagnosis 65 years (28-91), 71% were females. Median follow up time was 3 years. Median survival was 71.5 months. Patients with del(5q) as a sole chromosomal aberration had a median survival of 73 months as compared to 19.3 months in patients with more than 1 additional aberrations. Patients who had red cell transfusion need at diagnosis had a median survival of 39 months vs. 97 months in transfusion independent patients (p=0.00005). Transfusion need at diagnosis was the most important parameter for survival. Patients in the WPSS very low risk group had a median survival of 107 months, as compared to 73 and 56 months in the low and intermediate risk group and 37 months in the high risk group. 44 of the 303 patients (15%) progressed to AML (>20% marrow blasts). The cumulative AML progression rate calculated with the Kaplan-Meier method was 7% at 2 years and 18.2% at 5 years. The cumulative risk of AML progression calculated with the competing risk method was 6.6% at 2 years and 15.1% at 5 years. Factors associated with the risk of AML transformation were intermediate-I IPSS risk and high risk WPSS score, marrow blast count >5%, and red-cell transfusion need at diagnosis. Survival and progression rates did not differ among the participating centers. In conclusion, survival of patients with MDS and del(5q) is high and is comparable to patients with RCUD and RARS, but is associated with a risk of AML-transformation similar to RCMD without del(5q). Further cytogenetic and molecular studies are warranted in order to identify patients at greater risk of progression. Disclosures: Germing: Novartis, Celgene: Honoraria, Research Funding. Lauseker:Celgene: Research Funding. Hildebrandt:Celgene: Research Funding. Symeonidis:Celgene: Research Funding. Cermak:Celgene: Research Funding. Pfeilstöcker:Celgene: Research Funding. Nösslinger:Celgene: Research Funding. Sekeres:Celgene: Research Funding. Maciejewski:Celgene: Research Funding. Haase:Celgene: Research Funding. Schanz:Celgene: Research Funding. Seymour:Celgene: Research Funding. Weide:Celgene: Research Funding. Lübbert:Celgene: Research Funding. Platzbecker:Celgene: Research Funding. Valent:Celgene: Research Funding. Götze:Celgene: Research Funding. Stauder:Celgene: Research Funding. Blum:Celgene: Research Funding. Kreuzer:Celgene: Research Funding. Schlenk:Celgene: Research Funding. Aul:Celgene: Research Funding. Kündgen:Celgene: Research Funding. Hasford:Celgene: Research Funding. Giagounidis:Celgene: Research Funding.

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Effectiveness in Predicting the Response and Outcome with Three Prognostic Scoring Systems in Pediatric CML CP on Upfront Imatinib

Blood ◽

10.1182/blood.v124.21.4549.4549 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4549-4549

Author(s):

Ganta Ranga Raman ◽

Srividya Nasaka ◽

Sadashivudu Gundeti ◽

Vijay Gandhi Linga ◽

Narendra Anukonda ◽

...

Keyword(s):

High Risk ◽

Risk Score ◽

Scoring Systems ◽

Risk Groups ◽

Cytogenetic Response ◽

Low Risk ◽

P Value ◽

Intermediate Risk ◽

Hematological Response ◽

Prognostic Scoring Systems

Abstract Introduction: The Sokal and Hasford (Euro) scores were developed in the chemotherapy and interferon era and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML).Recently, European Treatment and Outcome Study (EUTOS) scoring system was introduced. Data on risk stratification in pediatric CML population was lacking due to its rarity [<3%]. Objective: To study the effectiveness in predicting the response and outcome with three prognostic scores in pediatric CML-chronic phase patients on front line Imatinib. Materials and methods: We retrospectively analyzed the hospital records of newly diagnosed CML CP patients [aged ≤18 years] from 2004 to 2010 for their risk score, cytogenetic response and outcome at the end of 4 years. Outcome was measured in terms of event free survival (EFS) at the end of 48 months. Events include loss of hematological response, loss of cytological response, progression to accelerated/ blast phase (AP/BC). All received free Imatinib under Gleevac international patient assistance program. Results: Data of 106 children was analyzed with median age of 13.5 years [ranged 5-18 years] and male preponderance [M:F =1.14:1]. The distribution of children was 63%, 32% and 5% in Sokal low, intermediate and high risk respectively, 50%, 43% and 5% in Hasford/Euro low, intermediate and high risk respectively, 71% and 29% in EUTOS low and high risk respectively. The overall cumulative complete hematological response at the end of 3 month was 94%, and complete cytogenetic response at 18 months was 75%. The CCyR at 18 month was seen in 72%,76% and 100% among Sokal low, intermediate and high risk groups respectively, 74%, 73% and 100% among Hasford/Euro low, intermediate and high risk groups respectively, 81% and 86% EUTOS low and high risk groups respectively. The EFS at the end of 48 months was seen in 72%,64% and 83% among Sokal low, intermediate and high risk groups respectively; 70%, 63% and 83% among Hasford/Euro low, intermediate and high risk groups respectively; 73% and 66% EUTOS low and high risk groups respectively. Conclusion: None of the scoring systems predicted the response and outcome effectively in children with CML CP. Children with EUTOS low risk score had better EFS than high risk score but not statistically significant. These age group CML patients need to be studied and new prognostic scoring systems are needed to risk startify. Limitation of the study: small sample size, not a prospective study Table 1EventsEUTOS low risk n=76 (71%)EUTOS high risk n=30 (29%)p value (Fishers test)CHR at 3mon72/76 (94%)26/30 (86%)0.21CCyR at 12mon58/76 (76%)22/30 (73%)0.8CCyR at 18mon62/76 (81%)26/30 (86%)0.77EFS at 4 yrs56/76 (73%)20/30 (66%)0.48 Table 2 Events Sokal low risk n=66 (63%) Sokal intermediate risk n=34 (32%) Sokal high risk n=6 (5%) p value (Fishers test) CHR at 3mon 60/66 (100%) 34/34 (100%) 6/6 (100%) 0.18 CCyR at 12mon 32/66 (48%) 20/34 (58%) 5/6 (83%) 0.23 CCyR at 18mon 48/66 (72%) 26/34 (76%) 6/6 (100%) 0.4 EFS at 4 yrs 48/66 (72%) 22/34 (64%) 5/6 (83%) 0.6 Table 3 Events Euro low risk n=54 (50%) Euro intermediate risk n=46 (43%) Euro high risk n=6 (5%) p value (Fishers test) CHR at 3 mon 50/54 (92%) 46/46 (100%) 6/6 (100%) 0.16 CCyR at 12 mon 36/54 (66%) 26/46 (56%) 5/6 (83%) 0.36 CCyR at 18 mon 40/54 (74%) 34/46 (73%) 6/6 (100%) 0.46 EFS at 4 yrs 38/54 (70%) 30/46 (63%) 5/6 (83%) 0.94 Disclosures No relevant conflicts of interest to declare.

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Decitabine Can Induce Complete Cytogenetic Responses When Used as Initial Therapy in Older AML Patients.

Blood ◽

10.1182/blood.v114.22.4123.4123 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4123-4123

Author(s):

Amanda F Cashen

Keyword(s):

Bone Marrow ◽

High Risk ◽

Median Time ◽

Phase Ii ◽

Older Patients ◽

Response Rate ◽

Cytogenetic Response ◽

Prior Therapy ◽

Poor Risk ◽

Complete Cytogenetic Response

Abstract 4123 Background The incidence of acute myeloid leukemia (AML) increases with advancing age. At present, there are limited treatment options available for older patients because of lack of efficacy and increased toxicity. In a previously reported Phase II AML trial (n = 55), older patients not previously treated for AML experienced an overall response rate of 25% with decitabine (Cashen et al. Blood 2008). Response rate was similar in patients with poor or intermediate cytogenetic risk at baseline. In addition, 5 (15%) of the 34 patients who had cytogenetic abnormalities at baseline achieved a complete cytogenetic response in this trial. As older AML patients are more likely to present with unfavorable cytogenetic profiles, it was of interest to review the patient characteristics and describe the responses of the 5 patients who had a complete cytogenetic response. Methods The patients for this analysis were from a multicenter, Phase II study. In this study, patients over the age of 60 with AML (>20% bone marrow blasts) and no prior therapy for AML were treated with decitabine, 20 mg/m2 IV for 5 consecutive days of a 28-day cycle until disease progression or unacceptable adverse event. Cytogenetic profile was assessed at screening and after every cycle, beginning with cycle 2. Results The 5 patients (2 males, 3 females; 5 white; 2 M1, 1 each for M2, M6, and M7) with a complete cytogenetic response had baseline characteristics that are associated with high risk. Three were >70 yrs of age, and all 5 had AML secondary to prior therapy (n=2) or MDS (n=3). Four patients had poor-risk cytogenetics: 2 pts with -7, -5q, and ≥ 3 abnormalities and 2 pts with deletions of chromosome 5 and ≥ 3 abnormalities. One patient had intermediate-risk cytogenetics. The median baseline bone marrow myeloblast count was 33% (range 21 to 60). These patients were treated with a median 10 cycles (range 6 to 19) of decitabine. The median time to a complete cytogenetic response was 5 cycles (range 2.3 to 6). The median time to relapse from a complete cytogenetic response was 8.1 cycles (range 3.4 to 19.8). The overall median survival was 21.6 months (95% CI: 9.5, 24.7), which compares favorably to the median overall survival of the entire study cohort (21.6 months vs. 7.7 months, Cashen et al. Blood 2008). Conclusions Treatment with decitabine can induce complete and durable cytogenetic responses, even in older patients with high risk disease characteristics and poor risk cytogenetics. Patients who achieve a cytogenetic response may have a survival benefit. A presently ongoing Phase III survival trial with decitabine will help further characterize the effect of decitabine on cytogenetic responses in older AML patients. Disclosures: Cashen: Eisai, Inc.: Consultancy.

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Decitabine in Myelodysplastic Syndromes: Argentine Initial Multi-Institutional Clinical Experience

Blood ◽

10.1182/blood.v112.11.5086.5086 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5086-5086

Author(s):

Marcelo Iastrebner ◽

Virginia Prates ◽

Jorge Arbelbide ◽

Isolda Fernandez ◽

Gabriela Flores ◽

...

Keyword(s):

High Risk ◽

Partial Response ◽

Stable Disease ◽

De Novo ◽

Complete Response ◽

Dosing Schedule ◽

Improvement Rate ◽

Hematological Response ◽

Best Response ◽

Secondary Mds

Abstract Epigenetic therapy with a hypomethylating agent is becoming the standard of care in some intermediate and high-risk myelodysplastic syndromes (MDS). The DNA-targeted hypomethylating agent, decitabine (DACOGEN, Janssen Cilag Farmaceutica S.A. and Eisai Inc.), has been approved for patients (pts) with intermediate-1 (INT-1), intermediate-2 (INT-2), and high-risk MDS in Argentina. An alternative regimen with decitabine 20 mg/m2 IV over 1 hour once daily for 5 consecutive days repeating every 4 weeks, permits its use in the outpatient clinic. Clinical and hematological response and safety were analyzed retrospectively for pts with all FAB subtypes of MDS who had received this dosing regimen at 17 centers in our country between July 2007 and June 2008. Inclusion criteria were: ≥18 years of age; de novo or secondary MDS; and International Prognosis Scoring System (IPSS) score ≥0.5. Exclusion criteria were: diagnosis of acute myeloid leukemia (AML) or other progressive malignant disease. Patients with prior therapy were not excluded. The primary endpoint was overall response, assessed by IWG 2006 criteria. Thirty-eight pts were enrolled: median age 67 years; 71% male and 29% female. The diagnosis was de novo MDS in 34 pts (89%) and secondary MDS in 4 (11%). The median time from diagnosis to first dose of decitabine was 7 months. Eastern Cooperative Oncology Group performance status scores were 0 (21%), 1 (47%), 2 (26%) and 3 (5%). IPSS scores were INT-1 (50%), INT-2 (8%), and high-risk (42%). Cytogenetic abnormalities were found in 37% of pts. FAB classification was: RA (21%), RARS (8%), RAEB (18%), RAEB-T (24%) and CMML (29%). A median of 3.5 cycles (range, 1–8) were given. Dosage had to be reduced in 7 pts (18%) due to comorbidity and cytopenias. Overall improvement rate in the intent-to-treat population was 45% (Table), including: 9% complete response (CR), 5% marrow complete response (mCR), 5% partial response (PR) and 26% hematological improvement (HI). Two pts (5%) had stable disease. Four pts (11%) were non-evaluable for response. Most pts had their first hematological response by cycle 2 and their best response by cycle 4. The mean ± SD time to best response was 2.7±3 months. No differences in clinical and hematological response were observed between pts with INT-2/High compared to INT-1 (8/19 and 9/19, respectively); red cell and platelet transfusion requirements resolved during the first 2 cycles in 13/16 and 7/8 pts, respectively. Overall improvement rates were similar in pts with more and less than 1 year since MDS diagnosis (9/18 and 8/20, respectively). Overall survival was 71% during the observational period (up to 11 months). The most frequent adverse events were neutropenia without fever (47%) and with fever (21%), especially during cycle 2, and thrombocytopenia (23%). This study showed prompt clinical activity for an alternative 5-day dosing schedule of decitabine in the outpatient setting and an overall improvement rate of 45%, with an initial response by cycle 2, the best response by cycle 4, and acceptable tolerability. <>Table. Response to 5-Day Decitabine Dosing Schedule IWG 2006 Criteria ITT (N=38) Overall Improvement Rate (CR+mCR+PR+HI) 17 (45%) CR (Complete Response) 3 (9%) mCR (Marrow Complete Response) 2 (5%) PR (Partial Response) 2 (5%) HI (Hematological Improvement) 10 (26%) SD (Stable Disease) 2 (5%) Failure (Progressive Disease or Death) 15 (39%) Non-Evaluable 4 (11%)

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Pomalidomide in Myelofibrosis with Cytopenia: First Results of the Mpnsg 01–09 Study (ClinicalTrials.gov Identifier: NCT00949364).

Blood ◽

10.1182/blood.v120.21.2840.2840 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2840-2840

Author(s):

Richard F Schlenk ◽

Andreas Reiter ◽

Norbert Gattermann ◽

Holger Hebart ◽

Edgar Jost ◽

...

Keyword(s):

High Risk ◽

Blood Cell ◽

Clinical Improvement ◽

Median Time ◽

Red Blood Cell ◽

Stable Disease ◽

Disease Stage ◽

Red Blood Cell Transfusion ◽

Transfusion Independence ◽

Rbc Transfusion

Abstract Abstract 2840 Background: Pomalidomide in a single arm phase-I/II study and one randomized four arm phase-II study in primary myelofibrosis (MF) and post-polycythemia vera/essential thrombocythemia (post-PV/ET) MF showed efficacy in particular with respect to improvement in anemia. To date, pomalidomide has been evaluated in MF at two dose levels, 0.5mg and 2.0 mg/day. Aims: To evaluate clinical efficacy of pomalidomide alone and in combination with prednisolone (PRED) in patients with primary or post-PV/ET MF and cytopenia. Methods: The main inclusion criteria for primary or post-PV/ET MF patients were red blood cell (RBC)-transfusion-dependence or hemoglobin <10 g/dl, and/or thrombocytopenia <50/nl and/or neutropenia <1.0/nl; patients >=50 years were eligible. Treatment consisted of pomalidomide (POM) 2mg/day; prednisone (PRED) 30mg/day was added in patients who did not respond (≤ stable disease) within three months of therapy. The primary endpoint was response assessed by IWG criteria and extended by the criterion red blood cell transfusion-independence (Gale RP et al., Leuk Res. 2011). Concurrent hydroxyurea in patients with proliferative disease and aspirin 100 mg/d in patients with platelets between 50/nl and 1000/nl were administered. The statistical design of the study was based on the Simon optimal two-stage design. Here we report on the first stage of the study. Median follow-up according to the method of Korn was 18 months. Results: Thirty-eight patients were treated with POM 2 mg/d, the median age was 71 years (range 51–83), 34% were female. Twenty-seven had primary and 11 post-PV/ET MF. Disease stage at study-entry according to the DIPSS was high-risk in 13 (34%), intermediate-2 risk in 22 (58%) and intermediate-1 risk in 3 (8%). Incidence of high-risk cytogenetics, JAK2 V617F mutation and MPL W515L mutation were 29% (10/34), 55% (21/38) and 18% (7/38), respectively. Twenty-seven patients (71%) were RBC-transfusion- and 7 (18%) platelet-transfusion dependent. Median duration of treatment with POM was 11.4 months with 5 patients continue on treatment 24+ months. PRED was added after 3 months in 19 of 28 eligible patients. POM dose-reduction (n=8, 1mg/d; n=2, 0.5mg/d) was performed after a median time of 34 days (range 3–308 days) due to fatigue (n=2), thrombo- and/or neutropenia (n=7), rash (n=1). Seven patients with high risk characteristics (n=6 RBC-transfusion dependent, n=4 high risk cytogenetics) experienced transformation into blast phase (BP), the actuarial probability of transformation to BP measured from diagnosis was 6.0% (SE 4.1%) at 2 years and 22.4% (SE 8.4%) at 5 years. Response was observed in 14 patients (37%) after a median time of 4.8 months (n=1 complete remission, n=5 clinical improvement-platelets, n=3 clinical improvement-erythrocytes, n=5 red cell transfusion-independence); 8 responders received concomitant PRED and responded after a median of three months (range 0.8–11.7 months) of the addition of PRED. In 5 of 14 responders POM dose was reduced due to toxicity, notably before response occurred. Responses were observed within the first 3 months (n=4), between month 4 to 6 (n=4) and beyond month 6 (n=6) with the latest response seen at 12.7 months. There was no correlation between response and JAK2/MPL mutation status or cytogenetics. Basophilia defined as greater than 50% increase in absolute basophil count at month 3 was in trend associated with response (p=0.06). Conclusions: POM with or without PRED in patients with different risk groups of patients with primary and post-PV/ ET MF was effective with a response rate of 37%. Based on results of this first cohort the protocol was amended; i) POM dose has been adjusted to 0.5 mg/d, ii) up-front randomization of PRED at month 4 or month 7 in patients without response but stable disease to single agent POM was introduced. Disclosures: Schlenk: Celgene: Research Funding. Off Label Use: Pomalidomide is so far not approved for the treatment of primary and secondary myelofibrosis.

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Should We Use Preoperative Epoetin-α in the Mildly Anemic Patient Undergoing Simultaneous Total Knee Arthroplasty?

The Open Orthopaedics Journal ◽

10.2174/1874325001307010047 ◽

2013 ◽

Vol 7 (1) ◽

pp. 47-50 ◽

Cited By ~ 1

Author(s):

Lawrence A Delasotta ◽

Fabio Orozco ◽

S. Mehdi Jafari ◽

Jamie L Blair ◽

Alvin Ong

Keyword(s):

Total Knee Arthroplasty ◽

High Risk ◽

Length Of Stay ◽

Blood Loss ◽

Knee Arthroplasty ◽

Red Cell ◽

Anemic Patient ◽

Total Knee ◽

Red Cell Transfusion ◽

Inpatient Length Of Stay

Simultaneous knee arthroplasty is associated with significant blood loss. To prevent transfusion, three preoperative doses of epoetin-α were offered to mildly anemic simultaneous knee arthroplasty patients. A retrospective review, using ICD-9 codes, identified twenty patients from 2007-2009. Epoetin-α increased hemoglobin levels preoperatively (12.6 to 13.9, p<0.01). Twenty patients who did not receive epoetin-α were matched to study patients. Study patients were transfused less (55% vs 95%, p=0.012) and had similar inpatient length of stay. The average blood loss without transfusion was 4.6g/dL. The mildly anemic patient is at high-risk for packed red cell transfusion during simultaneous knee arthroplasty. Three preoperative doses of epoetin-α in the mildly anemic patient decreased total transfusions; however, it did not affect inpatient length of stay.

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Efficacy and Safety of a 5-Day Regimen of Azacitidine for Patients with High-Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v124.21.1929.1929 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1929-1929

Author(s):

Katsumichi Fujimaki ◽

Kazuho Miyashita ◽

Rika Kawasaki ◽

Naoto Tomita ◽

Yoshiaki Ishigatsubo

Keyword(s):

Overall Survival ◽

High Risk ◽

Adverse Events ◽

Blood Cell ◽

Median Time ◽

Median Overall Survival ◽

Line Therapy ◽

First Response ◽

Grade 3 ◽

Secondary Mds

Abstract Background: In the AZA-001 trial, azacitidine (AZA; 75 mg/m2per day for 7 consecutive days of every 28-day cycle) demonstrated improved survival compared with conventional care regimens in patients with high-risk myelodysplastic syndromes (MDS). Although a 7-day regimen of AZA is the standard treatment of high-risk MDS, it is difficult to administer AZA treatment in outpatient settings on weekends. In this study, we investigated outcomes of a 5-day regimen of AZA in patients with high-risk MDS. Methods: Clinical data were retrospectively collected from consecutive high-risk MDS patients treated with AZA at Fujisawa City Hospital. “High-risk MDS” was defined as MDS with transfusion dependency or MDS with an International Prognostic Scoring System (IPSS) risk of intermediate-2 or high. Every month, AZA was administered at 75 mg/m2per day: for 5–7 days in the hospitalization for the first cycle, and for 5 days in an outpatient center for all subsequent cycles. Patients with neutropenia received antimicrobial prophylaxis with levofloxacin. Responses to AZA were evaluated according to the International Working Group 2006 criteria. Results: Between April 2011 and December 2013, 50 patients with MDS (40 men and 10 women; age, 40–86 years; median age, 73 years) initiated the AZA treatment. All patients had an Eastern Cooperative Oncology Group performance status of 0–2. Thirty-nine patients had primary MDS and 11 patients had secondary MDS. According to the World Health Organization MDS classifications, 13 patients had RCMD, 12 had RAEB-1, 15 had RAEB-2, 1 had CMML and 9 had AML with 20–30% bone marrow blasts. The IPSS risk was intermediate-1 in 19 patients, intermediate-2 in 19 patients, and high in 11 patients. The IPSS of 1 RAEB-2 patient could not be estimated due to insufficient data of chromosome analysis. The cytogenetic risk, known for 49 patients, was good for 23 patients, intermediate for 14, and poor for 12. Thirty-six patients were red blood cell transfusion-dependent and 17 patients were platelet transfusion-dependent. With the exception of 1 AML patient who received AZA as consolidation therapy after induction of chemotherapy, all other 49 patients received AZA as first-line therapy. The median time to treatment from diagnosis was 1.5 months (range, 1–153). The median number of AZA cycles was 7 (range, 1–27). AZA was discontinued before the third cycle in 12 patients due to: 3 cases of hematopoietic stem cell transplantation, 2 cases of pneumonia, 2 cases of insufficient blood cell recovery, 1 case of cerebral hemorrhage, 1 case of gastrointestinal hemorrhage, 1 case of stomach cancer, 1 case of rash, and 1 case involving a geographical move. Among 37 patients who received more than 3 cycles of AZA as fist-line therapy, 23 (62%) achieved any hematological improvement. The median time to first response was 3 cycles (1–5). Hematological improvement was obtained irrespective of IPSS risk or of primary and secondary MDS classifications. Grade 3/4 neutropenia occurred in 39 patients, and grade 3/4 thrombocytopenia occurred in 38 patients. Most of these hematological adverse events occurred during cycles 1–2. The most common grade 3 or higher non-hematological adverse events were pneumonia (9 patients), febrile neutropenia (8 patients), and sepsis (5 patients). According to IPSS risk, median overall survival was 12 months (range, 1–24) in high risk MDS and 16 months (range, 1–28) in intermediate-2 risk MDS. Median overall survival in intermediate-1 risk MDS had not yet been reached (range, 6–29 months, p = 0.03). Median overall survival in primary and secondary MDS was 24 months (range, 1–29) in primary MDS and 12 months (range, 1–19) in secondary MDS (p = 0.05). Twenty-four patients died: 9 of overt leukemia, 9 of pneumonia, 2 of cerebral hemorrhage, 1 of sepsis, 1 of gastrointestinal hemorrhage, 1 of stomach cancer, and 1 of senility. Conclusion: In the AZA-001 trial, the median time to first response was 2 cycles. In our study, the median time to first response was 3 cycles. Although the first response was delayed, the 5-day regimen of AZA showed respectable continuation rates lasting longer than 3 cycles with equivalent efficacy to the 7-day regimen. Future studies comparing the 5-day regimen and the 7-day regimen would provide valuable follow-up information to the findings in this study. Disclosures No relevant conflicts of interest to declare.

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Updated Efficacy of Eltanexor Monotherapy in Patients with Higher Risk Hypomethylating Myelodysplastic Syndrome Primary Refractory to Hypomethylating Agents

Blood ◽

10.1182/blood-2021-151359 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3676-3676

Author(s):

Sangmin Lee ◽

Sanjay R Mohan ◽

Jessica Knupp ◽

Kamal Chamoun ◽

Igor Karasik ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Publicly Traded ◽

Advisory Committees ◽

Prior Therapy ◽

Transfusion Independence ◽

Secondary Mds

Abstract Background: Patients with higher-risk myelodysplastic syndrome (MDS) refractory to hypomethylating agents (HMAs) have limited therapeutic options and poor prognosis with a median overall survival (mOS) of 4-6 months. Lack of response to HMA therapy, advanced age at relapse, male sex, bone marrow blasts >5% and high risk disease classification by International Prognostic Scoring System (IPSS) confer worse outcomes. Eltanexor is a second-generation, oral, selective inhibitor of nuclear export (SINE) compound with markedly reduced brain penetration relative to selinexor in preclinical models. This is believed to result in attenuation of centrally mediated anorexia, weight loss, and nausea, allowing for more frequent dosing. Early results from a phase 1/2 study of eltanexor in patients with higher-risk HMA-refractory MDS demonstrated marrow complete responses (mCRs), hematologic improvement (HI) and stable disease (SD); side effects were primarily low-grade, dose-dependent, and reversible (Lee EHA 2021). Here we provide an update on baseline characteristics, blast reduction in mCR patients, extent of transfusion independence and additional subgroup analyses. Methods: This phase 1/2 study (NCT02649790) evaluated oral eltanexor monotherapy in patients with high-risk or intermediate-2 by IPSS and 5%-19% myeloblasts. Of 20 patients enrolled, 15 patients were evaluable for efficacy and constitute the population studied in this analysis; 5 patients were non evaluable for efficacy due to trial discontinuation prior to response assessment. Two doses of eltanexor were evaluated: 10 mg (n=5) or 20 mg (n=10) each given qd 5 days per week. Results: Amongst the 15 efficacy evaluable patients, there were 8 males, median age 76 years (range 62-89), 10.0% (range 7-18%) median bone marrow blasts at enrollment, and with a median of two prior regimens (range 1-4). All patients primary HMA-refractory MDS; 9 patients (60%) with high risk and 5 (33%) with intermediate-2 per IPSS, 1 with intermediate-1 per IPSS. Similarly, using the global MD Anderson Cancer Center risk prognosis model, 14 patients (93%) had intermediate-2 or high-risk MDS. The overall response rate (mCR+HI) was 53% including 47% mCRs. Additionally, 5 patients (33%) had SD. Median blast reduction in the 7 patients with mCR was 78.6% (range 55.6%, 85.7%). Four patients had hematologic improvement (HI) including 2 patients with tri-lineage HI. Of the 7 patients who achieved mCR, 4 had significant reduction in transfusion requirements with 3 of these patients achieving complete transfusion independence for 5-10 cycles. In the 10-mg cohort (n=5), all patients derived clinical benefit with 3 patients reaching mCR and 2 patients with SD. In the 20-mg cohort (n=10), 4 patients had mCR and 3 had SD. Median overall survival for all efficacy evaluable patients was 9.86 months. OS for patients who reached mCR (n=7) was significantly longer than for patients who did not reach mCR (n=8): median 11.86 vs 8.67 months (hazard ratio [HR]=0.27, p=0.05), and significantly longer than OS for patients with PD (n=3, mOS=3.15 months, HR=0.23, p=0.04). Notably, mCR was seen in the 3 patients treated with >2 prior therapies and/or with secondary MDS: 1 patient with secondary MDS and 4 prior therapies; 1 with secondary MDS and one prior therapy; and 1 with de novo MDS and 3 prior therapies). Conclusions: Single-agent oral eltanexor was active in patients with higher-risk, primary HMA-refractory MDS including those with secondary MDS or with >2 lines of prior therapy. Patients with mCR had significantly longer mOS than patients without mCR and had median blast reduction of 78.6%. Further evaluation of eltanexor in MDS as a single agent and in combination with other agents is ongoing. Disclosures Lee: Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mohan: Astex: Research Funding; Incyte: Research Funding. Knupp: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Chamoun: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Karasik: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Bai: Abbvie: Current equity holder in publicly-traded company; Takeda: Current Employment, Current equity holder in publicly-traded company; Karyopharm Therapeutics Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Ingalls: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Bhatnagar: Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Pfizer: Honoraria; Kite: Honoraria; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Novartis: Honoraria; Sumitomo Dainippon Pharma: Research Funding.

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