10 research outputs found
It’s all about the CD3+ T-cells: how circulating immune cell subset analyses can predict early relapse in Hodgkin lymphoma
Investigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin
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Haploidentical Donors in Addition to Transplantation in Chronic Phase Associate with Improved Gvhd-Free Relapse-Free Survival (GRFS) for Patients with Advanced CML
Abstract Introduction: Despite the successes of treatment with tyrosine kinase inhibitors (TKIs) in patients with CML, allogeneic hematopoietic stem cell transplantation (ASCT) continues to be a potentially curative option for patients with advanced disease of who fail TKI therapy. Here we analyzed outcomes of patients with advanced CML (aCML) (beyond first chronic phase-CP1) who received an ASCT at our institution to identify factors associated with improved survival. Methods:207 consecutive patients withaCML treated at The University of Texas MD Anderson Cancer Center after year 2000 were included. The median age was 44 years (range 2-70 years), 135 (65%) were male, 77% had less than 5% bone marrow (BM) blasts, 129 (65%) had persistentPh-chromosome positive, and 176 patients (85%) were less than a major molecular response at transplant. Forty of 114 tested patients (35%) had resistant BCR-ABL mutations and 10 patients (8.7%) had T315I mutation at transplant. Conditioning regimen wasmyeloablative (MAC) in 140 patients (68%). Donors were matched related (MRD), matched unrelated (MUD),haploidentical (HAPLO), mismatched unrelated (MMUD), umbilical cord blood (UCB) and 1Ag mismatched related (MMRD) in 79 (38%), 75 (36%), 18 (9%), 17 (8%), 11 (5%) and 7 (3%) patients, respectively. The median time from diagnosis to transplant was 27 months (range 1-318 months) while the median follow-up duration was 20 months (range 1-194 months). Results:At 30 days post-transplant, 180 of 200 tested patients (90%) and 134 of 201 tested patients (67%) achieved a complete cytogenetic and at least a major molecular response, respectively. The response to transplant by day 30assessment correlated significantly with the disease status before transplant. A higher percentage of patients who experienced cytogenetic response before transplant experienced molecular response post-transplant (77%) compared with those who did not (61%; p=0.027). For the entire group, the 1-year cumulative incidence (CI) of acute GVHD (aGVHD) grade II-IV and grade III-IV were 41% and 15%, respectively; 5-year CI of extensive chronic GVHD (cGVHD) was 31%.Haploidentical transplant patients had lesscGVHD compared with HLA matched donor transplants (14% vs. 32% for HLA matched transplants). The CI of non-relapse mortality at 100 days and 1 year was 14% and 30%, respectively. Sixty-five patients (31%) had molecular relapse after transplant, which correlated with the degree of disease control before transplant. The CI of cytogenetic and molecular relapse at 5 years was 22% and 31%, respectively. Overall the 5-year survival (OS), progression free survival (PFS) and GVHD-free, relapse-free survival (GRFS)was49%, 34%, and 22%, respectively. Adjusting for all significant measures, percentage of BM blasts before transplant and donor type were significantly associated with PFS and GRFS (Table1, Figure 1).Haplodenticaltransplant patients had longer PFS and GRFS compared with other donor types including matched related or unrelated donor (5-year GRFS for HAPLO, MRD, MUD, MMUD, UCB and MMRD were 53%, 19%, 23%, 29%, 9%, and 0%, respectively; p=0.033) (Table 1, Figure 1). Cytogenetic and molecular response before transplant as well as year of transplant did not predict survival after transplant. Conclusions: ASCT is curative for a proportion of patients withaCML. PFS and GRFS are favorably influenced by percentage of BM blasts and donor type, withhaploidentical donor having at least as good outcomes as HLA matched donors, while molecular and cytogenetic response before transplant do not appear to correlate with survival post-transplant. Table 1 Multivariable analysis for PFS and GRFS Table 1. Multivariable analysis for PFS and GRFS Figure 1 PFS and GRFS based on percentage of BM blasts before transplant and donor types Figure 1. PFS and GRFS based on percentage of BM blasts before transplant and donor types Disclosures Cortes: Arog: Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Research Funding; Ambit: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties. Ciurea:Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership
Incident Kaposi sarcoma during the expansion of antiretroviral therapy eligibility in Nigeria: a retrospective cohort study
Abstract Introduction The expansion of antiretroviral therapy (ART) eligibility could lead to earlier initiation of Human Immunodeficiency Virus (HIV) treatment and consequently reduce the risk of HIV-associated Kaposi Sarcoma (KS). We investigated the impact of changes in the Nigerian HIV treatment guidelines on KS incidence among adults enrolled in HIV care in Nigeria. Methods We analyzed data of adults who enrolled for HIV care from January 2006 to December 2016 at one of Nigeria’s largest HIV treatment centers. Based on changes in HIV treatment guidelines, we classified 2006–2009 as the pre-expansion period and 2010–2016 as the post-expansion period. We used Kaplan Meier curves to compare the incidence of KS in the pre-expansion to the post-expansion period. We used Cox regression models to assess the hazard for incident KS between the two periods after adjusting for potential confounders. Results Among 14,479 patients with HIV, the overall KS incidence was 2.35; 95% CI 2.01–2.74/1,000 person-years. The incidence of KS decreased from 2.53 to 1.58 per 1,000 person-years from 2006 to 2009 to 2010–2016. In models adjusting for age, sex, CD4-T cell count, and ART use, the risk for KS remained lower in 2010–2016 compared to 2006–2009. In analyses restricted to time on ART, there was no significant difference in KS incidence between HIV patients who enrolled in 2006–2009 and 2010–2016 after adjusting for age, sex, and CD4 T-cell count. Conclusion The expansion of ART eligibility was associated with a reduced incidence of HIV-associated KS among adults initiating HIV care in Jos, Nigeria. The reduction was likely driven by earlier enrollment for HIV care and ART initiation
Additional file 1 of Incident Kaposi sarcoma during the expansion of antiretroviral therapy eligibility in Nigeria: a retrospective cohort study
Additional file 1: Table S1. Characteristics of adults who initiated ART in Jos, Nigeria (2006-2018). Figure S1. Box plot of time from enrollment in care to initiation of antiretroviral therapy in adults with HIV in Jos, Nigeria (2006-2016). Table S2. Cox regression of predictors of Kaposi Sarcoma using Multiply Imputed Data from adults with HIV in Jos, Nigeria (2006-2016) (n=14,479, events=160). Table S3. Missing Data Pattern. Table S4. MICE model and corresponding populations and variables. Figure S2. MICE Mode A (Analytical Models 1 to 3). Figure S3. MICE Model B (Analytical Model 4) and MICE Model C (Analytical Model 5). Figure S4. MICE Model D (Analytical Model 6). Table S5. Cox Regression models of predictors of Kaposi Sarcoma among adults with HIV in Jos Nigeria (2006-2016). Table S6. Multivariate cox regression models of predictors of Kaposi Sarcoma among adults with HIV in Jos, Nigeria based on use of antiretroviral therapy (2006-2016
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Limitations to Receiving Allogeneic Hematopoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia: A Large Multi-Center Prospective Longitudinal Observational Study
Abstract
Introduction: Acute myeloid leukemia (AML) is most frequently diagnosed in older patients (pts), whose median survival is less than 1 year. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. However, older pts often have significant comorbidities and other geriatric health problems, and the effect of these on the probability of receiving HCT is unknown. To this end, we designed a prospective, multi-center, longitudinal, observational study dating from first presentation of adult pts with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We examined the effects of different variables (see methods) on the probability to 1) survive long enough to receive HCT and 2) to receive HCT if such survival occurred.
Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including instrumental activities of daily living (IADL) and activities of daily living (ADL); frailty including walk test; geriatric assessment (GA) including cognition; Karnofsky performance status (KPS); QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale (EQ-5D), ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. High-risk myelodysplastic syndromes (MDS) receiving AML-like therapy were included.
We used competing risk Cox regression analyses, treating HCT as the event of interest and death without HCT as a competing risk, with staggered entry (left truncation) at time of consent. Associations between variables were assessed both at enrollment and over time.
Results: The overall rate of HCT at 9 months after enrollment was 43% (Figure 1) and 92% of pts who received HCT did so by the 9 month mark.
In multivariate analyses, death without HCT (Table 2) was associated with augmented HCT-CI scores ≥5 (HR:2.11, p<0.0001), age ≥50 years with those aged ≥70 years having the highest association (HR:2.71, p<0.0001), ELN intermediate (HR:2.43, p=0.0003) or unfavorable risks (HR:4.3, p<0.0001), receiving low-intensity induction regimens (HR:1.42, p=0.04), relapsed/refractory disease at enrollment (HR:2.04, p<0.0001), dependent status per ADL scores <14 (HR:1.59, p=0.005), and depression per PHQ-9 (HR:1.56, p=0.009).
Among survivors (Table 3), low likelihood to receive HCT was associated with age ≥70 years (HR:0.40, p=0.0001), low ELN risk (HR:0.28, p<0.0001), low-intensity induction (HR:0.56, p=0.02), poor KPS (HR:0.49, p=0.0005), and relapse after initial complete remission (CR) (HR:0.41, p=0.001); while pts with high-risk MDS (HR:2.43, p<0.0001), relapsed/refractory disease at enrollment (HR:2.43, p<0.0001), and CR after induction (HR:4.59, p<0.0001) were more likely to receive HCT. Among pts aged ≥60 years, and after considering previous factors, impaired cognition (HR:0.45, p=0.007) and impaired hearing (HR:0.71, p=0.009) were associated with lower likelihood to receive HCT.
Conclusions: In a prospective, observational, multi-center study, increasing age, comorbidity burden, ELN risk, low-intensity initial AML induction regimen, depression, and functional dependence increase risks of early mortality without HCT.
In those who survived long enough to potentially receive HCT, age up to 69 years and/or multiple comorbidities were not found to be barriers to HCT, likely reflecting the widespread use of reduced-intensity conditioning regimens. However, the independent sharp decline in receipt of HCT in pts aged 70-80 years suggests continued bias, although pts in this age group have been shown to derive similar benefit from HCT as younger pts. Use of objective comorbidity and GA tools rather than age per se to decide on HCT is encouraged.
The adverse impact of impairments in psychological health and function on survival and of impairments of cognition, geriatric health, and performance status on receipt of HCT emphasize the need for interventions that target these health limitations in conjunction with AML treatment to improve outcomes.
Finally, the benefit of intensive vs. less-intensive induction therapies should be addressed with a randomized trial.
Disclosures
Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Rizzieri:Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang:Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Otsuka: Consultancy; Alexion: Consultancy, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding
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Survival Differences Among Patients (pts) with Acute Myeloid Leukemia (AML) Treated with Allogeneic Hematopoietic Cell Transplantation (HCT) Versus Non-HCT Therapies: A Large Real-Time Multi-Center Prospective Longitudinal Observational Study
Abstract
Introduction: Survival rates continue to improve after allogeneic HCT (Gooley et al, NEJM, 2013). Population-based studies also indicate overall improvement in survival of older (60-80 years old) AML patients (pts) (Bower, Blood Cancer Journal, 2016). Yet, only a small minority (6%-8%) of them receive HCT (Medeiros, Ann Hematol. 2015). Given these potentially incongruent findings and the changing face of survival in AML, we designed the first prospective multi-center longitudinal study dating from first presentation of adults with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We compared survival according to whether or not pts received HCT at later time points.
Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including activities of daily living (ADL); frailty; geriatric assessment including cognition; QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale, ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter.
We used time-dependent Cox regression analyses to identify baseline and time-dependent risk factors associated with mortality in the overall population. The factors identified as significantly associated with mortality (p<0.05) were used to develop multivariate models examining the association between HCT and mortality within 1) the general population as well as those with 2) intermediate vs 3) unfavorable ELN risk, and 4) vulnerable pts (age ≥60 years or HCT-CI scores ≥4). The latter group constituted the majority (76%). In these analyses, all pts were considered to be in the non-HCT group until receipt of HCT at which time they enter the HCT group. The contribution of deaths to the hazard ratio (HR) for HCT reflects the relative number and characteristics of pts remaining at risk in the two groups at the time a death occurs.
Results: Median follow-up was 16.8 months (range 0.1-52.4). In the initial multivariate analyses, the following were identified as significantly associated with an increased risk of mortality (Table 2): HCT-CI scores ≥5 (p<0.0001), age ≥70 years (p<0.0001), intermediate (p=0.03) and high ELN risk (p<0.0001), relapsed/refractory AML at enrollment (p=0.0005), relapse or refractory response to initial treatment after enrollment (p<0.0001), frailty per walk test (p=0.004), impaired QOL per FACT-G scores (p=0.02), increased depression per PHQ-9 (p=0.03), and dependent status per ADL scores <14 (p=0.05).
Survival after HCT was 58% at 2-years. Initial unadjusted analyses showed significantly lower risks of mortality in association with receiving allogeneic HCT (p=0.0003). These findings were similar in pts with intermediate (p=0.0005) or unfavorable (p<0.0001) ELN risk and in vulnerable pts (p<0.0001) (Table 3).
However, in the adjusted models, the advantage of HCT in reducing mortality rates was lost both in the overall population (p=0.21, see figure) as well as in the other groups (p>0.54, 0.40, and 0.51, respectively, Table 3). Formal tests of interactions (Table 3) showed no statistically compelling evidence that the association of HCT and mortality varies with respect to the timing of mortality or to the underlying ELN risk.
Conclusions: In a prospective observational study, adjusting for key AML-specific and pt-specific variables negated the observed benefit of HCT over non-HCT therapies in reducing mortality rates among AML pts. Our results might reflect 1) improvement in supportive care and non-HCT therapies, 2) a relatively high non-relapse mortality early after HCT and the need for longer follow-up to demonstrate an adjusted benefit of HCT, and 3) the high selectivity of the transplant eligibility process, as we accounted here for variables that are often ignored in "genetic assignment" randomized studies (i.e. comorbidities and function).
New randomized trials are needed; however, these trials have to be more inclusive of vulnerable pts and measure pt-specific variables. Trials focusing on reducing burden of comorbidities, frailty and poor function are needed alongside trials to treat AML with or without HCT.
Disclosures
Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Shami:JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy. Rizzieri:Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Alexion: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Otsuka: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding
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Limitations to Receiving Allogeneic Hematopoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia: A Large Multi-Center Prospective Longitudinal Observational Study
Older pts with AML often have significant comorbidities and other geriatric health problems, and the effect of these on the probability of receiving HCT is unknown. We designed a prospective, longitudinal, observational study of adult pts with AML dating from first presentation at one of 13 centers. We examined the effects of different variables on the probability to 1) survive long enough to receive HCT and 2) to receive HCT if such survival occurred.
We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), response, age, comorbidities per the HCT-comorbidity index (CI), function, frailty, geriatric assessment, cognition, Karnofsky performance status (KPS), QOL, social support, and depression were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter.
We used competing risk Cox regression analyses, treating HCT as the event of interest and death without HCT as a competing risk, with staggered entry (left truncation) at time of consent. Associations between variables were assessed both at enrollment and over time.
The overall rate of HCT at 9 months after enrollment was 43% (Figure 1) and 92% who received HCT did so by 9 months.
In multivariate analyses, death without HCT (Table 2) was associated with augmented HCT-CI scores ≥5, age ≥50 years with those aged ≥70 years having the highest association, ELN intermediate or unfavorable risks, receiving low-intensity induction regimens, relapsed/refractory disease at enrollment, dependent status per ADL scores <14, and depression per PHQ-9.
Among survivors (Table 3), low likelihood to receive HCT was associated with age ≥70 years, low ELN risk, low-intensity induction, poor KPS, and relapse after initial complete remission (CR); while pts with high-risk MDS, relapsed/refractory disease at enrollment, and CR after induction were more likely to receive HCT. Among pts aged ≥60 years, and after considering previous factors, impaired cognition and hearing had a lower likelihood to receive HCT.
Increasing age, comorbidity burden, ELN risk, low-intensity initial AML induction regimen, depression, and functional dependence increase risks of early mortality without HCT.
In those who survived long enough to potentially receive HCT, age up to 69 years and/or multiple comorbidities were not found to be barriers to HCT, likely reflecting the widespread use of reduced-intensity conditioning regimens.
The adverse impact of impairments in psychological health and function on survival and of impairments of cognition, geriatric health, and performance status on receipt of HCT emphasize the need for interventions that target these health limitations in conjunction with AML treatment to improve outcomes.
Finally, the benefit of intensive vs. less-intensive induction therapies should be addressed with a randomized trial