A Complete Remission (CR) Is Not a Prerequisite for Prolonged Survival after Autotransplants for Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 926-926 ◽  
Author(s):  
Guido Tricot ◽  
Maureen Reiner ◽  
Jeffrey Sawyer ◽  
John Crowley ◽  
Bart Barlogie
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Tumor Burden ◽  
Time Dependent ◽  
Prolonged Survival ◽  
P Value ◽  
High Dose ◽  
Cytogenetic Abnormalities ◽  
Variate Analysis ◽  
The Impact

Abstract In acute leukemia prolonged survival is impossible without obtaining a CR. Based on the acute leukemia model, myeloma therapy has gradually been intensified with the aim to increase the CR rate as a first important step to improve overall survival (OS). Although patients with abnormal metaphase cytogenetics have a significantly inferior outcome in terms of event-free and overall survival, the CR rate is similar for patients with and without cytogenetic abnormalities, indicating that CR may not be a good prognostic indicator of ultimate outcome. To address the importance of obtaining a CR for OS, we analyzed our Total Therapy I (VADx3-high dose cyclophosphamide 6g/m2 with stem cell collection-EDAP-melphalan-based tandem transplants-α interferon maintenance) data in those patients who had not received any treatment prior to enrollment (N=155), received at least one transplant (N=135) and were alive one year after the first transplant (N=132). Kaplan-Meier curves were generated using a 1 year landmark to compensate for the guaranteed time of CR patients, but thereby excluding patients who died within the first year after the first autotransplant (N=3). The 1-year landmark was chosen because the large majority of CR patients (75%) had achieved their CR at 1 year after the first transplant. In addition, a time-dependent co-variate analysis for CR was performed, including the 135 patients. The median follow-up of these patients was 10.5 years. The 9 year OS after the landmark, i.e., 10 years after the first transplant, was 41% (95% confidence interval: 26, 55) for CR patients versus 37% (26, 47) for no CR patients (i.e., PR and <PR) with a logrank p value of 0.71 (Figure 1). Using a time-dependent co-variate analysis for CR, achieving a CR was not significantly related to OS (Hazard Ratio: 0.83; p value 0.39). Only the presence of metaphase cytogenetic abnormalities (HR: 2.0; p=0.005), LDH > 190 U/L (upper limit of normal) (HR: 2.0; p=0.01) and CRP >4.0mg/L (HR: 1.6; p=0.03) were significant for OS. When the importance of CR was assessed separately for patients with (N=43) and without (N=84) abnormal cytogenetic (cytogenetic information was missing on 5 patients), no survival benefit for CR patients was seen in either subgroup (p values 0.52 and 0.32, respectively) and similarly, using the time-dependent co-variate analysis for CR, there was no significant benefit for OS of attaining a CR in either group (p value: 0.7 and 0.5, respectively). We conclude that prolonged survival (>10 years) is observed in a substantial proportion of myeloma patients receiving a tandem autotransplant-based regimen, irrespective of the completeness of response to tandem transplants. The inherent genetic features of the myeloma and the impact on the micro-environment of the myeloma cells appear to be more important than the absolute tumor burden reduction accomplished by tandem transplants. Our findings may also be a reflection of the insensitivity of CR as an assessment of remaining tumor burden in myeloma and a new definition of CR may be required. Figure Figure

Adults with Acute Lymphoblastic Leukemia and T(1;19) Abnormality Have a Favorable Outcome with Hyper-CVAD Chemotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3955-3955
Author(s):  
Ravin Jain Garg ◽  
Hagop M Kantarjian ◽  
D. A Thomas ◽  
Stefan Faderl ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Response Duration ◽  
Complete Response ◽  
Cancer Center ◽  
P Value ◽  
Small Subset ◽  
High Dose ◽  
Cytogenetic Abnormalities

Abstract Among the well-described cytogenetic abnormalities in adults with acute lymphoblastic leukemia (ALL), a translocation involving chromosomes 1 and 19 [t(1;19) (q23;p13)] occurs in a small subset but has varyingly been associated with a good or bad prognosis in different studies. Adults with ALL and t(1;19) treated at M.D. Anderson Cancer Center were reviewed. Their clinical features and outcome were compared to those with other cytogenetic abnormalities. Endpoints included complete remission rate (CR), complete response duration (CRD) and overall survival (OS). Of 411 adults with pre-BALL, 12 patients had t(1;19). Ten of the 12 patients with t(1;19) received Hyper-CVAD (Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone alternating with Methotrexate and high-dose Cytarabine); the other 2 were treated with VAD (Vincristine, Adriamycin, Dexamethasone). All 12 patients achieved CR; the 3-year survival rate was 73%. Patients with t(1;19) had significantly better CRD and OS when compared to all other patients combined as well as individually to patients with Ph+, t(4;11), and lymphoma-like abnormalities [6q(−), 14q+, t(11;14), t(14;18)]. Adults with ALL and t(1;19) have an excellent prognosis when treated with the Hyper-CVAD regimen. Outcome of patients by cytogenetic group: t(1;19) vs. individual cytogenetic groups OVERALL SURVIVAL N Fail 3-Year % Median (weeks) P-value T(1,19) 12 3 73 Not recorded Diploid 138 72 52 179 0.09 Lymphoma-like 20 17 35 54 0.008 Ph+ 117 88 23 68 0.0002 Miscellaneous 112 56 56 236 0.17 T(4,11) 12 10 0 58 0.002 COMPLETE RESPONSE DURATION (CRD) N Fail 3-Year % Median (weeks) P-value T(1,19) 12 2 80 Not recorded Diploid 133 59 54 177 0.06 Lymphoma-like 16 13 34 89 0.009 Ph+ 102 52 42 63 0.006 Miscellaneous 100 41 59 401 0.16 T(4,11) 11 7 NR 45 0.018

scholarly journals OR32-02 Immune Checkpoint Inhibitor-Induced Hypophysitis Is Associated with Improved Overall Survival in Cancer Patients

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Anupam Kotwal ◽  
Samuel G Rouleau ◽  
Lisa Kottschade ◽  
Mabel M Ryder ◽  
Yogish C Kudva ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Cancer Prognosis ◽  
P Value ◽  
High Dose ◽  
Mass Effects ◽  
Mri Features ◽  
The Impact

Abstract Context: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies against checkpoints namely CTLA-4, PD-1 and PD-L1. These can cause pituitary dysfunction due to hypophysitis in addition to other endocrinopathies. While the prevalence and course of hypophysitis have been described extensively, the relationship between hypophysitis and cancer prognosis has only been investigated in melanoma patients on ipilimumab. Additionally, the impact of high dose glucocorticoids for hypophysitis treatment on survival has been unclear. Objective: In order to address these important questions, we aimed to characterize the frequency and course of hypophysitis from various ICIs, and to investigate a possible impact on overall survival in cancer patients.Design and Methods: We conducted a single center retrospective cohort study of adult cancer patients that received an ICI from 1/1/2012 - 12/31/2016, followed for a median of 14.8 months. A total of 896 patients were identified that received ipilimumab alone (n=120); ipilimumab and nivolumab (n=50); ipilimumab followed or preceded by pembrolizumab (n=70), pembrolizumab alone (n=406), and nivolumab alone (n=250). Results: Twenty-six patients (2.9%) developed hypophysitis after a median of 2.3 months (range 0.8 to 11.7). Their median age at initiation of ICI was 57.9 years (range 42.4 to 78.5), 54% were males, and the most common malignancy was melanoma (81%). All had hypopituitarism showing secondary adrenal insufficiency (100%), central hypothyroidism (38.5%) and central hypogonadism (28.5% in men, 25% in premenopausal women). Sixty-four percent demonstrated pituitary enlargement on imaging which resolved on follow-up. Mass effects occurred in 50% and were managed by initial high dose glucocorticoids. Thyroiditis occurred in 19.2% of those with hypophysitis. Occurrence of hypophysitis was associated with better overall survival (median 50.7 vs 16.5 months; p value 0.015) and reduced mortality (RR 0.52, 95% CI 0.28 to 0.99; p value 0.036) after adjusting for age, sex and malignancy type. Conclusions: Hypophysitis, usually but not always accompanied by classic MRI features, occurrs within a few weeks in cancer patients most frequently after ipilimumab alone or in combination with a PD-1 inhibitor, rarely after pembrolizumab and never after nivolumab alone. ICI-induced hypophysitis presents as mass effects in half and as hypopituitarism in all patients involving the corticotrophs more commonly than thyrotrophs and gonadotrophs. The improved survival with a 48% lower mortality rate in patients with hypophysitis suggests its possible role as a marker for better efficacy of ICIs against malignancy.

Impact of Consolidation Radiotherapy in Patients With Advanced Breast Cancer Treated With High-Dose Chemotherapy and Autologous Bone Marrow Rescue

1999 ◽  
Vol 17 (3) ◽  
pp. 887-887 ◽  
Author(s):  
Dennis L. Carter ◽  
Lawrence B. Marks ◽  
Joseph M. Bean ◽  
Gloria Broadwater ◽  
Atif Hussein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Overall Survival ◽  
Advanced Breast Cancer ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
Advanced Breast ◽  
High Dose ◽  
Autologous Bone ◽  
The Impact

PURPOSE: To examine the impact of consolidation radiotherapy (RT) after high-dose chemotherapy with autologous bone marrow rescue (HDC) in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1988 and 1994, 425 patients with metastatic or recurrent breast cancer received doxorubicin, fluorouracil, and methotrexate (AFM) induction chemotherapy in a single-institution prospective trial. One hundred patients who achieved a complete response were randomized to receive HDC (cyclophosphamide, cisplatin, carmustine), with autologous bone marrow rescue immediately after AFM, or to observation, with HDC to be administered at next relapse. Seventy-four of the 100 became eligible for RT; 53 received consolidation RT (HDC RT+ and 21 did not (HDC RT−). The assignment of RT was not randomized. The RT+ and RT− groups were similar with regard to number of involved sites, the fraction of patients with only local-regional disease, age, and interval since initial diagnosis. Local control at previously involved sites and distant sites was assessed with extensive radiologic and clinical evaluations at the time of first failure or most recent follow-up. The impact of RT on failure patterns, event-free survival, and overall survival was evaluated. RESULTS: Sites of first failure were located exclusively at previously involved sites in 28% of RT+ patients versus 62% of RT− patients (P < .01). Event-free survival at 4 years was 31% and 21% in the RT+ and RT− groups, respectively (P = .02). Overall survival at 4 years was 30% and 16% in the RT+ and RT− groups, respectively (P = .20). CONCLUSION: Patients with advanced breast cancer who were treated with HDC without RT failed predominantly at the initial sites of disease. The addition of RT appeared to reduce the failure rate at initial disease sites and may improve event-free and overall survival. Our observations await verification in a trial in which assignment to RT is randomized.

Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3090-3090 ◽  
Author(s):  
Muzaffar H. Qazilbash ◽  
Rima M. Saliba ◽  
Marilyn S. Davis ◽  
Floralyn L. Mendoza ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Cell Transplantation ◽  
Hematopoietic Progenitor Cell ◽  
High Dose ◽  
Significant Difference ◽  
Preparative Regimen ◽  
The Impact

Abstract Backround: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as preparative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity. Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age: 54, range: 3570) were treated between 4/04 and 8/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2) and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had disease progression or relapse after a prior autograft. Median CD34 cells dose infused was 4.5 x 106/kg (range 2.3–10.9). Results: Patients in all 3 arms were evenly matched. With a median F/U of 14.0 months (range 6–25) post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Toxicity was limited to grade I or II nausea, vomiting and diarrhea. Median ATO levels on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Melphalan PK was not altered by ATO pretreatment. Median time to neutrophil engraftment (ANC >500/ dl) was 9 days. There were no engraftment failures or delays in the ATO arms. CR rate for the entire group was 23%, and total response rate (CR + PR) was 75%. 1-year Progression-free survival (PFS) and overall survival (OS) were 75% and 95%, respectively. There was no significant difference in CR, RR, PFS or OS between the 3 arms (p = 0.9, 0.9, 0.4 and 0.6, respectively). A prior autologous transplant (p = 0.02) and abnormal cytogenetics at transplant (p = 0.04) were associated with a significantly shorter remission. Conclusions: ATO + melphalan + ascorbic acid is a safe, effective and well tolerated preparative regimen for patients with multiple myeloma undergoing an autotransplant. A longer follow up is needed to assess the impact of ATO on progression-free and overall survival.

Treatment Intensification of Traditional BFM Therapy with 3 Chemotherapy Blocks and Double Delayed Intensification (Protocol II) Improves Outcome in Infants with High Risk (HR) Acute Lymphoblastic Leukemia (ALL): Results of Two Consecutive AIEOP Studies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 871-871 ◽  
Author(s):  
Carmelo Rizzari ◽  
Maria Grazia Valsecchi ◽  
Paola De Lorenzo ◽  
Maurizio Aricò ◽  
Giuseppe Basso ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
High Dose Chemotherapy ◽  
P Value ◽  
High Dose ◽  
Treatment Intensification ◽  
Treatment Protocols ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.

Chromosome 17 Abnormalities Are Associated with Worse Overall and Relapse Free Survival in Patients with Acute Myelogenous Leukemia and Poor-Risk Cytogenetics.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1501-1501
Author(s):  
Gautam Borthakur ◽  
Constantine Tam ◽  
Hagop Kantarjian ◽  
E. Lin ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Chromosome 17 ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Kaplan Meier ◽  
Variate Analysis ◽  
Acute Myelogenous

Abstract Purpose: Chromosome 17 abnormalities define a group of patients with acute myelogenous leukemia (AML) (Nahi, H. et al. Leukemia and Lymphoma2008;49:508) with poor outcomes. We analyzed the additional impact of chromosome 17 abnormalities (−17, −17p, −17q, der17) among patients with AML and cytogenetic abnormalities traditionally considered to be of adverse prognosis. Patients and Methods: 1086 patients with AML [excluding inv 16, t (8;21), t (15;17), Diploid/-y abnormality] were included in this analysis. Based on cytogenetic abnormalities patients were grouped into: −5,−7,−5and −7, complex. The following parameters were included in uni and multi-variate analysis: age, performance status, WBC, hemoglobin, platelets, marrow blast percentage, bilirubin, creatinine, albumin, LDH, chromosome 17 abnormality (yes/no). Results: Four hundred and fourteen (45%) patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 267 (64.5%) patients relapsed. Two hundred seventy (24.9%) patients had abnormalities of chromosome 17. Abnormalities of chromosome 17 were associated with lower CR or CRp rate (p=0.02) and higher possibility of having cytogenetic abnormality of −5 or −7 (p&lt;0.0001). Multivariate analysis showed that patients with abnormalities of chromosome 17 had worse overall survival (OS) compared to patients without (p= 0.003)(Fig.1). Multi-variate analysis within cytogenetic subgroups showed that chromosome 17 abnormalities were associated with worse OS in patients with chromosome 5 abnormality(p=.02) (data not shown) and in those with complex cytogenetics (p=.04)(Fig.2) and not in patients with chromosome 7 (p=.17)or combined 5 and 7 abnormalities (p=.33). Similar analysis restricted to patients achieving CR/CRp after induction therapy showed that impact of chromosome 17 abnormalities on relapse free survival (RFS) mirrored their impact on OS. Conclusion: chromosome 17 abnormalities are associated with worse OS and RFS in patients with AML and adverse cytogenetics and have additional negative impact on the outcomes in certain well-known adverse cytogenetic subgroups. Figure 1: Kaplan-Meier estimates of overall survival by status of chromosome 17 Figure 1:. Kaplan-Meier estimates of overall survival by status of chromosome 17 Figure 2: Kaplan-Meier estimates of overall survival by status of chromosome 17 in subgroup of patient, complex Figure 2:. Kaplan-Meier estimates of overall survival by status of chromosome 17 in subgroup of patient, complex

GM-CSF in Stem Cell Transplant (SCT) Recipients: Impact of Graft-Versus Host Disease on Invasive Fungal Infections (IFIs)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4367-4367
Author(s):  
Amar Safdar ◽  
Gilhen Rodriguez ◽  
Georgina Georgescu ◽  
Richard Champlin
Keyword(s):  
Fungal Infections ◽  
Underlying Disease ◽  
P Value ◽  
High Dose ◽  
Cell Transplant ◽  
Retrospective Case ◽  
Graft Versus Host ◽  
Gm Csf ◽  
Younger Age ◽  
The Impact

Abstract Background: GM-CSF is thought to be beneficial in SCT patients with IFI. The impact of GM-CSF in SCT recipients with GVHD and IFI was evaluated Methods: A retrospective case-matched (GM-CSF [n = 12] vs. no GM-CSF [n = 27]) study was undertaken to compare outcomes if IFIs diagnosed &gt;100 days following transplantation during 2000–2006. A response was defined as complete or partial response (CR/PR) and considered 3 months after IFI diagnosis or earlier in patients with earlier response. All value are given as median ± s.d. The systemic antifungal therapy in &gt; 60% of patients included echinocandin and anti-mold triazole, or polyene agent. Results: Please refer to the table below. Patients who received GM-CSF were younger (age 36 ± 17 vs. 51 ± 13 years); neutropenic (&lt;500 cells/uL) at onset of infection (50% vs. 11%; P = 0.014); had lower monocyte counts (10 ± 236 vs. 220 ± 575 cells/uL; P = 0.021) and frequently required intensive care unit stay (50% vs 15%; P = 0.043). A 50% response was observed in the GM-CSF treated SCT recipients with GVHD and IFIs, whereas, 41% response occurred in the group who received no concurrent Gm-CSF (P = 0.6). Similarly, IFI-associated deaths were less frequently observed in GM-CSF treated patients (41%) compared with 55% seen in patients who had not received GM-CSF (P = 0.7). There was a slight increase in survival among SCT recipients treated with GM-CSF (48 ± 21 days vs. 34 ± 19 days in no GM-CSF group P = 0.05) Conclusions: Late fungal infections in SCT recipients with GVHD, when treated with GM-CSF-based therapy had comparable outcomes despite having significantly more neutropenia, severe monocytopenia and ICU stay. Characteristics GM-CSF N = 12 (5% No GM-CSF N = 27 (%) p-value Underlying Disease-Leukemia Relapsed/refractory Cancer 10 (83) 5 (42) 18 (67) 6 (22) 0.12 0.26 Proven and probable IFI 9 (75) 21 (78) 1 GVHD (extensive) 5 (42) 14 (52) 0.57 High Dose Steroids 7 (58) 18 (67) 0.72 Disseminated IFI 3 (25) 4 (15) 0.65 Breakthrough IFI 10 (83) 25 (93) 0.57 APACHI II Score at time of IFI diagnosis 11+/−4 (range 5–18) 12+/−3 (range 5–19) 0.47

Maintenance Thalidomide May Improve Progression Free but Not Overall Survival; Results from the Myeloma IX Maintenance Randomisation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 656-656 ◽  
Author(s):  
Gareth J Morgan ◽  
Graham H Jackson ◽  
Faith E Davies ◽  
Mark T Drayson ◽  
Roger G Owen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Recovery Time ◽  
Cell Clone ◽  
Cox Model ◽  
Continuous Variable ◽  
Hazard Ratio ◽  
High Dose ◽  
Prognostic Features ◽  
Significant Difference ◽  
The Impact

Abstract The role of maintenance therapy for the long term control of the plasma cell clone in patients induced into response with either intensive or conventional treatment is an important outstanding question. We addressed this in the MRC Myeloma IX study which incorporates intensive and non-intensive pathways selected according to PS and age. In the intensive pathway patients were randomised to either CTD or CVAD induction, followed by High Dose Melphalan (HDM) before being randomised to either thalidomide or no maintenance. In the non-intensive pathway patients were randomised to either MP or attenuated CTD prior to the maintenance randomisation. For patients randomised to thalidomide it was initiated at d100 following HDM or at the end of induction in the non-intensive arm with the aim of delivering 100mg daily until relapse. A dose reduction algorithm for side effects was used. Between the years of 2003–8, 820 patients were entered into the maintenance randomisation, median age 64 (intensive 59, non-intensive 73), median follow-up 32 months. Prognostic features were evenly distributed between the arms. FISH and cytogenetics were done using standard methods. Response was assessed by IWG criteria. For overall survival (OS) there was a non-significant trend in favour of the no maintenance arm, which enables us, by calculating confidence limits on the hazard ratio, to make the assertion that no maintenance could be up to 7% worse than thalidomide at 5 years (p=.005). Further analysis showed that there was no significant difference in OS in either the intensive or the non-intensive arm. The duration of time on thalidomide maintenance appeared to make no difference to OS. There was a non-significant improvement in progression free survival (PFS) across the maintenance randomisation as a whole and in the intensive pathway a significant benefit of maintenance was seen in the patients achieving less than a VGPR post initial induction therapy prior to HDM, (hazard ratio 1.9, p=.007). This PFS difference did not translate into a survival benefit because the survival after progression in the PR patients receiving maintenance thalidomide was poor (p=.002). In addition we looked at the time spent off thalidomide, the recovery time, (the time between stopping thalidomide and progression) as a possible predictor of survival after progression. Treated as a continuous variable in the Cox model this showed a trend for longer survival after relapse in those with longer recovery time (p=.056). In the non-intensive pathway a similar but less pronounced effect of thalidomide maintenance on PFS was seen. These results are consistent with a consolidation rather than a maintenance effect for thalidomide in this setting. The impact of maintenance in different cytogenetic subgroups was also determined [17p-, 13q-, 14q abnormalities including t(4;14), t(14;16), t(6;14), t(14;20) and t(11;14)]. For the 17p- group, the difference in OS between no thalidomide and thalidomide is large (HR = 4.55, p=.02) with the thalidomide patients faring worse, although this is based on only 30 patients. For the non 17p- group there is no difference in PFS (HR = 1.24, p=.37), in the 17p- group, however, the PFS is worse. In addition, of the 22, 17p- patients receiving CTD or CTDa as initial therapy, the 10 who received no thalidomide maintenance are all still alive, whereas 9/12 of those who went on to receive thalidomide maintenance have died. It seems that thalidomide given at induction and again in maintenance, may be particularly detrimental in 17p- patients. Although thalidomide maintenance may improve PFS, there is no demonstrable benefit on OS. It is important to identify 17p- in order to exclude these patients from receiving thalidomide maintenance.

Acquisition of Cytogenetic Abnormalities (CA) Is a Very Poor Prognostic Feature in Patients (pts) with Low and Intermediate-1 (int-1) Risk Myelodysplastic Syndromes (MDS),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3802-3802
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Xuemei Wang ◽  
Lynne V. Abruzzo ◽  
A Megan Cornelison ◽  
...  
Keyword(s):  
Lower Risk ◽  
Research Funding ◽  
Regression Models ◽  
Cox Model ◽  
Time Dependent ◽  
P Value ◽  
Increased Risk ◽  
History Of ◽  
Previously Treated ◽  
The Impact

Abstract Abstract 3802 Background and Aim: The impact of the CA on prognosis and transformation into acute myeloid leukemia among pts with low and int-1 risk MDS is not known. The aims of the study were to assess the impact of CA on the natural history of pts with lower risk MDS and to identify factors associated with its development. Methods: We reviewed 721 pts clinical records of low and intermediate risk MDS pts from 2000–2010 and conducted a retrospective analysis of all pts with at least two consecutive cytogenetic analysis (365 patients, 51%). The acquisition of CA was defined by structural change or gain in at least 2 metaphases and loss in 3 metaphases, or otherwise confirmed by FISH. Cox proportional hazards regression models were fit to assess the association between transformation-free survival (TFS) or overall survival (OS) and pt characteristics. The acquisition of CA was fitted in the Cox model as a time-dependent covariate. The association between the acquisition of CA and pt characteristics was assessed through univariate and multiple logistic regression models. Results: CA was detected in 107 pts (29%) after a median follow-up of 34 months (mos). CA was observed in a median number of 4 metaphases (range, 2–30). At diagnosis, 21% and 79% of pts who acquired CA were low-and int-1risk MDS; 50% were diploid, 22% harbored chromosome 5 /7 abnormalities. At the time of acquisition of CA, the median percentage of bone marrow blasts was 4% (range, 0% to 89%), the median WBC, hemoglobin and platelets were 3.1 × 109/L, 9.5 g/dL, and 65 × 109/L, respectively; pts were low, int-1, int-2, and high-risk MDS in 3%, 42%, 26%, 29%, respectively. The median TFS and OS were 31 (95% CI: 27– 37) and 34 (95% CI: 30 – 44) mos respectively. Assessing CA as time-dependent covariate, patients with CA had a worse TFS and OS, with a median TFS and OS of 16 and 18 mos compared to 56 and 60 mos, respectively in pts without CA. Based on the multivariable Cox model and after adjusting for effects of all other covariates, pts who had acquired CA had an increased risk of transformation (HR=1.46; p-value = 0.01) or death (HR=1.50; p-value = 0.01). By multivariate analysis, female pts with prior chemotherapy had an increased risk of developing CA (OR= 5.26; p-value <0.0001). 96 pts had history of previous malignancy treated with chemotherapy +/− radiation therapy. Of those, 34 (35%) patients acquired CA. Median time from previous chemotherapy to the acquisition of CA was 61 mos (range, 11 to 180). Pts previously treated who did not acquire CA had similar outcomes to those who had never been treated and did not develop CA, while those who did develop CA whether they were previously treated or not had worse TFS and OS. Conclusion: CA occurs at a rate of 29% of pts with lower risk MDS, more common among pts with previously treated malignancy, and has a significant impact on TFS and OS, possibly reflecting genomic instability in the natural history of MDS. Disclosures: Cortes: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Encouraging Outcomes In Older Patients (Pts) Following Nonmyeloablative (NMA) Haploidentical Blood or Marrow Transplantation (haploBMT) With High-Dose Posttransplantation Cyclophosphamide (PT/Cy)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 158-158 ◽  
Author(s):  
Yvette L. Kasamon ◽  
Gabrielle Prince ◽  
Javier Bolaños-Meade ◽  
Hua-Ling Tsai ◽  
Leo Luznik ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Acute Gvhd ◽  
Older Age ◽  
Low Risk ◽  
Aggressive Lymphoma ◽  
High Dose ◽  
Platelet Recovery ◽  
Gvhd Prophylaxis ◽  
The Impact

Abstract Background Recent advances in NMA haploBMT have expanded potentially curative treatment options for pts lacking a matched donor. However, there is a paucity of data on the safety and efficacy of haploBMT in pts aged ≥ 60 y. This study evaluated the impact of older age on outcomes of NMA haploBMT with PT/Cy. Patients and methods We retrospectively analyzed the outcomes of 273 consecutive pts with poor-risk or advanced hematologic malignancies, aged 50-75 y, who received NMA related haploBMT with PT/Cy at Johns Hopkins. Eligibility included ECOG PS ≤ 1 or 2, LVEF ≥ 35%, adequate pulmonary and renal function and no uncontrolled infection. Morphologic CR was required for acute leukemia, ≥ PR for aggressive lymphoma. All pts received Cy (14.5 mg/kg IV days -6 and -5), fludarabine (30 mg/m2 IV days -6 to -2), TBI (200 cGy day -1) and T-cell replete bone marrow (272 pts) or peripheral stem cells (1 pt). GVHD prophylaxis consisted of high-dose PT/Cy (50 mg/kg IV) either once (day 3; 10 pts) or twice (days 3 and 4; 263 pts), mycophenolate mofetil and tacrolimus. Maintenance therapy was permitted and included rituximab in 55/126 B-NHL or CLL cases (44%). Results Of the 273 pts (median age 61 y, range 50-75), 154 were aged ≥ 60, including 27 pts aged 70-75. Diagnoses were aggressive lymphoma (79 pts), mantle cell lymphoma (25), indolent lymphoma or CLL (41), acute leukemia or lymphoblastic lymphoma (76), MDS (20), MPD (17), Hodgkin lymphoma (8) or multiple myeloma (7). Forty-one pts (15%) had prior autoBMT, and 138 (51%) had a high-risk comorbidity index score (HCT-CI ≥ 3). There were no statistically significant differences in HCT-CI risk category, histology (lymphoid vs myeloid), graft dose or CMV mismatch according to age by decade. By Disease Risk Index (DRI) category (Blood 2012; 120: 905), 32 pts (12%) were low-risk, 197 (72%) intermediate-risk, 44 (16%) high-risk and none very high-risk. No pts aged ≥ 70 were in the low-risk group. a) Overall results: With a median follow-up of 2.1 (range < 1 - 7.9) y in event-free pts, 2-y probabilities of PFS and OS were 39 (95% CI, 32-44)% and 53 (47-60)%, respectively. The probability of neutrophil recovery was 89% at day 30 (median 16 days). The probability of platelet recovery ≥ 20,000/µL was 85% at day 60 (median 26 days). Graft failure occurred in 12% of evaluable pts, with autologous count recovery in most cases. By competing-risk analysis, the 180-day probability of nonrelapse mortality (NRM) was 11 (95% CI, 7-14)%, grade 2-4 acute GVHD was 32 (27-38)%, and grade 3-4 acute GVHD was 3 (1-6)%. The 1-y probabilities of NRM and chronic GVHD were 14 (95% CI, 10-19)% and 12 (8-16)%. b) Age-specific results: Notably, as compared to age 50-59, we found no statistically significant association between advanced pt age and either NRM (fig A) or PFS. On univariate analysis, older age relative to ages 50-59 was associated with a tendency toward more grade 2-4 acute GVHD, without an evident increase in severe acute GVHD. The 2-y PFS probabilities for pts in their 50's, 60's and 70's were 39%, 36% and 39%, respectively (p = 0.9; fig B), with corresponding 2-year OS probabilities of 51%, 56% and 44 % (p = 0.9). In univariate analyses, no statistically significant association was seen between PFS and older age as a continuous variable (HR 1.01, 95% CI 0.99-1.03, p = 0.44) or categorical variable (ages 60-69 and ≥ 70, relative to 50-59). In contrast, the DRI category was significantly associated with both PFS (p < 0.003; fig C) and OS (p = 0.01). Likewise, in a multivariate analysis adjusted for year of BMT, the DRI was independently associated with PFS (p = 0.047). However, in multivariate analyses of PFS and NRM, no statistically significant association was seen with older age. Conclusion These data suggest that in NMA related haploBMT with PT/Cy, advanced pt age is not associated with prohibitive toxicities. In fact, there was no apparent decrement in overall outcome in pts aged ≥ 70 when compared to those in their 50's. Additionally, the DRI is useful for risk stratification. Advanced age is thus no longer a barrier to successful outcomes with partially HLA-mismatched BMT. Disclosures: Off Label Use: Posttransplantation cyclophosphamide for GVHD prophylaxis.

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