**102 Chemoimmunotherapy with Ofatumumab,Fludarabine and Cyclophosphamide (O-FC) in Previously Untreated Patients with Chronic Lymphocytic Leukemia

Results from an international, randomized phase II trial showed that ofatumumab, a human CD20 monoclonal antibody (mAb), in combination with fludarabine and cyclophosphamide (O-FC), was active and well tolerated in treatment-naïve patients with chronic lymphocytic leukemia (CLL), including patients with high-risk disease features.

Full Abstract

Introduction: Chemoimmunotherapy with CD20 mAb is standard frontline treatment for physically fit patients with CLL. Ofatumumab, a human mAb, binds to a membrane-proximal epitope composed of both the small- and large-loop domains of CD20. The pivotal international study of ofatumumab monotherapy demonstrated high overall response rates (ORR) of 47%–58% in patients with fludarabine-refractory CLL. This international, randomized, phase II trial evaluated efficacy and safety of 2 dose levels of

Methods

Previously untreated patients with active CLL were randomized to ofatumumab 500 mg or 1000 mg day 1, with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 days 2–4, course 1; days 1–3, courses 2–6; every 4 weeks for 6 courses. All patients received ofatumumab 300 mg for course 1. The primary endpoint was complete response (CR) rate, as assessed by an Independent Review Committee using the 1996 NCI-WG criteria.

Results

61 patients were randomized (500 mg, n=31; 1000 mg, n=30). The median (range) age was 56 (38–73) years; 13% of patients had 17p deletion; 64% had β2-microglobulin >3.5 mg/L. CR rate (95% confidence interval [CI]) was 32% (17%–51%) for 500 mg and 50% (31%–69%) for 1000 mg cohort; ORR (95% CI) was 77% (59%–90%) and 73% (54%–88%), respectively. Median progression-free survival (PFS) and overall survival (OS) have not been reached with current follow-up (median 8 months). Based on univariable

Conclusion

O-FC, at the ofatumumab dose levels evaluated, was active in previously untreated patients with CLL, including in patients with high-risk features.

     

Rituximab monotherapy with eight weekly infusions for relapsed or refractory patients with indolent B cell non-Hodgkin lymphoma mostly pretreated with rituximab: a multicenter phase II study

Information regarding rituximab monotherapy with eight weekly infusions for relapsed or refractory indolent B cell non-Hodgkin lymphoma (B-NHL), in particular for patients pretreated with rituximab, is limited. To evaluate the efficacy and safety of eight doses of rituximab monotherapy, 52 patients with relapsed or refractory indolent B-NHL were enrolled in the present study. Forty of 45 eligible patients (89%) had follicular lymphoma and 24 (53%) were at intermediate or high risk group according to the Follicular Lymphoma International Prognostic Index. The median number of prior chemotherapy regimens was 1 (range 1-7). At the median follow-up of 12.2 months, the overall response rate (ORR), complete response rate (%CR), and median progression-free survival (PFS) were 69% (95% confidence interval [CI] 53%-82%), 47% (95% CI 32%-62%), and 15.6 months (95% CI 10.6- months), respectively. In the 33 patients pretreated with rituximab, the ORR, %CR, and median PFS were inferior compared with values for the 12 patients who had not received rituximab previously (64%vs 83% for ORR; 39%vs 67% for %CR; and 13.8 vs 17.5 months for median PFS, respectively). All mild-to-moderate infusion-related toxicities were reversible. Grade 3/4 non-hematologic adverse events occurred in six of the 52 patients. Two patients developed Grade 4 late-onset neutropenia and a decrease (>50%) in serum immunoglobulin was observed in six patients. In conclusion, rituximab monotherapy with eight weekly infusions is effective in relapsed patients with indolent B-NHL, with acceptable toxicities, including in patients pretreated with rituximab; however, careful monitoring is recommended for infections associated with late-onset neutropenia and hypogammaglobulinemia. (University Hospital Medical Information Network no. UMIN000002974.)     

Ofatumumab: a new CD20 monoclonal antibody therapy for B-cell chronic lymphocytic leukemia

Though most patients with chronic lymphocytic leukemia (CLL) respond to first-line therapy, all patients eventually relapse, after which therapeutic options are limited. Fludarabine-refractory patients have a particularly poor prognosis. The addition of the CD20 monoclonal antibody (MoAb) rituximab to chemotherapy in CLL has improved outcomes, particularly in early lines of therapy; however, the efficacy of rituximab monotherapy in CLL is limited, potentially in part because of reduced cell lysis via complement-dependent cytotoxicity (CDC) in this setting. Rituximab CDC is dependent on CD20 expression; CLL cells underexpress CD20. Ofatumumab is a human MoAb that targets an epitope encompassing the membrane-proximal small-loop on the CD20 molecule, which differs from the binding location of rituximab. In vitro studies with ofatumumab have demonstrated that it is significantly more effective than rituximab at corresponding dose levels at lysing CLL cells and B-cell lines, especially those with low CD20 copy numbers. In patients with CLL refractory to both fludarabine and alemtuzumab or refractory to fludarabine with bulky lymphadenopathy and, therefore, less suitable for treatment with the CD52 MoAb alemtuzumab, results from the planned interim analysis showed an encouraging response rate with ofatumumab (Independent Endpoint Review Committee evaluated) and survival parameters, which seemed to be higher than those reported from a historical assessment of other salvage therapies in a corresponding group of patients. Ofatumumab was also well tolerated; the most common adverse events were transient grade 1 or 2 infusion reactions and infections. Ongoing trials will help confirm the role of ofatumumab in CLL, in addition to the effect of this agent in combination with chemotherapies and other MoAbs.     

Long-Term Results of Chemoimmunotherapy With Fludarabine,Cyclophosphamide, and Rituximab for Patients With Relapsed and Refractory Chronic Lymphocytic Leukemia

IntroductionThe majority of patients with progressive chronic lymphocytic leukemia (CLL) will relapse after front-line treatment and will require salvage therapy. The addition of rituximab (R) to fludarabine (F) and cyclophosphamide (C) is associated with improved responses and relapse-free survival in untreated patients with CLL (Hallek et al, 2009) and patients with CLL in first relapse (Robak et al, 2008). We present an update of FCR in patients with relapsed or refractory CLL.Patients and MethodsWe administered FCR between November 1999 and 2008 to 284 patients with relapsed CLL. Patients received a combination of fludarabine 25 mg/m² day 1-3, cyclophosphamide 250 mg/m² day 1-3, and rituximab on day 1 at 375mg/m² for cycle 1, and 500 mg/m² for cycles 2 to 6. Patients were assessed for response by 1996 National Cancer Institute (NCI) Working Group response criteria and for time to failure of therapy (TTF) and overall survival (OS). We assessed standard pretreatment characteristics including response to prior therapy.ResultsPatients entered into the study had a median age of 60 years (31-84 years). Median number of prior treatments was 2 (range, 1-10). Responses included 86 patients with CR (31%), 41 nPR (15%), and 84 PR (30%); OR was 75%. Median OS is 46 months (95% CI, 41-54 months), and median TTF is 21 months (95% CI, 19-27 months). On multivariate analysis, the variables independently associated with longer TTF were younger age, higher platelets, lower lactate dehydrogenase (LDH) or serum creatinine, lower number of prior treatment, fludarabine sensitivity, and absence of chromosome 17 abnormalities on karyotype. Six full dose cycles of FCR were administered to 104 patients (36%). The most common hematologic toxicity was grade 3 and 4 neutropenia complicating 22% and 34% of treatment courses. Forty-six patients (16%) experienced one or more episodes of pneumonia or sepsis during or following treatment.ConclusionFCR is an effective regimen in patients with relapsed CLL. FCR should be considered as salvage therapy for patients in third relapse or less, not refractory to fludarabine or without chromosome 17 abnormalities or complex karyotype. Elderly patients (> 70 years) experienced more treatment-related toxicity and should be assessed for comorbidities prior to therapy.     

Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma.

BACKGROUND: To evaluate the efficacy and feasibility of rituximab monotherapy in Japanese patients with relapsed or refractory aggressive B-cell lymphoma. PATIENTS AND METHODS: Sixty-eight patients were treated with rituximab at 375 mg/m(2) by eight consecutive weekly infusions. Pretreatment variables affecting overall response rate (ORR) and progression-free survival (PFS) and the relationship between pharmacokinetic parameters and efficacy were analyzed. RESULTS: The ORRs of 68 enrolled patients and 57 eligible patients were 35% [95% confidence interval (CI) 24% to 48%] and 37% (95% CI 25% to 51%), respectively. Median PFS of 53 evaluable patients was 52 days, whereas time to progression of 21 eligible responders was 245 days. Mild to moderate infusion-related toxicities were observed frequently at the first infusion, but all of them were reversible. Elevated lactate dehydrogenase (LDH) and refractoriness to prior chemotherapy were unfavorable factors affecting ORR and PFS (P <0.01). Serum trough levels of rituximab and area under the concentration-time curve for responders were higher than for non-responders (P <0.05). CONCLUSIONS: Eight consecutive weekly infusions of rituximab have significant anti-lymphoma activity for relapsed or refractory aggressive B-cell lymphoma. Several pretreatment variables and serum rituximab levels are useful for predicting its efficacy.     

Ofatumumab for newly diagnosed and relapsed/refractory chronic lymphocytic leukemia

Monoclonal antibodies have become an increasingly utilized treatment option for many hematological malignancies, including chronic lymphocytic leukemia (CLL). Ofatumumab is a second-generation fully human anti-CD20 monoclonal antibody that binds to the small extracellular loop of CD20, thereby producing complement-dependent cell lysis and antibody-mediated cell cytotoxicity in cells expressing CD20. Ofatumumab has shown efficacy in the treatment for relapsed or refractory CLL. This success has resulted in the recent US FDA approval of ofatumumab for the treatment of CLL in patients who are refractory to fludarabine and alemtuzumab-based regimens. Major side effects of ofatumumab include infusion reactions, neutropenia and increased risk for infection. This article provides an overview of the current data supporting the use of ofatumumab for CLL and projects the future role of ofatumumab as monotherapy and combination therapy.     

Clinical outcome of pretreated B-cell chronic lymphocytic leukemia following alemtuzumab therapy: a retrospective study on various cytogenetic risk categories

BackgroundPatients with B-cell chronic lymphocytic leukemia (CLL) with 17p deletion respond poorly to chemotherapy. This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced CLL in the various cytogenetic subgroups.Patients and methodsData were collected from 105 consecutive, pretreated, cytogenetically defined patients who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) were assessed.ResultsThe hierarchic incidence of cytogenetic abnormalities was: 13q deletion (as sole abnormality), 18%; trisomy 12, 13%; 11q deletion, 19%; 17p deletion, 33%; and none of these, 16%. Overall response rate (ORR) was 43% in the total cohort and 49% in the subgroup of 17p-deleted patients (n = 35). From the start of alemtuzumab monotherapy, median PFS in the total cohort and in the subgroup of 17p-deleted patients was 7.0 and 7.1 months, respectively. Median OS in the total cohort and in 17p-deleted patients was 32.8 and 19.1 months, respectively. The poor-risk group of patients with CLL (i.e. fludarabine resistant, 17p deletion; n = 20) showed encouraging ORR, PFS, and OS (35%, 7.0 and 19.2 months, respectively).ConclusionsAlemtuzumab was effective in treating patients with CLL across the cytogenetic categories evaluated, but there were differences. In patients with CLL with 17p deletion quite favorable ORR, PFS, and OS were achieved.     

Safe and prolonged survival with long-term exposure to pomalidomide in relapsed/refractory myeloma

BackgroundThe IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide.DesignWe separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment.ResultsThe overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8–6.4] with only 6% at 12 months, and the median OS was 15 months (11.7–20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7–35.4), median OS not reached, and 91% at 18 months.ConclusionPomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide–dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.     

Chemoimmunotherapy with oral low-dose fludarabine,cyclophosphamide and rituximab (old-FCR) as treatment for elderly patients with chronic lymphocytic leukaemia

Median age at diagnosis for chronic lymphocytic leukaemia (CLL) patients is now 72 years, thus a consistent number of patients may not tolerate standard doses i.v. of fludarabine, cyclophosphamide and rituximab (FCR), the best available therapy, due to unacceptable myelotoxicity and risk of severe infections. We studied safety and efficacy of the addition of rituximab to the oral low-dose FC regimen (old-FCR) in a selected population of 30 elderly (median age 75, 15 untreated, 15 treated with 1 prior therapy) CLL patients. Complete remission (CR) rate was 80% in the untreated patients (overall response rate, ORR 93%), and 30% in pretreated patients (ORR 74%). Progression free survivals (PFS) were 45 months and 30 months in the untreated and treated patients, respectively. In patients achieving CR, old-FCR led to PFS of 67 months. Moreover, haematological toxicity was mild (grade 3–4: 15%) and patients were treated mostly in outpatient clinic. Old-FCR could be a good therapy option for elderly CLL patients outside clinical trials, larger studies are needed to confirm our findings.     

A phase II randomized study evaluating the addition of iniparib to gemcitabine plus cisplatin as first-line therapy for metastatic non-small-cell lung cancer

BackgroundIniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine–cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients.Patients and methodsPatients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m², days 1/8) and cisplatin (75 mg/m², day 1) with [gemcitabine/cisplatin/iniparib (GCI)] or without [gemcitabine/cisplatin (GC)] iniparib (5.6 mg/kg, days 1/4/8/11) every 3 weeks for six cycles. The primary end point was the overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. The study was not designed for formal efficacy comparison, the control arm being to benchmark results against the literature.ResultsOne hundred and nineteen patients were randomized (39 GC and 80 GCI). More GCI patients were male (80% GCI and 67% GC) and had PS 0 (61% GCI and 49% GC). The ORR was 25.6% [95% confidence interval (CI) 13.0%–42.1%] with GC versus 20.0% (95% CI 11.9%–30.4%) with GCI, which did not allow rejection of the null hypothesis (ORR with GCI ≤20%; P = 0.545). Median PFS was 4.3 (95% CI 2.8–5.6) months with GC and 5.7 (95% CI 4.6–6.6) months with GCI (hazard ratio 0.89, 95% CI 0.56–1.40). Median OS was 8.5 (95% CI 5.5 to not reached) months with GC, and 12.0 (95% CI 8.9–17.1) months with GCI (hazard ratio 0.78, 95% CI 0.48–1.27). More GCI patients received second-line treatment (51% GC and 68% GCI). Toxicity was similar in the two arms. Grade 3–4 toxicities included asthenia (28% GC and 8% GCI), nausea (3% GC and 14% GCI), and decreased appetite (10% in each).ConclusionsAddition of iniparib to GC did not improve ORR over GC alone. The GCI safety profile was comparable to GC alone. Imbalances in PS and gender distribution may have impacted study results regarding PFS and OS.Trial RegistrationClinicalTrial.gov Identifier NCT01086254.     

Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial

BackgroundWe report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT).Patients and methodsmCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups.ResultsBetween November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2–10.3] and 8.4 (95% CI 7.2–9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70–1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia.ConclusionsThe addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population.Clinical trial numberNCT01878422.     

Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease

BackgroundCurrent standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy.Patients and methodsWe retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy.ResultsAfter a median follow-up of 58.6 months (range 27.9–89.2), the median second progression-free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04–5.16] and overall survival (OS) was 6.4 months (95% CI 4.36–8.51). Multivariate Cox-regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (≥2), and presence of B symptoms were associated with inferior OS (P < 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy.ConclusionsMost patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL.     

Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non–small-cell Lung Cancer

BackgroundImmune checkpoint inhibitors (ICIs) are available for first- and further lines of treatment of patients with advanced non–small-cell lung cancer (NSCLC). These treatments are associated with adverse events called immune-related adverse events (IRAEs). The incidence, diagnosis, and treatment of IRAEs are quite acknowledged; however, the link between IRAEs and the efficacy of ICIs requires further clarification. The objectives of this study were to assess the association between IRAEs incidence and severity and ICIs efficacy in patients with advanced NSCLC.MethodsIn this retrospective study, clinical, biological, treatment, and outcome data were collected from patients with advanced NSCLC who received at least 1 cycle of ICIs from April 2013 to February 2017. The primary endpoint was to assess the association of IRAEs incidence with overall survival (OS). Secondary endpoints were the association of IRAEs with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR).ResultsOverall, 270 patients were studied. The median OS was 14 months, median PFS was 2.6 months, ORR was 13%, and DCR was 51%. OS, PFS, and ORR were significantly better for patients with IRAEs compared with patients with no IRAEs, translating to median OS not reached versus 8.21 months, respectively (hazard ratio, 0.29; 95% confidence interval [CI], 0.18-0.46; P < .001); PFS was 5.2 versus 1.97 months (hazard ratio, 0.42; 95% CI, 0.32-0.57; P < .001); and ORR was 212.9% versus 5.7% (odds ratio, 4.9; 95% CI, 2.18-11.05; P < .001).ConclusionsThis report presents the largest case series showing longer OS and PFS and better ORR when IRAEs occurred in a population of patients with advanced NSCLC treated with ICIs. The biological background for this phenomenon is being explored prospectively.     

Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a retrospective analysis

For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy because of comorbidities, advanced age, or relapse after heavy salvage regimens, treatment options are very limited and prognosis is poor. We retrospectively analyzed 29 patients with relapsed/refractory DLBCL treated with combination bendamustine plus rituximab (BR) between July 2010 and January 2014 to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and treatment safety. Twenty-eight patients were available for this analysis. ORR was 50% (14 patients), with 39.3% CR (11 patients), and 10.7% PR (3 patients). SD was reported in 2 patients (7.2%) and PD in 12 patients (42.8%). At the median follow up of 8 months (range 1–37.4 months), the median PFS was 8 months for all patients (95% CI 5.5–26.6). The median DOR was 24.7 months (95% CI 3.2–24.7). Grade 3/4 toxicity observed included hematologic events: lymphopenia (42.8%), neutropenia (32.1%), anemia (17.2%), and thrombocytopenia (14.2%). BR can be considered to have a role in the treatment of patients with relapsed/refractory DLBCL with limited therapeutic options, in that it can induce long-term remission in some patients with an acceptable toxicity profile.     

Phase II study of bevacizumab with liposomal doxorubicin for patients with platinum- and taxane-resistant ovarian cancer

BackgroundSuppression of neoangiogenesis and pegylated liposomal doxorubicin (PLD) each contribute to the management of platinum-resistant/refractory ovarian cancer. The aim of this study is to test the combination of bevacizumab and PLD in women with resistant or refractory ovarian cancer.MethodsEligibility criteria were no more than two prior treatments with platinum-containing regimens and one additional regimen, without anthracyclines. Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m²). The primary end point was progression-free survival (PFS) at 6 months; the secondary end points included side-effects, overall response rates (ORR) and survival (OS).ResultsForty-six patients were enrolled. The average number of courses administered was 7. The median PFS was 6.6 months (range 1–24.6 months) according to Gynecologic Cancer Intergroup Committee (GCIC) criteria and 7.8 months (range 2–13.3 months) according to Response Evaluation Criteria in Solid Tumors (RECIST). The median OS was 33.2 months (range 3–37.5+ months). The ORR was 30.2% [95% confidence interval (CI) 17.2–46.1] and the clinical benefit rate (CBR) was 86.1% (95% CI 72.1–94.7). Adverse events included mucosal and dermal erosions (30% grade 3) and asymptomatic cardiac dysfunction. Additional toxic effects included hypertension, headache, renal dysfunction and proteinuria, wound healing delay, and one episode each of central nervous system (CNS) ischemia and hemolytic uremic syndrome.ConclusionPLD with bevacizumab has improved activity in recurrent ovarian cancer with increased toxicity.     

Geriatric assessment measures are predictive of outcomes in chronic lymphocytic leukemia

IntroductionChronic lymphocytic leukemia (CLL) commonly affects older adults. However, few studies have examined the relationship between baseline geriatric domains and clinical outcomes in this population. Here, we aim to evaluate the use of a comprehensive geriatric assessment in older (>65 years) untreated patients with CLL to predict outcomes.Materials and MethodsWe conducted a planned analysis of 369 patients with CLL age 65 or older treated in a phase 3 randomized trial of bendamustine plus rituximab versus ibrutinib plus rituximab versus ibrutinib alone (A041202). Patients underwent evaluations of geriatric domains including functional status, psychological status, social activity, cognition, social support, and nutritional status. We examined associations among baseline geriatric domains with grade 3+ adverse events using multivariable logistic regression and overall survival (OS) and progression-free survival (PFS) using multivariable Cox regression models.ResultsIn this study, the median age was 71 years (range: 65–87). In the combined multivariable model, the following geriatric domains were significantly associated with PFS: Medical Outcomes Study (MOS) - social activities survey score (hazard ratio [HR] [95% confidence interval (CI)] 0.974(0.961, 0.988), p = 0.0002) and nutritional status (≥5% weight loss in the preceding six months: (HR [95% CI] 2.717[1.696, 4.354], p < 0.001). MOS - social activities score [HR (95% CI) 0.978(0.958, 0.999), p = 0.038] was associated with OS. No geriatric domains were significantly associated with toxicity. There were no statistically significant interactions between geriatric domains and treatment.DiscussionGeriatric domains of social activity and nutritional status were associated with OS and/or PFS in older adults with CLL. These findings highlight the importance of assessing geriatric domains to identify high-risk patients with CLL who may benefit from additional support during treatment.     

FC与FCR方案治疗慢性淋巴细胞白血病的临床回顾性分析

  目的  比较FC（氟达拉滨和环磷酰胺）和FCR（氟达拉滨、环磷酰胺和利妥昔单抗）方案治疗慢性淋巴细胞白血病（CLL）的临床疗效和预后影响。  方法  回顾性分析本院2002年12月至2012年1月应用FC或FCR方案治疗的58例CLL患者病例资料,比较两种方案的疗效和预后影响。  结果  FC组31例,FCR组27例。FCR组完全缓解（CR）率和总反应率（ORR）均高于FC组（44.4% vs. 19.4%,P=0.039;81.5% vs. 51.6%,P=0.017）。疗程结束后,FCR组患者获得微小残留病（microscopice residual disease,MRD）阴性比例高于FC组（37.0% vs. 12.9%,P=0.032）。FCR和FC组患者中高危遗传学亚组患者PFS较非高危遗传学亚组患者短（P值分别为0.011,0.027）,OS时间无明显差别。  结论  FCR方案是治疗CLL患者的更为有效的方案。      

Final Overall Survival and Other Efficacy and Safety Results From ASCEND-3: Phase II Study of Ceritinib in ALKi-Naive Patients With ALK-Rearranged NSCLC

IntroductionThe phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)–naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results.MethodsEligible patients (including those with asymptomatic or neurologically stable brain metastases) received oral ceritinib (750 mg/day, fasted). The primary end point was investigator-assessed overall response rate (ORR). Secondary end points were Blinded Independent Review Committee–assessed ORR; investigator- and Blinded Independent Review Committee–assessed overall intracranial response rate, duration of response, time to response, disease control rate, and progression-free survival (PFS); overall survival (OS); and safety. Exploratory end points included patient-reported outcomes.ResultsOf the 124 patients enrolled, 122 (98.4%) had received previous antineoplastic medications (31 patients [25.0%] received at least three regimens), and 49 (39.5%) had baseline brain metastases. The median follow-up time (data cutoff: January 22, 2018) was 52.1 (range, 48.4–60.1) months. The investigator-assessed ORR was 67.7% (95% confidence interval [CI]: 58.8–75.9), and the median PFS was 16.6 months (95% CI: 11.0–23.2). The median OS was 51.3 months (95% CI: 42.7–55.3). Most common adverse events (all grades, ≥60% of patients, all-causality) were diarrhea (85.5%), nausea (78.2%), and vomiting (71.8%). Overall, 18 patients (14.5%) had an adverse event leading to treatment discontinuation. Health-related quality of life was maintained during ceritinib treatment.ConclusionsCeritinib exhibited prolonged and clinically meaningful OS, PFS, and duration of response in chemotherapy-pretreated (at least three lines), ALKi-naive patients with ALK+ NSCLC. The safety profile was consistent with that reported in previous studies.     

The relationship between treatment-induced hypertension and efficacy of anlotinib in recurrent or metastatic esophageal squamous cell carcinoma

Objective:In this post-hoc analysis, we evaluated anlotinib treatment-induced hypertension as a potential predictive factor of efficacy in esophageal squamous cell carcinoma (ESCC) patients.Methods:A total of 109 patients enrolled in the anlotinib group in a phase 2 trial were included. The tumor response was assessed by computed tomography at week 3, week 6, and then every 6 weeks until progressive disease was observed. The primary endpoint of the study was progression free survival (PFS). The secondary endpoints included overall survival (OS) and objective response rate (ORR).Results:In all patients, the median PFS was 3.02 months [95% confidence interval (CI): 2.63–3.65 months] and the OS was 6.11 months (95% CI: 4.40–7.79 months). The ORR was 7.34% (95% CI: 3.22%–13.95%). A total of 59 (54%) patients were diagnosed with treatment-induced hypertension (Group A), and the remaining patients (n = 50, 46%) were in Group B. Baseline prognostic factors were similar between the 2 groups. Patients in Group A had a longer PFS and OS and higher ORR. When stratifying patients using a previously known history of hypertension, treatment-induced hypertension was a predictor only for patients without previous hypertension, who had longer PFS [hazard ratio (HR): 0.40, 95% CI: 0.24–0.68] and OS (HR: 0.37, 95% CI: 0.21–0.67).Conclusions:We showed, for the first time, a correlation between treatment-induced hypertension and better prognoses in recurrent or metastatic ESCC patients treated with anlotinib, without a previously known history of hypertension. Treatment-induced hypertension may be a simple and low cost predictor for anlotinib antitumor efficacy in these patients, which may also reflect the intended target inhibition.     

The European Medicines Agency review of ofatumumab (Arzerra®) for the treatment of chronic lymphocytic leukemia in patients refractory to fludarabine and alemtuzumab: summary of the scientific assessment of the European medicines agency committee for medicinal products for human use

On April 19, 2010, the European Commission issued a conditional marketing authorization valid throughout the European Union (EU) for ofatumumab (Arzerra®; Glaxo Group Ltd, Greenford, Middlesex, U.K.). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a conditional marketing authorization for ofatumumab for the treatment of chronic lymphocytic leukemia (CLL) in patients refractory to fludarabine and alemtuzumab. A conditional marketing authorization means that additional data to confirm the benefit–risk balance of ofatumumab are awaited. The active substance of Arzerra® is ofatumumab, a monoclonal antibody medicinal product (ATC code L01XC10). The recommended dose is 300 mg of atumumab for the first infusion and 2,000 mg of atumumab for all subsequent infusions. The infusion schedule is eight consecutive weekly infusions, followed 4–5 weeks later by four consecutive monthly (i.e., every 4 weeks) infusions. Ofatumumab targets CD20, a cell surface marker of B lymphocytes, which is followed by cell lysis via complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The benefit of ofatumumab is the control of CLL in patients who are refractory to both fludarabine and alemtuzumab, which was indicated by a high response rate. The most common side effects are infections and infusion reactions. The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).