Consolidation therapy using cyberknife radiosurgery in NSCLC patients with low-volume residual disease upon completion of systemic therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18213-18213
Author(s):  
M. P. McLaughlin ◽  
R. Bordoni ◽  
T. Whitaker ◽  
P. Zolty ◽  
M. Andrews ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Residual Disease ◽  
Local Therapy ◽  
Standard Of Care ◽  
Initial Therapy ◽  
Consolidation Therapy ◽  
Current Standard ◽  
End Point ◽  
Ecog Ps

18213 Background: Pts with unresectable IIIB and IV NSCLC with PS 0–1 are usually treated with chemotherapy (CH) ± targeted therapy (TT) with overall survival (OS) improvement. Upon completion, standard of care is observation. Pts eventually progress within 9 to 12 months. If still in good PS, they are treated with salvage CH or TT; otherwise, they receive palliative care. We evaluated 12 patients with PR to initial therapy, found to have small volume residual disease (SVRD) defined as one or two sites to receive “consolidation” local therapy with Cyberknife Radisurgery (CRS). Methods: Since September 2006, 12 pts with NSCLC, stage IIIB unresectable (3) or IV (9), median age 64 (range 61–78), adenocarcinoma (7), squamous cell carcinoma(5), 9 males, all ECOG PS 0–1, were treated with induction CH (carboplatin/paclitaxel ± bevacizumab, cisplatin/gencitabine) with PR. CT/PET imaging showed SVRD. Eight patients had only one site; four had 2. These patients received CRS consolidative therapy to the following areas: lung-9, mediastinal node - 3, adrenal-2, liver-2. CRS dose depended on the disease site. Peripheral lung lesions - 54 Gy in 3 fractions (fx); medistinal lesions - 50 Gy in 4 fx; adrenal - 24 Gy in 3 fx and liver - 16 Gy. in 1 fx. The primary end point was efficacy (response rate, time to progression in or out of the radiosurgical fields, and OS) compared with historical matched controls. The secondary end point was safety and tolerability of CRS. Results: After a median follow up period of 65 days, all evaluable pts are still alive and without clinical or radiological (CT/PET) evidence of disease progression in or outside the sites of CRS. The treatment was well tolerated with no Grade 3–5 complications. PS remained 0–1 in all patients. Conclusions: Patients with advanced NSCLC benefit from systemic therapy with symptoms control and improved QoL and OS. Upon completion of therapy, observation is the current standard or care. Patients with good PS and SVRD tolerated CRS consolidation therapy remarkably well and may benefit with added symptoms control, improved TTP and even OS. At the June meeting efficacy and toxicity data of a projected population of 30+ patients, with a medial follow up of 8 months, will be presented. No significant financial relationships to disclose.

Adjuvant chemotherapy with temozolomide and radiation therapy in patients with high grade gliomas

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 12534-12534
Author(s):  
R. Pedersini ◽  
E. Vattemi ◽  
M. Lusso ◽  
S. Baier ◽  
M. Campello ◽  
...  
Keyword(s):  
Haematological Toxicity ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
High Grade ◽  
Current Standard ◽  
Newly Diagnosed Glioblastoma ◽  
High Grade Gliomas ◽  
Ecog Ps ◽  
Grade Iii

12534 Background: Temozolomide, a novel alkylating agent, has shown activity in the treatment of patients with high-grade gliomas. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant chemo- radiotherapy according to Stupp regimen. Methods: We reviewed our experience with a combination of radiotherapy (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). Results: 43 patients , median ECOG PS= 0, were treated with concomitant RT and Temozolomide at our institution since March 2004. Median age was 63 (range 33–73), with 62% over 60 years. All patients had histologically confirmed high grade gliomas: glioblastoma multiforme (32), grade III oligodendroglioma (3), grade III oligoastrocytoma (2), grade III astrocytoma (6). 2/43 patients underwent only a biopsy, the remaining underwent debulking surgery. At a median follow-up of 17 months, the median progression-free survival (PFS) was 6 mo and median overall survival (OS) was 12 mo. Median PFS and median OS were similar in elderly ( = 60 years). Treatment was well tolerated. Only one patient had grade IV haematological toxicity. One patient discontinued treatment due to hepatotoxicity. Conclusions: Our findings confirm the results of the EORTC trial(Stupp R et al., 2005) No significant financial relationships to disclose.

P14.90 Survival outcomes and prognostic factors in glioblastoma patients treated with radiotherapy plus concomitant and adjuvant temozolomide - real-world study

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii55-ii55
Author(s):  
M J Sousa ◽  
J Magalhães ◽  
R Basto ◽  
C Costa ◽  
A Pego ◽  
...  
Keyword(s):  
Survival Rate ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Rank Test ◽  
Survival Outcomes ◽  
Hematologic Toxicity ◽  
Current Standard ◽  
Adjuvant Temozolomide ◽  
Standard Of Care Treatment ◽  
Ecog Ps

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour in adults. The current standard of care for newly diagnosed GBM is maximal surgical resection, followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ). This study aimed to evaluate the survival outcomes and identify predictors of survival among these patients. MATERIAL AND METHODS We performed a single-centre retrospective analysis of GBM patients treated with radiotherapy plus concomitant and adjuvant TMZ from 2013 to 2020. The analyses of progression-free survival (PFS) and overall survival (OS), each one evaluated starting from initial diagnosis, were performed. Survival curves were estimated with the Kaplan- Meier method and compared using the log-rank test. RESULTS Fifty-eight patients were identified. The median age was 61 years (range 18- 80), 51 (88%) patients were in ECOG-PS 0–1, 6 (10%) patients had isocitrate dehydrogenase (IDH) mutation and 53 (91%) of patients had undergone debulking surgery. At a median follow-up of 21 months, median OS was 12.8 months (95% confidence interval [CI] 9.7–15.9), whereas median PFS was 9.5 months (95% CI 8.5–10.5). The 1-year survival rate was 42% and the 2-year survival rate was 10%. Grade 3 or 4 hematologic toxicity occurred in 11 (19%) patients. Twenty-five (42%) patients completed at least 6 cycles of TMZ monotherapy with statistically significant differences between this sub-group and those who weren’t able to continue TMZ monotherapy [median OS 19.3 months (95% CI 14.4–24.2) vs 10.6 months (95% CI 7.8–13.4) p<0.001]. ECOG-PS = 0 [median OS 16.7 months (95% CI 13.4–20.0, p=0.001)] and patients under 65 years of age [median OS 15.6 months (95% CI 12.3–18.9, p=0.02) were associated with significantly better median OS. CONCLUSION The current standard of care treatment for GBM remains poor. An important factor predictor of survival is the completion of the 6 maintenance cycles of TMZ. At baseline, ECOG PS and the patient’s age could be used to define patient prognosis.

scholarly journals A community-based comprehensive intervention to reduce syphilis infection among low-fee female sex workers in China: a matched-pair, community-based randomized study

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Wei Dong ◽  
Chu Zhou ◽  
Ke-Ming Rou ◽  
Zun-You Wu ◽  
Jun Chen ◽  
...  
Keyword(s):  
Sex Workers ◽  
Standard Of Care ◽  
Matched Pair ◽  
Intervention Package ◽  
Current Standard ◽  
Community Based ◽  
Syphilis Infection ◽  
Intervention Measures ◽  
Comprehensive Intervention

Abstract Background Low-fee female sex workers (FSWs) are at high risk of acquiring and spreading human immunodeficiency virus (HIV)/sexually transmitted diseases (STDs) in China. There is an urgent need to develop comprehensive intervention measures targeted towards low-fee FSWs to reduce HIV/STD infections. Thus, this study aimed to reduce HIV/STD infections among low-fee FSW through a matched-pair, community-based randomized intervention trial carried out in 12 cities in three provinces in China. Methods Four cities from Guangxi Zhuang Autonomous Region, four from Yunnan Province, and four from Hunan Province were paired and participants received either the intervention package (including condom promotion, HIV and syphilis testing, reimbursement for syphilis treatment costs, and free anti-retroviral therapy or the current standard of care. Venue-based, convenience sampling was used to recruit FSWs. A face-to-face interview and HIV and syphilis blood testing was conducted at baseline and follow-up intervals of 24 months. Generalized linear mixed models (GLMM) were used to evaluate the effect of the intervention package on reducing HIV/STD infection in the FSWs. Results A total of 1024 eligible FSWs were enrolled in the baseline survey and 843 in the follow-up. GLMM results showed that syphilis infection was reduced by 49% in the intervention group compared to the current standard of care group (P = 0.0378, OR = 0.51, 95% CI: 0.27–0.96). FSWs aged 35 years or older were 2.38 times more likely to get syphilis infection compared to those younger than 35 years old (P <  0.0001, OR = 2.38, 95% CI: 1.55–3.65). The risk of syphilis infection among more educated FSWs was 0.43 times less than those with lower levels of education (P <  0.05, OR = 0.43, 95% CI: 0.63–0.93). Conclusions This study demonstrates that comprehensive interventions can lead to significant declines in syphilis infection amongst low-tier FSWs. Integrating both behavioral and biomedical intervention measures should be considered when developing programs for low-fee FSWs. Trial registration CHiCTR-TRC-12002655.

scholarly journals ATIM-13. MULTIMODAL IMMUNOTHERAPY WITH IO-VAC® FOR PATIENTS WITH GBM: A SINGLE INSTITUTION EXPERIENCE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi4-vi4
Author(s):  
Stefaan Van Gool ◽  
Jennifer Makalowski ◽  
Wilfried Stuecker
Keyword(s):  
Tumor Antigens ◽  
Residual Disease ◽  
Local Therapy ◽  
Autologous Tumor ◽  
Line Treatment ◽  
First Line ◽  
Advanced Therapy Medicinal Product ◽  
Advanced Therapy ◽  
First Line Treatment

Abstract Multimodal immunotherapy (Newcastle Disease Virus (NDV) + modulated electrohyperthermia + IO-VAC® + immunomodulatory strategies) is an innovative treatment for primary GBM and might prolong overall survival (OS). IO-VAC® consists of DCs loaded with autologous tumor antigens and matured with cytokine cocktail and NDV. We retrospectively reviewed 132 cases of primary GBM. Multimodal immunotherapy was integrated as individualized treatment approach and following different scenario’s in combination with standard treatment in the first line treatment in 71 patients, used at time of first or subsequent relapse as treatment with or without chemotherapy in 61 cases. Median ages were resp. 55 and 53 y. Median KPI at start of immunotherapy was 90 and 80. Median OS for the patients treated with immunotherapy as part of first-line treatment was 20 months with 2-y OS of 40% (CI95%: -13,+13). Median OS for patients treated at time of relapse was 7 months with but still with 18-m OS of 16% (CI95%: -12,+9). Two resp. 1 patients were lost of follow up. A subgroup of 34 GBM patients (10 females) with median age 58y (20–67) was detected, who received NDV + modulated electrohyperthermia during Temozolomide maintenance cycles followed by two IO-VAC® DC vaccinations, and further NDV + modulated electrohyperthermia courses. Median KPI was 70 (60–100). MGMT status was methylated (12), unmethylated (13), unknown (9). Median OS for this subgroup was 23.4 months with 2-year OS of 48% (CI95%: -18,+20). Immunotherapy was feasible without immunotherapy-related side effects of grade III or more. The data suggest that multimodal immunotherapy with IO-VAC® already during and after maintenance chemotherapy, at time of achieved minimal residual disease with local therapy, might help in prolongation of OS. Prolongation of OS in a small group of patients at time of relapse was also demonstrated. IO-VAC® is an approved advanced therapy medicinal product (DE-NW-04-GMP-2015-0030).

scholarly journals Update on mantle cell lymphoma

Blood ◽  
2018 ◽  
Vol 132 (16) ◽  
pp. 1647-1656 ◽  
Author(s):  
Kami Maddocks
Keyword(s):  
Mantle Cell Lymphoma ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Response Duration ◽  
Standard Of Care ◽  
Initial Therapy ◽  
World Health ◽  
Molecular Features ◽  
Therapeutic Decisions ◽  
Mantle Cell

AbstractMantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is most commonly treated with combination chemo-immunotherapy at diagnosis because of the poor prognosis. More indolent presentations have been described including patients who can defer initial therapy without adverse impact on survival. The 2016 World Health Organization updated classification describes 2 major subtypes, classical and leukemic nonnodal MCL, each with unique molecular features and clinical presentations. Although there is no standard of care for MCL, aggressive chemo-immunotherapy regimens containing rituximab and cytarabine, followed by consolidation with autologous stem cell transplantation and maintenance rituximab, are the most used approach in young fit patients, and chemo-immunotherapy, followed by rituximab maintenance, is most commonly used in older patients. Despite the improvement in response durations with currently available therapies, patients will inevitably relapse. A number of targeted therapies are approved in the relapsed setting and are now under evaluation in combination with standard frontline therapy. Although the approval of ibrutinib changed the landscape of therapy for relapsed MCL, prognosis remains poor after progression on ibrutinib supporting the development of ibrutinib combinations to prolong response duration as well as the development of other novel agents for ibrutinib refractory disease. With ibrutinib being incorporated into initial therapy regimens, new options will be needed at relapse. Prognostic markers, such as minimal residual disease, have been shown to correlate independently with outcomes along with predicting relapse, with the potential to guide therapeutic decisions. The future treatment of MCL therapy will need to incorporate therapy based on risk-stratification and nonchemotherapeutic approaches.

Intraperitoneal interferon-alpha-2b for patients with no macroscopic disease following second-look laparotomy

1993 ◽  
Vol 3 (5) ◽  
pp. 324-328 ◽  
Author(s):  
A. Proietto ◽  
N. F. Hacker
Keyword(s):  
Interferon Alpha ◽  
Residual Disease ◽  
The Other ◽  
Consolidation Therapy ◽  
Interferon Alpha 2B ◽  
Second Look ◽  
Microscopic Residual Disease ◽  
Time To Relapse ◽  
Mean Time

Low to intermediate doses of interferon-alpha-2b (10–30 million units every 2 weeks for six cycles), were administered intraperitoneally to 14 patients with no macroscopic disease at the completion of second-look laparotomy. Eight patients had a negative second-look so the treatment was given as consolidation therapy. Five patients had a microscopically positive second-look and one patient had small macroscopic disease completely resected. Toxicity was low. However, four of the eight patients with a negative second-look relapsed (two in the peritoneum) and five of the other six patients have also relapsed, all in the peritoneum. Four of these latter six patients received intraperitoneal cisplatinum in addition to the interferon. Mean time to relapse for the group with a negative second-look was 18 months, while it was 16 months for the group with microscopic residual disease. Median follow-up was 38 months. Intraperitoneal interferon in the dosages given in this trial does not seem to be effective as consolidation therapy, nor is it effective for patients with microscopic residual disease at second-look laparotomy.

Complete Eradication of Minimal Residual Disease (MRD) in Patients with Hairy Cell Leukemia (HCL) after Cladribine (2CDA) Followed by an Extended Course of Rituximab.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3258-3258
Author(s):  
Farhad Ravandi-Kashani ◽  
Susan O’Brien ◽  
Keating Michael ◽  
Dan Jones ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Residual Disease ◽  
Nucleoside Analogs ◽  
Response Duration ◽  
Initial Therapy ◽  
Chromosome 17 ◽  
Median Response ◽  
Mutational Status ◽  
Hairy Cells ◽  
Extended Course

Abstract The nucleoside analogs 2CDA and pentostatin are effective in the initial therapy of patients with HCL, but relapses are common. We have investigated whether an 8 week course of therapy with weekly rituximab after 2CDA can eradicate MRD assessed by flow cytometry as well as by immunoglobulin heavy chain (IgH) polymerase chain reaction (PCR) assay using framework-1, -2 and -3 primer sets. Treatment constituted 2CDA 5.6 mg/m2 IV given over 2 hours daily for 5 days. One month after initiation of 2CDA, bone marrow (BM) MRD was assessed and rituximab 375 mg/m2 IV was given weekly for 8 weeks. BM MRD was reevaluated again after the completion of rituximab. To date, 12 patients have been treated including 10 with newly diagnosed disease and 2 after relapse from prior therapy (2CDA in one patient and chlorambucil in another). The median age of the patients was 55 years (range 31–73). Two patients had variant HCL. Fluorescent in situ hybridization (FISH) was positive for the presence of a clone with p53 deletion/monosomy 17 in 2 patients. One patient with variant HCL had complex cytogenetics. Seven of 10 evaluable patients had mutated IgVH gene whereas IgVH was unmutated in 3 patients. All 12 patients (100%) have achieved CR defined as no hairy cells in BM and blood with normalization of counts (ANC &gt;1.5 x 109/L, Hgb &gt;12.0 g/dL, Plt &gt; 100 x 109/L) after completion of all therapy; 5 patients still had 1% to 50% hairy cells in BM after 2CDA therapy. MRD by flow was positive in 11 patients after 2CDA therapy but became negative in all 12 patients after rituximab. MRD by PCR was positive in 5 of 10 evaluable patients after 2CDA therapy and became negative in 10 of 11 evaluable patients (equivocal in 1) after rituximab. With a median duration of follow-up of 11 months (range 3–13) no patients have relapsed (median response duration 6+ months, range 1–13). One patient has developed a second cancer (pancreatic). We conclude that therapy with an extended course of rituximab is effective in eradicating MRD in HCL. The predictive value of achievement of negative MRD, presence of chromosome 17 abnormalities, or the mutational status of IgVH on the risk of relapse should be evaluated in larger series and with longer follow-up.

Quantitative Monitoring of NPM1 Mutation A Minimal Residual Disease Identifies Patients At High Risk for Relapse within the ELN Favorable Risk Group

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1404-1404
Author(s):  
Max Hubmann ◽  
Marion Subklewe ◽  
Thomas Köhnke ◽  
Stephanie Schneider ◽  
Annika Dufour ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Residual Disease ◽  
Risk Group ◽  
Disease Recurrence ◽  
Consolidation Therapy ◽  
Rt Pcr ◽  
Npm1 Mutation ◽  
Minimal Residual

Abstract Abstract 1404 Introduction: Molecular analyses of leukemia-specific markers has led to an improvement of the prognosis evaluation in patients (pts) with acute myeloid leukemia (AML). The European Leukemia Net (ELN) has published a classification which separates different subgroups by cytogenetic and molecular genetic analyses. Nevertheless, there are still pts suffering from disease recurrence within the ELN favorable risk group. To identify these pts at high risk for relapse the monitoring of minimal residual disease (MRD) of leukemia-specific markers could become an important diagnostic tool. In this study the potential of MRD monitoring by quantitative real-time PCR (RT-PCR) of NPM1 A mutation (NPM1 A) at different checkpoints within the ELN favorable risk group of pts with NPM1 A and without FLT3-ITD was investigated. Methods: Pts participating in the AMLCG99, AMLCG2004, and AMLCG2008 trial were prospectively or retrospectively screened for NPM1 mutation and FLT3-ITD by melting curve analyses. 334 pts were screened positive for NPM1 mutation and 262 pts showed a NPM1 A, 78.4 % of all NPM1 mutations. For MRD monitoring a relative RT-PCR was performed in 538 samples of 178 NPM1 A positive pts with a sensitivity of 10-6. MRD was monitored at diagnosis, in aplasia, after induction therapy, after consolidation therapy, and during the follow-up. MRD levels were normalized to the housekeeping gene ABL1 and expressed as a ratio to an internal control of known concentration. Results: In the analysis of the NPM1 A positive and FLT3-ITD negative pts (ELN favorable risk group) 82.5% (n=85) achieved complete remission (CR) after induction therapy. With a median follow-up of 26 (range 1–118) months, 36 (42.9%) pts relapsed within this subgroup. In aplasia, and after induction therapy, pts with a long-lasting remission showed significantly lower NPM1 A ratios in contrast to pts who relapsed during the follow-up. Via Receiver-Operating Curves (ROC) we analyzed the diagnostic power to identify pts at high risk for relapse and determined clinical useable cut-offs at the different checkpoints. ROC were significantly associated with disease recurrence at the checkpoints in aplasia and after induction therapy, but not after consolidation therapy. After induction therapy, a cut-off with a ratio of 0.01 was determined. This cut-off separates the patient cohort into two prognostic groups. NPM1 A MRD levels above the cut-offs result in an increased risk of relapse compared to pts with MRD level below this cut-off. This is reflected in a significantly lower 2-year relapse free survival (RFS) of 18% versus 72% (Figure 1). In 25 pts of this favorable risk group follow-up samples in CR were available for analysis of an upcoming relapse within 100 days of sampling. Only 2 of these pts developed relapse within of the next 100 days, but both pts showed increasing MRD levels prior to relapse. 18 relapse samples were available in this subgroup and interestingly, one patient (5.5%) was NPM1 A negative at relapse. When we further enrolled the FLT3-ITD positive pts into our analyses, not surprisingly we found a negative impact on the RFS of MRD positive and MRD negative pts. Conclusions: Our results confirm the observations of other studies that showed the prognostic impact of NPM1 MRD monitoring by RT-PCR. With the MRD monitoring we could identify pts at high risk for relapse within the ELN favorable risk group. Particularly high MRD levels after the induction therapy were strongly associated with a worse RFS. This and previously published data of others demonstrate that in addition to pre-therapeutic factors, the individual MRD course should be used as prognostic factor for the guidance of treatment and pts with high or increasing levels of MRD should undergo allogeneic stem cell transplantation, if eligible. Disclosures: No relevant conflicts of interest to declare.

Minimal Residual Disease Monitored With Fluorescence In Situ Hybridization (FISH) In CD34+CD38- Population Predicts Clinical Outcome In Core Binding Factor Acute Myeloid Leukemia (CBF-AML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1356-1356
Author(s):  
Xiaoxia Hu ◽  
Libing Wang ◽  
Lei Gao ◽  
Sheng Xu ◽  
Shenglan Gong ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
Consolidation Therapy ◽  
Rt Pcr ◽  
Binding Factor ◽  
Minimal Residual

Abstract Acute myeloid leukemia (AML) is generally regarded as a stem cell disease, known as leukemic initiating cells (LIC), which initiate the disease and contribute to relapses. Although the phenotype of these cells remains unclear in most patients, they are enriched within CD34+CD38- compartment. In core binding factor (CBF) AML, the cytogenetic abnormablities are also existed in LIC. The aim of this study was to determine the prognostic power of minimal residual disease measured by fluorescence in situ hybridization (FISH) in flow sorted CD34+CD38- cells (FISH+CD34+CD38- population) at different period during the therapy. Thirty-six patients under 65 years of age with de novo CBF AML and treated with CHAML 2010 protocol were retrospectively included in this study. FISH efficiently identified the LICs (FISH+CD34+CD38-) in the CD34+CD38- population. The last follow-up was March 31, 2013, and the median follow-up was 336 days (range: 74-814 days). 33 patients with complete remission (CR) were eligible for the study, and 23 patients (23/33, 69.7%) with t (8;21) or AML1/ETO, and the remaining (10/33, 30.3%) with inv(16)/t(16;16) or CBFβ/MYH11. Flow-cytometry based FISH (F-FISH) procedure was performed at diagnosis, before every cycle of consolidation therapy, and every 3 months during follow-up. The FISH+ percentage at diagnosis constituting an average of 2.1% (range: 0.01%-27.5%) of the blast cells and 64.6% (range: 14%-87.8%) of the CD34+CD38- cells. Before the consolidation, FISH+CD34+CD38- population was detected in 13/33 (39.4%) patients. At this checkpoint, we have found the existence of FISH+CD34+CD38- population had prognostic value for the end points relapse free survival (RFS, 12% versus 68%, P=.008), and retained prognostic significance for RFS in multivariate analysis. Furthermore, the detection of FISH+CD34+CD38- before consolidation was found to be significantly associated with decreased OS. (11% versus 75%, P=.0005) Minimal residual disease (MRD) detected with F-FISH had a prognostic value at an earlier checkpoint when compared with flow cytometry and RT-PCR. Meanwhile, the concordance of flow cytomety, RT-PCR and F-FISH was investigated in the same patient cohort. 14 (70%) of 20 samples with detectable fusion transcripts by PCR did not have detectable leukemic cells by F-FISH. Therefore, the concordance for PCR and F-FISH was 63.7%. The concordance of FC and F-FISH was 64.3%: in 40 samples MRD was detected by both methods and in 61 samples MRD was ruled out by a negative result with the tests. With further analysis, the discrepancies among MRD detected with different MRD monitoring approaches before consolidation and after the first consolidation therapy contribute to 84% of the disconcordance. In summary, the detection of FISH+CD34+CD38- cells before consolidation therapy was significantly correlated with long-term survival in de novo CBF AML patients. F-FISH might be easily adopted as MRD monitor approach in clinical practice to identify patients at risk of treatment failure from the early stage during therapy. Disclosures: No relevant conflicts of interest to declare.

A Phase II Add-on Study of Vorinostat (VOR) in Higher Risk Myelodysplastic Syndrome with Failure of Hypomethylating Agents (HMA): The GFM Azavor Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2900-2900
Author(s):  
Thomas Prebet ◽  
Jacques Delaunay ◽  
Eric Wattel ◽  
Thorsten Braun ◽  
Pascale Cony-Makhoul ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rate ◽  
Standard Of Care ◽  
Median Number ◽  
Current Standard ◽  
Stage Design ◽  
Early Evaluation ◽  
Positive Results

Abstract Background: Azacitidine (AZA) is the current standard of care for patients treated for higher risk MDS, but 40-50% patients do not respond and most responders eventually relapse. Median survival after AZA failure is only 5 months and no standard of care is defined for this population. Preclinical studies and positive results of phase I-II trials support a synergistic effect of the histone deacetylase (HDAC) vorinostat (VOR) and AZA in terms of response, although no survival advantage of the combination has as yet been demonstrated. We hypothesized that adding VOR to AZA in patients with primary or secondary AZA resistance could rescue response and prolong survival. Methods: inclusion criteria inGFM AZAVOR study (NCT 01748240) were: 1/IPSS int 2 or high risk MDS at the time of initiation of AZA 2/treatment with at least 6 cycles of AZA and either failure to achieve any response or loss of response (per IWG2006 criteria) 3/a maximum of 3 months between AZA failure and inclusion with no other treatment in between. Patients received VOR 300mg bid from day 3 to day 9 of each cycle. AZA was given at standard 75mg/m2/d day 1 to 7 or at the maximum previously tolerated dose in case of dose reduction. Patients were evaluated after 6 cycles and responding patients treated until progression. The trial used a two-stage design, and accrual was to be stopped if less than 3 responses were seen in the first 14 evaluable patients. Results 21 patients were included between march 2013 and September 2014. Nineteen patients were treated (1 patient died and 1 progressed before treatment). Median age was 72 years. All pts had higher risk MDS and had received a median of 6 cycles of AZA before entering the trial. The median number of AZA+ VOR cycles administered was 3 (range: 1-12). No unexpected SAEs were seen, and the most common AEs were infection, thrombocytopenia, GI toxicities, and fatigue. After 6 cycles of treatment, only 2 patients (11%) achieved response (1 erythroid hematological improvement, 1 partial remission), , which, per protocol, triggered the stop of accrual. At last follow-up, 18 patients were off study and one patient was still on treatment. Nine patients stopped treatment because of progression (42%), 4 stopped treatment for lack of response (21%), 2 stopped treatment because of intolerance (11%), 1 patient stopped at his request (5%), and 1 patient died of complications of cytopenias while on treatment (5%). Median overall survival was 13 months. Conclusion This is the first report of an add-on study in high risk MDS, a strategy that may be useful for the early evaluation of drugs for which synergy with AZA is expected. Our results show that the proposed regimen of AZA +VOR can be used safely. However, the observed response rate was not above the "background" response rate expected from AZA alone continuation in a comparable patient population, indicating that the addition of VOR cannot reverse resistance to AZA. Disclosures Prebet: CELGENE: Research Funding. Off Label Use: lenalidomide. Wattel:Janssen: Consultancy, Honoraria, Research Funding; PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.

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