scholarly journals The Direct Medical Costs of Treatment Discontinuation Among Higher-Risk Myelodysplastic Syndrome Patients Receiving Hypomethylating Agents

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Namita Joshi ◽  
Hrishikesh P Kale ◽  
Shelby Corman ◽  
Kala Hill ◽  
Tim Wert ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Research Funding ◽  
Healthcare Spending ◽  
Medical Costs ◽  
Refractory Anemia ◽  
Cell Transplant ◽  
Hypomethylating Agents ◽  
Publicly Traded ◽  
Direct Medical Costs

Introduction: Non-persistence to treatment with hypomethylating agents (HMA) in higher-risk myelodysplastic syndrome (HR-MDS) patients can result in loss of response or ability to achieve a primary response. HMA treatment is recommended to be given to HR-MDS patients for least 4-6 treatment cycles to elicit a clinical response and premature termination is likely to result in poor outcomes and considerable healthcare spending. The study objective was to assess direct medical costs associated with HMA treatment non-persistence among HR-MDS patients. Methods: Using a retrospective cohort design, MDS patients with refractory anemia with excess blasts (RAEB) were analyzed using 2010-2016 Surveillance, Epidemiology and End Results-Medicare linked database. RAEB diagnosis is considered to substantially overlap with HR-MDS and has been used as a surrogate for HR-MDS. The study cohort included RAEB patients diagnosed between 01/2011 and 12/2015. Patients were included if they had ≥ 1 year of continuous Medicare enrollment prior to diagnosis and did not receive stem cell transplant or lenalidomide in the follow-up period. HR-MDS patients receiving HMAs were stratified into HMA persistent (receiving 4 or more HMA cycles without any gap of ≥90 days between cycles) and HMA non-persistent (receiving less than 4 cycles or a gap of ≥90 days between cycles) groups. Healthcare resource use (HCRU) and associated direct medical costs incurred during the follow-up period were described as per-patient-per-month (PPPM). To account for baseline differences between HMA persistent and non-persistent groups, propensity score-based inverse probability of treatment weights (IPTW) were calculated. Weighted HCRU and costs (PPPM) were further estimated using generalized linear models (GLMs). Costs were inflated to 2019 USD using medical component of consumer price index. Results: There were 664 patients identified with RAEB, of which 295 (44.4%) patients were classified in the HMA non-persistent group and 369 (55.6%) patients in the HMA persistent group. HMA persistent and non-persistent groups were similar in baseline demographic and clinical characteristics; however, non-persistent HMA users were older at diagnosis and a lower proportion of patients were married. Results from weighted GLM analysis indicated higher PPPM resource utilization in HMA non-persistent patients compared to HMA persistent patients specifically for hospitalizations (Incident rate ratio [IRR], 1.543, 95% Confidence interval [CI]: 1.181 - 2.018]), ER visits (IRR= 1.322, 95% CI: 1.146 - 1.524), SNF use (IRR = 2.158, 95% CI: 1.308 - 3.560), home health (IRR = 1.335, 95% CI: 1.039 - 1.714] and hospice care use (IRR = 2.555, 95% CI:1.972 - 3.309) (Table 1). Further, HMA non-persistent patients had significantly (P<0.05) higher total PPPM costs than HMA persistent patients ($18,039 vs. $13,893, p<0.05); particularly for hospitalizations ($3,375 vs. $2,131), and ER costs ($5,517 vs. $2,867) (Figure 1). Conclusions: A significant proportion of HR-MDS (RAEB) patients discontinue guideline-recommended HMA treatment. Non-persistence with HMA treatments was associated with substantial cost burden. The study findings call for closer care management by healthcare providers to ensure HMA treatment is completed as scheduled (unless directed otherwise by the provider) to manage outcomes and healthcare spending. Disclosures Joshi: Pharmerit International: Current Employment. Kale:Pharmerit International: Current Employment. Corman:Pharmerit International: Current Employment. Hill:Taiho Oncology: Current Employment, Current equity holder in publicly-traded company. Wert:Taiho Oncology: Current Employment, Current equity holder in publicly-traded company. Zeidan:Otsuka: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Astex: Research Funding; CCITLA: Other; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; MedImmune/Astrazeneca: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding.

Lack of Association Between Costs of Care and Overall Survival (OS) Among Medicare Beneficiaries with Myelodysplastic Syndromes (MDS) in the United States (US)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 873-873
Author(s):  
Amer M. Zeidan ◽  
Rong Wang ◽  
Amy J. Davidoff ◽  
Steven D. Gore ◽  
Pamela R Soulos ◽  
...  
Keyword(s):  
Research Funding ◽  
State Level ◽  
Refractory Anemia ◽  
Study Cohort ◽  
Hypomethylating Agents ◽  
Medicare Beneficiaries ◽  
Related Cost ◽  
Disability Status ◽  
One Year

Abstract Background: Blood products, supportive care, and hypomethylating agents (HMAs) are frequently used to improve outcomes of patients with MDS, and they may incur substantial costs. It is unclear whether disease-related costs of care are associated with OS in MDS patients. We evaluated the relationship between MDS-specific costs and survival among Medicare-enrolled beneficiaries with MDS in the US. Methods: The study cohort consisted of patients aged ≥66 years who were diagnosed with MDS (International Classification of Diseases for Oncology, 3rd edition, codes: 9980, 9982, 9983, 9985-7, 9989) between 1/1/2005 and 12/31/2011 in the linked Surveillance, Epidemiology, and End Results (SEER) - Medicare database. Only patients with continuous enrollment in Medicare Parts A and B from one year before MDS diagnosis through death or end of study follow up (12/31/2012) were included. OS was calculated from date of diagnosis to date of death, and patients alive at the end of the study were censored. Medicare payments were used to estimate costs and adjusted to 2012 US dollars. Cumulative costs in a matched group of cancer-free Medicare beneficiaries were subtracted from costs in the MDS cohort in each of the 12 SEER states to estimate MDS-related costs for each state. Comorbidities within one year before diagnosis were identified and used to calculate a modified Elixhauser comorbidity score and a disability status score (a proxy measure of performance status). We used 2-year OS for primary analysis as it was the major endpoint in several clinical trials evaluating MDS therapies. States were separated into 3 tertiles according to 2-year MDS-related costs per patient. Kaplan-Meier methods were used to compare OS probabilities at various time points, stratified by MDS-related cost groups (3 levels). Cox proportional hazard regression models were used to assess the impact of MDS-related costs (3 levels) on survival, controlling for age at diagnosis, sex, race, comorbidities, disability status, pre-diagnosis cost, median household income at the zip code level, "ever" use of HMA, and MDS histologic subtype. We also performed a sensitivity analysis involving patients who did not use any HMAs (HMA non-user subcohort) and separate analyses using 3-year MDS-related costs. Results: Of 24,347 patients diagnosed with MDS, 8,564 met eligibility criteria. Of those, 86.7% were white, 53.0% males, 52.5% ≥80 years at diagnosis, and 15.7% received hypomethylating agents (HMAs). By end of follow-up, 6,011 patients (70.2%) had died. Median follow-up was 1.57 years for all patients and 3.17 years for living patients. The 2-year OS was 48.7% and the median OS was 1.84 years. The median 2-year MDS-related cost of care per patient was $67,717 (California), and it ranged between $43,950 and $83,961 across 12 states. As expected, the costs were higher among HMA-users (Range: $109,447 - 156,156) than non-users (Range: $36,250 - 55,446). In a multivariate model of the entire study cohort, factors associated with improved survival included female gender, non-white race, younger age at diagnosis, refractory anemia and refractory anemia with ring sideroblasts histologic subtypes, pre-diagnosis health costs, and lower Elixhauser comorbidity and lower disability status scores. The 2-year state-level MDS-related cost was not associated with MDS survival [reference: lowest tertile, hazard ratio (HR) for middle tertile was 1.02, 95% confidence interval (CI): 0.93-1.12, p = 0.74, and HR for the highest tertile was 0.99, 95% CI: 0.92-1.06, p = 0.73] (Figure 1). Among the HMAs non-users (n=7,222), there was also no association between the 2-year MDS-related costs and MDS survival (Figure 2). When we conducted separate analyses using 3-year MDS-related costs, we observed no association between costs and survival in the overall study cohort or in the HMA non-user subcohort. Conclusions: Medicare expenditures for elderly patients with MDS varied substantially across states, but were not associated with overall survival. The lack of association between costs and outcome warrants additional research, as it may help identify potential areas for cost saving interventions without compromising outcomes. Figure 1. Survival of MDS patients by two-year state-level MDS-related costs per patient (in 3 levels); p=0.50. Figure 1. Survival of MDS patients by two-year state-level MDS-related costs per patient (in 3 levels); p=0.50. Figure 2. Survival of MDS patients who did not use any HMAs, by two-year state-level MDS-related costs per patient (in 3 levels); p = 0.15. Figure 2. Survival of MDS patients who did not use any HMAs, by two-year state-level MDS-related costs per patient (in 3 levels); p = 0.15. Disclosures Davidoff: Celgene: Consultancy, Research Funding. Gore:Celgene: Consultancy, Research Funding. Gross:21st-Century Oncology LLC: Research Funding; Johnson and Johnson: Research Funding; Medtronic: Research Funding. Ma:Incyte Corp: Consultancy; Celgene Corp: Consultancy.

scholarly journals First Results from a Nationwide Prospective Non-Interventional Study of Venetoclax-Based 1st Line Therapies in Patients with Acute Myeloid Leukemia (AML) - Revive Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Ofir Wolach ◽  
Itai Levi ◽  
Jonathan Canaani ◽  
Tamar Tadmor ◽  
Sigal Tavor ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Performance Status ◽  
Hypomethylating Agents ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Related Factors ◽  
Real World Setting

Background: The outcome of elderly patients with Acute Myeloid Leukemia (AML) is poor and treatment options in these high-risk groups are limited. Recently, venetoclax combinations with hypomethylating agents or low dose cytarabine were approved to treat patients with AML ineligible for intensive chemotherapy. However limited prospective data is available on the safety and efficacy of venetoclax treatment in routine clinical practice. Israel is among the first countries to have approved venetoclax-based combinations as first line therapy for AML and this treatment is fully reimbursed via the national health system. Here we present the initial results of a prospective, multicenter, nationwide trial that sought to assess the use of venetoclax-based therapy in a real-world setting. Methods: A prospective observational nationwide multicenter trial. Newly diagnosed patients with AML were enrolled at the time of venetoclax-based therapy initiation. Demographic, clinical and patient-related baseline characteristics were documented. Treatment patterns, safety and efficacy outcomes are reported. Patient related outcomes were assessed at baseline and after cycle 3 using the EQ-5D-5L and EORTC QLQ-C30 questionnaires. Results: A total of 70 patients were enrolled between August 2019 and June 2020 (data cut off) with a median age of 75 years (range 45-88) and a median follow-up of 74 days (8-232). Two-thirds of patients were males (62.9%). Over one-quarter (28.6%) of patients had an ECOG performance status of 2 or higher; the median modified Charlson Comorbidity Index (CCI) was 0 (range 1-4) with 27.1% with a CCI ≥2. De-novo AML was documented in 44.3%, secondary AML was diagnosed in 52.8% (secondary to MDS (27.1%), MPNs (11.4%) and therapy related AML (14.3%)). European LeukemiaNet (ELN) risk category was favorable, intermediate and adverse in 8.6%, 30% and 42.9%, respectively (Table 1). Time from diagnosis to initiation of therapy was 8 days (median, range 1-38). The main reasons for choosing venetoclax-based low intensity therapy as reported by treating physicians were patient related factors (mainly age>75 years, performance status) in the majority of cases and adverse disease biology predicting poor response to intensive chemotherapy in 17.1%. Of the 57 patients with available data, 38 (67%) initiated therapy in an inpatient setting with a median hospitalization duration of 12 days (range 1-62 days) and 19 (33%) patients started therapy as outpatients. By data cutoff, of 63 patients that initiated therapy 45, 23 and 7 patients completed cycle 1, cycle 3 and cycle 6 assessments, respectively. Complete remission (CR) or CR with incomplete count recovery (CRi) was achieved in 23/44 (52.3%) patients that were assessed for best response. Of responding patients, 6 (23%, 5 CRi and 1 Partial Remission (PR)) went on to receive an allogeneic transplantation (median age 70.5 years). Ninety percent of patients received venetoclax in combination with hypomethylating agents (azacytidine n=56, decitabine n=1). The full dose of 400mg was administered in 87% of cases with a median ramp-up duration of 3 days. Dose interruptions, dose modifications and dose discontinuations during follow-up were frequent and occurred in 41%, 35% and 27%, respectively. During therapy 63.5% of patients experienced adverse events (AE) of any grade; severe AE's were recorded in 41.3% of patients. Febrile neutropenia was documented in 22.2% and Tumor Lysis Syndrome (TLS) was documented in 2 patients (grade 2; 3.2%). Early death rates at 30 and 60 days were 6.3% and 11.1%, respectively. Conclusion: In the real-world setting venetoclax-based therapies are effective and associated with manageable toxicity including in the outpatient setting. In routine practice patient-related factors and disease-related factors (disease-risk) both seem to play a role in choice of therapy. Venetoclax treatment in real-life practice in Israel appears to follow general recommendations, is tolerable with approximately 90% of patients achieving target dose. These observational data are expected to provide information on patient selection patterns, efficacy and safety and patient related outcomes in patients not in clinical trial. Table Disclosures Wolach: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures and Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Amgen: Other: Fees for lectures and Consultancy; Janssen: Other: Fees for lectures and Consultancy. Levi:Abbvie Inc: Consultancy, Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Tavor:Abbvie: Consultancy, Honoraria, Research Funding. Hellmann:Abbvie: Research Funding. Stemer:Abbvie: Research Funding. Cohen:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Afik:Abbvie Inc: Current equity holder in publicly-traded company. Ofek:Abbvie Inc: Current Employment. Banayan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Kan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Grunspan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Ofran:AbbVie: Membership on an entity's Board of Directors or advisory committees. Moshe:Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding.

Chromosomal Abnormalities In Philadelphia Chromosome (Ph)-Negative Metaphases Appearing During Second Generation Tyrosine Kinase Inhibitors (2nd TKI) Therapy In Patients (pts) with Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1232-1232
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
A. Megan Cornelison ◽  
Tapan Kadia ◽  
Mary-Alma Welch ◽  
...  
Keyword(s):  
Organ Failure ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Refractory Anemia ◽  
Cell Transplant ◽  
Trisomy 8 ◽  
Cytogenetic Abnormalities

Abstract Abstract 1232 The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized in pts with CML. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. This phenomenon has not yet been systematically assessed to date in patients treated with 2ndTKIs such as dasatinib, nilotinib and bosutinib. By definition, this phenomenon is evaluable only among pts who achieve at least a minor cytogenetic response. We assessed the frequency and the significance of this event among 453 pts with CML treated with 2nd TKIs either after imatinib failure (n=299; 124 pts treated with dasatinib, 116 pts treated with nilotinib, and 59 pts treated with bosutinib) or as frontline therapy (n=154; 76 pts treated with dasatinib, and 78 pts treated with nilotinib) between June 2003 and August 2010. After a median follow-up of 37 months (range, 12–67 months), 41 pts (9%) 35 in chronic phase, 2 accelerated phase, and 4 in blast phase) receiving dasatinib (n=11), nilotinib (n=21) or bosutinib (n=9) developed 72 chromosomal abnormalities in Ph-negative metaphases. 32 (44%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of the 2nd TKI to appearance of abnormalities was 8 months (range, 2 – 57 months). The most common cytogenetic abnormalities were: –Y (n=7, 10%), trisomy 8 (n=6, 8%), and del20q (n=5, 7%). Excluding loss of chromosome Y abnormalities and abnormalities observed in only one metaphase, the incidence was 4%. At the time abnormalities were detected, 33 pts were in major cytogenetic response (complete in 26) and 8 in minor cytogenetic response. In all but 14 pts, these events have been transient and disappeared after a median of 3 months (range, 1 – 42 months). In14 pts (+8 n=3, -Y n=3, and del20q n=2), they persisted for a median of 10+ months (range, 3+-60+ months). One pt on dasatinib developed refractory anemia with ringed sideroblasts (associated with trisomy 8); she had CML for 16 years, failed prior therapy with interferon, imatinib, and nilotinib, and achieved a complete cytogenetic response on dasatinib for 24 months, lost her response, progressed and died of multiple organ failure. None of the other pts had any features of myelodysplasia. At the last follow-up, all but 7 pts are alive: 29 in major cytogenetic response (complete in 24), 1 in minor cytogenetic response, and 4 alive with disease. Causes of death included stem cell transplant related morbidities (n=2), multisystem organ failure related to sepsis (n=2), and unknown causes (n=3). We conclude that cytogenetic abnormalities occur in Ph-negative cells in a small fraction of pts (9%; 4% if loss of Y and abnormalities in one metaphase are excluded) treated with the 2nd TKIs. These are frequently transient and usually have no clinical significance, but in rare instances they could signal the emergence of a new malignant clone. Disclosures: Jabbour: Novartis: Honoraria; BMS: Honoraria. Kadia:Novartis: Consultancy. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.

ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14 ◽  
Author(s):  
Tae Min Kim ◽  
Nehal Lakhani ◽  
Justin Gainor ◽  
Manali Kamdar ◽  
Philip Fanning ◽  
...  
Keyword(s):  
Immune Response ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Tolerability Profile ◽  
Low Grade ◽  
Publicly Traded ◽  
Private Company ◽  
Non Hodgkin Lymphoma ◽  
Time Of Presentation

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. The high affinity CD47 blocker fusion protein, ALX148, is linked to an inactive immunoglobulin Fc region to minimize toxicity. ALX148 is half the size of an antibody, has been well tolerated, and enhances the innate and adaptive immune response against cancer in combination with anticancer therapeutics across solid and hematologic tumors (ASCO 2020 #3056, EHA 2020 #EP1247). Characterization of ALX148's tolerability profile and antitumor activity in combination with rituximab are reported in patients (pts) with non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW or 15 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety population was dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Data are reported as of 30Jun2020 in these fully enrolled cohorts with final data to be updated at the time of presentation. Results: A total of 33 patients with NHL were administered ALX148 in combination with rituximab. Twenty-two pts with median age of 66 years (range 32-80) were administered ALX148, 10 mg/kg QW (ALX10), in combination with rituximab [DLBCL, n=11; mantle cell lymphoma (MCL), n=4; follicular lymphoma (FL), n=5; and marginal zone lymphoma (MZL), n=2]. Eleven pts with median age of 64 years (range 53-78) were administered ALX148, 15 mg/kg QW (ALX15), in combination with rituximab (DLBCL, n=6; MCL, n=1; FL, n=3; and MZL, n=1). There have been no DLTs reported in the fully enrolled safety cohorts, and the MTD of ALX148 in combination with rituximab has not been reached. The maximum ALX148 administered dose is 15 mg/kg QW. Twenty-eight pts experienced any AE, while 16 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (21%, n=7), fatigue (9%, n=3), anemia, nausea, neutropenia, and pruritus (6%, n=2 each). With a median follow up of 14 months, objective responses were observed across all histologies in response-evaluable ALX10 pts: 40.9% ORR (4CR,5PR, 6SD, n=22 total) and with a median follow up of 9 months in ALX15 pts: 63.6% ORR (3CR, 4PR, 1SD, n=11 total). Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Final results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with durable responses in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity and favorable PK/PD characteristics in combination with rituximab were observed at all dose levels with greater objective response rates reported at the MAD of 15 mg/kg QW. Disclosures Kim: Boryung: Consultancy; Voronoi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding; AstraZeneca: Consultancy. Lakhani:incyte: Research Funding; merck: Research Funding; mersana: Research Funding; northern biologics: Research Funding; odonate: Research Funding; pfizer: Research Funding; ikena: Research Funding; symphogen: Research Funding; taiRx: Research Funding; tesaro: Research Funding; livzon: Research Funding; loxo: Research Funding; macrogenics: Research Funding; inhibRx: Research Funding; cytomx: Research Funding; formation biologics: Research Funding; forty seven inc: Research Funding; alexion Pharmaceuticals: Research Funding; Alpine Biosciences: Research Funding; ALX Oncology Inc.: Research Funding; Apexian: Research Funding; asana biosciences: Research Funding; ascentage pharma: Research Funding; beigene: Research Funding; celgene: Research Funding; cerulean pharma: Research Funding; constellation pharma: Research Funding; coordination therapeutics: Research Funding; regeneron: Research Funding; sapience therapeutics: Research Funding; shattuck labs: Research Funding; innovent bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; jounce therapeutics: Research Funding. Gainor:theravance: Consultancy; adaptimmune: Research Funding; ariad: Research Funding; astrazeneka: Research Funding; blueprint medicines: Research Funding; lily: Consultancy; gilead sciences: Consultancy; merck: Consultancy, Research Funding; moderna therapeutics: Consultancy, Research Funding; tesaro: Research Funding; blueprint medicines: Consultancy; novartis: Research Funding; oncorus: Consultancy; regeneron: Consultancy; bristol-myers Squibb: Consultancy, Research Funding; amgen: Consultancy; array biopharma: Consultancy, Research Funding; agios: Consultancy; ironwood pharmaceuticals: Consultancy; takeda: Consultancy; genentech: Consultancy, Research Funding; jounce therapeutics: Consultancy, Research Funding. Kamdar:Roche: Research Funding. Fanning:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Squifflet:ALX Oncology Inc.: Consultancy; IDDI: Current Employment. Jin:ALX Oncology Inc.: Current Employment. Forgie:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company; Pfizer Inc.: Ended employment in the past 24 months. Wan:Tallac Therapeutics: Current Employment, Current equity holder in private company; ALX Oncology Inc.: Consultancy, Current equity holder in publicly-traded company. Pons:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Randolph:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Kim:F. Hoffmann-La Roche: Research Funding; Pfizer: Research Funding; JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 945-945 ◽  
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.

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 ◽  
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.

Outcome After Failure to Second Generation Thyrosine Kinase Inhibitors(TKI) Treatment as Frontline Therapy for Patients with Chronic Myeloid Leukemia (CML) In Chronic Phase(CP).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3442-3442
Author(s):  
Alireza Eghtedar ◽  
Hagop Kantarjian ◽  
Elias Jabbour ◽  
Susan O'Brien ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Subsequent Treatment ◽  
Cell Transplant ◽  
2Nd Generation ◽  
Frontline Therapy

Abstract Abstract 3442 Background: Imatinib has been the standard frontline therapy for patients with CML in early CP. 2nd generation TKIs (nilotinib, dasatinib) have been reported to be more effective than imatinib as frontline therapy in rates of response and transformation. Nilotinib has received regulatory approval for this indication and others (dasatinib, bosutinib) may come soon. Although fewer patients are expected to experience failure to therapy with the use of these agents, these patients will represent a management challenge. The characteristics, management and outcome of patients who fail therapy with 2nd generation TKI used as initial therapy has not been reported. Aim: To analyze the characteristics of patients who fail therapy with 2nd generation TKI used as initial therapy, their management, and outcome after failure to initial therapy. Methods: Two parallel studies of 2nd generation TKI as initial therapy for CML early CP are being conducted at MDACC, one with nilotinib and one with dasatinib. The study with nilotinib includes also patients in accelerated phase (AP) that have received no other prior therapy. The records of all patients who were taken off therapy from these trials were reviewed to investigate the reasons for failure, subsequent management and outcome. Results: A total of 172 pts have been treated with dasatinib (n=82) or nilotinib (n=90; 9 in AP) since 2005. After a median follow-up of 18.9 months, 23 pts (14%) have discontinued therapy: 13 (16%) pts in the nilotinib study (2 of them treated in AP), and 10 (12%) in the dasatinib study. Their median age 48 years (range:19–73) and they had received therapy with nilotinib or dasatinib for a median of 5.2 (0.03-48) months. Reasons for nilotinib treatment discontinuation include: toxicity 4 pts (elevated lipase, acute pancreatitis + atrial fibrillation, pericardial effusion and acute renal failure, one each), transformation to blast phase (BP) 3 pts (2 of them treated in AP), and other reasons 6 pts (2 each for insurance issues, patient request and non-compliance). Reasons for discontinuation of dasatinib include: toxicity 5 pts (2 pleural effusion, 1 prolonged thrombocytopenia, 1 bone pain, 1 congestive heart failure), 2 pts for loss of response, and 3 pts for pts' choice. Best response to frontline treatment with nilotinib or dasatinib was 6 (26%) pts major molecular response, 6 (26%) pts complete cytogenetic response, 1 (4%) pt partial cytogenetic response, 3 (13%) pts minor cytogenetic response, 1 (4%) pt with no response and 6 (26%) pts nonevaluable. At the time of failure 18 pts were in CP, 4 pts in BP (one pt transformed shortly after discontinuation) and 1 AP. At the time of treatment interruption, 14 pts had BCR-ABL sequencing and 2 were found to have mutations (F359C, Y253H); 3 pts had new additional chromosomal abnormalities (ie, clonal evolution). Subsequent treatment after failure to initial therapy include: imatinib in 8 pts, nilotinib in 2 pts, dasatinib 1 pt, Hyper CVAD with dasatinib 1 pt, Hyper CVAD with imatinib 1 pt, stem cell transplant 2 pts, bafetinib 1 pt, and unknown 4 pts (lost to follow-up). One pt died shortly after failure without further therapy. Best response to subsequent therapies were 1 pt with CMR (after stem cell transplant), 7 pts with MMR (3 pts after imatinib, 1 pt after dasatinib, 1 pt after nilotinib, 1 pt after Hyper CVAD with imatinib and 1 pt after stem cell transplant), 1 pt CHR, 1 pt minor CyR, 3 pts without response, and 8 pts were not evaluable. Of the 5 pts that achieved MMR with subsequent TKI, all were in CP and had discontinued initial therapy because of toxicity (4 pts) or personal reasons (1pt). Median duration of ongoing subsequent treatment is 8 months (range 1.7–25). The survival rate after a median follow-up of 3.9 months since failure to frontline therapy is 87%. Conclusion: Failure after frontline therapy with second generation TKI is an uncommon event, most frequently associated with toxicity or patient preference. Most of these patients respond well to alternative TKI. This adequate response should alleviate the fear of not having available effective therapy if patients fail to respond to 2nd generation TKI when used as frontline therapy. Disclosures: Kantarjian: BMS: Research Funding; NOVARTIS: Research Funding. Cortes:BMS: Research Funding; NOVARTIS: Research Funding; Pfizer: Consultancy, Research Funding.

Clofarabine, Idarubicin, and Cytarabine (CIA) As Frontline Therapy for Patients Younger Than 61 Years with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1550-1550
Author(s):  
Aziz Nazha ◽  
Farhad Ravandi ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
De Novo ◽  
Phase Iii ◽  
Molecular Profile ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Elevated Bilirubin

Abstract Abstract 1550 Background: Clofarabine is a second generation nucleoside analogue with activity in adults with AML. A recent randomized phase III study in AML relapse showed higher response rates and better event-free survival with the combination of clofarabine and cytarabine (CA) compared to cytarabine alone. We have also reported the feasibility and safety of the addition of idarubicin to CA (CIA) in a previous phase I and II study. To explore this combination further, we conducted a phase II study of CIA in pts</= 60 years with previously untreated AML. Patients and Methods: Patients (Pts) were eligible if they were </=60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, cardiac ejection fraction < 45%, or active and uncontrolled infection. For the first 30 pts, induction therapy consisted of Clofarabine 22.5 mg/m2 iv daily (days 1–5), Idarubicin 6 mg/m2 daily (days 1–3), and Cytarabine 0.75 g/m2 daily (days 1–5). From pt 31 onward, induction doses were amended to Clofarabine 20 mg/m2 × 5, Idarubicin 10 mg/m2 × 3, and Cytarabine 1 g/m2 × 5. Pts who have not achieved a complete remission following the induction could receive one re-induction course. Pts in CR or CRp continued with up to 6 consolidation cycles with Clofarabine 22.5 mg/m2 × 3, Idarubicin 6 mg/m2 (days 1–2), and Cytarabine 0.75 g/m2 × 3, subsequently amended to Clofarabine 15 mg/m2 × 3, Idarubicin 8 mg/m2 × 2, and Cytarabine 0.75 g/m2 × 3. Supportive care was standard. Pts ≥ 50 yrs were admitted to a laminar air flow room for the duration of the induction. Results: From April 2010 until August 2011, 51 pts have been accrued with a median age of 49 yrs (range 19–59): 33 pts (65%) with de novo AML and 18 pts (35%) with secondary AML (18 related to MDS, 7 related to therapy). Three pts (5%) had a PS of 2. Median WBC at diagnosis was 3.4 × 109/L (0.6-92.3). Thirty-three (65%) pts had abnormal cytogenetics (21/33[64%] poor risk and 5/33 [15%] intermediate risk). Molecular profile: 6 pts (11%) had FLT3/ITD, 3 pts (6%) CEBPA, and 8 pts (16%) NPM1 mutations. Thirty-five pts (69%) achieved CR and 1 (2%) CRp for an overall response rate (ORR) of 71%. 61% pts (31/51) achieved CR following one induction cycle. 18% (9/51) pts required a re-induction and 44% (4/9) of them responded after the re-induction. Responding pts received a median of 2 courses (1–8) courses. With a median follow-up of 23 weeks (3–36+) median remission duration has not been reached with a 1-yr remission probability of 85%. Ten pts (19%) died on study including 2 (4%) who died < 28 days from treatment start (one from septic shock and multi-organ failure, and one from Steven Johnson syndrome). Median overall survival (OS) for responding pts has not been reached (2–36 weeks). One-yr survival probability is 65%. Sixteen pts (31%) proceeded with an allogenic stem cell transplant in CR1. Most toxicities were </= grade 2 and included rash (41 %), nausea (29%), diarrhea (23%), elevated transaminases (21%), and elevated bilirubin (17%). Toxicities > grade 2 included elevated bilirubin (4%), hypokalemia (4%), cellulitis (4%) and seizure (1%). Myelosuppression was ubiquitous but prolonged myelosuppression > 42 days was infrequent. 76 % (39/51) pts had neutropenic fever. Conclusion: Clofarabine, Idarubicin and Cytarabine achieve a response rate of 71% in patients </=60 yrs with previously untreated AML. Induction mortality was low and the toxicity profile was expected and manageable. Longer follow up and comparisons with standard induction therapy will be needed to further assess the role of this combination in AML therapy. Disclosures: Off Label Use: Clofarabine, use of Clofarabine in AML. Ravandi:Genzyme: Research Funding. Kantarjian:Genzyme: Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3150-3150 ◽  
Author(s):  
Raymond L. Comenzo ◽  
Daniel E Fein ◽  
Hani Hassoun ◽  
Christina Bello ◽  
Joanne F Chou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Initial Therapy ◽  
Novel Agents ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematologic Response

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

Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Survival for Patients with Chronic Myelomonocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4347-4347 ◽  
Author(s):  
Piyanuch Kongtim ◽  
Uday R. Popat ◽  
Antonio M. Jimenez ◽  
Sameh Gabella ◽  
Riad O. El Fakih ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Hypomethylating Agents ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Unrelated Donors ◽  
Conditioning Regimens

Abstract Introduction Allogeneic hematopoietic stem cell transplant (allo-SCT) is the only curative treatment modality for patients with CMML. Here we retrospectively reviewed the data for patients with CMML who received an all-SCT at our institution to identify factors associated with improved survival and determine whether treatment with hypomethylating agents (HMA) before transplant improves survival for these patients. Methods All 83 patients 18 years of age or older with a diagnosis of CMML confirmed at The University of Texas MD Anderson Cancer Center who underwent allo-SCT between April 1991 and December 2013 were identified through review of the institutionÕs medical records and included in this analysis. Forty, 7, and 36 patients had CMML-1, CMML-2 and CMML that had progressed to AML (CMML/AML) respectively. The median age was 57 years. CMML specific cytogenetic risk at diagnosis (Such E, hematologica, 2011) was good, intermediate, and high risk in 46, 19, and 18 patients respectively. Seventy-eight patients received induction treatment before transplant, 37 receiving HMA (either 5-azacytidine or decitabine) for at least 3 courses and 41 receiving 1-2 courses of cytotoxic chemotherapy. Among the patients who received induction therapy, 15 patients in HMA group and 9 patients in convention chemotherapy group achieved a complete remission before transplant. Thirty, 47 and 6 patients received transplants from matched related donors (MRD), matched unrelated donors (MUD), and mismatched related or unrelated donors (MMD), respectively. The sources of hematopoietic stem cells were peripheral blood for 48 patients (57.8%) and bone marrow for 35 patients (42.2%). Conditioning regimens varied; most patients received either fludarabine in combination with busulfan or fludarabine combined with melphalan. Sixty-four patients received myeloablative and 19 patients received reduced intensity conditioning regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Patient and transplant characteristics did not significantly differ between the patients treated with HMA and the patients treated with conventional chemotherapy or given supportive care alone. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), Treatment related mortality (TRM), relapse incidence through last follow-up and incidences of acute GVHD and chronic GVHD. All of these outcomes were measured from the time of allo-SCT. Results Median follow up duration for 29 survivors was 48 months. Seventy-five patients engrafted (90.4%) with median time to neutrophil and platelet engraftment of 13 and 15 days respectively. Patients treated with a HMA had a significantly lower cumulative incidence (CI) of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03), whereas TRM at 1 year post-transplantdid not significantly differ between the groups (27% and 30%, respectively; p=0.84). Acute GVHD all grades and grade 2-4 were seen in 28.2% versus 35.8% (p=0.05) and 12.8% versus 11.3% (p=0.72) in patients who received a HMA compared to those who treated with other agents respectively. CI of chronic GVHD was 35% in patients treated with a HMA versus 19.2% in those treated with other agents (p=0.36) while CI of chronic extensive GVHD was seen in only 26.7% versus 19.2% respectively (p=0.64). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a HMA (43%) than in those who received other treatments (27%; p=0.04) (Figure 1). However, therapy with HMA before transplant did not significantly influence the 3-year OS rate (45% in those treated with HMA and 39% in those treated with other agents; p=0.22). The independent prognostic factors for PFS were a blast count of < 5% before transplant (HR 0.36, 95%CI 0.14-0.78), treatment with a HMA (HR 0.44, 95% CI 0.23-0.86), a transplant from an MRD (HR 0.41, 95% CI 0.22-0.94), development of grade 2-4 acute GVHD (HR 2.7, 95% CI 1.27-5.77), and development of chronic GVHD (HR 0.15, 95% CI 0.05-0.45). Conclusion We conclude that treatment with hypomethylating agents before allo-SCT may improve survival in patients with CMML. Figure 1. Progression free survival Figure 1. Progression free survival Disclosures Alousi: Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

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