Anthracycline-based Combination Chemotherapy Research Articles

Evaluation of clinical response and prognostic factors in canine multicentric lymphoma treated with first rescue therapy.

Despite an initial strong response in most dogs with multicentric lymphoma treated with chemotherapy, relapse remains common. There is no clearly superior first rescue protocol described either for resistant or relapsed canine multicentric lymphoma. The objectives of this study were to assess clinical response and outcomes for canine multicentric lymphoma treated with first rescue protocols. The secondary objective was to assess prognostic variables for dogs undergoing these protocols. This was a bi-institutional retrospective cohort study. Two hundred and sixty-five dogs were treated with first rescue chemotherapy, including anthracycline-based combination chemotherapy (CHOP-like, n = 50), nitrosourea alkylating agent-rich chemotherapy (n = 45), anthracycline-based or related compound chemotherapy (n = 34), or nitrosourea single-agent chemotherapy (n = 136). The overall median progression free survival time of first rescue protocol was 56.0 days (0-455 days). Important prognostic factors identified for first rescue protocol included the attainment of a complete response to the first rescue chemotherapy (p < .001), the use of a CHOP-like first rescue protocol (p = .009), duration of first remission (HR 0.997, p = .028), and if prednisolone was included in the first rescue protocol (HR 0.41, p = .003). Adverse events (AE) were common, with 81.1% of dogs experiencing at least one AE during first rescue chemotherapy. This study highlights the need for improved first rescue therapies to provide durable remission in canine resistant or relapsed lymphoma.

Myxoid Liposarcomas: Systemic Treatment Options.

Myxoid/round-cell liposarcoma (MRCL) account for 30% of liposarcomas and are the most chemo-sensitive subtype of liposarcoma. The 5-year local relapse and distant metastasis rates are 10% and 20%, respectively. In the advanced setting, the first-line median progression-free survival and overall survival is 9 and 30months, respectively. The overall response rate (ORR) by RECIST with anthracycline-based chemotherapy is around 40% and with trabectedin is 20%, although response is higher when captured by CHOI criteria. Anthracycline-based combination chemotherapy regimens remain the standard of care first-line treatment option. However, trabectedin is also effective and may be considered in the first-line setting when anthracyclines cannot be prescribed. Beyond chemotherapy, new therapeutic classes are being developed, including autologous adoptive modified T cell receptor cellular therapies which have shown promising results thus far. These new therapies utilize the immunogenic potential of cancer testis antigens, NY-ESO-1 and MAGE-A4, which are expressed in the vast majority of MRCL. Early phase trials have shown encouraging results with up to 40% ORR and a median progression-free survival up to 8.7months. Other innovative strategies are being developed, tailored to the molecular biology of MRCL. This review summarizes current evidence for the use of standard chemotherapy and the new biomarker-selected treatments under development.

Impact of Geriatric Assessment on the Tolerability of Combination Chemotherapy in Older Patients with Advanced Cancer: A Matched-Pair Analysis

Because of their individual vulnerabilities, treatment decisions for older patients can be difficult. Geriatric assessment (GA) may help to select patients for systemic treatment, but its value is still unproven. Older cancer patients (≥65 years of age) with and without complex GA followed by discussion in the geriatric-oncologic conference, who had been treated in palliative intention with standard combination chemotherapy at the Evang. Kliniken Essen-Mitte, were retrospectively evaluated. All patients had been orally informed about the treatment options and had chosen chemotherapy beside supportive care. To reduce selection bias, the method of propensity-score matching was performed. Patient groups treated in the years 2011–2013 (without GA, group 1) and in the years 2014–2015 (with GA, group 2) were compared regarding different toxicity endpoints. The primary endpoint of the study was defined as numbers of patients with unplanned admission to the hospital or death during first-line chemotherapy and GA should reduce these events by 15%. Overall, 114 patients were evaluated in both groups. The median age was 74 years. Patients suffered from gastrointestinal carcinomas (47%), lung cancer (28%), breast cancer (12%), and other cancer types (3%). Consequently, most patients were treated with platinum-based (41%), fluoropyrimidine-based (35%), or anthracycline-based (13%) combination chemotherapy. In group 2, the events were numerically lower for all toxicity endpoints. The need for a premature stop of treatment was 54.4% in group 1 compared to 29.8% in group 2 (p < 0.01) and also the treatment-related mortality was significantly lower in group 2 (17.5% vs. 5.3%; p = 0.04). The primary endpoint, the rate of unplanned hospital admission, and death was 49.1% versus 35.1% (difference 14.0%), which did not reach the predefined border of 15%. There was a nonsignificant overall survival benefit in the group with GA (22.6 vs. 18.4 months). GA appears useful to better select older patients with advanced cancer for combination chemotherapy. The significant reduction of mortality during chemotherapy justifies the efforts and costs which need to be expended. To evaluate the effect of GA on overall survival, prospective trials are required.

Presentation and management of female breast cancer in Egypt.

There have been system inefficiencies in the profiling and management of female breast cancer in Alexandria, Egypt. To identify barriers to full implementation of international guidelines for the management of female breast cancer patients. Female breast cancer data were extracted from records of 3 public oncology services in Alexandria, Egypt, from 2007 to 2016 and analysed. A total of 5236 of the available 7125 records were usable. Median age of the patients was 54 years, and the median duration of pre-diagnosis complaint was 3.1 months. Some 522 (31.5%) of the patients had a family history of cancer. For tumour stage, 2527 (55.2%) were early, 1717 (37.6%) were locally advanced, and 331 (7.2%) were at stage IV. Estrogen receptor, progesterone receptor, and HER2 were positive in 3869 (85%), 3545 (78%), and 461 (15.3%) patients, respectively. Chemotherapy started after a median 1.03 months. Adjuvant chemotherapy was given to 3667 (91.7 %) patients and neoadjuvant chemotherapy to 333 (8.3%); 3686 (92.1%) received anthracycline-based combination chemotherapy, and 3613 (86%) received hormonal treatment. One hundred and eighty of 317 eligible patients received Trastuzumab. Local and/or distant recurrence was seen in 1109 (21.2%) patients. In nonmetastatic cases, median overall and disease-free survival were 149.1 and 77.1 months, respectively. In metastatic cases, median progression-free survival was 19.6 months. We observed defects in the record system, there was delay in diagnosis and treatment, and nonadherence to targeted therapy in many patients. Strengthening of national and hospital-based registries is needed in Alexandria, Egypt, with a robust patient navigation system and targeted information, education and communication strategies. Continuous outcomes monitoring and adaptation to implementation needs should be sustained.

Safety considerations with the current treatments for peripheral T-cell lymphoma

ABSTRACT Introduction Peripheral T-Cell Lymphomas (PTCL) constitute a heterogeneous group of aggressive T – and natural killer (NK)-cell disorders and are associated with a poor prognosis. Frontline treatments often consist of anthracycline-based combination chemotherapy with the exception of NK-T cell lymphomas, where such combinations are ineffective due to the presence of P-glycoprotein which leads to multidrug resistance. Infectious and immune mediated side effects might be more pronounced in or unique to T-cell lymphomas due to the selection of agents which target multiple T-cell subtypes and also an immunocompromised state induced by the lymphomas themselves. Areas covered This review provides a comprehensive overview of safety considerations of treatment regimens used for peripheral T-cell lymphomas. We cover regimens used in both frontline and relapsed settings including combination chemotherapy, single agent chemotherapies and immunotherapies. Expert opinion Treatment of T-cell lymphomas often requires sequencing of several therapies due to lower efficacy of available treatment regimens in curing the disease compared to that seen in B-cell non-Hodgkin lymphomas. In addition, certain complications are more common in T-cell lymphomas due to their unique immunobiology. An understanding of these salient aspects is important for all providers who treat patients with this challenging disease group.

Abstract 16: Presentation and Management of Egyptian Female Breast Cancer In Alexandria, Egypt: An Implementation Study

Abstract Purpose: Exploration of the population profile and management of female breast cancer in a representative sample from Alexandria, Egypt, to identify system inefficiencies and barriers preventing full implementation of international guidelines, negatively impacting the outcome. Methods: The study surveyed 7125 records from three major public oncology services at Main University Hospital, Gamal Abd-elnasser Hospital and Ayadi Almostakbel Oncology Center, between 2007 and 2016. Results: 73.4% (5236 records) of the records contained usable information. The median age was 54 years, with positive family history in 31.5%. The median duration of complaint before diagnosis was 3.1 months (IQR 1.6-7.5). 55.2% were early stage, 37.6% were locally advanced and 7.2% were stage IV. Breast surgery was performed for 4976 cases. Axillary surgery was done for 4945 cases. Most cases were hormone receptor positive. 15.3% were HER2 positive. The median duration to start chemotherapy was 1.03 months (IQR 0.7-1.6). Adjuvant chemotherapy was given to 3667 and neoadjuvant chemotherapy was given to 333. Anthracycline-based combination chemotherapy, with or without Taxanes was the commonest. 86% received hormonal treatment. 180/317 trastuzumab-eligible patients received trastuzumab. 69.5% started radiotherapy &amp;gt; 6 months from presentation. Conventionally and hypofractionated regimens were used in 46.6% and 53.5%, respectively. 1109 developed relapse (local in 155, distant in 130 and 794 had both). In non-metastatic cases, median overall and disease free survivals were 149.1 and 77.1 months respectively. In metastatic cases, the median progression free survival was 19.6 months. Conclusion: The study revealed defects in the record system, delayed diagnosis and treatment, and inadherence to targeted therapy protocols in a significant part of eligible patients. Suggested implementation strategies include promotion of national or hospital based registries, information, education and communication with target populations and health carers, establishing a patient navigation system and monitoring outcomes of the interventions. Citation Format: Yousri Rostom, Salah Abdelmonem, Marwa Shaker, Nayera Mahmoud, Nevine Labib, Abdelsalam A. Ismail, Maher Soliman. Presentation and Management of Egyptian Female Breast Cancer In Alexandria, Egypt: An Implementation Study [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 16.

Anthracycline-based combination chemotherapy (Doxorubicin and Dacarbazine) for the desmoid tumor in a neoadjuvant setting. Report of a case

Anthracycline-based combination chemotherapy (Doxorubicin and Dacarbazine) for the desmoid tumor in a neoadjuvant setting. Report of a case

Association of Sperm-Associated Antigen 5 and Treatment Response in Patients With Estrogen Receptor–Positive Breast Cancer

There is no proven test that can guide the optimal treatment, either endocrine therapy or chemotherapy, for estrogen receptor-positive breast cancer. To investigate the associations of sperm-associated antigen 5 (SPAG5) transcript and SPAG5 protein expressions with treatment response in systemic therapy for estrogen receptor-positive breast cancer. This retrospective cohort study included patients with estrogen receptor-positive breast cancer who received 5 years of adjuvant endocrine therapy with or without neoadjuvant anthracycline-based combination chemotherapy (NACT) derived from 11 cohorts from December 1, 1986, to November 28, 2019. The associations of SPAG5 transcript and SPAG5 protein expression with pathological complete response to NACT were evaluated, as was the association of SPAG5 mRNA expression with response to neoadjuvant endocrine therapy. The associations of distal relapse-free survival with SPAG5 transcript or SPAG5 protein expressions were analyzed. Data were analyzed from September 9, 2015, to November 28, 2019. The primary outcomes were breast cancer-specific survival, distal relapse-free survival, pathological complete response, and clinical response. Outcomes were examined using Kaplan-Meier, multivariable logistic, and Cox regression models. This study included 12 720 women aged 24 to 78 years (mean [SD] age, 58.46 [12.45] years) with estrogen receptor-positive breast cancer, including 1073 women with SPAG5 transcript expression and 361 women with SPAG5 protein expression of locally advanced disease stage IIA through IIIC. Women with SPAG5 transcript and SPAG5 protein expressions achieved higher pathological complete response compared with those without SPAG5 transcript or SPAG5 protein expressions (transcript: odds ratio, 2.45 [95% CI, 1.71-3.51]; P < .001; protein: odds ratio, 7.32 [95% CI, 3.33-16.22]; P < .001). Adding adjuvant anthracycline chemotherapy to adjuvant endocrine therapy for SPAG5 mRNA expression in estrogen receptor-positive breast cancer was associated with prolonged 5-year distal relapse-free survival in patients without lymph node involvement (hazard ratio, 0.34 [95% CI, 0.14-0.87]; P = .03) and patients with lymph node involvement (hazard ratio, 0.35 [95% CI, 0.18-0.68]; P = .002) compared with receiving 5-year endocrine therapy alone. Mean (SD) SPAG5 transcript was found to be downregulated after 2 weeks of neoadjuvant endocrine therapy compared with pretreatment levels in 68 of 92 patients (74%) (0.23 [0.18] vs 0.34 [0.24]; P < .001). These findings suggest that SPAG5 transcript and SPAG5 protein expressions could be used to guide the optimal therapies for estrogen receptor-positive breast cancer. Retrospective and prospective clinical trials are warranted.

Treatment and Other Healthcare Use of Breast Cancer Patients With a Previous Cancer Diagnosis.

To quantify the association between a previous cancer diagnosis and healthcare use among breast cancer (BC) patients, and estimate five-year recurrence-free survival (RFS). Women with BC were classified according to a previous cancer diagnosis (BC or other). Healthcare use during the first year and five-year RFS were obtained through clinical and administrative records. Adjusted odds ratios and hazard ratios (HR) were estimated. Among 681 BC patients, 21 had a previous BC and 32 a previous non-BC. The latter were less likely to receive anthracycline-based combination chemotherapy. The former had higher odds of mastectomy and genetic testing. Five-year RFS HRs (95% confidence interval) were 2.75 (0.79-9.52) and 0.52 (0.07-3.89) for previous BC and non-BC, respectively. Previous cancer was associated with less anthracycline-based combination chemotherapy, and patients were more likely to undergo mastectomy and genetic testing. These findings highlight the need for assessment of previous treatments, personal genetic risk and current BC characteristics.

Evidence that neoadjuvant anthracycline based combination chemotherapy (NACT) in breast cancer (BC) induces phenotypical changes which guides the optimal adjuvant therapy.

590 Background: We hereby evaluated the histopathological and radiological alterations of tumor characteristics after receiving NACT and the clinical significance of the changes of adjuvant therapy based on these findings. Methods: A pathological assessment of tumor features including ER, PR, HER2 and proliferation markers (Ki67 and SPAG5) status in pre and post NACT tumors tissue have been centrally evaluated in two cohorts [Nottingham University Hospital (NUH; n=850) and Australian cohort (n=250 patients)]. Since 2013 any change in the ER and HER2 status from negative (-) [in the pre NACT biopsies] to positive (+) [in the post NACT surgical specimens] received additional adjuvant therapy (Endocrine therapy (ET) for ER+ and Trastuzumab for HER2+ cases) in NUH. MRI volumetric and texture changes have been assessed in 400 cases. The primary end point was disease free survival (DFS; median follow-up = 62 months). Results: 10% of pre NACT HER2- cases had been converted to post NACT HER2+ and those cases who subsequently received adjuvant Trastuzumab had achieved 92% 5-year DFS compared to those who remained HER- in post NACT specimens (58% 5-year DFS); (HR (95% CI)= 0.25 (0.08-0.80); p=0.016). While 13% of pre NACT HER2+ tumors were converted into HER2- in post NACT surgical specimens and had similar 5-year DFS to those who remained post NACT HER2+ (5-year DFS= 94% vs., 87%; p=0.613). Loss of PR in the residual disease of pre NACT ER+ BC was associated with shorter 5-year DFS after ET compared to those who remained post NACT PR+ (HR (95% CI)=2.1 (1.25-3.46); p=0.005). After NACT, 40% of pre NACT SPAG5+ cases were converted into post NACT SPAG5- and these patients had prolonged DFS compared to those who remained SPAG5+ in post NACT specimens (27%) [5-year DFS=84% vs 49%; (HR (95% CI)= 3.8 (2.1-6.9); p&lt;0.0001). A prognostic model has been generated including factors in table (AUC = 0.854 (95% CI) = 0.777-.0.931; p= 0.00000001]. Conclusions: We hereby showed evidences a change of treatment strategy based on the changes in the tumor post NACT phenotype gives the optimal choice of treatment eg., the introduction of HER2 targeting therapy for the conversion of HER2– to HER2+ phenotype after NACT improved DFS. Multivariate Cox regression model for 5-year DFS. [Table: see text]

High-dose Therapy and Autologous Hematopoietic Cell Transplantation as Consolidation Treatment for Primary Effusion Lymphoma

BackgroundPrimary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma. The limited disease-free survival after chemotherapy has resulted in a poor prognosis. The outcomes data for high-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) for PEL are limited owing to the rarity of the disease. Patients and MethodsThe present study included 9 patients with PEL from 2 major academic centers. Of these patients, 4 had received auto-HCT after high-dose therapy. Of the 9 patients, 8 (89%) had immunodeficiency (7 with human immunodeficiency virus seropositivity; 1, a solid organ transplant recipient) at the diagnosis. Human herpesvirus-8 by immunohistochemistry was positive in 8 patients. Anthracycline-based combination chemotherapy was used as first-line treatment in 7 patients; 4 underwent auto-HCT after attaining first complete remission. ResultsThe median follow-up of the surviving patients was 25 months (95% confidence interval [CI], 8%-29%). The 2-year progression-free and overall survival for the 8 patients who had received treatment was 58% (95% CI, 22%-95%) and 73% (95% CI, 41%-100%), respectively. The 2-year progression-free and overall survival for the patients who had received auto-HCT was 50% (95% CI, 1%-99%) and 75% (95% CI, 33%-100%), respectively. Of the 4 auto-HCT recipients, all had been in first complete remission at the time of autografting. The cumulative incidence of relapse was 50% (95% CI, 19%-100%). No deaths were attributable to auto-HCT at 2 years after autografting. ConclusionDespite the small sample size, our data have shown that consolidative auto-HCT is safe and effective and should be considered for eligible patients with PEL after demonstration of an objective response to induction chemotherapy. However, the high relapse rate remains a concern and warrants the development of new strategies to mitigate post-transplantation relapse.

SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment

BackgroundSHON nuclear expression (SHON-Nuc+) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα+ breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT).MethodsSHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n = 1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα− early-stage-BC (n = 697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre-operative ACT with/without taxanes (Neo-ACT, n = 120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed.ResultsAs previously reported, SHON-Nuc+ in high risk/ERα+ patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc− [HR (95% CI) = 0.52 (0.34–0.78), p = 0.002]. Meanwhile, in ERα− patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto+) was significantly associated with a 50% death risk reduction compared with SHON-Cyto− [HR (95% CI) = 0.50 (0.34–0.73), p = 0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc− or SHON-Cyto+ was associated with an increased pathological complete response (pCR) compared with SHON-Nuc+ [21 vs 4%; OR (95% CI) = 5.88 (1.28–27.03), p = 0.012], or SHON-Cyto− [20.5 vs. 4.5%; OR (95% CI) = 5.43 (1.18–25.03), p = 0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc+ had a significantly lower distant relapse risk compared to those with SHON-Nuc− [HR (95% CI) = 0.41 (0.19–0.87), p = 0.038], whereas SHON-Cyto+ patients had a significantly higher distant relapse risk compared to SHON-Cyto− patients [HR (95% CI) = 4.63 (1.05–20.39), p = 0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto+ was independently associated with a higher risk of distant relapse after Neo-ACT and 5-year tamoxifen treatment [HR (95% CI) = 5.08 (1.13–44.52), p = 0.037]. The interaction term between ERα status and SHON-Nuc+ (p = 0.005), and between SHON-Nuc+ and tamoxifen therapy (p = 0.007), were both statistically significant.ConclusionSHON-Nuce+ in tumours predicts response to tamoxifen in ERα+ BC while SHON-Cyto+ predicts response to ACT.

Abstract P1-15-11: Predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) based on pre- and post-NACT digital mammography and digital breast tomosynthesis findings

Abstract Background: In invasive breast cancer patients being treated with neoadjuvant chemotherapy (NACT), achieving pathological complete response (pCR) is a useful goal of treatment. Monitoring response to NACT and predicting pCR is helpful in planning further therapy and providing robust prognostic information. Digital mammography (DM) and additional digital breast tomosynthesis (DBT) features are important tell-tales of tumor characteristics and behaviour. Following NACT, the mammographic features- both DM and DBT- of responding tumors can vary considerably. In this prospective study, we correlated the DM and DBT features of pre-NACT and post-NACT mammograms to investigate if these can reliably predict pCR to NACT. Methods: Following approval by institutional ethics committee, starting January 2016, 200 consecutive invasive breast carcinoma patients (mean age 51.2 years, all palpable breast masses) undergoing diagnostic breast imaging had their DM and DBT reviewed by two radiologists independently, who were blinded of the cyto/histology and the original DM and DBT reporting. Of these, 47 patients who were treated with NACT and had pre- and post-NACT DM and DBT were recruited. After a core-biopsy, radio-opaque marker(s) were placed in tumor core/margin. The pre- and post-NACT DM and DBT findings were compared and correlated with the extent of response of the primary breast tumor to NACT. DM and DBT characteristics predictive of (in-breast) pCR of index breast lesion were identified. Results: Of the 47 patients who underwent NACT, 44 received both anthracycline and taxane, and 3 received only an anthracycline based combination chemotherapy. Twelve patients underwent breast conservative surgery and the remaining underwent mastectomy. pCR was seen in 17 (36.2%) patients based on the surgical specimen histology. On clinical examination, 19 (40.4%) patients had clinical complete response (cCR) of the breast tumor, 11 (64.7%) of whom had pCR as well. Five patients had radiological complete response (rCR, no breast lesion visualised on post-NACT imaging)- 2 patients on DM alone, 2 patients on DBT alone, and one patient on both DM and DBT. Radio-opaque clips had some obscuring effects in 3 of these 5 patients, especially on DBT, in form of reduced visibility of breast lesion on DBT, c.w. corresponding DM images. All 5 patients with rCR had pCR (sensitivity=29.4%, specificity=100%), in contrast to only 11 (57.9%) patients with cCR having pCR. Patients with pCR had benign appearing (forced Bi-RADS 2 and 3) lesions on mammography more commonly on DM (p&amp;lt;0.001) than on DBT (p=0.042) (41.2% vs 23.5%). Post NACT lesion morphology varied significantly between patients with and without pCR on DM (p=0.038) but not on DBT (p=0.182). Pre-NACT forced Bi-RADS score, lesion morphology or margin characteristics on DM and DBT did not vary significantly amongst patients with and without pCR. Conclusions: Post-NACT DM and DBT features can predict pCR with high specificity but with low sensitivity. Pre-NACT DM and DBT features did not reliably predict response to NACT, and pCR in this study. DM may be better than DBT for assessing response to NACT in the presence of radio-opaque markers/clips. Citation Format: Agarwal G, Sonthineni C, Mohindra N, Jain N, Neyaz Z, Agrawal V, Krishnani N, Maylivahnan S, Mishra A, Lal P. Predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) based on pre- and post-NACT digital mammography and digital breast tomosynthesis findings [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-11.

Peripheral T-Cell Lymphoma, not Otherwise Specified (PTCL-NOS).

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a World Health Organization (WHO)-defined diagnostic category within the highly heterogeneous group of mature post-thymic T-cell neoplasms. It is the most common subtype of mature post-thymic T-cell neoplasms globally, accounting for up to 35% of PTCL cases in Europe and North America. PTCL-NOS is a diagnosis of exclusion, comprising several disease entities that differ in biology, clinical presentation, and outcome. The diagnosis of PTCL-NOS is made based on the presence of typical histopathological features of lymphoma, an aberrant T-cell immunophenotype, often with a loss of CD5 and CD7, and a clonal T-cell receptor (TCR) gene rearrangement, in the appropriate clinical context. Unlike other types of T-cell lymphoma, recurrent mutations to assist with the diagnosis have not been identified. Patients often present with advanced stage. Prognosis is poor, with a 5-year overall survival (OS) of 20-30%. Anthracycline-based combination chemotherapy remains the most frequently used frontline strategy, with overall response rates (ORR) of 50-60%, and complete response rates (CRR) of 20-30%. Prospective studies with intent-to-treat analyses have shown that consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT) results in progression-free survivals (PFS) that compare favorably with historical cohorts and may improve OS in selected patient populations. However, randomized data are still lacking. Over the past decade, therapeutic agents approved in the relapsed and refractory setting have produced response rates of up to 33% and median PFS up to 18 months. Overall, outcomes remain poor and there is a dire need for more effective treatments. This review discusses the latest information on the diagnosis and treatment of PTCL-NOS.

Single Institution Experience of Gastrointestinal Involvement of Diffuse Large B- Cell Lymphoma: Presentation, Outcomes and Patterns of Treatment Failure

IntroductionExtranodal (EN) involvement of the gastrointestinal (GI) tract in diffuse large B-cell lymphoma (DLBCL) presents heterogeneously across different anatomic sites and often occurs at initial diagnosis. Rituximab, anthracycline-based combination chemotherapy, radiation, and surgery have all been studied separately and in various combinations. However, given the variability in how patients may present in these contexts, there remains no consistent standard of care or pattern of treatment failure. We hypothesized these patients have different outcomes than those lacking this EN site of involvement.MethodsWe conducted a single-institution, retrospective analysis of consecutive cases who presented at initial diagnosis with DLBCL involving the GI tract including the esophagus, stomach, small intestine, or portion of large intestine. We performed a search in the University of Virginia Pathology database to identify all patients age >/= 18 years with DLBCL involving the GI tract and excluded those without additional clinical information available for review. A total of 51 patients were identified and we retrospectively collected data on demographics, date of diagnosis, involvement of extranodal sites, stage, International Prognostic Index (IPI) score, treatment, response to treatment, relapse, and survival at last follow-up.ResultsOf the 51 DLBCL patients, 65% of patients were male and 82% were Caucasian. Median age was 65 years (range 22-92). Three patients had HIV infection and no patients had active hepatitis B or C. Sites included gastric (51%), colon (27%), small bowel (12%), esophagus (4%), and rectum (2%); 4% had multiple GI sites involved. Forty-nine percent of patients presented with abdominal pain. Other common presentations included gastric/bowel perforation (12%), GI bleed (12%), gastric/small bowel obstruction (12%). Three cases (6%) were discovered on a screening colonoscopy. Forty-three percent of patients presented as stages I-IIIE versus 57% presented as stage IVE. Fifty-five percent were IPI 0-2 while 45% were IPI 3-5. Six patients (12%) had CNS involvement at presentation. Median follow-up was 20 months (range 26 days to 17 years). Six patients were lost to follow-up prior to assessment of response, and 4 had treatment discontinued early (3 due to grade 5 infection, 1 for GI perforation leading to death). One patient was still undergoing treatment.Forty patients were available to assess for response to treatment. The majority were treated with R-CHOP (57%) or DA-R-EPOCH (29%). Sixty-eight percent (n=27) had a complete response (CR), 22.5% (n=9) a partial response (PR), and 10% (n=4) were primary refractory. Of the 27 CRs, 13 (48%) had presented as stage 1-3 and 14 (52%) had presented as stage 4; 16 (59%) had an IPI score of 0-2 and 11 (41%) had an IPI score of 3-5. Of the four patients who had primary refractory disease, 3 had multiple EN sites involved at diagnosis, including 2 with CNS involvement. Of those who had a response (including CR or PR), median duration of response was 1 year (range 4 months to 13 years). Eleven patients (28%) had a relapse: 3 in the CNS, 5 in the GI tract (3 at the same site of initial involvement, 1 with a different GI site involved, and 1 with a different GI site in addition to systemic disease), and 3 in lymph nodes alone. Time to relapse ranged 1 month to 13 years with a median of 8.4 months. Fifty-seven percent of patients were alive at time of last follow-up. Median Overall survival (OS) was 5.7 years and Median Progression Free Survival (PFS) was 5.6 years (Figure 1).ConclusionThere is limited data on how patients with DLBCL involving the GI tract initially present and respond to therapy. This study encompassing almost twenty years of experience at a single institution, suggests that though patients present at all stages and as low risk vs high risk IPI, outcomes are poor compared to prior studies, especially when additional extranodal sites are involved. Duration of response can be substantial, however relapses are common and may present years later indicating ongoing follow-up is imperative. [Display omitted] DisclosuresPortell:AbbVie: Research Funding; Amgen: Consultancy; Kite: Research Funding; TG therapeutics: Research Funding; BeiGene: Research Funding; Genentech/Roche: Consultancy, Research Funding; Acerta: Research Funding; Infinity: Research Funding. Williams:Sandoz: Consultancy; Pharmacyclics: Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Abbvie: Consultancy; Novartis: Research Funding; Gilead: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Juno: Consultancy.

Phase II Trial of CH5424802 (alectinib hydrochloride) for Recurrent or Refractory ALK-Positive Anaplastic Large Cell Lymphoma

Introduction: Anthracycline-based combination chemotherapy is a standard first-line treatment for anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) both in adults and children, which results in favorable clinical outcomes. However, a standard therapy has not been established for recurrent or refractory diseases. Because many treatment options, such as hematopoietic stem cell transplantation, are available, patients with diseases that are resistant to conventional chemotherapies have particularly poor prognosis. Brentuximab vedotin, an anti-CD30 antibody drug conjugate, has improved the prognosis of recurrent or refractory ALCL; however, other types of novel agents have not yet been investigated. ALK inhibition could be a promising therapeutic strategy for ALK-positive malignancies. Therefore, this study aimed to determine the efficacy and safety of alectinib, a second-generation ALK inhibitor, in patients with recurrent or refractory ALK-positive ALCL.Methods: In this open-label, phase II trial, patients with recurrent or refractory ALK-positive ALCL diagnosed by histological examination were eligible. Other major inclusion criteria were as follows: age >6 years, ECOG performance status 0-2, at least one measurable lesion, and preserved organ functions. Alectinib 300 mg was administered orally twice a day (600 mg/day). Patients who weighed <35 kg were administered reduced doses of alectinib, i.e., 150 mg twice a day (300 mg/day). The primary endpoint was the response rate according to the Revised Response Criteria for Malignant Lymphoma. The secondary endpoints were pharmacokinetics, safety in children, complete response rate, response duration, progression-free survival, event-free survival, overall survival, and adverse events (AEs). All patients who received at least one dose of alectinib were evaluated for responses and toxicities. We expected that a response rate of 85% and a statistical power of 79% could be obtained for 10 patients with an alpha level of 0.05 (one tailed). This study is registered in UMIN-CTR (UMIN 000016991).Results: Ten patients were enrolled in the study from May 2015 to November 2017. The median age was 19.5 (range, 6-70) years. Of 10 patients, 8 were administered alectinib 600 mg/day and 2 were administered with 300 mg/day. Objective tumor responses were documented in 8 of 10 patients (80%; 90% confidence interval: 56.2-95.9), with CR in 6 and PR in 2 according to the independent review committee. Two patients underwent stem cell transplantation after alectinib treatment. Five patients continued to take alectinib at the data cut-off. One-year overall survival and progression-free survival rates were 70.0% and 58.3% (Fig), respectively. Three patients died owing to disease progression. A severe AE was observed in 1 patient (grade 3 acute pharyngitis). Grade 4 AEs were observed in 1 patient (neutropenia). Common AEs observed were diarrhea in 2 patients, upper respiratory infection in 3, elevated alkaline phosphatase in 3, and maculopapular rash in 4. No unexpected AEs were experienced. The mean steady state peak concentration of alectinib was 479.5, 676.7, and 391.1 ng/mL in patients aged <15 years administered 300 mg/day, those aged <15 years admisnitered 600 mg/day, and those aged >15 years administered 600 mg/day, respectively. The mean time to reach the peak concentrations was 4, 4, and 5 h, respectively.Conclusion: Alectinib showed favorable clinical activity and was well tolerated in patients with ALK-positive ALCL who progressed on standard chemotherapy. This study demonstrated similar pharmacokinetic profiles between pediatric and adult patients. Therefore, alectinib could be a suitable treatment for both pediatric and adult patients with recurrent or refractory ALK-positive ALCL. [Display omitted] DisclosuresSekimizu:Eli Lilly and Company: Speakers Bureau. Kada:Bayer Yakuhin, Ltd: Membership on an entity's Board of Directors or advisory committees. Nagai:HUYA Bioscience International: Research Funding; Bayer Yakuhin Ltd.: Research Funding; Esai Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AstraZeneca plc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Roche Ltd.: Honoraria; SymBio Pharmaceuticals Limited: Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi K. K.: Honoraria; Mundipharma K.K.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Gilead Sciences Inc.: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Zenyaku Kogyo Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Abbvie G. K.: Research Funding.

An International Assessment of Event-Free Survival at 24 Months (EFS24) and Subsequent Survival in Peripheral T-Cell Lymphoma

▪Background: Peripheral T-cell lymphomas (PTCLs) comprise a group of non-Hodgkin lymphomas (NHLs) of mature T-cell origin with generally aggressive clinical behavior. Most systemic PTCLs are treated with anthracycline-based combination chemotherapy; however, outcomes remain relatively poor for most subtypes except ALK-positive anaplastic large cell lymphoma (ALCL). We have used landmark analyses based on event-free survival (EFS) to identify clinically useful endpoints in B-cell NHLs, with EFS at 24 (EFS24) months identified to stratify overall survival (OS) in aggressive B-cell NHL. Here we examined the ability of EFS24 to predict subsequent OS in a large, multinational PTCL cohort.Methods: A cohort of newly diagnosed PTCL patients treated with curative intent combination chemotherapy regimens was assembled from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), Swedish Lymphoma Registry (SWE), and British Columbia Cancer Agency (BCCA). Subtypes included ALK-negative ALCL, angioimmunoblastic T-cell lymphoma (AITL), PTCL, not otherwise specified (NOS), enteropathy-associated T-cell lymphoma (EATL), extranodal NK/T-cell lymphoma, nasal type (ENKTL), and hepatosplenic T-cell lymphoma (HSTCL). Patients were followed based on local institution guidelines, and EFS was defined as time from the date of pathologic diagnosis to progression, re-treatment, or death due to any cause. EFS24 was defined as being alive and event-free 24 months from diagnosis. Subsequent OS was defined as time from achieving EFS24 (24 months from diagnosis) or time from progression in patients failing to achieve EFS24 (progression within 24 months of diagnosis). OS was compared to the age-, sex-, and country-matched general population using United States, Sweden, and British Columbia rate tables via standardized mortality ratios (SMR) and expected survival.Results: 775 patients diagnosed from 2000-2012 were included in the combined analysis with diagnosis by the WHO classification at the respective institutions (MER=138, SWE=422, BCCA=215). Median age at diagnosis was 64 years (range 18-89) and 63% were male. Patient characteristics are summarized in the table. 736 (95%) received anthracyline-based therapy at diagnosis. At a median follow-up of 77 months (range 1-185), 516 patients (67%) had died. The percentage of patients achieving EFS24 was similar across the 3 cohorts (MER=39%, SWE=35%, BCCA= 36%, combined=36%). Median survival after progression within the first 24 months was only 4.9 months (95% CI: 3.8-5.9), with a 5-year OS of 11% and SMR of 46.4 (95% CI: 41.8-51.3). In contrast, median survival after achieving EFS24 was not reached, with a 5-year OS of 78% (95% CI: 73%-84%). This was inferior to the expected survival of 92% in the age-, sex-, and country matched population (SMR=3.16; 95% CI: 2.48-3.98). In EFS24 subgroup analyses, more favorable outcomes were observed in younger patients (age <=60 years, N=137, 5-year survival of 91% vs. 98% expected) and in patients receiving autologous stem cell transplant in first remission (N=72, 5-year survival of 88% vs. 96% expected). Patients achieving EFS24 who were not transplanted in first remission (N=189) had a 5-year survival of 74% vs. 90% expected.Conclusions: Assessment of EFS24 stratifies subsequent outcome in PTCL. Patients with early relapse from PTCL have extremely poor outcomes. However, over one-third of patients with PTCL remain in remission two years from diagnosis after initial chemotherapy and have encouraging OS rates, although survival remains significantly worse than the matched general population. Subset analysis suggests that younger patients and patients who receive autologous stem-cell transplant in first CR have 5-year survival rates that approach 90%, though still below the expected survival of the background population. The marked differences in OS after failing or achieving EFS24 in PTCL patients suggest that this endpoint may be useful for patient counseling, as a clinical trial endpoint, and as an endpoint to assess novel biomarkers for risk stratification. [Display omitted] [Display omitted] [Display omitted] DisclosuresMaurer:Celgene: Research Funding; Kite Pharma: Research Funding. Jerkeman:Mundipharma: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Celgene: Research Funding. Connors:Seattle Genetics: Research Funding; Millennium Takeda: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Dielectrophoretic Microfluidic Chip Enables Single-Cell Measurements for Multidrug Resistance in Heterogeneous Acute Myeloid Leukemia Patient Samples.

The front-line treatment for adult acute myeloid leukemia (AML) is anthracycline-based combination chemotherapy. However, treatment outcomes remain suboptimal with relapses frequently observed. Among the mechanisms of treatment failure is multidrug resistance (MDR) mediated by the ABCB1, ABCC1, and ABCG2 drug-efflux transporters. Although genetic and phenotypic heterogeneity between leukemic blast cells is a well-recognized phenomenon, there remains minimal data on differences in MDR activity at the individual cell level. Specifically, functional assays that can distinguish the variability in MDR activity between individual leukemic blasts are lacking. Here, we outline a new dielectrophoretic (DEP) chip-based assay. This assay permits measurement of drug accumulation in single cells, termed same-single-cell analysis in the accumulation mode (SASCA-A). Initially, the assay was optimized in pretherapy samples from 20 adults with AML whose leukemic blasts had MDR activity against the anthracyline daunorubicin (DNR) tested using multiple MDR inhibitors. Parameters tested were initial drug accumulation, time to achieve signal saturation, fold-increase of DNR accumulation with MDR inhibition, ease of cell trapping, and ease of maintaining the trapped cells stationary. This enabled categorization into leukemic blast cells with MDR activity (MDR(+)) and leukemic blast cells without MDR activity (MDR(-ve)). Leukemic blasts could also be distinguished from benign white blood cells (notably these also lacked MDR activity). MDR(-ve) blasts were observed to be enriched in samples taken from patients who went on to enter complete remission (CR), whereas MDR(+) blasts were frequently observed in patients who failed to achieve CR following front-line chemotherapy. However, pronounced variability in functional MDR activity between leukemic blasts was observed, with MDR(+) cells not infrequently seen in some patients that went on to achieve CR. Next, we tested MDR activity in two paired AML patient samples. Pretherapy samples taken from patients that achieved CR to front-line chemotherapy were compared with samples taken at time of subsequent relapse. MDR(+) cells were frequently observed in leukemic blast cells in both pretherapy and relapsed samples, consistent with MDR as a mechanism of relapse in these patients. We demonstrate the ability of a new DEP microfluidic chip-based assay to identify heterogeneity in MDR activity in leukemic blasts. The test provides a platform for future studies to characterize the mechanistic basis for heterogeneity in MDR activity at the individual cell level.

Complete response in a critically ill patient with ALK-negative anaplastic large cell lymphoma treated with single agent brentuximab-vedotin

ABSTRACTAnaplastic large cell lymphoma (ALCL) is a rare hematological malignancy and a distinct subtype of mature T-cell lymphomas. ALCL is comprised of two clinically distinct but morphologically similar sub-class under 2008 WHO classification: cutaneous and systemic. Primary systemic ALCL is further sub-categorized into tumors that carry the anaplastic lymphoma kinase (ALK) gene rearrangement or not; ALK-positive versus ALK-negative disease respectively. Traditionally, both forms of primary systemic ALCL have been treated upfront with an anthracycline based combination chemotherapy such as CHOP. More recently an antibody drug conjugate, brentuximab-vedotin (BV), directed against CD30 antigen has shown promise in CD30 expressing hematologic malignancies such as Hodgkin's lymphoma and ALCL. At the present time, this novel antibody-drug conjugate has been approved in the treatment of patients with ALCL after failure of at least one prior multi-agent chemotherapy regimen in the United States. We present a case describing a previously healthy 48 year-old female diagnosed with ALK-negative ALCL who achieved complete response with upfront single agent brentuximab-vedotin. It is the first case described in the literature utilizing BV in the first line setting particularly in a patient with multi-organ failure and critically ill at time of diagnosis. This case highlights the full potential that targeted therapies can exert over hematological malignancies while also minimizing treatment related toxicities.Abbreviations: AE: adverse event; ALCL: anaplastic large cell lymphoma; ALK: anaplastic lymphoma kinase; ASCT: autologous stem cell transplant; BEAM: BCNU/carmustine, etoposide, ara-C, and melphalan; BV: brentuximab vedotin; CHEOP: cyclophosphamide, daunorubicin, vincristine, prednisone, etoposide; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; CR:complete response; G3+: grade 3 or higher; MTD: maximum tolerated dose; ORR: overall response rate; OS: overall survival; PFS: progression-free survival.

Peripheral T cell lymphomas in elderly patients: a retrospective analysis from the Hematology Association of South East Korea (HASEK).

Limited data are available on the clinical features and the outcomes of elderly patients with peripheral T cell lymphomas (PTCLs). We identified PTCL patients of age 60years or older from the records of the Hematology Association of South East Korea between 2001 and 2014. The median age of the patients (70.4% male) was 71years (range 60-88years). The majority (80.2%) had stage III/IV disease, and 61.7% of patients had Charlson comorbidity index (CCI) score 0. Out of 74 patients treated with chemotherapy, 62 were administered anthracycline-based combination chemotherapy (CHOP: 47 patients, CHOEP: 15 patients), and 12 received non-anthracycline-based combination chemotherapy (IMEP: 8 patients, and CVP: 4 patients). The overall response rate for the 74 patients treated with chemotherapy was 70.2% (CR 37.8% and PR 32.4%). With a median follow-up of 23.8 (range 0.5-156) months, the estimated 5-year progression-free survival (PFS) and overall survival (OS) were 16.6 and 45.9%, respectively. There were no significant differences in PFS and OS between patients treated with anthracycline-based and non-anthracycline-based combination chemotherapy. In the univariate analysis, increased age, elevated serum lactate dehydrogenase, Eastern Cooperative Oncology Group performance status >1, higher CCI, high or high-intermediate IPI, and PIT groups 3-4 were associated with shorter OS. Our findings may provide valuable information on the management and outcomes of elderly patients with PTCL in clinical practice.