Primary therapy for older patients with aggressive histology lymphoma

Author(s):  
Ralph M Meyer ◽  
C. Tom Kouroukis ◽  
Julie Makarski
Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3197-3197
Author(s):  
Efstathios Kastritis ◽  
Marie-Christine Kyrtsonis ◽  
Evdoxia Hatjiharissi ◽  
Argiris S. Symeonidis ◽  
Amalia Vassou ◽  
...  

Abstract WM is a disease of the elderly with a protracted course in many patients. There are limited data which indicate that several WM patients die due to causes which are not directly related to their underlying malignancy. However, the realization and the estimation of the contribution of unrelated mortality in WM are important for the design of treatment strategy in patients of advanced age. To our knowledge there are no such data published for WM patients. Thus, we analyzed the outcomes of 408 patients with symptomatic WM who received therapy within the centers of the Greek Myeloma Study Group in order to assess disease related survival. In this analysis unrelated death was considered to be a competing risk event. Causes of death other than WM, treatment toxicity or myelodysplasia/transformation were considered as unrelated deaths. Median age of patients was 68 (28-92) years; 21% were >75 years and 9% were ≤50 years of age. Patients who started therapy after 2000 were older (median age 70 vs. 65 years before 2000, p<0.001) while 25% were >75 years (vs. 13% before 2000). In terms of ISSWM stage, more patients had high and intermediate risk disease after 2000 (41% & 42% vs. 25.5% & 38% before 2000, p<0.001), probably due to increased proportions of older patients in the recent era. Only 4% of patients before 2000 vs. 79% after 2000 received primary therapy with rituximab; however, similar rates of at least 50% IgM reduction were recorded (63% vs. 58%, p=0.361). Median follow up for all patients was 5.5 years (9 years in the pre-2000 and 4.5 years in the post-2000 group) and 52% of patients have died (77% in the group before 2000 and 40% in the group after 2000). However, 23% of deaths were considered unrelated to WM. Thus, 5-year and 8-year overall survival (OS) was 70% and 54% respectively, with a median OS of all patients of 8.8 years. When we performed survival analysis with unrelated deaths as competing risk, then 5-year risk of WM-related death was 21.4% (95% CI 17-26%) and of unrelated death was 7.6% (95% CI 5-10.5%), while 8-year WM-related death rate was 32% (95% CI 27-37%) and unrelated death 11.5% (95% CI 8-15%). Because older patients are at higher risk of unrelated deaths we performed an age-specific analysis. The median survival of patients >75 years was 5.3 vs. 9.7 years for patients ≤75 years (p<0.001). However, for patients >75 years, the 5-year death rate due to WM was 22% (95% CI 13-32%) vs. 21% (95% CI 16-26%) for patients ≤75 years (p=0.193), while the 5-year unrelated death rate was 17% (95% CI 10-27%) and 5.1% (3-8%), respectively (p<0.001). Thus, in patients with advanced age (>75 years) >40% of deaths are unrelated to WM, while WM-specific death rates were similar for patients >75 or ≤75 years. In patients ≤50 years there were no WM-unrelated deaths. We then evaluated the prognostic significance of IPSSWM, which discriminated 3 groups with 5-year overall survival of 86%, 68% and 51% for low, intermediate and high risk groups, respectively (p<0.001). However, because intermediate and high risk IPSS groups are enriched for older patients we performed the analysis with unrelated deaths as competing event. The 5-year WM-specific death rate was 10%, 19% and 27% for the three risk groups (p=0.035), while the 5-year unrelated death rate was 1.5%, 5% and 14%, respectively (p=0.003). The median OS for patients who started therapy before and after 2000 was similar (9 vs. 8.1 years, respectively, p=0.474). However, when we performed competing event survival analysis, then the 5-year WM-related death rate was 21% for both groups, but the 5-year unrelated death rate was 4.6% for patients before 2000 vs. 9.1% for patients after 2000 (p=0.026). Thus, the lack of a significant improvement of survival after the era of monoclonal antibodies is partly due to the doubling of WM-unrelated deaths as a result of the increasing numbers of patients of advanced age who are diagnosed and treated for WM. Additional follow up is needed for patients after 2000 in order to evaluate the WM-related risk of death at later time points (at 10 or 15 years). In conclusion, this is the first analysis in a large cohort of patients with symptomatic WM in which WM-unrelated death is treated as a competing risk. Many patients of advanced age die of causes unrelated to WM and this fact should be taken into account in the evaluation of long term outcomes and the design of clinical trials in patients with WM, especially since more patients of advanced age are diagnosed and treated for WM. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 422-422 ◽  
Author(s):  
Jeffrey Lancet ◽  
Maria R. Baer ◽  
Larry D. Cripe ◽  
Alan F. List ◽  
John F. Marcelletti ◽  
...  

Abstract Pgp expression in AML increases with age and adversely affects treatment response and survival. Zosuquidar is a potent and highly specific Pgp inhibitor with minimal pharmacokinetic (PK) interaction with conventional xenobiotic antineoplastics. Previous studies established that plasma concentrations &gt; 170 ng/mL achieve complete functional inhibition of Pgp. Prolonged Pgp blockade is necessary to optimize antineoplastic sensitization in resistant cells in vitro, but was not applied previously. Specifically, the 72-hour CIV schedule of zosuquidar in this trial differs from the 6-hour infusion employed in the E3999 Phase III trial of this agent. We initiated a Phase I/II trial of zosuquidar as a 72-hr CIV in older patients with newly diagnosed AML. Objectives of the Phase I study were to establish safety and determine the dose necessary to achieve a sustained zosuquidar plasma level &gt; 170 ng/mL with in vivo validation of Pgp functional inhibition. Eligibility included ages 55–75, ECOG PS 0–2, adequate end-organ function, and Pgp activity by functional assay (Phase II only). Phase II objective is to determine the complete remission rate (CR) in Pgp+ patients. Planned zosuquidar dose levels of 700 mg/d and 800 mg/d were based upon PK modeling predicting achievement of plasma inhibitory concentrations [&gt; 170 ng/mL] in 93% and 97% of patients, respectively, within 4 hours. Zosuquidar was initiated 4 hrs prior to the first doses of DNR (45 mg/m2/d x 3d) and ARA-C (100 mg/m2/d CIV x 7d) and continued for 72 hrs. Patients who achieved a CR received up to 2 cycles of consolidation with the same agents using an abbreviated schedule. The Phase I portion of the trial has been completed with 16 patients: 10 patients received 700 mg/d of zosuquidar and 6 patients, 800 mg/d. The median age was 66; M/F was 9/7; cytogenetics: adverse (6), intermediate (7), favorable (1) and unknown (2); de novo/secondary AML: 8/8; Pgp+ by functional assay (11). Phase I DLTs included one death due to respiratory failure on Day 8 of induction (700 mg/d); one patient with delayed bone marrow recovery and one patient with Grade 3 reversible delirium (800 mg/d). Early death (&lt; 30 days) occurred in 1 patient. Other adverse events attributed to zosuquidar include reversible tremor (48%), dizziness (15%) and confusion (11%). Mean zosuquidar steady-state concentrations were 220±57 ng/mL (700 mg/d) and 462±222 ng/mL (800 mg/d), with a median of 49–52 hours above 170 ng/mL. Pharmacodynamic studies using circulating NK cells as an index of Pgp activity showed near complete inhibition (&gt;90%) by 4 hours that was sustained throughout the infusion in all patients tested. Based upon these data, the recommended Phase II dose of zosuquidar by 72-hr CIV is 700 mg/d. An additional 9 Pgp+ patients have been enrolled to the Phase II trial. Among the total 20 evaluable Pgp+ patients, 10 (50%) have achieved CR or CRp. Zosuquidar 700 mg/d administered by CIV with DNR/ARA-C is well tolerated and achieves rapid and sustained Pgp inhibition at steady state plasma levels, with preliminary evidence of clinical benefit in Pgp+ patients. Accrual to the Phase II trial is ongoing.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 299-299 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Jason Gotlib ◽  
Meir Wetzler ◽  
Selina Luger ◽  
Larry D. Cripe ◽  
...  

Background: Pgp expression in AML increases with age and correlates with inferior therapeutic response and survival. Zosuquidar is a potent and highly specific Pgp inhibitor with minimal pharmacokinetic (PK) interaction with conventional xenobiotic antineoplastics. Prolonged Pgp blockade is believed necessary to optimize antineoplastic sensitization in resistant cells in vitro. We previously reported that 72-hour CIV Zosuquidar at 700 mg/d resulted in rapid and sustained Pgp inhibition during the entire period of anthracycline administration in Pgp+ AML (Lancet, et al. ASH 2006). Methods: We report interim results from a Phase I/II trial of 72-hr CIV zosuquidar in older adults with newly diagnosed Pgp+ AML. Primary objective: to determine the response (CR + CRp) rate in Pgp+ patients. Eligibility included ages 55–75, ECOG PS 0-2, adequate end-organ function, and Pgp+ by functional assay. Zosuquidar was initiated 4 hrs prior to the first doses of DNR (45 mg/m2/d x 3d) and ARA-C (100 mg/m2/d CIV x 7d) and continued for 72 hrs. Reinduction with the same dosing schedule was permitted in patients with significant cytoreduction without aplasia. Patients who achieved a CR/CRp received up to 2 cycles of consolidation with the same agents using an abbreviated schedule. Results: 67 patients with Pgp+ AML were enrolled on the study; 80 patients were included in the safety analysis. Sixty-two of the 67 Pgp+ patients received Zosuquidar at 700 mg/day, while 5 received 800 mg/day (during phase I). Median age was 66; M/F was 46/21; cytogenetics: adverse (19), intermediate (29), and unknown/not done (19); de novo/secondary AML: 36/31. Mean percentage of planned Zosuquidar actually administered was 94%. CR/CRp was achieved in 32 of 66 (48%) evaluable Pgp+ patients (CR=25, CRp=7). Fifteen of 31 (48%) patients with secondary AML, and 6 of 19 (32%) with adverse-risk cytogenetics achieved CR/CRp. Eight of 14 (57%) patients age ≥ 70 responded. Induction-related death (< 30 days) occurred in 10% of patients. Other common toxicities included infection/febrile neutropenia (89%), tremor (42%), hallucinations (11%), nausea (52%), and diarrhea (51%). Median times to neutrophil (≥ 1000/μL) and platelet (≥ 100,000/μL) recovery were 34 and 33 days, respectively. With a median followup of 7.5 months, the median overall survival was 8.9 months and the median relapse-free survival was 9.3 months. Conclusions: CIV Zosuquidar 700 mg/d with DNR and ARA-C is well tolerated, with signs of clinical benefit in poor-risk older patients with Pgp+ AML, warranting continued study of this combination. Accrual to the current trial is ongoing.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4577-4577
Author(s):  
B. Konety ◽  
J. Cowan ◽  
J. Duchane ◽  
P. Carroll

4577 Background: It is generally acknowledged that men who are most likely to derive benefit from therapy for prostate cancer are those with a life expectancy of greater than 10 years. We examined the patterns of primary treatment for prostate cancer in men ≥75 years of age who would have a life expectancy of approximately 10 years. Methods: We examined data from the multi-institutional CaPSURE database on type of primary therapy received for prostate cancer in men < and ≥75 years. Primary therapy was defined as watchful waiting (WW), radical prostatectomy (RP), brachytherapy (BT), BT plus external beam radiotherapy (BT+EBRT), EBRT or primary androgen deprivation therapy (PADT). Chi square tests and multinomial logistic regression analysis were performed to identify predictors of type of primary therapy. Results: The median age of the entire population (n = 10,764) was 67 years and 18% of the dataset were patients ≥75 years. A greater proportion of patients ≥75 years were white, single, had multiple co-morbidities, had low income and low education levels and were classified as high risk (43% vs. 25%) compared to those <75 years. Men ≥75 years were more likely to have received EBRT, PADT or WW (all p < .01). In a multivariate analysis adjusted for socio-demographic factors, diagnostic risk category, and number of co-morbidities at diagnosis, patients ≥75 years were less likely to be managed with primary therapy than with WW regardless of risk category or level of co-morbidity: BT (OR 0.21, 95%CI 0.15–0.31), BT/EBRT (OR 0.21, 95%CI 0.16–0.28), EBRT (OR 0.29, 95%CI 0.22–0.37), PADT (OR 0.64, 95%CI 0.51–0.81), and RP (OR 0.01, 95%CI 0.01–0.02). Conclusions: Older patients are far more likely to received WW as primary therapy regardless of burden of co-morbidity or risk level of primary cancer. A more tailored approach to prostate cancer therapy taking into account co-morbidity and functional level to decide primary therapy may be more appropriate in elderly men. Well selected older patients with high risk disease, particularly those with low co-morbidity levels, may derive survival benefit from primary therapy other than WW. [Table: see text]


2012 ◽  
Vol 17 (2) ◽  
pp. 69-75 ◽  
Author(s):  
Pamela A. Smith

In this article, I will review the available recent literature about the aging population with autism, a patient group that researchers know little about and a group that is experiencing a growing need for support from communication disorders professionals. Speech-language pathologists working with geriatric patients should become familiar with this issue, as the numbers of older patients with autism spectrum disorders is likely to increase. Our profession and our health care system must prepare to meet the challenge these patients and residents will present as they age.


2005 ◽  
Vol 38 (11) ◽  
pp. 56
Author(s):  
MITCHEL L. ZOLER
Keyword(s):  

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