scholarly journals Adult T-Cell Leukemia/Lymphoma: A Cohort of 41 Cases Recorded in the Brazilian T-Cell Project

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Daniel Silva Nogueira ◽  
Marcia Torresan Delamain ◽  
Eliana Cristina Miranda ◽  
Yung Bruno de Melo Gonzaga ◽  
Juliana Pereira ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advanced Stage ◽  
Line Treatment ◽  
Cell Leukemia ◽  
Advisory Committees ◽  
Stage Disease ◽  
Ann Arbor

Introduction:Adult T cell Leukemia/Lymphoma (ATLL) is a mature T-Cell-neoplasm related to human T-cell lymphotropic virus type 1 (HTLV-1) infection that shows variable clinical presentation and adverse prognosis with shorter overall survival (OS) when compared to other peripheral T-cell lymphomas (PTCL). Previous epidemiological studies estimated cumulative incidence in endemic regions around the world. In Brazil, mainly due to its vast dimension, data collection has limitations and is subject to bias. In April 2015 theBrazilianT-cell longitudinal project initiative was launched. One of the primary purposes was the collection of epidemiological and clinical data from the most frequent subtypes of newly diagnosed PTCL. Among them, 41 cases of ATLL were recorded. Objectives:The aim of this study is to describe clinical features, frequency and overall survival (OS) of 41 cases of ATLL registered in the ongoingBrazilianT-Cell Project. Methods:This is an ambispective observational study design collecting baseline characteristics, clinical features including date of diagnosis, clinical subtypes, B symptoms, performance status, Ann-Arbor staging, HTLV-1 status, number of sites, nodal and extra nodal presentation and types of skin lesions, peripheral blood counts and biochemical tests, front-line treatment and best response after first-line treatment. REDcap Platform has been used to collect and store data and for descriptive analysis the IBM-SPSS version 24 was applied. Kaplan-Meier method estimated the OS, whereas Log-Rank tests to compare its curves. OS period was calculated from diagnosis date until death or last seen date, and event was death by any cause. Results:Out of 281 cases of PTCL registered so far, 41 were ATLL cases. The median age was 50 years (34-88), 25 (64%) female; a higher incidence of lymphoma subtype was observed (46%), followed by acute (29%), chronic (17%) and smoldering (8%). Most of the patients (85%) had advanced-stage disease (III-IV, Ann-Arbor) and 56% had B symptoms (Table 1); 73% received chemotherapy with anthracycline-based regimens (46.5% CHOEP; 33.5% CHOP; 20% others) whereas 17% were managed with immunotherapy and antiviral therapy. The overall response rate was 30%; no response or progression 46%; stable disease 9% and 15% no data available yet (Table 2). Median follow-up was 13 months and 25 months for 41% of alive patients. Two year OS was 39% (95%CI: 23-55%) (Figure 1). Smoldering and Chronic subtypes showed better OS when compared with acute and lymphoma (100% smoldering, 86% chronic; 30% lymphoma type and 13% acuteP=0.04) (Figure 2). The multivariate Cox Regression analysis found male gender (HR 10.9 95%CI: 3.0-39.7, P<0.0001) and albumin (HR 0.23 Beta -1.45 95%CI: 0.10-0.55, P=0.001) as significant prognostic factors for OS. Discussion:ATLL prognosis remains poor regardless of the type of treatment regimen and may be associated with the high incidence of lymphoma and acute subtypes, as well as advanced stage disease presentation. Despite the high number of cases seen in southeastern region of Brazil, it is important to emphasize there are still limited data from other regions. Albeit the sample size is small, these findings confirmed literature review data so far, with poor overall survival in a short time and gender and albumin as predictors of OS in the multivariate analysis. Conclusion:This study highlights the poor prognosis associated with ATLL. Moreover, it seems relevant to expand this study to all Brazilian regions. Hence, the need for early diagnosis and new treatment strategies, able to reduce mortality is warranted, that could possibly change the nature and spectrum of disease. Disclosures Federico: Spectrum:Consultancy, Membership on an entity's Board of Directors or advisory committees;Sandoz:Consultancy, Membership on an entity's Board of Directors or advisory committees;Cephalon/Teva:Research Funding;Mundipharma s.r.l.:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Millennium/Takeda:Research Funding;Roche:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda:Consultancy, Membership on an entity's Board of Directors or advisory committees.

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 ◽  
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.

scholarly journals Pathologic Misdiagnosis in Children with Suspected Burkitt Lymphoma Associated with Early Mortality

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2271-2271
Author(s):  
Chloe Stiggelbout ◽  
Megan Real-Hall ◽  
Innocent Mutyaba ◽  
Elizabeth M Krantz ◽  
Scott Adams ◽  
...  
Keyword(s):  
Sample Size ◽  
Board Of Directors ◽  
Burkitt Lymphoma ◽  
Research Funding ◽  
Early Mortality ◽  
Disease Stage ◽  
Advanced Stage ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Stage Disease

Abstract INTRODUCTION Burkitt lymphoma (BL) is one of the most common childhood cancers across sub-Saharan Africa (Walusansa et. al, 2012). Unfortunately, the one-year survival rate of children with BL treated in low- and middle- income countries (LMICs) remains low, compared to higher-resource settings (Howard et al., 2008, Stanley et al., 2016, Buckle et al., 2016). Factors in LMICs contributing to this disparity include inability to give high-dose chemotherapy, lack of supportive care measures, and treatment abandonment (Gopal, 2018). The impact of diagnostic inaccuracies on BL outcome has not been well-studied to date. PURPOSE To determine the frequency and impact of an incorrect histopathologic diagnosis in children with suspected BL presenting to the Uganda Cancer Institute (UCI). METHODS Study Design and Participants -A sample of subjects with available tissue biopsies was selected from a cohort of children presenting to the UCI with suspected BL between July 2012 and July 2017. Laboratory Methods - Formalin fixed, paraffin embedded (FFPE) tumor blocks were obtained from local Ugandan pathology laboratories and sectioned in a single, central Ugandan histology lab. Slides were then shipped to a US-based reference laboratory for front-line evaluation by Hematoxylin and Eosin (H&E) staining, by intentionally streamlined immunohistochemistry (IHC) for CD20, c-Myc, and TdT detection, and by EBER-1 in situ hybridization (ISH) for EBV detection. A diagnosis of BL required the expected H&E appearance and prominent tumor expression of CD20, c-Myc, and EBER-1, with no significant TdT expression. For equivocal cases, additional CD10, CD21, bcl-2, and Ki67 IHC could be employed. Misdiagnosis Definition - A discrepancy between the pathologic diagnosis confirmed by IHC/ISH at the US-based laboratory, and the diagnosis that determined treatment in Uganda. Clinical and Statistical Analysis - Advanced disease stage included Ziegler stage C, D, or AR based on physical exam. Kaplan-Meier and Cox regression analysis were applied to evaluate survival. RESULTS We enrolled 97 participants of with a median age of 7 (interquartile range (IQR) 4-10); 69% were male, 47% had ECOG status 0-1, and 48% had advanced stage disease (though 22% had missing staging information - Table 1). The majority of patients had facial involvement, while less than half of the evaluable patients had abdominal involvement. Twenty percent of biopsies (19/97) were misdiagnosed. Median follow-up time was 7.1 (IQR 1-12) months, during which 68% (13/19) of misdiagnosed patients died, compared to 49% (38/78) of correctly diagnosed patients. The Kaplan Meier estimate of survival among the entire cohort was 42% (95%CI 31-52%); those with and without a misdiagnosis had survivals of 20% (95% CI 5-42%) and 46% (95% CI 34-57%), respectively (Figure 1). The logrank value comparing survival among those with and without a misdiagnosis was 0.0047. CONCLUSIONS BL diagnosis remains challenging in resource-limited areas, with a high misdiagnosis rate of 20% in this cohort. Misdiagnosed patients tended to be younger and to have more advanced stage disease. We observed a significant positive association between misdiagnosis and early mortality. Misdiagnosis likely contributes to poorer BL survival in low-resource settings by increasing the chance of treatment for the wrong tumor type. SIGNIFICANCE Study limitations include relatively small sample size and the potential for selection bias among patients who had tissues samples available; however, the 12-month survival of all patients diagnosed with BL at the UCI during the study period was around 55%, and not markedly different from the 42% seen here. Next steps include a repeat study with a larger sample size. Finally, our novel IHC/ISH diagnostic algorithm, requiring 6 total slides (including 1 control slide to assess RNA quality), worked with high sensitivity and specificity, and will be described separately. Disclosures Real-Hall: Phenopath Laboratories: Employment. Adams:Burkitt Lymphoma Fund for Africa: Membership on an entity's Board of Directors or advisory committees, Research Funding. Uldrick:Celgene: Research Funding; Celgene: Patents & Royalties: 10,001,483 B2; Merck: Research Funding. Casper:Janssen: Consultancy, Research Funding; Up to Date: Patents & Royalties; TempTime: Consultancy, Other: Travel, Accommodation, Expenses; GSK: Other: Travel, Accommodation, Expenses; Roche: Consultancy, Other: Travel, Accommodation, Expenses. McGoldrick:Burkitt Lymphoma Fund for Africa: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Employment. Kussick:Phenopath Laboratories: Employment, Equity Ownership.

Impact of Cutaneous Involvement on the Clinical Outcome of Adult T-Cell Leukemia/Lymphoma: A Study from the Latin American Group of Lymphoproliferative Disorders (GELL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-23
Author(s):  
Luis E Malpica Castillo ◽  
Denisse A. Castro ◽  
Camila Peña ◽  
Henry Idrobo ◽  
Daniel J Enriquez ◽  
...  
Keyword(s):  
T Cell ◽  
Skin Lesion ◽  
Board Of Directors ◽  
Latin American ◽  
Research Funding ◽  
Skin Lesions ◽  
Cell Leukemia ◽  
First Line ◽  
Advisory Committees ◽  
Cutaneous Involvement

INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T-cell neoplasm caused by the Human T-cell Leukemia Virus Type 1 (HTLV-1). HTLV-1 infects up to 10 million people worldwide and is most endemic in Southwestern Japan, Western Africa, the Caribbean basin and South America. Cutaneous signs of ATLL are varied and may consist of macules (M), plaques (P), multiple papules (MP), tumoral nodules (TN), erythroderma (E) or mixed-lesions (≥2 predominant lesions, ML). M and P forms are believed to carry a better prognosis. However, data on cutaneous presentation of ATLL remains scarce. Herein, we report cases of ATLL with cutaneous involvement diagnosed in 4 Latin American countries over the last 3 decades. METHODS: We retrospectively analyzed patients (pts) diagnosed with ATLL between January 1995 and December 2019. ATLL subtypes were classified according to the Shimoyama criteria into acute, lymphomatous, chronic and smoldering. Primary cutaneous tumoral (PCT) variant was classified according to the 2019 International Revised ATLL Consensus. We designed 2 cohorts: the first, ATLL pts with cutaneous involvement, and the second, matched cases without cutaneous involvement. We determined the type of skin lesion as well as the survival associated with the various types of skin lesions. We compared the frequency of clinical features using Fisher's exact test. Treatment response was assessed according to Tsukasaki et al. (JCO 2009) criteria. To be classified as complete response (CR), partial response, and stable disease, these had to persist for a period of at least 4 weeks. We analyzed survival data according to ATLL subtype, cutaneous involvement status, and type of skin lesion using the Kaplan-Meier method and Log rank test. RESULTS: A total of 169 pts with ATLL were identified; 63 had cutaneous involvement and 106 did not. Clinical features are shown in Table 1. In both groups the median age was 57 years with a female predominance. Cutaneous involvement was most frequently found in acute (41%) and lymphomatous (37%) ATLL pts. The E (24%) and P (22 %) types were the most frequent skin lesions. Disease stage, presence of B symptoms, hypercalcemia, ECOG ≥2, elevated LDH, and IPI/ PIT score were not different among groups. Table 2 and Table 3 summarize the first-line therapy used and response rates. The use of first-line zidovudine plus interferon alpha (AZT-IFN), regardless of the type of skin lesion, resulted in relatively high response rates [overall response (OR) 100%, n=8; CR 62.5%] as compared to multi agent-chemotherapy (OR 33.3%, n=12). Overall, the presence of cutaneous involvement was associated with better overall survival (OS) compared to non-cutaneous involvement (aHR 0.55 [95% CI: 0.37-0.82], p<0.01; 1-year OS 53% vs. 27%, respectively, p=0.012) (Figure 1). PCT pts had better outcome compared to acute and lymphomatous ATLL forms (1-year OS 75% vs. 39% vs. 25%, respectively, p=0.002). The presence of P and MP skin lesions was associated with better OS compared to other subtypes (1-year OS: P/MP 65% vs. others 41%, respectively, p=0.027) (Figure 2, supplemental figure 1). In a multivariate analysis, hypercalcemia was an independent poor prognostic factor for survival among ATLL pts with cutaneous involvement (aHR 3.99 [95% CI: 139-11.45], p=0.01) (supplemental figure 2). One patient with lymphomatous ATLL and plaque lesions underwent allogeneic stem cell transplant with high-dose chemotherapy after achieving CR with AZT-IFN; patient remains alive and progression-free for 17 months. Illustrative cases of cutaneous ATLL are shown in Figure 3. CONCLUSION: In Latin American pts with aggressive ATLL, cutaneous involvement appears to be associated with better survival compared to non-cutaneous involvement. PCT subtype, an ATLL variant characterized by isolated skin lesions with no organ involvement and poor outcome, appeared to have a better prognosis compared to acute and lymphomatous ATLL forms. P and MP skin lesions were both associated with better survival. Hypercalcemia was found as an independent prognostic factor for survival in pts with cutaneous involvement. Finally, AZT-IFN appears to be reasonable first-line option for aggressive ATLL subtypes with cutaneous involvement regardless of the type of skin lesion at diagnosis, based on the relatively high response rates observed in this subset; further investigation in randomized clinical trials is needed. Disclosures Peña: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; BindingSite: Research Funding. Idrobo:Takeda: Honoraria, Speakers Bureau; Tecnofarma: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Altamirano:Hospital Nacional Guillermo Almenara Irigoyen: Other: Servicio de Hematologia. Perini:Abbvie: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria. Castillo:Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Abbvie: Research Funding; Kymera: Consultancy; TG Therapeutics: Research Funding; Janssen: Consultancy, Research Funding. Ramos:NIH: Research Funding. Villela:amgen: Speakers Bureau; Roche: Other: advisory board, Speakers Bureau.

90Y-Ibritumomab Tiuxetan (Zevalin®) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin's Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 594-594 ◽  
Author(s):  
Anton Hagenbeek ◽  
John Radford ◽  
Achiel Van Hoof ◽  
Umberto Vitolo ◽  
Ama Z.S. Rohatiner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Myelogenous Leukemia ◽  
Control Group ◽  
Advanced Stage ◽  
Ibritumomab Tiuxetan ◽  
Advisory Committees

Abstract Abstract 594 The FIT trial was conducted to evaluate the safety and efficacy of 90Y-ibritumomab tiuxetan (0.4 mCi/kg; maximum dose 32 mCi) when used as consolidation of first complete or partial remission in patients with previously untreated, advanced-stage follicular lymphoma (FL). Patients were randomly assigned to either 90Y-ibritumomab treatment (n = 207) or observation (n = 202) within 3 months (mo) of completing initial induction therapy (chemotherapy only: 86%; rituximab in combination with chemotherapy: 14%). Response status prior to randomization did not differ between the groups: 52% complete response (CR)/CR unconfirmed (CRu) to induction therapy and 48% partial response (PR) in the 90Y-ibritumomab arm vs 53% CR/CRu and 44% PR in the control arm. The primary endpoint was progression-free survival (PFS) of the intent-to-treat (ITT) population. Results from the first extended follow-up after a median of 3.5 years revealed a significant improvement in PFS from the time of randomization with 90Y-ibritumomab consolidation compared with control (36.5 vs 13.3 mo, respectively; P < 0.0001; Morschhauser et al. JCO. 2008; 26:5156-5164). Here we report a median follow-up of 66.2 mo (5.5 years). Five-year PFS was 47% in the 90Y-ibritumomab group and 29% in the control group (hazard ratio (HR) = 0.51, 95% CI 0.39–0.65; P < 0.0001). Median PFS in the 90Y-ibritumomab group was 49 mo vs 14 mo in the control group. In patients achieving a CR/CRu after induction, 5-year PFS was 57% in the 90Y-ibritumomab group, and the median had not yet been reached at 92 months, compared with a 43% 5-year PFS in the control group and a median of 31 mo (HR = 0.61, 95% CI 0.42–0.89). For patients in PR after induction, the 5-year PFS was 38% in the 90Y-ibritumomab group with a median PFS of 30 mo vs 14% in the control group with a median PFS of 6 mo (HR = 0.38, 95% CI 0.27–0.53). Patients who had received rituximab as part of induction treatment had a 5-year PFS of 64% in the 90Y-ibritumomab group and 48% in the control group (HR = 0.66, 95% CI 0.30–1.47). For all patients, time to next treatment (as calculated from the date of randomization) differed significantly between both groups; median not reached at 99 mo in the 90Y-ibritumomab group vs 35 mo in the control group (P < 0.0001). The majority of patients received rituximab-containing regimens when treated after progression (63/82 [77%] in the 90Y-ibritumomab group and 102/122 [84%] in the control group). Overall response rate to second-line treatment was 79% in the 90Y-ibritumomab group (57% CR/CRu and 22% PR) vs 78% in the control arm (59% CR/CRu, 19% PR). Five-year overall survival was not significantly different between the groups; 93% and 89% in the 90Y-ibritumomab and control groups, respectively (P = 0.561). To date, 40 patients have died; 18 in the 90Y-ibritumomab group and 22 in the control group. Secondary malignancies were diagnosed in 16 patients in the 90Y-ibritumomab arm vs 9 patients in the control arm (P = 0.19). There were 6 (3%) cases of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) in the 90Y-ibritumomab arm vs 1 MDS in the control arm (P = 0.063). In conclusion, this extended follow-up of the FIT trial confirms the benefit of 90Y-ibritumomab consolidation with a nearly 3 year advantage in median PFS. A significant 5-year PFS improvement was confirmed for patients with a CR/CRu or a PR after induction. Effective rescue treatment with rituximab-containing regimens may explain the observed no difference in overall survival between both patient groups who were – for the greater part – rituximab-naïve. Disclosures: Hagenbeek: Roche Global Advisory Board: Consultancy. Radford:Schering (May 2009): Honoraria, Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche Italy: Membership on an entity's Board of Directors or advisory committees; Celgene Italy: Membership on an entity's Board of Directors or advisory committees. Soubeyran:Roche: Honoraria, Research Funding; Cephalon: Research Funding. Bischof Delaloye:Expert Statement (questions of reimbursement in Switzerland): Honoraria. Morschhauser:Roche: Honoraria, Paid expert testimony within the past 2 years; Bayer: Honoraria.

scholarly journals Outcome of Initial Observation in Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1803-1803 ◽  
Author(s):  
Anita Kumar ◽  
Zhitao Ying ◽  
Anna Alperovich ◽  
Ahmet Dogan ◽  
Paul A Hamlin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Early Stage ◽  
Advisory Committees ◽  
Ki 67 ◽  
Early Stage Disease ◽  
Genetics Research ◽  
Stage Disease ◽  
Leukemic Phase

Abstract Background Mantle cell lymphoma (MCL) is a biologically heterogeneous disease with a variable clinical course, ranging from indolent to highly aggressive. A subset of MCL patients with an indolent clinical course can be initially monitored and previous studies show that this strategy is not associated with inferior overall survival (Martin JCO 2009, Cohen Cancer 2016). However, uniform clinical or biologic criteria do not exist to identify appropriate candidates for observation. Prior studies have described features of indolent MCL including clinical presentation with leukemic phase disease and minimal lymphadenopathy and biological characteristics including low proliferative index, lack of expression of SOX-11 transcription factor, genetic stability without TP53 alterations, and IGHV somatic hypermutation. The aim of this study was to describe the clinical and biological characteristics of MCL patients who were initially observed (OBS) versus immediately treated (TX) and the associated outcomes. Methods Patients with histologically confirmed MCL diagnosed between 2000-2014 who were initially managed and subsequently followed at Memorial Sloan Kettering Cancer Center were included. Patients were considered to have been observed if the treating oncologist documented an intent to expectantly monitor the patient as an initial management strategy. There were no predefined criteria for observation versus immediate treatment. Overall survival was defined as date of tumor diagnosis to death from any cause. Results 404 patients met the study inclusion criteria. 91 were initially observed and 313 were immediately treated. Treating oncologists documented different reasons for observation including: asymptomatic patient, lack of GELF criteria / low tumor burden, favorable biologic features (low Ki67, SOX-11 negative), leukemic phase disease without lymphadenopathy, or GI tract only disease. Patients in the OBS group were significantly more likely to have classic MCL morphology (versus blastic/blastoid morphology), normal LDH, less than two extranodal sites, leukemic phase disease, lower SUVmax, low-risk or low-intermediate risk IPI, and lower Ki-67 (<30%). MIPI scores were not significantly different across the two groups. With a median follow up of 5 years for all patients, there was a superior overall survival (OS) for OBS patients versus TX patients, P=0.042, see Figure 1. The median OS for the OBS versus TX patients was 10.6 and 9.4 years, respectively. There was no difference in outcome between OBS and TX patients when comparing time from start of treatment to death, P=0.79. In univariate analyses, the factors associated with inferior OS were age>60, Karnofsky performance status (KPS) ≤70%, advanced stage disease, elevated LDH, bone marrow involvement, higher SUVmax, MIPI, IPI, Ki-67 ≥30%, and treatment decision at diagnosis (TX vs. OBS). In multivariate analysis of individual factors, only age>60 and KPS ≤70% were associated with inferior OS. In propensity score-adjusted analyses, OS was similar in both OBS and TX groups (hazard ratio 0.74, 95% confidence interval 0.43, 1.26, P=0.26). Among the 91 observed patients, 65 were started on therapy after a period of observation while 26 continue to be expectantly monitored. The median time from diagnosis to start of treatment was 23 months, see Figure 2. Of note, 25 patients have been monitored for 2-5 years and 5 patients have been monitored for ≥5 years. Using a Cox proportional hazards model to identify predictors of time from diagnosis to initiation of treatment in the OBS patients, early stage disease (P=0.037) and absence of lymphadenopathy (P=0.021) were significantly associated with a more prolonged period of observation. Conclusions Observation is an appropriate initial management strategy for a subset of newly diagnosed MCL patients and is not associated with a negative impact on overall survival. Due to limited availability of pathologic information, including Ki-67, SOX-11, and IGHV status, this report cannot correlate biologic features with outcome; however, this is the focus of ongoing studies. Based on our data, there are various clinical criteria that can be used to select appropriate candidates for observation, among them presence of early stage disease or non-nodal clinical presentation. Figure 1 Overall Survival in OBS vs. TX patients Figure 1. Overall Survival in OBS vs. TX patients Figure 2 Time from diagnosis to start of treatment in OBS patients (N=91) Figure 2. Time from diagnosis to start of treatment in OBS patients (N=91) Disclosures Kumar: Celgene: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Honoraria, Other: Scientific Advisory Board; Pharmacyclics: Research Funding. Hamlin:Novartis: Research Funding; Molecular Templates: Research Funding; Seattle Genetics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Xencor: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding. Moskowitz:Celgene: Consultancy; Genentech: Consultancy; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding. Zelenetz:Gilead Sciences: Research Funding.

scholarly journals Epidemiology, Clinical Features, and Outcome of HTLV-1-Related Adult T-Cell Leukemia/Lymphoma in Latin America: A Study from the Latin American Group of Lymphoproliferative Disorders (GELL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-21
Author(s):  
Luis E Malpica Castillo ◽  
Daniel J Enriquez ◽  
Denisse A. Castro ◽  
Camila Peña ◽  
Henry Idrobo ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Clinical Features ◽  
Latin American ◽  
Research Funding ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
First Line ◽  
Advisory Committees ◽  
Adult T Cell Leukemia

INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is a mature peripheral T-cell neoplasm caused by the Human T-cell Leukemia Virus Type 1 (HTLV-1). HTLV-1 infects up to 10 million people worldwide and is most endemic in Southwestern Japan, the Caribbean basin, South America, and Western Africa. In Latin America (LA), Peru and Brazil have the highest prevalence of HTLV-1-related diseases, however, data on ATLL in other LA countries is scarce. ATLL carries a dismal prognosis and is essentially incurable by conventional drugs. We describe the epidemiology, clinical features, treatment, and disease outcome of ATLL encountered in 11 countries in LA. METHODS: We retrospectively analyzed patients (pts) diagnosed with ATLL between January 1995 and December 2019. ATLL cases were classified according to the Shimoyama criteria into acute (A), lymphomatous (L), chronic (C) and smoldering (S). Treatment approaches used as first-line therapy were: 1) chemotherapy alone; 2) combined chemotherapy with zidovudine/interferon-alpha (AZT-IFN); and 3) AZT-IFN alone, as previously done with Miami cohort (Malpica and Ramos et al. Blood Advances 2018). Treatment response was assessed according to Tsukasaki et al. (JCO 2009) criteria. To be classified as complete response (CR), partial response and stable disease, these had to persist for a period of at least 4 weeks. Survival curves were estimated using the Kaplan-Meier method and Log rank test. RESULTS: A total of 253 pts with ATLL were identified. Two hundred twenty six pts (L=122, A=73, C=26, S=5) had sufficient data for analysis. Demographic and clinical features are shown in Figure 1 and Table 1. Median age at diagnosis was 57 years, with a female predominance in A (58%) and S (100%) types. Most ATLL pts were from Peru (n=159, 63%) followed by Chile (n=44, 17%), Argentina (n=20, 8%) and Colombia (n=17, 7%). B symptoms were high present in A, L and C types (73%, 72%, 58% vs. 8% S type, respectively, p=0.011). Hypercalcemia was highly associated with A type (57% vs. L 27%, p=0.014). The PIT score yielded to a more aggressive risk classification compared to the IPI score (high-risk: 55% vs. 29%, respectively, p&lt;0.001). Strongyloidiasis (n=5) and pneumocystis jirovecii pneumonia (n=5) were the most commonly observed co-infections at diagnosis. Commonly affected extranodal sites other than bone marrow in all subtypes were skin 25% (n=63) and liver 9% (n=24). The therapy approach used during the first 2 therapy evaluations are summarized in Table 2. The median survival (MS) times were 4.3 months, 7.9 months, 21.1 months, and not reached for A, L, C and S form, with 4-year survival of 8%, 22%, 40% and 80%, respectively (Figure 2). First-line AZT-IFN resulted in overall response (OR) rate of 63% (CR 24%) for A (n=8) and 75% (CR 50%) for L (n=8), respectively (Table 3). The OR rates after first-line multi-agent chemotherapy alone for A vs. L were 21% (CR 8%) and 41% (CR 29%), respectively (Table 3). The most commonly used regimens were CHOP/CHOP-like (n=117, 59%) and CHOEP (n=40, 20%) regimens with OR rates of 29% (CR 12%) and 60% (CR 42%), respectively (Table 3). Progression-free survival (PFS) rates in pts with aggressive ATLL who achieved CR after chemotherapy vs. AZT-IFN (alone or in combination with chemotherapy) were 2.8 months vs. 30.4 months for A (n=8) type and 67.1 months vs. 17.7 months for L (n=30) type, respectively (Figure 3). Only 2 pts with L type underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) with PFS of 12 and 17 months (Table 4). CONCLUSION: ATLL continues to carry a dismal outcome with conventional therapies thus urging the development of novel approaches. Our study found that Latin American ATLL variant presents at a younger age, has a female predominance, high incidence of L type, low incidence of indolent types and lower survival rates, suggesting that Latin American ATLL variant presents earlier and more aggressively than in Japanese pts. AZT-IFN produced durable responses in A type patients who achieved CR as compared to chemotherapy alone. Chemotherapy responses were more durable in L types who achieved CR as compared to A type. In conclusion, in the management of aggressive ATLL, chemotherapy remains the preferred choice for L type (with consideration of allo-HSCT upfront), while AZT-IFN is a good option to attempt for A type upfront. Figure Disclosures Peña: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; BindingSite: Research Funding. Idrobo:Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Tecnofarma: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Altamirano:Hospital Nacional Guillermo Almenara Irigoyen: Other: Servicio de Hematologia. Perini:Abbvie: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria. Castillo:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; TG Therapeutics: Research Funding; Kymera: Consultancy; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding. Ramos:NIH: Research Funding. Villela:Roche: Other: advisory board, Speakers Bureau; amgen: Speakers Bureau.

scholarly journals Literature Review of All Cases of Aggressive T-Cell Large Granular Lymphocytic Leukemia Cases and Report of an Additional Case

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5421-5421
Author(s):  
Vanessa Brunet ◽  
Michel Pavic ◽  
Sofia Marouan ◽  
Isabelle Fleury ◽  
Jean-Francois Castilloux
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoproliferative Disorder ◽  
Clinical Presentation ◽  
Nk Cell ◽  
Leukemic Cells ◽  
Cell Leukemia ◽  
Advisory Committees ◽  
Lgl Leukemia

Abstract Large granular lymphocyte (LGL) leukemia is a spectrum of rare lymphoproliferative disorders, classified into T-cell LGL leukemia, chronic lymphoproliferative disorder of NK-cells and aggressive NK-cell leukemia; chronic NK-cell leukemia is a provisional diagnosis. However, we identified fourteen cases of aggressive T-LGL leukemia retrieved in the literature. Considering this unusual and rare clinical presentation, we are reporting a literature review and presenting an additional case. Leukemic cells of T-LGL leukemia have a characteristic phenotype (CD3+CD8+CD16+CD57+) and show clonal TCR gene rearrangement, while leukemic cells of aggressive NK cell leukemia show a distinguishable phenotype (CD3-CD4-CD8-CD16+CD56+CD57-) and are EBV-related. In contrast with the aggressive NK cell leukemia, the chronic lymphoproliferative disorder of T-cell is not EBV-associated and has a distinguishable immunophenotype (CD16+CD56−CD57+). While T-LGL leukemia and chronic lymphoproliferative disorder of NK-cells have a more chronic disease (years), mainly reported with autoimmune disease (rheumatoid arthritis), numerous infections due to neutropenia and a mild-to-moderate splenomegaly, aggressive NK-cell leukemia is characterized by systemic manifestations and a disseminated disease after a few weeks of presentation despite treatment instauration. In contrast to the T-LGL leukemia, aggressive T-LGL leukemia has a clinical presentation similar to the aggressive NK-cell leukemia, characterized by constitutional symptoms, rapidly progressive hepatosplenomegaly, cytopenia and organ infiltration. The atypical clinical presentation and pathological findings of the aggressive T-LGL leukemia explain the diagnostic challenge of this entity for clinicians. In fact, cases of aggressive T- LGL leukemia retrieved atypical size, irregular nuclei and atypical immunophenotype. Some cases had features similar to those described for patients with NK-cell leukemia (CD56+CD57-) while others did not present neither NK nor T-cell classical immunophenotype (CD56-57-). Facing the heterogeneity of aggressive LGL leukemia, the rapidly evolutive disease (multi-organic infiltration) and the absence of randomized trials on large numbers of patients, no consensus on the treatment approach exists. (Table 1) Our patient presented, at the age of 24 yo, with transitory and autonomous resolution of hepatosplenomegaly and pancytopenia. Almost 30 years later, the patient developed a similar and persistent episode, which lead to a diagnosis of aggressive T-cell LGL leukemia. Was this first episode the early and indolent presentation of his T- LGL leukemia or was it only related to an indolent and transitory etiology? Considering the clinical evolution of previously reported case and of our patient, LGL leukemia tends to evolve in many ways; resolution, indolent and chronic or aggressive evolution and transformation into a lymphoma. As the cases retrieved in literature, the diagnosis of our patient was complicated by atypical clinical presentation and unusual pathological findings; massive medullary involvement without real images of intra-sinusal lymphocytosis and atypical T- LGL based on their small-medium size with slightly irregular nuclei and the lack of expression of CD56/CD57. Facing the heterogeneity of treatments attempted for aggressive T-LGL leukemia and their unpredictable response, we believe that the treatments given to our patient were consistent with the current literature and did not add an additional mortality risk (3 cycles of CHOP, 4 cycles of ESHAP, methotrexate, splenectomy). As reported in literature, even though our patient was treated with varying regimens, his disease rapidly evolved into a multi-organic infiltration (skin, lungs, liver, kidney, facial cranial nerves, conus medullaris and bone marrow involvement) Large granular lymphocyte (LGL) leukemia represent a spectrum of indolent and aggressive diseases, whereby an indolent form can evolve into an aggressive form. Aggressive T-cell LGL leukemia are characterized by a multisystem disease, an atypical immunophenotype (CD56-CD57- or CD56+CD57-) and are associated with an uncertainty regarding therapeutics.Our case report of an aggressive T-cell LGL leukemia adds to the few available studies on the subject. Disclosures Pavic: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Prednisone, Vinblastine, Doxorubicin and Bendamustine (PVAB) Regimen in First Line Therapy for Older Patients with Advanced-Stage Classical Hodgkin Lymphoma: Results of a Prospective Multicenter Phase II Trial of the Lymphoma Study Association (LYSA)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2832-2832 ◽  
Author(s):  
Herve Ghesquieres ◽  
Olivier Casasnovas ◽  
Emmanuelle Nicolas-Virelizier ◽  
Damaj Gandhi Laurent ◽  
Vincent Delwail ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Metabolic Response ◽  
Advanced Stage ◽  
Advisory Committees ◽  
First Line Therapy ◽  
End Of Treatment ◽  
Ann Arbor

Introduction: Older patients with an age above 60 years with classical Hodgkin lymphoma (cHL) represent a proportion of 20% to 30% of all cHL. Older cHL patients are characterized by unfavorable prognostic factors with an aggressive disease, a poor tolerance to chemotherapy resulting to a significant reduced survival as compared to younger patients. In relapsed and refractory HL, prospective and retrospective studies showed that bendamustine in monotherapy provided interesting efficacy with 30% of complete response with an acceptable toxicity profile. We developed the PVAB (Prednisone, Vinblastine, Doxorubicin and Bendamustine) regimen in first line therapy to improve prognosis of older HL with advanced stage. Methods: In this prospective phase II, we recruited newly diagnosed classical HL patients age of 61 years or older with an advanced stage (Ann Arbor stage III, IV, IIB with risk factors). Inclusion criteria were: baseline 18-FDG PET scan performed before any treatment with at least one hypermetabolic lesion; ECOG performance status 0-2; adequate cardio-pulmonary function with LVEF ≥ 50%; adequate renal function with creatinine clearance ≥ 40 mL/min; HIV negative; For patients aged 70 years old and more, a Mini Nutritional Assessment (MNA) ≥ 17. Treatment consisted of 6 cycles of prednisone (40mg/m2 D1-5), vinblastine (6mg/m2, D1), doxorubicin (40mg/m2, D1) and bendamustine (120mg/m2, D1) every 21 days. A first evaluation was performed after 4 cycles by CT scan and a final evaluation by PET scan after 6 cycles. No radiotherapy was applied in this protocol. The primary endpoint was the complete metabolic response (CMR) rate after 6 cycles of study treatment or at premature treatment discontinuation according to Lugano Classification. The main analysis for the CMR rate was based on a Simon's phase II design. We selected P0 and P1 to be 70% and 85%, respectively for CMR rate. A total of 79 patients provided nominal power of 80% at the nominal one-sided 5% significance level. Using a drop-out rate of 10%, 90 patients should be included in this trial. Results: Between July 2015 and July 2018, 89 patients who signed the consent form and received at least one PVAB cycle corresponding to intention to treat (ITT) group were included in 34 LYSA centers. Among them, four patients did not respected major inclusion criteria (one patient had a nodular lymphocyte predominant subtype after histological review and three patients ≥ 70 years had no MNA evaluation at inclusion) corresponding to the modified ITT group (N=85). The median age of the 89 patients was 68 years (range, 61-88) with 35 patients ≥70 years old (39%) and 58 male (65%). According to the central review, the main histological subtype was nodular sclerosis cHL (66%). Ann Arbor stages were as follows: II (n=3, 3%), III (n=30, 34%), IV (n=56, 63%). B symptoms were present in 57% of patients and 70 patients (80%) had IPS≥3. 78 patients (88%) completed the 6 cycles of PVAB. In ITT, the CMR rate corresponding to the primary endpoint of the study was 77.5% (95%CI, 67-86) with 69 patients in CMR; 8 patients were in partial metabolic response; 2 and 5 patients had a stable and progressive disease, respectively and 5 were not evaluable. In the modified ITT group, the CMR rate at this end of treatment was 77.6% (95%CI, 67-86). With a median follow-up of 23 months (0.5-40.3), 25 patients relapsed or progressed (28%). The 2-year progression survival rate (PFS) rate was 61.3% (95%CI, 49-72). For the 69 patients achieving CMR, the 2-year disease free survival (DFS) rate was 73.3% (95%CI, 61-82). At the date of analysis (December 2018), 17 patients (19%) died: 7 cHL, 4 treatment toxicity, 3 second cancers, 3 other causes. The 2-year overall survival rate was 84.1% (95%CI, 73-91). For toxicity, 4 patients presented toxic death during treatment: one cardiogenic shock (71y, >cycle 1) one septic shock (70y, >cycle 1), one brain hematoma with grade 4 thrombocytopenia (76y, >cycle 1), one fungal infection (86y, >cycle 4). At least one serious adverse events (SAE) were presented by 28 patients (31.5%) mainly infections (13 patients, 15%), blood (11 patients, 12%) and cardiac disorders (4 patients, 4.5%). Conclusions: Six cycles of PVAB regimen provided high CMR (77.5%) with acceptable toxicity in older cHL patients with advanced stage. Patients with CMR at the end of treatment had a particular favorable outcome but long term follow-up is needed for a better evaluation of survival endpoints. Disclosures Morschhauser: Roche/Genentech: Consultancy; Celgene: Honoraria; Servier: Consultancy; Gilead: Consultancy; Janssen: Honoraria; BMS: Honoraria. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Brice:Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding; BMS: Honoraria. OffLabel Disclosure: Bendamustine is off-label drug use in Hodgkin lymphoma

Overall Survival Advantage and Acceptable Safety Profile with Fludarabine In Combination with Alemtuzumab (FluCam) In Previously Treated Patients with Advanced Stage Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 919-919 ◽  
Author(s):  
Andreas Engert ◽  
Liana Gercheva ◽  
Galina Pilipenko ◽  
Tadeusz Robak ◽  
Jingyang Wu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Stage Iii ◽  
Advanced Stage ◽  
Employment Equity ◽  
Advisory Committees ◽  
Previously Treated ◽  
Equity Ownership

Abstract Abstract 919 Background: Patients (pts) with Rai Stage III/IV CLL have a shorter median survival compared to Rai Stage I/II pts. We previously reported significant improvement in progression-free survival (PFS) with FluCam compared to single-agent fludarabine (Flu) in pts with previously treated CLL (Engert ASH 2009; EHA 2010). Here we report the efficacy and safety of FluCam and Flu in a subset of these pts with advanced stage CLL. Methods: In a Phase 3, multi-center, controlled trial, pts with relapsed/refractory CLL were randomized to receive either IV Flu 25 mg/m2 on days 1–5 every 28 days or IV alemtuzumab (Cam) in combination with IV Flu (FluCam). Prior to cycle 1, FluCam pts were required to undergo Cam escalation (3 mg, 10 mg, 30 mg); once the 30 mg dose was tolerated, pts began cyclic administration of Flu 30 mg/m2 IV and Cam 30 mg IV on days 1–3 every 28 days. Pts could receive up to 6 cycles of either therapy depending on response and toxicity. Randomization was accomplished utilizing the minimization method to ensure balance between treatment arms with respect to study center, disease status, prior therapy, Rai Stage, age, gender, and lymph node size. All pts received prophylaxis with cotrimoxazole and famciclovir until CD4+ counts were >200 cells/mcL. The primary endpoint of the study was PFS with FluCam compared to Flu. A pre-specified subgroup analysis in Rai Stage III/IV pts compared PFS, overall response rate (ORR=CR + PR), complete response rate (CR), overall survival (OS) and safety in FluCam vs Flu treated pts. Differences in PFS between the 2 treatment arms were tested using the log-rank test. Results: Of the 335 pts enrolled in this study, 123 (37%) were Rai Stage III or IV (61 FluCam pts, 62 Flu pts). For the overall study population, FluCam significantly prolonged PFS compared with Flu (24.1 months (mos) vs 15.4 mos, respectively; p = 0.002; HR: 0.618; 95% CI 0.46–0.83). Data presented herein focus on the subgroup of CLL pts with Rai Stage III/IV disease. Demographics for this subset of FluCam vs Flu treated pts include: median age (65 yrs [36-80] vs 64 yrs [46-80]); gender (70% male vs 61% male); and prior Flu exposure (10% vs 8%) respectively. Pts received a median of 6 cycles in the FluCam arm and a median of 5 cycles in the Flu arm. FluCam significantly prolonged PFS compared with Flu (24.5 mos vs 11.8 mos, respectively; p < 0.001; HR 0.46; 95% CI 0.29–0.73). Similarly, the ORR (77% vs 56%; p = 0.016) and CR (16% vs 3%; p = 0.014) improved significantly with FluCam compared to Flu. With a median follow-up of 21 mos, pts treated with FluCam had significantly improved median OS compared with those treated with Flu (not reached vs 23.5 mos, respectively, p = 0.005 HR 0.44; 95% CI 0.24–0.79), representing a 56% reduction in the risk of death (Figure 1). Treatment-related adverse events (AE) occurred in 97% and 88% of Rai Stage III/IV pts receiving FluCam (n=59) and Flu (n=60) arms, respectively. There were no clinically relevant differences in the AE profile in pts with Rai Stage III/IV between arms. In the Rai Stage III/IV subgroup, the AEs that occurred ≥10% and more frequently in the FluCam arm relative to the Flu arm included infusion-related events and leukopenia. Reported all-cause grade 3/4 hematologic AEs in the FluCam vs Flu arms were neutropenia (47% vs 48%), leukopenia (29% vs 8%), thrombocytopenia (15% vs 20%), and anemia (7% vs 23%), respectively. The total frequency of treatment-emergent infections was 42% in the FluCam arm vs 52% in the Flu arm. No CMV infections were reported in either arm in this subset of pts. All-cause serious AEs (SAE) occurred in 37% and 45% in the FluCam and Flu arms, respectively. The most commonly reported all-cause SAEs in ≥5% of pts in either arm were pyrexia (5% vs 2%), neutropenia (3% vs 5%), febrile neutropenia (2% vs 8%) and anemia (0% vs 8%) for FluCam vs Flu respectively. Deaths occurring on therapy or within 30 days after last dose were 3% on the FluCam arm vs 8% on the Flu arm. Conclusion: Data presented in this subset analysis of Rai Stage III/IV CLL pts demonstrate a survival advantage, longer PFS and improved ORR/CR in pts treated with FluCam compared to Flu. The safety profile of FluCam in pts with advanced stage was acceptable and in most respects, comparable to the Flu alone arm. Overall, FluCam is a compelling treatment option in pts with previously treated advanced CLL. Disclosures: Engert: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Alemtuzumab (Campath, MabCampath) is indicated for the treatment of CLL. This trial examined the use of alemtuzumab in combination with fludarabine monophospate. Gercheva:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pilipenko:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Robak:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wu:Genzyme: Employment, Equity Ownership. Sirard:Genzyme: Employment, Equity Ownership. Elter:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Durable Responses with Pembrolizumab in Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Final Results from a Phase 2 Multicenter Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2896-2896
Author(s):  
Michael S Khodadoust ◽  
Alain Rook ◽  
Pierluigi Porcu ◽  
Francine M. Foss ◽  
Alison J. Moskowitz ◽  
...  
Keyword(s):  
T Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Advanced Stage ◽  
Mass Cytometry ◽  
Advisory Committees ◽  
Whole Exome ◽  
Stage Disease ◽  
Heavily Pretreated ◽  
Malignant T Cells

Abstract Background: Current treatment of advanced stage Mycosis fungoides (MF) and Sézary syndrome (SS) remains unsatisfactory. Complete responses (CR) are typically <10% and partial responses (PR) tend to be short-lived. Antibodies targeting PD1 expressed by healthy tumor-infiltrating T cells can induce long-lasting and deep remissions in cancer patients by activating the host immune response. However, the malignant T-cells of MF/SS also express PD-1. Additionally, genomic alterations involving PD-1, PD-L1, and PD-L2 have been reported in MF/SS, suggesting an important role for the PD-1/PD-L1 axis. We hypothesized that PD-1 checkpoint blockade would be an effective treatment in targeting a T cell malignancy that itself expresses PD-1. Here, we report the efficacy of pembrolizumab in relapsed/refractory MF/SS and correlative biomarker studies. Methods: This single-arm, multicenter study by the Cancer Immunotherapy Trials Network (CITN) enrolled 24 patients with MF/SS stages IB-IV, with at least one prior systemic therapy. Pembrolizumab was administered at 2 mg/kg every 3 weeks for up to two years. The primary endpoint was overall response rate (ORR) using global response criteria according to the ISCL/EORTC consensus guidelines. Skin responses were measured by mSWAT. Secondary endpoints were safety/tolerability, time to response (TTR), duration of response (DOR) and progression-free survival (PFS). Correlative studies included immunohistochemistry (IHC), mass cytometry, whole exome sequencing, gene expression profiling, and serum cytokine analysis. Results: Patients had advanced stage disease (23/24 with stage IIB-IV MF/SS), and were heavily pretreated (median of 4 prior systemic therapies). The ORR was 38% with 2 CR and 7 PR. Of the 9 responding patients, 6 had ≥90% improvement in skin disease by mSWAT. The median TTR was 11 weeks. Responses were durable, with 8 of 9 responses ongoing at last follow up (median DOR 64 weeks, range 32-153 weeks). One responding patient progressed 2 months after discontinuing treatment due to an adverse event (AE). The median PFS was not reached. Overall, the toxicity profile was similar to prior studies of pembrolizumab. Four patients discontinued treatment due to treatment related serious AEs of duodenitis, pneumonitis, hepatitis, and corneal ulcer. Skin flare reactions were observed early in the treatment course in 40% of patients with SS, but none with MF. The skin flare reactions did not result in any treatment discontinuation, and did not correlate with subsequent response to treatment. There was no significant association between response and clinical characteristics including stage, disease type (MF vs. SS), or number of prior therapies. IHC assessment of PD-1, PD-L1, and PD-L2 did not predict response. Treatment resulted in an increase of PD-L1 expression by both IHC and nanoString analysis. A nanoString18 gene signature of tumor inflammation that is predictive of response to pembrolizumab in other tumor types was not predictive in this cohort. High dimensional mass cytometry enabled precise identification and phenotyping of malignant T cells. There was a positive correlation between PD-1 expression on the malignant T cells and development of the skin flare reaction. Whole exome sequencing revealed genomic disruptions of PD-1 signaling including copy loss of PD-1. No associations were found between outcomes and genomic events involving the PD1/PD-L1 axis, total mutation number, or neoantigen numbers. Conclusions: The 38% ORR rate in this heavily pretreated population was 38% with a highly encouraging DOR of 64 weeks. No predictive biomarkers have emerged thus far, but additional studies are ongoing. Additional combination studies with pembrolizumab are warranted to improve response rates. Figure. Figure. Disclosures Khodadoust: Innate Pharma: Research Funding. Porcu:Innate Pharma: Consultancy. Foss:Miragen: Consultancy, Speakers Bureau; Seattle genetics: Consultancy; Spectrum: Consultancy; Mallinkrodt: Consultancy. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding. Shustov:Seattle Genetics: Research Funding. Sokol:Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. Yearley:Merck: Employment. Horwitz:Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Trillium: Consultancy; Innate Pharma: Consultancy; Spectrum: Research Funding; Corvus: Consultancy. Kim:miRagen: Research Funding; Horizon Pharma: Consultancy, Research Funding; Neumedicine: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding.

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