Myeloablative Second Transplants Are Associated with High Non-Relapse Mortality and Poorer Survival Than Non-Myeloablative Second Transplants.

Abstract Abstract 3323 Poster Board III-211 Allogeneic hematopoietic stem cell transplantation (SCT) for patients who have previously undergone allogeneic or autologous SCT is potentially curative, but dangerous. In order to identify patient, disease and treatment characteristics associated with outcome, we analyzed prognostic factors in 101 consecutive patients who underwent second transplants using allogeneic donors at the Cleveland Clinic between May 1987 and October 2008. Inclusion criteria included age ≥ 18, first SCT either autologous or allogeneic, and second SCT allogeneic. The second transplant was myeloablative (MA) in 65.3% of patients and non-myeloablative (NMA) in 34.7%. Relative to NMA second transplants, patients who underwent MA second transplants were younger (median 34 vs. 45 years, P<0.001), were more likely to have undergone autologous first transplant (34.8% vs. 71.4%, P<0.001), and were more likely to have undergone their second transplant for a diagnosis of acute leukemia (56.1% vs. 17.1%, P<0.001). Patients whose second transplant was MA had higher rates of non-relapse mortality (NRM) (63.5% vs. 28.6%, P=0.008) and shorter survival than patients whose second transplant was NMA (median 3.2 vs. 20.5 months, P<.001; figure). Using recursive partitioning analysis, we found that 17 patients transplanted within 3 months of first transplant had higher NRM (hazard ratio [HR] 4.28, P<0.001) and worse survival (HR 3.03, P<0.001) than those transplanted >3 months after first transplant. 16 of these 17 patients underwent MA second transplant. Among all 17 patients transplanted within 3 months of first transplant, 1 year mortality was 91.4% and median survival was 2.3 months. Death was almost exclusively due to non-relapse causes. In multivariable analysis, we found that relative to undergoing second transplant more than 3 months after first transplant, transplant within 3 months of first transplant carried a higher rate of death and NRM (HR 2.97, P=0.001 and HR 4.58, P<0.001, respectively). Relative to NMA second transplant, MA second transplant carried higher risk of death and NRM (HR 3.69, P<0.001 and HR 4.81, P<0.001, respectively). This difference was also significant for patients transplanted more than 3 months after first transplant (HR 2.68, P<0.001 for death, and HR 3.24, P = 0.002 for NRM). Relative to autologous first transplant, having undergone myeloablative allogeneic first transplant was also prognostic for both death and NRM in multivariable analysis (HR 1.95, P = 0.024 and HR, 2.48, P = 0.018, respectively). Age, gender, diagnosis, disease status, and donor relationship were not prognostic for survival or NRM. Figure: Overall Survival of Second Transplant by Type Figure:. Overall Survival of Second Transplant by Type Kaplan-Meier estimates of overall survival for patients after MA allogeneic second transplant (thick line) or NMA allogeneic second transplant (thin line). We conclude that MA transplantation within 3 months of prior SCT carries an unacceptably high rate of NRM and should not be performed. Despite a lower incidence of relapse, MA second transplants were associated with substantially more NRM and significantly worse survival than NMA second transplants. Disclosures No relevant conflicts of interest to declare.

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Gvhd-Associated Early Impairment of Marrow Function Is Frequent after Allogeneic Transplantation and Is a Sensitive Biomarker for Prediction of Treatment Related Mortality and of Overall Survival

Blood ◽

10.1182/blood.v124.21.1160.1160 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1160-1160

Author(s):

Giuseppe Milone ◽

Giuseppe Avola ◽

Maria Grazia Camuglia ◽

Salvatore Leotta ◽

Alessandra Cupri ◽

...

Keyword(s):

Overall Survival ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Disease Status ◽

Risk Of Death ◽

Cd34 Cells ◽

Treatment Related Mortality ◽

Related Mortality

Abstract INTRODUCTION: Aim of our study was to determine the role of acute-GVHD in influencing early marrow function and whether assessment of “GVHD-associated marrow impairment” may predict transplant outcome. METHODS: We have prospectively studied 62 patients who received T-replete allogeneic stem cell transplantation because of various malignancies. At day +18/+19, we determined in bone marrow: CD34+ cells, frequency of clonogenic cell (CFU-GM and BFU-E) and, in 20 patients, also CD34+ cells showing apoptosis (AnnexinV/7-AAD). Results were related to acute-GVHD and to clinical outcome in terms of Treatment Related Mortality (TRM), Relapse Rate (RR) and Overall Survival (OS). To distinguish the effect of a-GVHD from that determined by corticosteroid, patients were divided in three groups according to time of presentation of a-GVHD: “Early a-GVHD, “No a-GVHD” and “Impending a-GVHD”. The latter group consisted of patients presenting a-GVHD after engraftment. RESULTS: In univariate analysis “Febrile neutropenia” and” Acute GVHD” were important factors for a reduction of frequency of marrow clonogenic cells assessed on day +18/+19. However, in multivariate analysis only “Acute GVHD” was able to influence frequency of marrow CFU-GM and BFU-E at day +18/+19. Patients not developing “a-GVHD” until day +90, had on day+18 a median growth of CFU-GM of 202/10e5 plated cells while patients suffering “early GVHD” had a marrow CFU-GM growth significantly reduced: 82/10e5 plated cells, (p= 0.0009). Median CFU-GM was found significantly reduced also in patients defined as “impending GVHD” (onset of a-GVHD at day +20-/+90) (p=0.01). Apoptotic CD34+ cells in marrow cells at day +18/+19 were inversely correlated to frequency of marrow BFU-E (r= -0.5, p=0.04). Taking into account competing risks, Cumulative Incidence of TRM at 2 y in the group of patients having a frequency of marrow CFU-GM over median was 5% while it was 30% in the group having CFU-GM below the median (log-rank: p=0.004). Cumulative incidence of Relapse was not significantly different in these two groups (31% versus 34%). OS was significantly better in group having CFU-GM over median: 62% versus 35% (logrank: p=0.02). Frequency of CFU-GM over median at day +18/+19 was a factor important for a reduced risk of death (HR=0.358; p=0.004) also after adjusting, using multivariate Cox analysis, for Disease Status (Early versus Advanced). CONCLUSIONS: acute-GVHD impairs early and significantly marrow function, marrow-GVHD is a sensitive biomarker for prediction of TRM and OS. Disclosures No relevant conflicts of interest to declare.

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Second Autologous or Allogeneic Transplantation after the Failure of First Autograft in Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.3329.3329 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3329-3329

Author(s):

Muzaffar H. Qazilbash ◽

Rima Saliba ◽

Marcos de Lima ◽

Daniel Couriel ◽

Chitra Hosing ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Univariate Analysis ◽

Disease Free Survival ◽

Disease Status ◽

Allogeneic Transplantation ◽

Albumin Level ◽

High Dose ◽

Hematopoietic Stem ◽

Common Causes

Abstract Background: Most patients undergoing high-dose therapy and autologous transplant for multiple myeloma eventually relapse. The optimal salvage treatment for these patients is not very well defined. Both autologous and allogeneic hematopoietic stem cell transplantations have been used for salvage. We analyzed the outcomes of second autologous or allogeneic transplants, performed as salvage in patients relapsing after an autograft. Methods: Fourteen patients received a second autograft for salvage, while thirty-four patients underwent allogeneic transplantation (related 24, unrelated 10). The median age at transplant was 52 years in the autologous group, and 51 years in the allogeneic group. The median interval between the first and the second transplant was 25 months in the autologous group and 17 months in the allogeneic group. The disease characteristics were similar in both autologous and allogeneic groups. Results: With a median follow-up of 10 months among survivors in each group, both autologous and allogeneic transplant groups had a response rate (complete + partial) of 64%. One hundred day nonrelapse mortality was 7% in the autologous group and 12% in the allogeneic group. Median disease-free survival (DFS) was 11 months in the autologous and 6 months in the allogeneic group. Median overall survival (OS) was 29 moths in the autologous and 14 months in the allogeneic group. 1-year DFS was 40% in the autologous group and 22% in the allogeneic group (p = 0.2). 1-year overall survival was 70% in the autologous and 53% in the allogeneic group (p = 0.3). The most common causes of non-relapse mortality were graft vs. host disease (62%) in the allogeneic group, and infections (100%) in the autologous group. On univariate analysis for DFS in allogeneic group, an interval of >1 year between the first and the salvage transplant was the only factor associated with a significantly better outcome (p = 0.01). Disease status at transplant, type of donor, tumor mass, β2 microglobulin level, and serum albumin level did not show any impact on the outcome. Conclusions: Both autografting and allografting are feasible as salvage for myeloma patients relapsing after the first autograft. A slightly better outcome with salvage autografting may be due to decreased toxicity.

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First Asia-Pacific Co-Operative Multicenter Multiple Myeloma Clinical Trial: Preliminary Results of the “dtZ”/“DAZZLE” Study.

Blood ◽

10.1182/blood.v114.22.4940.4940 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4940-4940

Author(s):

Gerrard Teoh ◽

Kihyun Kim ◽

Alok Srivastava ◽

Vasant Pai ◽

Sung-Soo Yoon ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Conflicts Of Interest ◽

Complete Response ◽

Osteonecrosis Of The Jaw ◽

High Rate ◽

Asia Pacific ◽

Hematopoietic Stem ◽

Asian Patients ◽

Tract Infections

Abstract Abstract 4940 Introduction Many physicians have anecdotally reported that Asian patients with multiple myeloma (MM) are frequently unable to tolerate full doses of dexamethasone (Dex) and/or thalidomide (Thal). Unfortunately, co-operative clinical studies from the Asia-Pacific countries are presently lacking and the effective dose of the Dex/Thal combination in Asians is unknown. Since higher doses of zoledronic acid (Zol) have been shown to exert an anti-MM effect in pre-clinical models of MM, we investigated whether higher frequency dosing of Zol combined with lower doses of Dex/Thal could be an effective and better tolerated regimen in Asian patients. Moreover, since attainment of very good partial response (VGPR), near complete response (nCR) or complete response (CR) prior to autologous hematopoietic stem cell transplantation (AHSCT) correlates with good outcome in MM, we wanted to determine if this lower-dose Dex/Thal with higher-frequency dosing Zol regimen could be a good preparative regimen in transplant-eligible patients. Patients and Methods In this international co-operative multicenter phase II non-randomized single arm study in previously untreated patients with MM (n=44), all patients received up to 6 cycles of three-weekly Dex/Thal/Zol (or “dtZ”). Doses of Dex ranged from 20 mg weekly to 20 mg four times a week; and doses of Thal ranged from 50 mg weekly to 100 mg every night. Zol 4 mg was given three-weekly. Response was graded using Blade's criteria. Results The study population included 67.3% Oriental (Korean and Chinese), 30.8% Indian and 1.9% Malay patients. 15.4% of patients were ISS stage I, 61.5% stage II and 23.1% stage III prior to treatment. 39 (88.6%) patients demonstrated at least a partial response (PR); and 23 (52.3%) of patients achieved VGPR (18.2%), near nCR (15.9%) or CR (18.2%). The fastest time to VGPR/nCR/CR was 1 cycle. Most patients tolerated treatment very well and were managed in the outpatient clinic. Sepsis was the most frequently reported grade 3 or 4 toxicity – 8 (18.2%) patients developed bronchopneumonia, and 3 (6.8%) gastrointestinal or urinary tract infections. 1 (2.3%) patient was suspected of having pulmonary embolism. There were 4 (9.1%) deaths – 3 from severe sepsis and 1 from an unknown cause. Importantly, there were no reports of peripheral neuropathy, osteonecrosis of the jaw (ONJ) or end stage renal failure. In fact, there was an overall 2.4% improvement in the median creatinine clearance time (CCT). Finally, the percentage of CD34 stem cells was not adversely affected by treatment with dtZ. Conclusions The dtZ regimen appears to be an effective and well-tolerated treatment regimen for Asian patients with newly-diagnosed MM. The high rate of VGPR/nCR/CR will greatly facilitate AHSCT in transplant-eligible patients. Judicious use of low-dose Thal has abrogated the numerous side-effects associated with Thal and greatly improved patient tolerance. Even though Zol is administered at a higher frequency, it is not associated with worsening of renal function or ONJ. Infections are the most frequent and worrisome complications of treatment. These are likely to be related to the dose of Dex. Accordingly, it is probably wise to further lower the dose of Dex in future studies. (This study is registered with NIH PRS # 00263484.) Disclosures No relevant conflicts of interest to declare.

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Major Improvement of Invasive Aspergillosis Outcome Is Not Enough to Improve Overall Survival In Allogeneic Hematopoietic Stem Cell Transplant Recipients: Results From a Single-Center Retrospective Analysis

Blood ◽

10.1182/blood.v116.21.1244.1244 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1244-1244

Author(s):

Géraldine Salmeron ◽

Raphaël Porcher ◽

Anne Bergeron ◽

Marie Robin ◽

Regis Peffault de Latour ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Risk Of Death ◽

First Line Treatment

Abstract Abstract 1244 Background. Voriconazole (V) treatment has been shown to improve the 12 week (W) survival rate of hematological patients (pts) with invasive aspergillosis (IA), including recipients of allogeneic hematopoietic stem cell transplants (HSCT). We investigated whether this early survival advantage could translate into a significant increase in overall survival. Methods. We retrospectively reviewed all consecutive pts who received a transplant between Sept. 1997 and Dec. 2008 at Saint-Louis Hospital and were diagnosed as having IA. The temporal origin of the study was the date of IA diagnosis for each patient. Factors associated with survival were analyzed using Cox proportional hazard models. Separate models were estimated for survival up to 12 W and for survival between 12 W and 24 months (M) in pts surviving longer than 12 W. The deaths of pts with and without IA were analyzed with a competing risk framework. Cumulative incidence curves were compared using Gray's tests. Results. Our study examined 89 IA pts. The median follow-up was 70 M (range, 11–130 M). Two pts did not receive any antifungal treatment and were excluded from subsequent analyses. Of the 87 pts, 42 received first-line V and 45 primarily received a lipid formulation of amphotericin B (n=25), amphotericin B deoxycholate (n=10), caspofungin (n=8) or itraconazole (n=2). The primary characteristics of pts with IA and their causes of death, separated by V as first-line treatment, are shown in the table below. The median survival was 2.6 M, and the overall survival at 24 M was 19% (95% CI 12–30 M) (see figure). Overall, the survival rates of the two groups were significantly different (P= 0.010). However, the differences in survival were quite dramatic prior to 10 M, whereas both survival curves became very close after one year. At 18 M, the numbers of surviving pts were almost identical in the two groups [19% (95% CI: 11–34%) in pts who did not receive V as first-line treatment vs. 21% (95% CI 11–38%) in pts who did]. Pts who did not receive V as a first-line treatment displayed a higher probability of dying from IA than those who did (P=0.004), whereas opposite results were found for mortality in pts without IA (P=0.006). The 24-M cumulative incidence of death from IA was 47% (95% CI 31–61%) in the no V group and 19% (95% CI 9–33%) in the group treated with V. The 24-M cumulative incidence of death in pts without IA was 4% (95% CI 7–14%) in the no V group and 27% (95% CI 14–42%) in pts treated with V. The probability of death from another cause, with IA, was similar in both groups (29% vs. 36% at 24 M; P=0.46). After adjusting for donor type, conditioning regimen, progressive GVHD at diagnosis of IA and cumulated steroid dose (mg/kg) in the W preceding IA diagnosis, administration of V as first-line treatment was found to decrease the risk of death during the first 12 W by approximately 70% [HR=0.31 (95% CI 0.16–0.60); P=0.0005]. Conversely, analysis of mortality between 12 W and 24 M failed to identify any significant predictor of risk of death; however, only 24 pts died during this period. Conclusions. The finding that first-line treatment with V, which is associated with a tremendous improvement in IA outcome, does not translate into an increase in overall survival (even in the context of early diagnosis) is striking. Diagnosis of IA following HSCT, whatever the outcome, appears to be a strong marker for poor long-term prognosis. Disclosures: Bergeron: Pfizer: Speakers Bureau, none; Merck: Speakers Bureau, none; Schering: Speakers Bureau, none. Sulahian:Pfizer: Research Funding, non; Merck: Research Funding, none. Ribaud:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, none; Schering: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, none; Gilead: Speakers Bureau, none.

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Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) in CLL: First Results of An EBMT Randomized Trial Comparing Autotransplant Versus Wait and Watch.

Blood ◽

10.1182/blood.v114.22.877.877 ◽

2009 ◽

Vol 114 (22) ◽

pp. 877-877

Author(s):

Mauricette Michallet ◽

Peter Dreger ◽

Laurent Sutton ◽

Ronald Brand ◽

Sue Richards ◽

...

Keyword(s):

Conflicts Of Interest ◽

Progression Free Survival ◽

Disease Status ◽

Primary Objective ◽

Phase Iii ◽

Induction Treatment ◽

Hematopoietic Stem ◽

Binet Stage ◽

The Impact

Abstract Abstract 877 This phase-III randomized EBMT-intergroup trial studied the impact of a consolidating autoHSCT vs no consolidation for patients with CLL in Binet stage A progressive, B or C , in CR, nodular PR or VGPR after first or second line therapy. The primary objective was to show that autoHSCT increased the 5-year progression-free survival (PFS) by 30%. Although it had been calculated that 270 patients were to be randomized, the study was terminated by the steering committee in July 2007 due to poor accrual. Here we present a first analysis based on 69% of expected follow-up forms. Results: Between November 2001 and July 2007, 223 patients were enrolled (SFGM-TC/FCLLG n=98, MRC n=62, GCLLSG n=32, SAKK n=10, other EBMT centers n=17). There were 74% males and 26% females. Binet stages were progressive A 13%, B 67%, C 20%; 59% were in CR, and 41% in very good or nodular PR. Of note, SFGM-TC/FCLLG included only patients in CR. 82% of the patients were enrolled in 1st, and 18% in 2nd remission. Patients were randomized between group 1 (autoHSCT n=112) and group 2 (observation n=111) after an induction treatment which was left at the discretion of the investigators. Median PFS was 43 months in the observation group but not reached in the autoHSCT group; 5-year PFS was 48% and 65%, respectively (p=0.005). Accordingly, autoHSCT halved the relapse risk (5-year relapse incidence 25% vs. 51%; HR 0.4 [0.23-0.71], p=0.002). Cox modeling for randomization arm, Binet stage, disease status, line of treatment, contributing group (country), and the interaction between randomization arm and contributing group confirmed that autoHSCT significantly improved PFS (HR 0.41 [0.23-0.75] p=0.004). The beneficial effect of autoHSCT was stable over all contributing groups although patients accrued by SFGM-TC/FCLLG overall had a significantly better PFS than patients from other countries (HR 0.2 [0.08-0.55], p=0.001). At 5 years, the probability of OS was 92% and 91% for autoHSCT and observation, respectively. Significant differences in terms of non-relapse death were not observed. At the last follow up, among 205 evaluable patients, 186 are alive (147CR, 39 relapse), 19 died (14 from relapse and 5 from non-relapse causes) . In conclusion, in patients with CLL in first or second remission, consolidating autoHSCT reduces the risk of progression (PFS) by more than 50%, but has no effect on overall survival. Disclosures: No relevant conflicts of interest to declare.

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Impact of Rapid Lymphocyte and Monocyte Recovery on Overall Survival Post-Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with Fludarabine/Melphalan Conditioning

Blood ◽

10.1182/blood.v118.21.3040.3040 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3040-3040

Author(s):

Lori DeCook ◽

Mary Thoma ◽

Tanya Huneke ◽

Nicole Johnson ◽

Robert Wiegand ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Acute Leukemia ◽

Hematopoietic Stem Cell ◽

Conflicts Of Interest ◽

Positive Impact ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Absolute Lymphocyte Counts ◽

Complete Blood Counts

Abstract Abstract 3040 We have previously shown that both lymphocyte and monocyte recovery are strongly associated with improved survival post-myeloablative allogeneic hematopoietic stem cell transplant for acute leukemia (Thoma et al, Biology of Blood and Marrow Transplantation, in press). We hypothesized that rapid lymphocyte and monocyte recovery would have a similarly positive impact on overall survival in reduced intensity conditioning (RIC) HSCT with fludarabine/melphalan. To test our hypothesis, we analyzed 118 consecutive patients who underwent allogeneic HSCT with fludarabine/melphalan conditioning for AML (n=49) and MDS/MPN (n=38), ALL (n=7) and other lymphoid malignancies (n=24) at our institution from 2001–2010. The absolute lymphocyte counts and monocyte counts (ALC and AMC, respectively) derived from routine complete blood counts were determined longitudinally at days +15, +30, +60, +100 and correlated with clinical outcomes. At the day +30 time point, both ALC and AMC > 0.3 × 10(9) cells/L were strongly associated with improved survival (OS 29.6 months vs. 5.4 months, p=0.006 and 25.3 months vs. 5.1 months, p=0.01 respectively), a pattern that continued through the day +100 evaluation. Multivariate analysis including age, CD34+ cell dose, unrelated vs. related HSCT, presence of aGVHD, remission status, and longitudinal hematologic parameters revealed that day +100 ALC (RR 0.21, 95% CI 0.07–0.66, p= 0.0096) and day +100 AMC (RR 0.41, 95% CI 0.2–0.9, p=0.047) were the only independent predictors of survival in the model. Pairwise correlations showed moderate negative associations between aGVHD and day +60 and day +100 ALC and AMC. To further explore whether any inherent patterns in the timing of lymphocyte and monocyte recovery had prognostic value post-HSCT, we performed unsupervised hierarchical clustering on the longitudinal hematopoietic parameters studied in this cohort and identified four clusters of patients, clusters A-D. Patient clusters A and C both demonstrated improved ALC and AMC recovery at the day +60 and day +100 time points and had significantly improved OS compared with clusters B and D (not reached for A and C vs. 54.9 and 22.3 months, respectively, p<0.001). No patient in cluster D had a day +100 AMC > 0.3 × 10(9) cells/L, and these patients experienced more acute GVHD (p=0.006) and relapse (8 of 14 patients, p=0.002) compared with clusters A, B, and C (p=0.002). 29 patients who were unable to be clustered with this algorithm, predominantly due to early toxic deaths, had a median survival of 6 months. Consistent with previous observations in our myeloablative cohort, both lymphocyte and monocyte recovery are predictive of overall survival post-RIC HSCT. However, compared to the myeloablative cohort, monocyte recovery in this series appears slightly less strongly associated with survival. Our results also extend the observation of improved survival of ALC and AMC recovery post-HSCT to diseases beyond acute leukemia. Disclosures: No relevant conflicts of interest to declare.

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Real-World Outcomes Among Elderly Acute Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v124.21.2271.2271 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2271-2271

Author(s):

Bruno C Medeiros ◽

Sacha Satram-Hoang ◽

Khang Q. Hoang ◽

Faiyaz Momin ◽

Deborah Hurst ◽

...

Keyword(s):

Overall Survival ◽

Real World ◽

Lower Risk ◽

Survival Benefit ◽

Older Patients ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

Risk Of Death ◽

Age Cohort ◽

Acute Myeloid

Abstract Introduction: The incidence of acute myeloid leukemia (AML) increases with age, however treatment efficacy and tolerability in older patients are poor compared to younger patients. Without treatment, patients succumb to their illness within a few months of diagnosis. Further, disease relapse is inevitable in the majority of cases without additional post-remission therapy after successful induction of remission. The use of allogeneic hematopoietic stem cell transplantation (HSCT) is considered a potential cure for AML but its use is limited in older patients because of significant comorbidities and increased transplant-related morbidity and mortality. This retrospective study assessed outcomes of older AML patients treated with chemotherapy with or without HSCT. Methods: The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, was utilized in this retrospective cohort analysis of 3327 first primary AML patients. Patients were diagnosed between January 1, 2000 to December 31, 2009, were >66 years, continuously enrolled in Medicare Part A and B with no HMO coverage in the year prior to diagnosis and received treatment with chemotherapy with or without HSCT. Chi-square test for categorical variables and ANOVA or t-test for continuous variables was used to compare patient characteristics between treated patients with and without HSCT. Kaplan-Meier curves and Cox proportional hazards regression assessed overall survival. Date of last follow-up was December 31, 2010. Results: There were 276 (8%) patients who underwent HSCT therapy and 3051 (92%) who did not. HSCT patients were younger at diagnosis with mean age of 73 compared to the non-HSCT group (75 years; p<.0001). Seventy percent of HSCT patients compared to 55% of non-HSCT patients were under the age of 75 at diagnosis. HSCT patients were also more likely to be male. There were no statistical differences in comorbidity burden, poor performance indicators (PPI) or prior myelodysplastic syndrome (MDS) between both groups. The unadjusted median overall survival was higher for HSCT (9.7 months) compared to the non-HSCT group (4.7 months; log rank p=<0.0001). In multivariate survival analysis, patients who underwent HSCT had a 20% lower risk of death compared to those who did not receive HSCT (Table 1). Increasing age, male gender, increasing comorbidity score, prior MDS and PPI were significantly associated with higher risks of mortality. In a subset analysis stratified by age, the survival benefit with HSCT was only demonstrated in the younger age cohort ≤75 years old, and no difference in mortality risks were noted in the older age cohort >75 years (Table 1). Conclusions: In this real-world analysis of elderly AML patients treated in community oncology practice, only 8% of patients receiving chemotherapy underwent subsequent HSCT therapy. Chronologic age appears to be the driving factor in receiving HSCT. HSCT therapy was associated with a 20% lower risk of death compared to patients receiving chemotherapy only and the survival benefit was more pronounced among the younger cohort, age ≤75 years with a 36% reduction in mortality risk. These findings provide further insight into disease management and provide an important context for identifying opportunities to improve the quality of treatment strategies in the real world setting. Table 1: Multivariate Overall Survival Analysis HSCT All (N=3327) ≤ 75 (n=1857) >75 years (n=1470) HR 95% CI HR 95% CI HR 95% CI No ref ref ref Yes 0.80 0.69-0.92 0.63 0.53-0.75 1.22 0.97-1.54 Disclosures Satram-Hoang: Genentech, Inc.: Consultancy. Hurst:Genentech, Inc.: Employment. Reyes:Genentech, Inc.: Employment.

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Thrombotic Complications Are Associated with Phlebotomy Therapy in Patients with Chuvash Polycythemia

Blood ◽

10.1182/blood.v126.23.936.936 ◽

2015 ◽

Vol 126 (23) ◽

pp. 936-936 ◽

Cited By ~ 1

Author(s):

Adelina Sergueeva ◽

Galina Miasnikova ◽

Ekaterina Lisina ◽

Mehdi Nouraie ◽

Sergei A. Nekhai ◽

...

Keyword(s):

Mononuclear Cells ◽

Conflicts Of Interest ◽

Negative Regulator ◽

High Rate ◽

Systolic Pulmonary Artery Pressure ◽

Risk Of Death ◽

Increased Risk ◽

History Of ◽

Baseline Characteristics

Abstract Background: In Chuvash polycythemia (CP) (Problemi Gematologii I Perelivaniya Krovi 1974, 10:30), impaired degradation of hypoxia inducible factor (HIF)-1α and HIF-2α from a homozygous germline VHLR200W mutation leads to augmented hypoxic responses during normoxia (Nat Genet 2002, 32:614). In addition to elevated hematocrit, CP is marked by leg varices, benign vertebral hemangiomas, decreased systemic blood pressure, increased systolic pulmonary artery pressure, and by the defining phenotypes of thrombosis and early mortality (Blood 2004, 103:3924; Haematologica 2012, 97:193). There is no effective therapy. While phlebotomy has been recommended for idiopathic polycythemia by the British Committee for Standards in Haematology (Br J Haematol 2005, 130:174) and is administered to some CP patients, its benefits are unknown. Phlebotomy-induced iron deficiency inhibits PHD2 enzyme, the principal negative regulator of HIFs, which further augments hypoxic responses. This affects the transcription of many genes (BCMD 2014, 52:35). Hypoxia-regulated IRAK1 is augmented in inflammation and may promote thrombosis (Circ Res. 2013, 112:103). Methods: 165 patients with CP were enrolled in a registry between 2001 and 2009 after providing written informed consent. Survival analysis was used to examine the predictors of new thrombosis and death during the follow-up period. mRNA from peripheral blood mononuclear cells (PBMCs) was profiled by Affymetrix Human Exon 1.0 ST Array in 42 of the subjects. Results: The median age at enrollment was 35 years and 90 participants were females, 25 had a history of one thrombosis, 5 of two thromboses and 3 of three thromboses. In the year prior to study entry, 72 had received phlebotomy therapy (Table 1). In July 2015 the median follow-up was 9.0 years (range 1-14.5). During this follow-up period, 30 (18.2%) participants had one new thrombosis, 6 (3.6%) had two new thromboses and 17 (10.3%) died. The median age of death was 55 years (range 16-76) and deaths were related to thrombotic cerebrovascular accident (n = 4), myocardial infarction (n = 4), mesenteric or portal vein thrombosis (n = 3), other major thromboembolic events (n = 2) and trauma or unknown cause (n = 2). Baseline characteristics of older age, prior thrombosis, pentoxifylline treatment, smoking and splenomegaly were independently associated with greater thrombosis risk during follow-up (P < 0.003). After adjustment for these variables, the estimated probability of new thrombosis at 10 years was 26% in those receiving phlebotomies compared to 12% in those not phlebotomized (log rank P = 0.014) (Figure 1). There was also a trend for increased risk of death with phlebotomy: estimated probability 8.7% versus 3.7% (P = 0.15). Examination of gene transcripts affecting thrombosis by logistic regression identified 12 protective and 16 risk genes at 5% false discovery rate. Upregulation of two mRNAs was of singular significance: 1) IL1RAP, a proximal signaling adaptor of IRAK1 (Immunity 1997, 7: 837) and 2) THBS1, encoding thrombospondin1 (Blood 2015, 125: 399). Both genes have known roles in thrombosis promotion and we previously reported that THBS1 is upregulated in CP (BCMD 2014, 52:35). Further analysis revealed a further upregulation of THBS1 in patients with baseline history of phlebotomy (β=0.41, P=0.046). Conclusion: These findings underscore a high rate of thrombosis and death in patients with CP and reveal a potential role of increased IRAK1/IL1RAP signaling in these complications. They raise the possibility that phlebotomy therapy has a detrimental rather than beneficial effect, possibly contributed to by increased THBS1 expression. Table 1. Baseline characteristics by phlebotomy in the year prior to enrollment. Results in median (interquartile range) or n (%); four without phlebotomy data. No phlebotomy N=89 Received phlebotomy N=72 Age (years) 32 (18-48) 37 (26-49) 0.08 Female gender, n (%) 52 (58%) 34 (47%) 0.16 Smoking, n (%) 18 (20%) 24 (33%) 0.060 History of thrombosis, n (%) 20 (23%) 12 (17%) 0.4 Splenomegaly, n (%) 2 (2.3%) 2 (2.8%) 0.8 ASA treatment, n (%) 27 (30%) 36 (50%) 0.011 Pentoxifylline, n (%) 7 (7.9%) 17 (23.6%) 0.005 BMI (kg/m2) 20.4 (18.3-22.9) 21.6 (19.9-24.6) 0.010 Systolic BP (mm Hg) 109 (100-123) 118 (105-124) 0.6 Diastolic BP (mm Hg) 76 (68-84) 78 (71-83) 0.8 Hemoglobin (g/dL) 18.1 (16.4-21.0) 17.9 (16.0-19.8) 0.5 WBC (per uL) 5.7 (4.6-7.0) 5.5 (4.6-6.7) 0.9 Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Treatment outcome after induction chemotherapy before allogeneic hematopoietic SCT in patients with advanced MDS

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6502 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6502-6502

Author(s):

C. A. Ramos ◽

A. A. Jakubowski ◽

F. Boulad ◽

E. B. Papadopoulos ◽

J. W. Young ◽

...

Keyword(s):

Induction Chemotherapy ◽

Remission Rate ◽

Standard Dose ◽

Disease Status ◽

High Rate ◽

High Dose ◽

Unrelated Donor ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Secondary Mds

6502 Background: The need for induction chemotherapy (IC) before allogeneic hematopoietic stem cell transplant (alloSCT) in advanced myelodysplatic syndrome (MDS) remains controversial. Methods: This is a retrospective analysis of the remission rate in 99 patients with advanced MDS (≥5% marrow blasts) and acute myeloid leukemia (AML, ≥ 20% blasts) evolving from MDS, who were treated with IC before receiving cytoreduction for SCT. These patients were referred to MSKCC for alloSCT from 6/1980 to 10/2004, and subsequently underwent an unmodified or T cell-depleted (TCD) SCT from a matched or mismatched related or unrelated donor after myeloablative cytoreduction in the majority. Results: All patients had MDS at diagnosis: 33% had high risk (HR), 22% intermediate risk (IR) and 42% good risk (GR) cytogenetics; 38% had HR, 32% IR-2 and 25% IR-1 IPSS. The median age was 43 (range 2–66). 76% had primary and 24% had secondary MDS (chemotherapy or radiation). At the time of IC, 64% had frank AML, 33% RAEB-1 and 2, and 3% CMML-2. A combination of an anthracycline (Ac) and standard dose (SD) cytarabine (AraC) was administered to 53% of the patients. Other regimens included Ac with high dose (HD) AraC (15%), Ac with SD AraC and etoposide (15%), HD AraC alone (8%), and HD AraC with etoposide (4%). 26% of patients required a second line regimen and 4% went on to a third. None of the patients died of complications due to IC. CR was achieved in 60% of patients overall (64% in those receiving Ac + SD AraC ± etoposide and 52% for HD AraC ± Ac ± etoposide). The CR rate was 65% in primary and 42% in secondary MDS, and was similar in adults (60%) and children (56%). CR rates were 44% in HR, 68% in IR, and 65% in GR cytogenetics; 58% in HR, 59% in IR-2, and 60% in IR-1 IPSS. According to disease status at IC, the CR rate was 60% for RAEB-1 and 2 and 59% for AML. 12% of complete responders relapsed prior to cytoreduction for SCT. 49% of all patients underwent a TCD SCT from an HLA identical sibling. There are no long term survivors after SCT in patients who did not achieve CR after IC, in contrast to 47% overall survival at 10 years for responders. Conclusions: IC in advanced MDS is associated with a high rate of CR. IC before cytoreduction for SCT is an effective approach to reduce the burden of disease particularly prior to TCD SCT. No significant financial relationships to disclose.

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HOUT-10. TREATMENT OUTCOME IN ADOLESCENTS AND YOUNG ADULTS (AYAS) WITH GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.475 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi114-vi114

Author(s):

Josiah An ◽

Adithya Chennamadhavuni ◽

Sarah Mott ◽

Rohan Garje

Keyword(s):

Overall Survival ◽

Cox Regression ◽

Private Insurance ◽

Multivariable Analysis ◽

Treatment Modalities ◽

Study Objective ◽

Risk Of Death ◽

Immortal Time Bias ◽

Survival Difference ◽

Increased Risk

Abstract BACKGROUND Glioblastoma is one of the most aggressive and commonly encountered brain tumors. Standard of care includes surgical resection with adjuvant or concurrent chemoradiation which is predominantly based on adult clinical trials. Our study objective was to assess whether survival differed in AYA compared to older adults. METHODS The National Cancer Database was used to identify patients with at least surgically resected glioblastoma from 2004 to 2016. Cox regression models were utilized to estimate the effect of treatment on overall survival (OS) while accounting for immortal time bias (3-months) and clustering within facility. RESULTS Among 51,718 patients with glioblastoma identified, 2,930 patients were AYA. Multivariable analysis (MVA) shows OS was significantly higher in AYA, female, non-white, high income, unilateral cancer patients with private insurance receiving treatments in high volume facilities. OS among AYA patients was significantly lower in surgery + (radiation or chemotherapy: S+(RT or CT) group compared to surgery only (S) (HR=1.33, 95% CI 1.06–1.65), but no significant survival difference between surgery + chemoradiation (S+C+RT) groups and surgery only (HR=0.97, 95% CI 0.83–1.14). Median survival is ~28 months in AYA among S and S+C+RT groups whereas significantly lower survival (median OS ~18 months) is seen in S+RT or CT. Non-AYA patients were at 2 times increased risk of death compared to AYA patients who received the same type of treatment. CONCLUSIONS In conclusion, AYA population has more than twice the median OS in comparison to non-AYA patients. Worse overall survival was seen among S+RT or CT in comparison to S and S+RT+CT in AYA group. For patients needing either chemotherapy or radiation with surgery, possibly a trimodal approach might provide better survival advantage. Prospective studies are needed to further explore optimal treatment modalities in this unique population.

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