Treatment with idelalisib in patients with chronic lymphocytic leukemia - real world data from the registry of the German CLL Study Group.

Idelalisib in combination with rituximab is an efficacious treatment for patients suffering from chronic lymphocytic leukemia (CLL) with known limitations due to toxicities. However, the benefit after prior Bruton tyrosine kinase inhibitor (BTKi) therapy remains unclear. For this analysis, 81 patients included in a non-interventional registry study of the German CLL study group (registered at www.clinicaltrials.gov as # NCT02863692) meeting the predefined criteria of a confirmed diagnosis of CLL and being treated with idelalisib containing regimens outside clinical trials were considered. 11 patients were treatment naïve (13.6%) and 70 patients (86.4%) pretreated. Patients had median of one prior therapy line (range 0-11). Median treatment duration with idelalisib was 5.1 months (range 0-55.0 months). Of 58 patients with documented treatment outcome, 39 responded to idelalisib containing therapy (67.2%). Patients treated with the BTKi ibrutinib as last prior treatment prior to idelalisib responded in 71.4% compared to a response rate of 61.9% in patients without prior ibrutinib. Median event free survival (EFS) was 15.9 months with a 16 versus 14 months EFS in patients with ibrutinib as last prior treatment or not, respectively. Median overall survival was 46.6 months. In conclusion, treatment with idelalisib appears to have a valuable impact in patients being refractory to prior ibrutinib therapy even though there are limitations in our analysis due to the low number of patients included.

Individual hematotoxicity prediction of further chemotherapy cycles by dynamic mathematical models in patients with gastrointestinal tumors.

PURPOSE: Hematotoxicity is a common side-effect of cytotoxic gastrointestinal (GI) cancer therapies. An unsolved problem is to predict the individual risk therefore to decide on treatment adaptions. We applied an established biomathematical prediction model and primarily evaluated its predictive value in patients undergoing chemotherapy for GI cancers in curative intent. METHODS: In a prospective, observational multicenter study on patients with gastro-esophageal or pancreatic cancer (n = 28) receiving myelosuppressive adjuvant or neoadjuvant chemotherapy (FLO(T) or FOLFIRINOX), individual model parameters were learned based on patients' observed laboratory values during the first chemotherapy cycle and further external data resources. Grades of hematotoxicity of subsequent cycles were predicted by model simulation and compared with observed data. RESULTS: The most common high-grade hematological toxicity was neutropenia [19/28 patients (68%)]. For the FLO(T) regimen, individual grades of thrombocytopenia and leukopenia could be well predicted for cycles 2-4, as well as grades of neutropenia for cycle 2. Prediction accuracy for neutropenia in the third and fourth cycle differed by one toxicity grade on average. For the FOLFIRINOX-regimen, thrombocytopenia predictions showed a maximum deviation of one toxicity grade up to the end of therapy (8 cycles). Deviations of predictions were less than one degree on average up to cycle 4 for neutropenia, and up to cycle 6 for leukopenia. CONCLUSION: The biomathematical model showed excellent short-term and decent long-term prediction performance for all relevant hematological side effects associated with FLO(T)/FOLFIRINOX. Clinical utility of this precision-medicine approach needs to be further investigated in a larger cohort.

Impact of the changing landscape of induction therapy prior to autologous stem cell transplantation in 540 newly diagnosed myeloma patients: a retrospective real-world study.

INTRODUCTION: Autologous stem cell transplantation (ASCT) is the standard treatment for younger patients with newly diagnosed multiple myeloma (MM). However, due to restrictive exclusion criteria, more than half of eligible patients are usually excluded from transplant studies. METHODS: This retrospective monocentric analysis included 540 patients with MM who received an ASCT between 1996 and 2019. RESULTS: Up to 2005, induction therapy consisted mainly of conventional chemotherapies, e.g. vincristine/doxorubicin/dexamethasone (VAD). In the following years, the triple-combinations based on bortezomib coupled with doxorubicin/dexamethasone (PAD), melphalan/prednisolone (VMP), cyclophposphamide/dexamethasone (VCD) or bendamustine/prednisolone (BPV) became the most popular treatment options. A progressive improvement in PFS was observed in patients treated with the two current induction therapies BPV (47 months) or VCD (54 months) compared to VAD (35 months, p < 0.03), PAD (39 months, p < 0.01 and VMP (36 months, p < 0.01). However, there was no significant difference in median OS (VAD 78, PAD 74, VMP 72, BPV 80 months and VCD not reached). In our analysis, we also included 139 patients who do fulfill at least one of the exclusion criteria for most phase 3 transplant studies (POEMS/amyloidosis/plasma cell leukemia, eGFR < 40 mL/min, severe cardiac dysfunction or poor general condition). Outcome for these patients was not significantly inferior compared to patients who met the inclusion criteria for most of the transplant studies with PFS of 36 vs 41 months (p = 0.78) and OS of 78 vs 79 months (p = 0.34). CONCLUSIONS: Our real-world data in unselected pts also stress the substantial value of ASCT during the first-line treatment of younger MM pts.

Prognostic impact of rapid reduction of involved free light chains in multiple myeloma patients under first-line treatment with Bendamustine, Prednisone, and Bortezomib (BPV).

INTRODUCTION: Light chain involvement is observed in almost every patient (pt) with newly diagnosed multiple myeloma (MM). Owing to a relatively short half-life, rapid reduction in the involved free light chain (iFLC) is of potential prognostic value. METHODS: This retrospective analysis included 92 pts with newly diagnosed MM treated with bendamustine, prednisone, and bortezomib (BPV). RESULTS: After a median number of two (range 1-5) BPV cycles, the majority of pts (n = 86; 93%) responded with either sCR (n = 21), CR (n = 1), nCR (n = 25), VGPR (n = 20), or PR (n = 19). PFS and OS at 48 months were 39% and 67%, respectively. At baseline, 79 out of 92 pts (86%) had iFLC levels above the upper standard level and an abnormal ratio of involved to uninvolved free light chain ≥ 8. In a subgroup analysis of these pts, we evaluated the prognostic importance of an early reduction of the iFLC during the first two BPV cycles. A reduction ≥ 50% of the iFLC on day 8 of the first cycle was observed in 31 of 69 pts. These pts had a significantly better median PFS of 49 months as compared to 20 months in 38 pts with a lower iFLC reduction (p = 0.002). In contrast, OS did not differ significantly with a 48 months survival of 77% vs 69% (p > 0.05). CONCLUSION: These results indicate that a rapid decrease in the iFLC on day 8 is an early prognostic marker for newly diagnosed MM pts undergoing BPV treatment.

[Long-term effectiveness of topical analgesics]. / Langzeiteffektivität topisch applizierter Analgetika.

BACKGROUND: Neuropathic pain consistently presents a significant therapeutic challenge. Topically applied analgesics have the advantage of showing low systemic side effects, but data on long-term effectiveness are lacking. Consequently, interviews were carried out with all patients being treated with topical analgesics in hospital. METHODS: Ethics 16-5690, German Clinical Trials Register (DRKS) 00011877. Between 2008 and 2017 a total of 265 patients were treated at least once with either capsaicin 8% (C), lidocaine 5% (L) and/or perineural botulinum toxin type A (B). From this sample, 205 patients (77%) were interviewed by telephone for feedback on pain reduction (first/last treatment: low/moderate/very good), the possible reduction of analgesic prescription and if applicable the reasons for discontinuation of use (time of interview C: 26 ± 19 months, L: 61 ± 23 months, B: 11 ± 6 months after start). Further pretreatment data and diagnoses were obtained from the in-house documentation system. Responders or long-term responders were defined as patients with at least one moderate pain reduction after the first or last treatment, as long as the effect was adequately maintained. RESULTS: In all treatment groups (56 ± 13 years, 62% male, C: 80, L: 84, B: 58 patients) patients with a long history of pain (C: 60 ± 73 months, L: 59 ± 66 months, B: 67 ± 71 months) and high pain intensity (numeric rating scale, NRS, C: 7 ± 2, L: 7 ± 2, B: 6 ± 2), were predominant. The highest primary and long-term responder rates were exhibited by L (57%/60%, B: 52%/37%, C: 23%/15%). With B, long-term responders were most frequently able to reduce analgesic use (74%, C: 58%, L: 38%). DISCUSSION: Despite the long duration of the disease, the most used off-label topical drugs L and B demonstrated a high primary response rate (in contrast to C), with most benefiting from long-term treatment.

Frailty impairs the feasibility of induction therapy but not of maintenance therapy in elderly myeloma patients: final results of the German Maintenance Study (GERMAIN).

PURPOSE: The German Maintenance Study (GERMAIN) was designed to evaluate the impact of lenalidomide maintenance after induction therapy with bortezomib, melphalan and prednisolone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (MM) patients. METHODS: Due to poor accrual and high dropout rate, only 85 patients (planned 286) entered the trial and 40 (planned 200) were randomized to lenalidomide maintenance (n = 19) vs. observation (n = 21). RESULTS: The primary endpoint, improved progression-free survival, was not met (p = 0.3572). After a median follow-up of 12.9 months, median progression-free survival in the lenalidomide arm was 14.4 months and 11.4 months with placebo. The hazard ratio 0.621 (95% confidence interval: [0.224, 1.725]) was about the same as expected (0.625). However, with only 40 patients randomized, the actual power to detect a difference was 11%. Of patients receiving at least one dose of induction, 54% were frail according to a modified International Myeloma Working Group frailty score. Discontinuations were high during induction (47%), and affected mainly frail patients (54%). Despite a higher rate of adverse events in the lenalidomide arm (p = 0.0061), only 2 patients discontinued lenalidomide due to toxicity. CONCLUSION: A frailty assessment with appropriate dose modification for induction therapy should be mandatory for all elderly non-transplant-eligible myeloma patients.

Pain management in opioid maintenance treatment.

Introduction: Opioid addiction is a worldwide disease with a significant impact. A multitude of physical and mental comorbidities are associated with opioid addiction, pain being one of the most relevant. Insufficient pain management may lead to a disruption in medical treatment, self-medication, and subsequent harm to patients. Areas covered: In this review, the authors provide a general overview of opioid addiction. A literature search for pain management and opioid maintenance treatment was conducted. Different settings of acute or chronic pain and situations specific to patients addicted to opioids are described. Pain management therapy in addiction is also addressed with an emphasis on treatment strategies such as the optimization of methadone and buprenorphine medication, additional opioid analgesia, and multimodal pain management. Expert opinion: Opioid addiction is a growing global health concern, and maintenance therapy remains an effective and lifesaving treatment option. However, there remains uncertainty on the appropriate pain management for this patient group. The backbone of pain management in opiate-addicted patients remains maintenance therapy while adjunctive treatment such as regional analgesia, non-opioid analgesia, antidepressants, steps to improve sleep, acceptance and commitment therapy, biofeedback, and hypnosis should be considered. Additional opioid medication is possible as well.

Intensity of Withdrawal Symptoms During Opioid Taper in Patients with Chronic Pain-Individualized or Fixed Starting Dosage?

OBJECTIVE: Controlled opioid withdrawal is recommended for patients with chronic noncancer pain (CNCP) with insufficient pain reduction or intolerable side effects while on opioid treatment. Few studies have investigated the management of opioid withdrawal (OW). Most common are protocols with an individualized starting dosage (ISD), calculated from the last opioid intake. After two cases of overdose, we introduced a novel withdrawal protocol using a low fixed starting dosage (FSD) for safety reasons. The present study compares the intensity of withdrawal symptoms using the Subjective Opioid Withdrawal Scale (SOWS) and incidences of serious adverse events (SAE) and dropouts in each taper schedule in 195 CNCP patients with OW in an inpatient facility. METHODS: Two protocols were compared: FSD (2014-2016): N = 68, starting dose: 90 mg morphine/d; and ISD (2010-2014): N = 127, starting dose: 70% of the patient's daily morphine equivalent dose (MED). Outcome criteria: primary: mean daily SOWS score during the first 10 days (16 questions, daily score 0-64); secondary: change in pain intensity on a numeric rating scale (0-10), rate of dropouts and SAEs. Statistics: Student test, Mann-Whitney U test, chi-square test, analysis of variance, P < 0.05. RESULTS: The mean daily SOWS score was lower in the FSD group (14.9 ± 9.4 vs 16.1 ± 10, P < 0.05) due to a lower rate of high-intensity withdrawal symptoms (12.4% vs 17.6%, P < 0.01), particularly in patients on >180 mg MED (9.7% vs 18.4%, P < 0.01). Pain intensity decreased after withdrawal, and the incidence of SAEs and dropouts was low in both groups. CONCLUSIONS: The FSD protocol provides a lesser burden of withdrawal symptoms and equal patient safety. It can be recommended for OW in CNCP patients.

Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the "Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" (PETAL) trial.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.

We miss the opportunity: Pretreament of osteoporosis in a German trauma center.

Osteoporosis remains a major health concern due to high incidence of fragility fractures followed by higher mortality and morbidity. Implementation of guidelines for diagnosis and treatment of osteoporosis is critically discussed internationally. Aim of this study was to evaluate implementation of these guidelines regarding diagnosis and therapy of osteoporosis in a developed western country. We hypothesized that (a) prior diagnosis of osteoporosis in patients with low-energy fractures is higher than the estimated incidence and (b) diagnosis and therapy of osteoporosis in patients with prior low-energy fractures is higher than in patients without prior low-energy fractures. 399 patients >60 years suffering low-energy-fractures of their spine, femur, humerus or forearm between 03/2014 and 04/2015 were recruited in a German trauma center. All received a standardized interview. In 21% (84/399) of all patients, osteoporosis was diagnosed prior to current admission. 34% (136/399) suffered a prior risk-fracture after age of 50. Of these, only 54% (73/136) reported about following dual-energy X-ray absorptiometry (DXA) to test for decreased bone-marrow-density with positive results in 68% (50/73). 38% (19/50) of these patients with fragility fractures and prior osteoporosis diagnosis received anti-osteoporotic medication. 66% (263/399) of all patients had no prior risk-fracture and were tested for osteoporosis by DXA in 36% (95/263), leading to positive results in 34% (32/95). 44% (14/32) of these patients received anti-osteoporotic medication. Applying FRAX, 33% of all patients showed a calculated 10-year-risk >20% for suffering a major osteoporotic fracture. 61% (83/136) of patients with a prior fracture had a 10-year-risk >20% of which 47% (39/83) patients received no prior DXA. Although guidelines recommend diagnosis and treatment of patients with low-energy fractures, opportunity for early treatment following risk fractures seems rarely used. Expedient risk assessment is necessary to indicate further diagnostics and therapy of osteoporosis to ensure adequate and efficient treatment for osteoporotic fractures.

[Pharmacological Basis of Pain Treatment]. / Grundlagen der medikamentösen Schmerztherapie.

Many chronic diseases or their consequences are associated with pain. Furthermore, the pain itself can become the disease. Pharmaceuticals are an important component in the treatment of pain. This article presents different analgesic drugs, their mode of action, indications, dosage and adverse drug reactions.

Rituximab in combination with chemotherapy for the treatment of chronic lymphocytic leukaemia in clinical practice.

OBJECTIVES: This study was conducted to investigate the real-world effectiveness and tolerability of rituximab-containing chemoimmunotherapies, which have become the standard of care for chronic lymphocytic leukaemia (CLL), particularly for physically fit patients. Furthermore, current treatment patterns in clinical practice were documented, and an unselected real-life population was compared with older, comorbid patients. METHODS: Prospective, multicentre, observational study with rituximab-containing chemoimmunotherapy in CLL patients. RESULTS: Of 681 patients in total, 485 were enroled in cohort 1 (unselected) and 196 in cohort 2 (comorbid "slow-go" patients). The median patient age was higher than in most randomised controlled trials (cohort 1: 70 years and cohort 2: 75 years). The most common treatment regimen in both first-line and relapsed patients was rituximab-bendamustine. Two-year progression-free survival rate for first-line therapy was 84.1% for cohort 1 and 69.8% for cohort 2 (with best overall response rate 81.8% for cohort 1 and 76.6% for cohort 2). General and B-symptoms declined during treatment and remained at low level or decreased further until study end. The safety profile observed in randomised clinical trials was confirmed. CONCLUSION: Chemoimmunotherapy with rituximab is feasible and safe in a wide variety of clinical settings in CLL, including the treatment of older patients with comorbidities (ClinicalTrials.gov NCT01178086).

Lenalidomide in combination with bendamustine and prednisolone in relapsed/refractory multiple myeloma: results of a phase 2 clinical trial (OSHO-#077).

INTRODUCTION: While lenalidomide monotherapy is established for relapsed and/or refractory multiple myeloma (MM) treatment, combination therapies including lenalidomide are still under investigation in a number of phase 2/3 studies. In the current study, a treatment regime of lenalidomide (Revlimid®), bendamustine and prednisolone (RBP) was tested in patients with relapsed/refractory MM. METHODS: In the previously completed phase 1 study RBP with a dose of 75 mg/m2 bendamustine days 1-2, prednisolone 100 mg days 1-4 and 25 mg lenalidomide days 1-21 was well tolerated. RESULTS: Between July 2011 and September 2013, 25 patients were included in this analysis. The median number of previous treatments was 1 (range 1-2). Twenty-two patients (88%) responded after at least two cycles of RBP (one sCR, five nCR, eight VGPR and eight PR). The median time to first haematological response was 28 days, and median time to best response was 56 days. Due to increased haematological toxicity a dose reduction in most patients required in subsequent cycles of therapy. The median progression-free and overall survival was 22 and 38 months, respectively. In conclusion RBP is a highly effective therapy for patients with relapsed/refractory MM. In contrast to our phase 1 study, dose reduction was necessary in many patients because of haematological toxicity.

Changes of the Sensory Abnormalities and Cortical Excitability in Patients with Complex Regional Pain Syndrome of the Upper Extremity After 6 Months of Multimodal Treatment.

Objective: The most prominent sensory sign of the complex regional pain syndrome (CRPS) is blunt hyperalgesia, but longitudinal studies on its relation to the outcome of long-term multimodal treatment are lacking. Methods: We examined 24 patients with CRPS type I using standardized Quantitative Sensory Testing on the affected hand and the contralateral hand at baseline and 6 months following treatment. Somatosensory evoked potentials after single and paired-pulse stimulation of the median nerve were performed to assess the paired-pulse suppression (n = 19). Treatment response at follow-up was defined as pain relief > 30% and improved hand function. Statistics: Wilcoxon test, Pearson correlation. Results: At baseline, similar to previous studies, the pressure pain threshold (PPT) was significantly decreased and the pain response to repeated pinprick stimuli was significantly increased, while all detection thresholds were within the normal range without any difference between the later treatment responders and non-responders. After 6 months of treatment, the PPT increased significantly in the whole study group. However, the pressure hyperalgesia improved only in treatment responders (n = 17, P < 0.05), whereas there was no improvement in non-responders (n = 7). The rest of the sensory profile remained nearly unchanged. There was a correlation between the paired-pulse suppression and the PPT only at follow-up (r = 0.49, P < 0.05), but not at baseline, where low pressure pain threshold was associated with impaired paired-pulse suppression. Conclusion: Thus, the persistence of blunt hyperalgesia seems to be associated with impaired paired-pulse suppression, both representing maladaptive central nervous changes in CRPS, which may account for the treatment non-response in this subgroup.

Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd -line therapy for relapsed and refractory multiple myeloma - a phase II trial.

The combination of lenalidomide (Revlimid® , R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose-limiting haematotoxicity restricted its use in extensively pre-treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46-83]) and were treated with B 75 mg/m2  days 1, 2; R 25 mg days 1-21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28-day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol-defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.