Ewa Chmielowska

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

BACKGROUND Brutons tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkins lymphoma, including mantle-cell lymphoma. METHODS In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

Long-term follow-up of MCL patients treated with single-agent ibrutinib: Updated safety and efficacy results

Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391.

CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

PURPOSE CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. PATIENTS AND METHODS Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m(2) per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m(2) per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, -1.6%; 95% CI, -2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. CONCLUSION CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.

Postibrutinib outcomes in patients with mantle cell lymphoma

Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval [CI], 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib.

A randomized, double-blind, placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naïve metastatic/unresectable non-small cell lung cancer

INTRODUCTION Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naïve patients with metastatic/unresectable non-small cell lung cancer (NSCLC). METHODS Patients with histologically or cytologically confirmed NSCLC stage IIIB/IV disease by RECIST (version 1.0) and ECOG-PS 0-1 were enrolled at 15 European sites. Patients received tigatuzumab or placebo intravenously with carboplatin/paclitaxel every 3 weeks (1 cycle) for up to 6 cycles. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate and safety. RESULTS 97 patients were analyzed for efficacy (49 tigatuzumab; 48 placebo). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for tigatuzumab compared with 4.3 months (4.1, 5.8) for placebo. Median OS (95% CI) was 8.4 months (6.9, 16.3) for tigatuzumab versus 9.0 months (7.6, 14.5) for placebo. 12 patients (24.5%) in the tigatuzumab arm and 11 patients (22.9%) in the placebo arm had partial response. No patient had complete response. In a prospectively-defined Fc gamma receptor genotype subset (n=25), there was a non-significant trend toward increased PFS with tigatuzumab versus placebo (HR=0.47; 95% CI: 0.16, 1.35) but no difference in OS. Tigatuzumab was well tolerated. However, grade 3/4 neutropenia was reported in 10 patients (20.4%) receiving tigatuzumab compared with 4 patients (8.3%) receiving placebo. CONCLUSIONS Tigatuzumab was well tolerated but did not improve efficacy of carboplatin/paclitaxel in systemic therapy-naïve, unselected advanced NSCLC patients.

Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer: ROSiA Single-Arm Phase 3B Study.

Objective The aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer. Patients and Methods In this multinational prospective single-arm study (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IV or grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator’s choice of 175 mg/m2 q3w or 80 mg/m2 weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety. Results Between December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1–50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7–27.6 months). Conclusion Extended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for frontline bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.

Brain Metastasis Prediction by Transcriptomic Profiling in Triple-Negative Breast Cancer

Background Triple‐negative breast cancer (TNBC) lacks expression of steroid hormone receptors (estrogen receptor &agr; and progesterone) and epidermal growth factor receptor type 2. This phenotype shows high metastatic potential, with particular predilection to lungs and brain. Determination of TNBC transcriptomic profiles associated with high risk of brain metastasis (BM) might identify patients requiring alternative, more aggressive, or specific preventive and therapeutic approaches. Patients and Methods Using a cDNA‐mediated annealing, selection, extension, and ligation assay, we investigated expression of 29,369 gene transcripts in primary TNBC tumor samples from 119 patients—71 in discovery cohort A and 48 in independent cohort B—that included best discriminating genes. Expression of mRNA was correlated with the occurrence of symptomatic BM. Results In cohort A, the difference at the noncorrected P < .005 was found for 64 transcripts (P = .23 for global test), but none showed significant difference at a preset level of false‐discovery rate of < 10%. Of the 30 transcripts with the largest differences between patients with and without BM in cohort A, none was significantly associated with BM in cohort B. Conclusion Analysis based on the primary tumor gene transcripts alone is unlikely to predict BM development in advanced TNBC. Despite its negative findings, the study adds to the knowledge on the biology of TNBC and paves the way for future projects using more advanced molecular assays. Micro‐Abstract We investigated expression of 29,369 gene transcripts in primary tumor samples from 119 patients with advanced triple‐negative breast cancer to identify genes with different expression between patients with and without brain metastases (BM). Our results indicate that analysis based on expression of gene transcripts from primary tumor does not allow prediction of BM development in this population.

Merkel cell carcinoma: an illustrative case and review

Merkel cell carcinoma (MCC) was first described by Toker in 1972, as trabecular carcinoma [1, 2]. It is a primary cutaneous tumor of neuroendocrine origin characterized by aggressive course and poor prognosis [3–5]. Agelli and Clegg in 2007 showed that the incidence of MCC in the U.S. was 0.24/100000 per year [6]. Merkel cell carcinoma has a high propensity for local recurrence, lymphatic spread and distal metastases. Metastases are usually found in the skin (28%), liver (13%), bones (10%), and brain (6%). Typically, at the time of diagnosis, local or distant metastases are present. Merkel cell carcinoma affects mainly the elderly, more often men, usually between 65 and 85 years of age. Primary lesions are frequently localized in sun-exposed areas. In 29–40% of cases it is the head and neck region, followed by extremities (21–38%), trunk (7–23%), and other skin regions (3.4–12%) [7]. Merkel cell carcinoma often arises in the setting of immunodeficiency (post-transplant immunosuppression or HIV infection), autoimmune connective tissue diseases and neoplasm, particularly Hodgkins disease, B-cell lymphoma, chronic lymphocytic leukemia, breast and ovary cancer [8, 9]. Established risk factors for MCC development are UV radiation, immunosuppression and Merkel cell polyomavirus infection [7, 10]. Clinically MCC appears as an indolent, rapidly growing blue-red nodule often with telangiectasias. Histological findings are: monomorphous indistinct bluish cells, often arranged in trabeculae or strands with numerous mitotic figures, apoptotic cells and occasionally necrosis. Lymphocyte intra- and peritumoral infiltration is common. Routine histological examination may be of limited diagnostic value. Immunohistochemical staining, particularly against cytokeratin 20 (CK20) or chromogranin A, increase the effectiveness of MCC diagnosis [11]. Therapeutic management of choice is wide surgical excision or Mohs micrographic surgery of the tumor with sentinel lymph node biopsy. Adjuvant radiotherapy or chemotherapy is administered according to the clinical staging of disease. Metastases are treated with protocols similar to small-cell lung carcinoma management [12, 13]. A 74-year-old woman presented to our clinic with blue-red colored, well-demarcated skin tumors ranging from 0.5 cm to 2.0 cm in diameter located on the left lower extremity. Lesions were hard and painful on palpation (Figure 1). The enlarged inguinal lymph nodes were present bilaterally. Additionally the patient had a history of arterial hypertension, type 2 diabetes, rheumatoid arthritis and post-thrombotic syndrome. Figure 1 Blue-red colored, hard and painful to the touch skin tumors of the left lower leg diagnosed as MCC Lesions appeared 2 years ago, initially they would remit spontaneously. One year after the first occurrence, a nodular, ulcerated lesion located in the proximity of the left medial malleolus was biopsied. Histopathological examination of skin biopsy revealed positive staining for chromogranin A and CD56 as well as positive staining for cytokeratin 7 and cytokeratin 20 with a dot-like pattern. Deep surgical margin was positive. During current hospitalization skin biopsy was repeated revealing nests of small undifferentiated cells with round nuclei and scant cytoplasm. Numerous mitotic figures and apoptotic cells were present with occasional necrosis. Abundant peritumoral lymphocyte infiltration was observed. Immunohistochemical stainings were positive for CK20 (with a characteristic dot-like pattern), CD56, epithelial membrane antigen (EMA, MUC1), neuron-specific enolase (NSE, focal expression). Leukocyte common antigen (LCA) expression was positive only in peritumoral infiltrate (Figure 2). Adjacent muscular tissue was infiltrated with tumor cells. Based on clinical appearance and histology, MCC was diagnosed. Figure 2 Merkel cell carcinoma. A, B – Hematoxylin and eosin staining. The obtained result of the histopathological examination found within the dermis area is low-differentiated small cancer cells with scanty cytoplasm and round nuclei with small grains. ... Routine laboratory blood and urine tests, X-ray and computed tomography (CT) scans of the thorax, chest examination, USG of the abdomen and histology of enlarged inguinal lymph nodes were normal. The patient was staged IIC T4 N0 M0, where IIC is for primary tumors > 2 cm in size with extracutaneous invasion, T4 stands for primary tumor invading the bone, muscle, fascia, or cartilage; N0 – no regional lymph node metastasis and M0 – no distant metastases. The patient has undergone two surgeries with skin grafting. Due to local spread of the tumor, the 2nd and 1st fingers with metatarsal head were amputated. Currently adjuvant chemotherapy is considered. Merkel cell carcinoma is a rare neuroendocrine skin tumor occurring in the elderly, more often in men (70%). Common localization is the head and neck area and limbs, several cases of MCC in the anogenital area and on the mucosae have been reported [14]. Clinical appearance of MCC is heterogeneous. It frequently presents as an asymptomatic, reddish, bluish, or purple tumor of the skin. The size at the time of the first consultation is usually smaller than 2 cm, although rapid growth is characteristic [15, 16]. Merkel cell carcinoma pathogenesis remains largely unknown, but ultraviolet radiation and immunosuppression may play a significant role in the development of this cancer. In recent years, the relationship between Merkel cell polyomavirus infection and the development of the tumor was observed [17]. In the patient presented in this report, the incidence of tumors on both legs and the history of spontaneously resolving nodules may indicate MCC metastases without an apparent primary tumor. Spontaneous regression of the primary MCC tumor is not uncommon, with a dozen of cases described in medical literature [18]. Enlarged inguinal lymph nodes in our patient could indicate changes in tumor spread via lymphatic vessels. Cases of micro-metastases in the lymph nodes without clinical lymphadenopathy have been reported as well. Therefore, the sentinel lymph node biopsy and chest and abdomen imaging are necessary. Ulceration is uncommon in MCC. We believe that coexistence of MCC with post-thrombotic syndrome in our patient may explain ulceration of MCC tumor in this case. Merkel cell carcinoma derives from neuroendocrine cells and typically has appearance of ‘blue-cell tumor’ comprised of small, monomorphous cells with scant cytoplasm. Cancer cells are usually restricted to the dermis and subcutaneous tissue with a little propensity to invade epidermis. Differential diagnosis should consider basal cell carcinoma, squamous cell carcinoma, lymphoma, melanoma, metastatic neuroblastoma and neuroendocrine carcinoma. Useful diagnostic features are a positive dot-like pattern of staining for CK20 and sometimes other cytokeratins as well as positive staining for chromogranin A, somatostatin, gastrin characteristic of cells of neuroendocrine origin. Merkel cell carcinoma cells also exhibit a positive reaction with CD117, CD99, but negative with LCA and S-100 protein and of TTF-1. In our case, MCC was positive for cytokeratin 7, CK20 chromogranin A and MUC1. The prognosis in MCC is usually poor. The size of the primary tumor below 2.0 cm is associated with better prognosis, unfortunately, because of the very rapid proliferation of tumor cells, and diagnostic difficulties delaying diagnosis, in most cases, patients are diagnosed with MCC at the stage when the primary lesion exceeds 2.0 cm [19]. The classification of TMN American Joint Committee on Cancer (AJCC) proposed a clinical staging of MCC (0 to IV) [20]. According to this classification, the estimated 5-year survival rate for patients with stage IIC T4 N0 M0 is 50%. Merkel cell carcinoma lesions are considered highly malignant, hence a combination of surgery, radiotherapy in stages IA to IIIB of the disease is recommended [21–24]. Because of a rapid progression of the disease, adjuvant chemotherapy is frequently administered [2]. One can consider both the chemotherapy and radiotherapy in order to reduce the tumor mass prior to surgery in stages IIC to IIIB. In our patient, due to the presence of coexisting diseases and general condition, only surgical treatment was applied. In the IV stage of disease, the treatment of choice is palliative chemotherapy with the assessment of response to therapy and toilet surgery or radiotherapy of the bone, central nervous system and extensive skin metastases. Because of its similarity to small lung cancer, recommended chemotherapy protocols are cisplatin with etoposide or doxorubicin and cyclophosphamide or ifosfamide. The value of adjuvant radiotherapy has been confirmed with meta-analysis [25–27].

Polish Lymphoma Research Group Experience With Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma

Bexarotene, a synthetic retinoid licensed for the treatment of refractory cutaneous T-cell lymphoma (CTCL), has been used clinically in Poland since 2007 in 21 patients. The objective of our retrospective, multicenter study was to evaluate our experience with bexarotene therapy, including efficacy, safety, and survival outcomes. We retrospectively identified 21 adult patients who were treated with bexarotene between the years 2007 and 2012. Starting dose of bexarotene was 300 mg/m2 per day. The analysis included 3 patients with early-stage mycosis fungoides (MF), 16 patients with advanced-stage MF, and 2 patients with Sézary syndrome (SS). The mean duration of therapy with bexarotene was 14.5 months. Use of bexarotene resulted in an overall response rate of 81.0%, although the overall mortality rate was 52.8%. In our study, early-stage CTCL responded better than advanced-stage CTCL (100.0% vs. 77.8%, respectively). The mean time to observable response was 1.8 months, and the mean duration of the response was 16.4 months. Most significant side effects were hyperlipidemia, hypothyroidism, and a bleeding gastric ulcer. Based on the results of our analysis, bexarotene is a valuable tool in the treatment of refractory early-stage CTCL. Although a majority of patients initially responded to therapy, the high mortality rate in the advanced-stage group suggests that bexarotene does not completely resolve the therapeutic problems in all stages of CTCL. Patient stratification for bexarotene treatment may need a thorough reassessment, in that bexarotene may not be an effective drug in the very advanced stages of CTCL.

Multicentre, Prospective Observational Study of Pegfilgrastim Primary Prophylaxis in Patients at High Risk of Febrile Neutropenia in Poland: PROFIL Study

Aim of the study PROFIL was a prospective observational study conducted to investigate physicians’ evaluation of febrile neutropenia (FN) risk and reasons for giving pegfilgrastim primary prophylaxis (PP) in routine clinical practice in Poland. Material and methods Adult cancer patients treated with chemotherapy (CT), assessed by investigators as having high overall FN risk, and who received pegfilgrastim in cycle 1 were enrolled between 03/2009 and 09/2010. Investigators assessed FN risk of the CT regimen, individual risk factors, and overall FN risk, and were asked to provide the most important reasons for providing pegfilgrastim PP. Investigator-assessed CT FN risk was compared with guideline classification. Results Data were analysed from 1006 breast, ovarian, and lung cancer, and non-Hodgkin (NHL) and Hodgkin lymphoma (HL) patients. The most important reasons for using pegfilgrastim PP were high CT FN risk and advanced disease; these were consistent across tumour types and treatment intent. The investigators generally assessed high CT FN risk in agreement with guideline classification. Febrile neutropenia occurred in 4% of patients, most commonly in HL, NHL, and patients with advanced disease. Conclusions High CT FN risk and advanced stage of disease were found to be the most important reasons for providing pegfilgrastim PP by physicians in Poland.