Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with relapsed or refractory multiple myeloma and light chain-induced renal failure

Introduction

Serious renal failure represents a severe complication of multiple myeloma (MM), with an estimated 25–50 % of patients being affected. Both bortezomib and bendamustine have been identified as quickly acting, effective and well-tolerated drugs and might therefore constitute an adequate combination regimen for patients presenting with light chain-induced renal failure.

Methods

Between March 2005 and March 2013, 36 patients with relapsed/refractory MM and light chain-induced renal failure (creatinine clearance <60 ml/min) were treated with bendamustine 60 mg/m² on days 1 and 2, bortezomib 1.3 mg/m² on days 1, 4, 8 and 11 and prednisone 100 mg on days 1, 2, 4, 8 and 11 (BPV). Patients were divided according to severity of renal impairment into group A (n = 20) with moderate or severe renal dysfunction (eGFR 15–59 ml/min) and group B (n = 16) with renal failure/dialysis (eGFR <15 ml/min).

Results

Twenty-four patients (67 %) responded with three CR, three nCR, six VGPR and 12 PR. Six patients had minor response, two stable and four progressive disease. With a median follow-up period of 22 months, median progression-free survival (PFS) and overall survival (OS) for patients of group A were 10 and 25 months, respectively. This outcome was significantly better compared to patients of group B with a median PFS and OS of 3 and 7 months, respectively. Eleven patients showed a CRrenal, five a PRrenal and 15 a MRrenal.

Summary

These results indicate that this BPV combination is feasible, effective and well tolerated in patients with relapsed/refractory MM and light chain-induced renal failure.     

Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with newly diagnosed/untreated multiple myeloma

Introduction

Bortezomib is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination in patients with multiple myeloma (MM). In the present protocol, bortezomib was combined with bendamustine and prednisone, in order to assess the efficacy and safety of this combination therapy in patients with newly diagnosed/untreated MM.

Methods

Between June 2006 and October 2013, 49 patients with newly diagnosed/untreated MM were treated with bendamustine 60 mg/m² on days 1 and 2, bortezomib 1.3 mg/m² on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11 bendamustine, prednisone and bortezomib (BPV) once every 21 days. Patients were divided into three groups: group A (n = 19) consisted of patients with normal renal function or mild dysfunction (eGFR ≥60 ml/min), group B (n = 15) patients with moderate or severe renal dysfunction (eGFR 15–59 ml/min) and group C (n = 15) patients with renal failure/dialysis (eGFR <15 ml/min).

Results

A median number of two (range 1–5) BPV treatment cycles were given to the patients. The majority of the patients (n = 40, 82 %) responded after at least one cycle of BPV therapy with five stringent complete responses (CRs), nine near complete responses, 12 very good partial responses and 14 partial responses. Five patients had MR, three stable and one progressive disease. After a median observation time of 13 months, progression-free survival (PFS) and overall survival (OS) at 12 months were 92 and 94 %, respectively, for patients with normal renal function or mild renal dysfunction (group A) and 83 and 93 %, respectively, for patients with moderate or severe renal dysfunction (group B). Outcome for these patients was slightly better but not statistically significantly better than that for patients with renal failure/dialysis (group C), who had a PFS, and OS of 66 % (p = 0.08) and 73 % (p = 0.05), respectively.

Summary

These results indicate that this BPV combination is feasible, effective and well tolerated in patients with newly diagnosed MM and normal or impaired renal function.     

Successful treatment of patients with newly diagnosed/untreated multiple myeloma and advanced renal failure using bortezomib in combination with bendamustine and prednisone

Purpose

Renal failure is a frequent complication of multiple myeloma (MM) and, if present at diagnosis, a considerable risk factor for outcome. Treatment with chemotherapy and/or new agents may result in recovery of renal function in up to 50?% of patients. The window of opportunity to reverse renal impairment is, however, rather small, making an immediate and highly active treatment strategy mandatory. Bortezomib as well as bendamustine has been demonstrated to be potent drugs in the treatment of MM.

Methods

A total of 18 patients with newly diagnosed/untreated MM and renal insufficiency (GFR?Results The majority of them (n?=?15; 83?%) responded after at least one cycle of chemotherapy with three sCR, five nCR, five VGPR, and two PR. With a median follow-up of 17?months, PFS at 18?months was 57?% and OS was 61?%. The myeloma protein decreased rapidly, reaching the best response after the first cycle in four and after the second cycle in additional seven patients. Thirteen patients (72?%) improved their renal function after treatment.

Conclusion

We conclude that the combination of bortezomib, bendamustine, and prednisone is effective and well tolerated in patients with a newly diagnosed MM and renal failure.     

Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma

Patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) are treated with salvage regimens and may be considered for high-dose chemotherapy and autologous stem cell transplantation if disease is chemosensitive. Bendamustine is active in indolent B cell lymphomas and chronic lymphocytic leukemia but has not been extensively studied in aggressive lymphomas. This trial examines the combination of bendamustine and rituximab in patients with relapsed and refractory DLBCL. Patients received bendamustine at 90 mg/m² (n?=?2) or 120 mg/m² (n?=?57) on days 1 and 2 and rituximab at 375 mg/m² on day 1 every 28 days for up to 6 cycles. The study evaluated objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and treatment safety. Fifty-nine patients were treated, and 48 were evaluable for response. Median age was 74; 89 % had stage III or IV disease, and 63 % had high revised International Prognostic Index scores; the median number of prior therapies was 1. Based on analysis using the intent-to-treat population, the ORR was 45.8 % (complete response, 15.3 %; partial response, 30.5 %). The median DOR was 17.3 months, and the median PFS was 3.6 months. Grade 3 or 4 hematological toxicities included neutropenia (36 %), leukopenia (29 %), thrombocytopenia (22 %), and anemia (12 %). The combination of bendamustine and rituximab showed modest activity in patients with relapsed and refractory DLBCL and has an acceptable toxicity profile.     

Bendamustine in combination with thalidomide and dexamethasone is a viable salvage option in myeloma relapsed and/or refractory to bortezomib and lenalidomide

Treatment options are limited in myeloma relapsed or refractory to both bortezomib and lenalidomide (double-relapsed/refractory multiple myeloma; DRMM). Bendamustine is an antitumour agent that has efficacy in relapsed myeloma. We retrospectively analysed data from 30 DRMM patients who received a combination of bendamustine, thalidomide and dexamethasone (BTD) in 28-day treatment cycles. Bendamustine was administered with a cumulative dose of up to 200 mg/m². Thalidomide (50–150 mg) was given daily as tolerated, and dexamethasone was given at an equivalent dose of up to 160 mg per cycle. A median of 5 (2–9) treatment cycles were administered per patient. Twenty-six patients (87 %) achieved stable disease or better. At a median follow-up time of 12.1 (2.3–21.5) months, median (95 % CI) progression-free survival and overall survival were 4.0 (2.6–5.3) months and 7.2 (5.2–9.2) months, respectively. The most common grade 3–4 adverse events were haematological: anaemia (n?=?8, 34.8 %), neutropenia (n?=?16, 69.6 %) and thrombocytopenia (n?=?10, 43.5 %). Non-haematological toxicities included pain (n?=?3, 13.0 %), infection (n?=?7, 30.4 %) and sensory neuropathy (n?=?1, 4.3 %). We propose that BTD is a viable salvage treatment option for DRMM patients.     

Bortezomib and dexamethasone for Japanese patients with relapsed and refractory multiple myeloma: a single center experience

Bortezomib is a novel proteasome inhibitor, which has shown high antimyeloma activity. APEX trial, phase III randomized study for relapsed or refractory myeloma established efficacy and feasibility of bortezomib. In our study, we retrospectively investigated 60 Japanese patients with relapsed or refractory multiple myeloma (MM) who underwent bortezomib and dexamethasone (BD) therapy in our institution. Overall response rate was 75%, including 7 cases (11.7%) of complete response and 13 cases (21.7%) of very good partial response. Stable disease and progressive disease were observed in 15 patients (25%). Major ≥grade 3 adverse events were hematological toxicities and grade 3 non-hematological toxicities included appetite loss, diarrhea and peripheral neuropathy. BD therapy was well tolerated, and produced significant response in relapsed or refractory MM patients. Recently, many worldwide trials including bortezomib or other new agents are ongoing to evaluate its efficacy not only as a therapy for relapsed or refractory disease but also as a frontline therapy. Further investigations are required to define how to use new antimyeloma agents for Japanese MM patients.     

Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia

Bendamustine demonstrated clinical activity in pre-treated hematological malignancies due to its unique mechanism of action distinct from standard alkylating agents. This study assessed its efficacy in patients with chronic lymphocytic leukemia pre-treated with an alkylator, in comparison to fludarabine. Patients with relapsed chronic lymphocytic leukemia requiring treatment after one previous systemic regimen (usually chlorambucil-based) were randomized to either receive bendamustine 100 mg/m² on days 1 and 2 of a 4-week cycle or standard fludarabine treatment consisting of 25 mg/m² on days 1 to 5 every 4 weeks. The primary objective was to achieve non-inferior progression-free survival (PFS) with bendamustine. Out of a total of 96 patients randomized, 92 were eligible, 49 allocated to bendamustine and 43 to fludarabine. About half of the patients received six or more cycles. Overall response rates were 76 % on bendamustine and 62 % on fludarabine, with clinical complete response rates of 27 and 9 %, respectively. Median PFS was 20.1 and 14.8 months (hazard ratio, 0.87; 90 % confidence interval, 0.60–1.27), median overall survival 43.8 and 41.0 months (hazard ratio, 0.82). Thrombocytopenia and gastrointestinal toxicities were marginally more frequent on bendamustine, albeit CTC grade 3/4 event incidence was similar. These data suggest at least comparable efficacy of bendamustine vs. fludarabine, pointing to an alternative treatment option in relapsing CLL patients after chlorambucil containing initial chemotherapy.     

Phase I/II trial assessing bendamustine plus bortezomib combination therapy for the treatment of patients with relapsed or refractory multiple myeloma

Bendamustine, active in multiple myeloma (MM), is a bifunctional mechlorethamine derivative with alkylating properties. Bortezomib, approved to treat MM, is effective in combination with alkylators. The tolerability and efficacy of bendamustine plus bortezomib in relapsed/refractory MM was assessed in an open‐label, dose‐escalating, phase I/II study. Patients aged ≥18 years received intravenous bendamustine 50, 70, or 90 mg/m² (days 1 and 4) plus bortezomib 1·0 mg/m² (days 1, 4, 8, and 11) for up to eight 28‐day cycles. No dose‐limiting toxicity was observed after cycle 1; bendamustine 90 mg/m² plus bortezomib 1·0 mg/m² was designated the maximum tolerated dose (MTD). The most common grade 3/4 adverse events were leucopenia (58%), neutropenia (50%), lymphopenia (45%), and thrombocytopenia (30%). Primary efficacy measure was overall response rate (ORR), which was the combined complete response (CR), very good partial response (VGPR), partial response (PR), and minimal response (MR). ORR was 48% (one CR, two VGPR, nine PR, and seven MR) for all 40 enrolled patients, 52% (16/31) at the MTD (90 mg/m²), and 42% and 46% for prior use of bortezomib (n = 31) or alkylators (n = 28) respectively. Bendamustine plus bortezomib was well tolerated with promising efficacy in this heavily pretreated population.     

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

Bendamustine plus rituximab (BR) showed efficacy and safety in indolent lymphomas and mantle cell lymphoma. However, there were limited experiences of real-world practice of BR in diffuse large B cell lymphoma (DLBCL). In this study, we report the Korean experiences with BR in relapsed or refractory DLBCL who are not eligible for intensive chemotherapy and autologous stem cell transplantation. This is an observational, multicenter, retrospective analysis. Between December 2011 and December 2015, a total of 58 patients with relapsed or refractory DLBCL were treated with BR in 11 tertiary hospitals in Korea. Patients received an intravenous (IV) infusion of rituximab at a dose of 375 mg/m² on day 1. On days 2 and 3, patients received an IV infusion of bendamustine at doses of 120 or 90 mg/m². Median age was 69 (range 18–86), 74.1% had stage III or IV disease, and 67.2% showed high-intermediate or high International Prognostic Index scores at diagnosis. In an intention-to-treat analysis, 18 patients (31.0%) showed a complete response and 14 (24.1%) showed a partial response, resulting in an overall response rate of 55.1%. The median duration of the response was 3.7 months (range 1.0–47.2 months). The median progression-free survival was 3.9 months (95% confidence interval [CI], 2.4–5.4 months), and the median overall survival was 6.7 months (95% CI, 4.7–8.7 months). The most common grade 3/4 adverse event was neutropenia (n?=?40; 68.9%). Febrile neutropenia was observed in 11 patients (18.9%). Grade 3/4 thrombocytopenia was observed in 34 patients (58.6%). Our study confirmed the high efficacy and acceptable toxicity profile of BR in relapsed or refractory DLBCL patients. However, we need to closely observe the higher tendency of grade 3/4 hematological toxicities in Korean patients.     

How to determine bortezomib-based regimen for elderly patients with multiple myeloma: PAD versus CBd, an observational study

Background

This was an open-label, observational, prospective assessment. We conducted an analysis of the impact of bortezomib-based therapy (PAD: bortezomib, doxorubicin, high-dose dexamethasone vs. CBd: cyclophosphamide bortezomib, low-dose dexamethasone) on the survival rates and adverse events in elderly patients with newly diagnosed multiple myeloma (MM).

Methods

Out of 303 patients, 128 received the PAD regimen and the other 175 patients received the CBd induction therapy (age 65–89 years). Baseline patient characteristics between the two cohorts were balanced in age (P = 0.69), international staging system (ISS) prognostic stages (P = 0.90), serum calcium (P = 0.70), and serum creatinine (P = 0.52).

Results

Overall response (OS) after the induction chemotherapy was achieved in 214 of 303 patients (70.6 %), with no significant differences observed between the two treatment groups (71.9 vs. 69.7 %, P = 0.68). Patients with ISS stage 2 reached the same 5-year OS advantages compared to patients with ISS stage 1, because they received bortezomib-based PAD or CBd treatments. Patients receiving CBd protocol gained similar satisfactory progression-free survival (PFS) results when compared to the PAD regimen group: PFS at 5 years reached 58.2 versus 58.9 % (P = 0.85). Five-year OS in the CBd arm had significant advantages compared to the PAD group, 79.9 versus 49.9 % (P < 0.05). The overall safety profiles showed that 26 of 128 (20.3 %) patients died in the PAD arm, while 13 of 175 patients died (7.4 %) in the CBd group (P < 0.01). Similarly, the PAD arm had a higher serious infection rate than that of the CBd arm (39.2 vs. 13.1 %, P < 0.01).

Conclusions

Bortezomib benefits elderly patients with newly diagnosed MM; they achieve satisfactory treatment responses and survival advantages. Further, patients treated with CBd have superior treatment advantages, with a predictable safety profile, when compared to the PAD regimen.     

Bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy for relapsed or refractory multiple myeloma: a multicenter phase 2 study

We previously conducted a phase 1 study of bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy and determined the optimal dose of bortezomib to be 1.0 mg/m². We then conducted a multicenter phase 2 study in patients with relapsed or refractory myeloma. Bortezomib 1.0 mg/m² was administered intravenously on days 1, 4, 8 and 11, in combination with intravenous doxorubicin 9 mg/m² on days 1–4, and dexamethasone 20 mg orally on days 1–2, 4–5, 8–9 and 11–12 at a 3-week interval for six cycles. The primary endpoint of this study was the complete remission (CR) rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Twenty-seven patients, median age of 63, were enrolled. An overall response rate was 89 % with CR rate of 30 %. The median PFS time was 12.1 months, and the median OS time was not reached. One patient died of pneumonia. Although the incidence of hematological toxicities was high, these were transient and manageable. The most common non-hematological toxicity was sensory neuropathy; grade 3 toxicity was observed in six patients (22 %) and treatment was discontinued in four. We conclude that iPAD therapy is feasible, and shows efficacy by inducing high response rates and long response duration.     

L-PROBe: A Novel Non-anthracycline Combination Chemotherapy Regimen for Aggressive B Cell Non-Hodgkin Lymphoma in Elderly Patients

The management of aggressive B cell lymphomas in elderly patients is associated with poor tolerability of commonly used chemotherapeutic agents. The safety and tolerability of a novel combination chemotherapy regimen utilizing rituximab, lenalidomide, bendamustine, vincristine and prednisolone was assessed in a series of elderly patients with new onset or relapsed/refractory aggressive B cell lymphoma and inability to receive conventional chemotherapy due to poor performance status and/or significant comorbidities. Ten patients (7 male, 3 female) with a median age of 72 years (range 58–79 years) received therapy with lenalidomide (10 mg/day on days 1–14), rituximab (375 mg/m² on day 1), bendamustine (90 mg/m² on days 1 and 2), vincristine (1.4 mg/m² on day 1) and prednisolone (60 mg/m²/day on days 1–5) with cycles repeated every 28 days. Grade 3/4 hematological toxicities included neutropenia (30 %), anemia (30 %) and thrombocytopenia (10 %). An overall response rate of 40 % was observed with a median survival of 120 days (range 14–286 days). Three of the patients who responded achieved complete remission at the end of six cycles of therapy. This combination chemotherapy appears to be well tolerated and effective in elderly patients with poor performance status. Larger controlled studies are indicated to clearly demonstrate applicability of this novel regimen.     

Incidence and predictors of hematological side effects in chronic HCV Egyptian patients treated with PEGylated interferon and ribavirin

Aim

The aim of this paper was to study the incidence and predictors of hematological abnormalities during treatment of chronic hepatitis C virus (HCV) patients with interferon and ribavirin.

Methods

One thousand and eighty-one chronic HCV patients who were treated with PEGylated interferon α-2a 180 μg (n?=?536) or α-2b 1.5 μg/kg (n?=?545) plus ribavirin for 48 weeks were included. Baseline demographic, laboratory, and histopathological data and, during treatment, hematological data were collected and analyzed using univariate and multivariate analyses to identify independent predictors of hematological side effects.

Results

During therapy, 168 of 1,018 (15.5 %) had moderate anemia (Hb?<10 and ≥8.5 g/dL) and 88 (8.1 %) had severe anemia (Hb?<8.5 g/dL). Two hundred and six patients (19.1 %) had moderate neutropenia (absolute neutrophil count (ANC)?<750 and ≥500/mm³); only 55 (5.1 %) had severe neutropenia (ANC?<500/mm³). Forty-three patients (4 %) had moderate (platelet <50,000 and ≥25,000/mm³) and 5 (1.4 %) had severe thrombocytopenia (platelet <25,000/mm³). Fibrosis stage, week 4 Hb level, and week 2 and 4 reduction level in Hb were independent predictors of moderate and severe anemia (p?<?0.001). Fibrosis stage and ANC at weeks 2 and 4 were predictors of neutropenia (p?<?0.001, 0.001, and 0.004, respectively). Fibrosis stage and platelet count at weeks 2 and 4 were predictors of thrombocytopenia (p?<?0.001, <0.001, and 0.005, respectively). There was no association between interferon type and anemia (p?=?0.57), neutropenia (p?=?0.6), or thrombocytopenia (p?=?0.79).

Conclusions

Fibrosis stage and week 2 and 4 hematological parameter reduction levels were independent predictors of hematological side effects, which are not related to interferon type.     

Lenalidomide in patients with cisplatin-refractory and multiply relapsed germ cell tumors

Objective

Treatment options are still limited in patients with cisplatin-refractory and multiply relapsed germ cell tumors. We evaluated the efficacy and tolerability of lenalidomide within a compassionate use concept.

Patients and methods

Four patients multiply relapsed after platin-based chemotherapies without any further standard treatment option received 25 mg lenalidomide orally on days 1–21 of a 28-day cycle.

Results

All four patients were pretreated with a median number of seven lines of previous chemotherapy (range 4–8), all including platin-based high-dose chemotherapy. After 4 weeks of lenalidomide treatment all patients had progressive disease with increase in serum tumor markers and progression in computed tomography. Median survival time was 8 weeks (range 5–17). The toxicity profile was favorable. No severe toxicities related to lenalidomide occurred in these patients.

Conclusion

Lenalidomide was well tolerated and showed efficacy in heavily pretreated patients with cisplatin-refractory and multiply relapsed germ cell tumors.     

Age-related fat deposition in multifidus muscle could be a marker for nonalcoholic fatty liver disease

Background

Although nonalcoholic fatty liver disease (NAFLD) is associated with visceral obesity, the relationship between visceral fat accumulation and skeletal muscle steatosis in patients with NAFLD has not been established. We evaluated: (1) the relationship between multifidus muscular tissue steatosis, visceral fat accumulation, and biochemical data in a cross-sectional study, and (2) the influence of weight reduction on multifidus muscular tissue steatosis in a longitudinal study.

Methods

Three hundred thirty-three NAFLD patients were enrolled. Hepatic steatosis, visceral fat area, and the multifidus muscle/subcutaneous fat attenuation ratio (MM/F ratio) were evaluated by computed tomography. To evaluate how weight reduction produced by diet and exercise affected the MM/F ratio, changes in the MM/F ratio were compared between weight reduction and non-weight reduction groups.

Results

There was a gender difference in MM/F ratios. The MM/F ratio was significantly correlated with age (male r = 0.613, P < 0.01; female r = 0.440, P < 0.01). The MM/F ratio was positively correlated with visceral fat area (male: r = 0.262, P < 0.01; female: r = 0.214, P < 0.01). A decrease in the MM/F ratio, concomitant with reduced visceral fat accumulation, led to alleviation of hepatic steatosis in 20 patients with weight reduction, but not in 22 patients without weight reduction.

Conclusions

The MM/F ratio was closely related to aging and visceral fat accumulation. The MM/F ratio was improved by weight reduction, indicating that fat accumulation in the multifidus muscle evaluated by computed tomography might be a therapeutic indicator of NAFLD.     

Identification of Subtypes of Refractory Asthma in Korean Patients by Cluster Analysis

Background

Refractory asthma, a subtype of asthma with uncontrolled symptoms despite antiasthma medications, is a heterogeneous syndrome with variable clinical features, presumably different etiologies, and pathophysiological mechanisms. The heterogeneity of refractory asthma, however, is poorly understood. We aimed to characterize refractory asthma and to improve our understanding of the heterogeneity of refractory asthma patients.

Methods

We identified refractory asthma patients (n = 96) as defined by the American Thoracic Society’s criteria from a cohort of Korean asthma patients (n = 2,187). Then, cluster analysis was conducted to classify subtypes of refractory asthma.

Results

Among the study group, 4.4 % (n = 96) of all asthma patients had refractory asthma. Cluster analysis identified four distinct groups of refractory asthma. Age at onset was younger in clusters 1 and 2 than in clusters 3 and 4. Patients in cluster 1 had the most well-preserved pulmonary function; patients in cluster 2 had a female predominance and the most severe airway obstruction; patients in cluster 3 were mostly female and had the most enhanced bronchial hyperresponsiveness; and patients in cluster 4 were most male and tended to be cigarette smokers.

Conclusions

The current results suggest that refractory asthma is a heterogeneous syndrome and could be classified into four subtypes. Underlying pathogenesis and therapeutic approaches may differ for the different subtypes and further research is needed.     

Role of pharmacogenetics on adjuvant chemotherapy-induced neutropenia in Chinese breast cancer patients

Background

Breast cancer patients regularly undergo adjuvant chemotherapies following surgery. However, these treatments are largely associated with chemotherapeutic toxicities ranging from nausea to severe myelosuppression. In this investigation, we examined the effects of four SNPs in NR1I2, CYP3A4 and CYP3A5 genes on chemotherapy-induced severe neutropenia in 311 female Chinese breast cancer patients undergoing a standard adjuvant chemotherapy regimen.

Methods

Patients were monitored for adverse reactions throughout the treatment, then divided into “none or mild” (80 %) or “severe” (20 %) toxicity groups according to whether they suffered grade 4 neutropenia defined as having an absolute neutrophil counts (ANC) of less than 0.5 × 10⁹/L anytime during the treatment. DNA was extracted from patients’ peripheral blood samples, then genotyped using allele-specific Tm-shift PCR and melting analysis.

Results

Logistic regression revealed that rs776746 or CYP3A5*3 strongly associated with grade 4 neutropenia (OR = 2.56, P = 0.023) after adjustment for covariates, one of which more significant factor was baseline ANC (OR = 0.68, P = 0.020). Although univariate analysis in all patients did not reveal any association at first, further analysis indicated that rs776746 is significantly associated with severe neutropenia in subgroup of breast cancer patients with normal baseline ANC (≥2.0 × 10⁹/L). These carriers of A-allele have 3.14-fold increased risk of developing severe neutropenia (P = 0.004).

Conclusion

Our results suggested that polymorphisms in CYP3A5 might be useful pharmacogenetic markers for the prediction of severe neutropenia during chemotherapy, however, only after screening patients by their baseline ANC in the presence of gene–environmental interaction. We demonstrate an approach of pharmacogenetic analysis, in which the genetic data should be analyzed in the perspective of other clinical parameters.     

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

Aims/hypothesis

The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant (‘PNPLA3 NAFLD’?=?PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity (‘obese NAFLD’).

Methods

Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat (¹H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2?±?0.7 kg/m²; non-obese 26.0?±?0.4 kg/m²) or PNPLA3 genotype. All groups were similar with respect to age and sex. The PNPLA3 subgroups were equally obese (PNPLA3-148MM, 31.1?±?1.3 kg/m²; PNPLA3-148II, 31.2?±?0.8 kg/m²), while the obese and non-obese subgroups had similar PNPLA3 genotype distribution. Gene expression of proinflammatory (MCP-1, CD68) and anti-inflammatory (Twist1, ADIPOQ) markers was measured using quantitative real-time RT-PCR.

Results

Liver fat was similarly increased in obese NAFLD (9.5?±?1.3% vs 5.1?±?0.9%, obese vs non-obese, p?=?0.007) and PNPLA3 NAFLD (11.4?±?1.7% vs 5.3?±?0.8%, PNPLA3-148MM vs PNPLA3-148II, p?<?0.001). Fasting serum insulin was higher in the obese than the non-obese group (76?±?6 vs 47?±?6 pmol/l, p?<?0.001), but similar in PNPLA3-148MM and PNPLA3-148II (60?±?8 vs 62?±?5 pmol/l, NS). In obese vs non-obese, MCP-1 and CD68 mRNAs were upregulated, whereas those of Twist1 and ADIPOQ were significantly downregulated. AT gene expression of MCP-1, CD68, Twist1 and ADIPOQ was similar in PNPLA3-148MM and PNPLA3-148II groups.

Conclusions/interpretation

PNPLA3 NAFLD is characterised by an increase in liver fat but no insulin resistance or AT inflammation, while obese NAFLD has all three of these features.     

Phase II study of bortezomib in combination with rituximab,cyclophosphamide and prednisone with or without doxorubicin followed by rituximab maintenance in patients with relapsed or refractory follicular lymphoma

This non‐comparative phase II study (ClinicalTrials.gov: NCT00715208) evaluated bortezomib in place of vincristine in established rituximab‐chemotherapy regimens in relapsed/refractory follicular (FL) or marginal zone lymphoma (MZL). Patients were allocated (physician/patient preference) to receive six 21‐d cycles of: bortezomib 1·6 mg/m² (days 1, 8), rituximab 375 mg/m² (day 1), cyclophosphamide 1000 mg/m² (day 1) and prednisone 100 mg (days 1–5; VR‐CP; 47 FL, 1 MZL patients); or bortezomib, rituximab, prednisone per VR‐CP, cyclophosphamide 750 mg/m² and doxorubicin 50 mg/m² (day 1; VR‐CAP; 4 FL, 2 MZL, 1 chronic lymphocytic leukaemia patients). With VR‐CP, the response rate was 77%, with a 27% complete response rate. After a median follow‐up of 10·9 months, 40% of patients had relapsed/progressed or died. Median duration of response and progression‐free survival was 21·9 and 14·9 months, respectively. Common drug‐related grade ≥3 adverse events were neutropenia (25%), thrombocytopenia (6%) and lymphopenia (6%). Thirteen (27%) patients reported peripheral neuropathy (one grade 3). With VR‐CAP, one FL patient achieved complete response and three FL and two MZL patients achieved partial responses. Three patients reported drug‐related grade 1/2 peripheral neuropathy. Weekly bortezomib and rituximab represents an active, feasible treatment platform in FL. VR‐CP was active and well tolerated in patients with relapsed/refractory FL.     

Transbronchial Cryobiopsy in Immunocompromised Patients with Pulmonary Infiltrates: A Pilot Study

Background

In immunocompromised patients with pulmonary infiltrates, transbronchial lung biopsies (TBB) obtained by forceps has been shown to increase the diagnostic yield over simple bronchoalveolar lavage. Cryo-TBB is a novel modality for obtaining lung biopsies. We aimed to evaluate for the first time the efficacy and safety of cryo-TBB in immunocompromised patients.

Methods

Fifteen immunocompromised patients with pulmonary infiltrates underwent cryo-TBB. During the procedure two to three biopsy samples were taken. Procedure characteristics, complications, and the diagnostic yield were retrospectively evaluated.

Results

Most patients (n = 11) were immunocompromised due to hematological malignancies. The remaining four patients were receiving chronic immunosuppressive treatment due to previous solid-organ transplantation (n = 2) or collagen-vascular disease (n = 2). No major complications occurred in the cryo-TBB group. The mean surface area of the specimen taken by cryo-TBB was 9 mm². The increase in surface area and quality of biopsy samples translated to a high percentage of alveolated tissue (70 %) that enabled a clear histological detection of the following diagnoses: noncaseating granulomatous inflammation (n = 2), acute interstitial pneumonitis consistent with drug reaction (n = 5), nonspecific interstitial pneumonia fibrotic variant (n = 1), diffuse alveolar damage (n = 3), organizing pneumonia (n = 3), and pulmonary cryptococcal pneumonia (n = 1). Diagnostic information obtained by cryo-TBB led to change in the management of 12 patients (80 %).

Conclusion

Cryo-TBB in immunocompromised patients with pulmonary infiltrates provides clinically important diagnostic data with a low complication rate. These advantages should be further compared with traditional forceps TBB in a prospective randomized trial.