Impact of Implementing a Bendamustine-Based Conditioning Regimen on Outcomes of Autologous Stem Cell Transplantation in Lymphoma while Novel Cellular Therapies Emerge
Silvy LachanceAlex BourguignonJosie-Anne BoisjolyPhilippe BouchardImran AhmadNadia M. BambaceLéa BernardSandra CohenJean‐Sébastien DelisleIsabelle FleuryThomas KissLuigina MollicaDenis‐Claude RoyGuy SauvageauOlivier VeilleuxJustine ZehrMiguel ChagnonJean Roy
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With the advent of new cellular and targeted therapies, treatment options for relapsed and refractory (r/R) lymphomas have multiplied, and the optimal approach offering the best outcomes remains a matter of passionate debate. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is still considered a treatment option for patients with chemosensitive lymphoma when cure is the expected goal. The myeloablative conditioning regimen preceding the stem cell infusion is considered the effective component of this approach. Carmustine (BCNU)-based preparative regimens, such as BEAM and BEAC, are considered the standard of care and have shown efficacy and low nonrelapse mortality (NRM). Comparative studies between conditioning regimens have failed to identify a better option. After a BCNU drug shortage in Canada followed by a steep increase in price, we elected to substitute BCNU for bendamustine (benda) in the preparative regimen. The purpose of this substitution was to improve response while preserving safety and controlling costs. From May 2015 to May 2018, a total of 131 consecutive lymphoma patients received benda-EAM conditioning. These patients were compared with 96 consecutive patients who received BCNU-based conditioning from January 2012 to May 2015. Apart from conditioning, supportive care measures were the same in the 2 groups. Patients receiving benda were older (55.7 years versus 51.1 years; P = .002). The development of grade ≥3 mucositis was more frequent with benda conditioning (39.5% versus 7.8%; P < .001) leading to a greater requirement for parenteral nutrition (48.9% versus 21.9%; P < .001). A transient creatinine increase >1.5 times the upper limit of normal (15.3% versus 4.2%; P < .008) and intensive care unit admission (6.9% versus 1.1%; P < .029) were more frequent with benda; however, there were no between-group differences in cardiac, pulmonary, or liver toxicity and NRM. With a median follow-up of 48 months for the benda group and 60 months for the BCNU group, benda was associated with significantly better progression-free survival (71% versus 61%; P = .040; hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.0 to 2.7) and overall survival (86% vs 71%; P = .0066; HR, 2.6; 95% CI, 1.3 to 5.4) compared with BCNU-based conditioning regimens. While novel therapies emerge, our study demonstrates that benda-EAM is safe and effective and should be considered a valid alternative to BCNU conditioning to improve outcomes of patients with chemosensitive r/R lymphomas undergoing ASCT.Keywords:
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Mucositis
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Introduction: Mucositis is an inflammatory illness that affects the mouth’s mucous membranes. It could be the result of an infection or an indication of something more serious. Oncology nurses play a crucial role in improving patient outcomes related to oral mucositis. Honey has long been used to prevent and cure oral mucositis. Aim: The aim of the study to assess effectiveness of topical application of pure honey on radiation induced mucositis in cancer patients undergoing radiotherapy. Material and Methods: The style adopted for the study is true experimental design with two group pre-tests with the experimental analysis approach was wont to judge the effectiveness of topical applications of pure honey on radiation evoked mucositis patients. This study was conducted in GSL Cancer hospital Rajahmundry. The sample size consisted of sixty patients suffering type oral mucositis patients who are admitted in GSL cancer hospital at Rajahmundry. Sample random sampling technique was used for the choice of sample. Knowledge was collected by mistreatment WHO mucositis assessment scales & one observation check list to assess the grade of radiation induced mucositis in patients. Modified WHO oral mucositis assessment scale. Data were analysed using descriptive and inferential statistics. Result: The results of this study showed that, oral mucositis score of experimental and control groups mean were 9.73 and1.7 respectively. The standard deviation was 0.927 and 14.55 respectively. Hence calculated t’ value 2.66 is greater than tabulated‘t’ value 2, ‘p’ value is 0.0101 shows that there was a significant oral mucositis scores between post test scores in both experimental and control groups. Applications of pure honey was effective. Conclusion: The findings of the study concluded that, the application of pure honey was effective on radiation induced mucositis in cancer patients undergoing radiotherapy and the level of mucositis is decrease.
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To investigate the prevalence and treatment of oral mucositis caused by concurrent chemoradiotherapy and/or molecular targeted therapy in the patients with advanced squamous cell carcinoma of the head and neck.A retrospective study of the incidence and treatment of oral mucositis was performed in 179 patients (155 male and 24 female;124 patients at stage III and 55 patients at stage IV) receiving concurrent chemotherapy and (or) molecular targeted therapy between November 2007 and November 2010. Grade I, II, III and IV oral mucositis occurred respectively in 49, 50, 67 and 13 patients. All the patients received oral mucositis prophylaxis. After the occurrence of oral mucositis, conventional treatment of mucositis combined with quinolone antibiotics were applied.Of the patients, 99 patients with grade I or II and 4 patients with grade III oral mucositis were effectively managed by conventional treatment; 76 patients with grade III or IV oral mucositis were also significantly controled by conventional treatment plus antibiotics. After the treatments, all patients with oral mucositis were under control, with the decrease in the grade of oral mucositis, the reduction of oral pain and the improvement in ability to eat. None of them had radiation treatment breaks.Combined modality therapy can effectively control chemoradiation-induced oral mucositis in patients with head and neck squamous cell carcinoma, grade I and II oral mucositis were cured by conventional treatment and quinolone antibiotics play a key role in the treatments for grade III and IV oral mucositis.
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First-line chemo-radiotherapy produces cure rates approaching 90% and 80% in early- and advanced-stage Hodgkin lymphoma (HL), respectively. However, 5–10% of patients with early-stage and 20–25% with advanced-stage disease experience either chemorefractoriness to, or disease relapse after, first-line chemotherapy. Whereas 50% of HL patients with chemosensitive relapse and a minority of patients with primary refractory disease will achieve long-term disease-free survival with autologous and eventually allogeneic stem cell transplantation (SCT), disease recurrence or progression after SCT is associated with very poor prognosis. The bifunctional alkylator bendamustine hydrochloride may be considered an attractive agent for use in this clinical setting because of a variety of mechanistic differences compared to other alkylating agents employed in HL. The efficacy of bendamustine in relapsed/refractory HL has previously been reported but limited information is available on bendamustine after allogeneic SCT failure (Corazzelli et al, 2013; Moskowitz et al, 2013). To extend the evaluation of bendamustine and further analyse its effect in HL patients failing allogeneic SCT, we performed a multicentre, retrospective analysis on 67 HL patients who relapsed or progressed after autologous SCT (n = 45, 67%) or autologous and allogeneic SCT (n = 22, 33%). Consecutive relapsed/refractory HL patients, who received single-agent bendamustine through patient-named off-label programmes approved by the ethical committees of 16 participating centres of the Fondazione Italiana Linfomi, were identified in the respective institutional databases. This study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the ethical committee of each participating centre. Tumour responses were assessed according to the revised response criteria of the International Working Group (Cheson et al, 2007). Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). The activity and efficacy of bendamustine were evaluated in terms of objective response rate (ORR), including complete remission (CR) and partial remission (PR), safety, progression-free survival (PFS) and overall survival (OS). Between October 2007 and May 2012, 67 HL patients (31 males, 36 females) with a median age of 34 years (range, 20–63 years) received salvage therapy with bendamustine. Patients had previously received a median of 4 (range, 2–11) lines of treatment, including autologous (n = 45, 67%) or autologous/allogeneic (n = 22, 33%) SCT. Poor prognostic features included refractory disease (n = 48, 72%), B symptoms (n = 27, 40%), bulky disease (n = 14, 21%) and extranodal involvement (n = 48, 72%). Bendamustine was administered at 90 mg/m2 (49 patients, 73%) or 120 mg/m2 (18 patients, 27%) on days 1 and 2 of each 28-d cycle for a median of three cycles (range, 1–10). Dose reduction to 90 mg/m2 was required in 15 of 18 patients receiving 120 mg/m2 bendamustine, mainly because of thrombocytopenia. Early drug discontinuation was necessary in 32 patients because of disease progression (n = 28), thrombocytopenia (n = 1) and investigator decision (n = 3). The ORR for the 67 patients was 57% [95% confidence interval (CI), 45–69%], including 17 CR (25%) and 21 PR (31%). Stable disease (SD) was observed in 3 (4·5%) and progressive disease (PD) in 26 (39%) patients. The only factor having a statistically significant impact on the likelihood of responding to bendamustine was disease status, with relapsed patients having a higher ORR than refractory patients [79% vs. 48%; Hazard Ratio (HR) = 4·1, 95% CI, 1·2–14·1, P = 0·029]. After a median follow-up of 13 months (range, 1–32 months), PFS was 49% (95% CI, 34–62%), and OS was 70% (95% CI, 56–81%) at 1 year. The median PFS was 10 months (95% CI, 37–64%), whereas the median OS was not established (Fig 1A–B). The median PFS for responding (CR + PR) and non-responding (SD + PD) patients was 11 and 3 months (P = 0·004), respectively (Fig 1D). The median OS for responding patients was not established, whereas that for non-responding patients was 7 months (P = 0·058) (Fig 1C). Forty-nine (73%) patients survived, and 18 (27%) patients died. In addition to lymphoma progression (n = 16, 89%), causes of death included acute respiratory distress syndrome (n = 1) and multi-organ failure (n = 1), which occurred at 6 and 2 months from the last dose of bendamustine, respectively. In multivariate analysis, bulky disease [HR = 3·0; 95% CI, 1·4–6·5; P = 0·006), and Eastern Cooperative Oncology Group performance status (ECOG PS) >1 [HR = 2·7, 95% CI, 1·3–5·8; P = 0·009] retained independent adverse prognostic values on PFS. Both bulky disease [HR = 3·8, 95% CI, 1·4–10·5; P = 0·011] and ECOG PS >1 [HR = 3·2, 95% CI, 1·2–8·8; P = 0·024] also retained independent adverse prognostic values for OS. Bendamustine was well tolerated without significant adverse events. Grade 3–4 therapy-related haematological adverse events included anaemia in four patients (6%), thrombocytopenia in 11 patients (16%) and neutropenia in 12 patients (18%). The most common non-haematological toxicities were grade 3–4 fever (10% of patients) and febrile neutropenia (13% of patients). Grade 3–4 sepsis, pneumonia and respiratory infections occurred in two, three and five patients, respectively. Our data add a substantial piece of information on the efficacy of bendamustine in HL failing autologous and allogeneic SCT, strongly supporting its use as an effective and well-tolerated treatment after allogeneic SCT failure. In this setting, the consistent efficacy and the limited toxicity of bendamustine qualifies this drug as one of the most promising, even when compared with brentuximab vedotin (Gopal et al, 2012). In conclusion, our results support prospective studies using bendamustine in combination with molecularly targeted agents to enhance tumour debulking in refractory patients and to reduce the risk of relapse, thereby ultimately improving survival. The authors thank the following investigators for providing patients data: A.M. D'Arco, MD (Division of Haematology, Nocera Inferiore, Italy); M. Gotti, MD (Department of Haematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo, Pavia, Italy); D. Russo, MD (Chair of Haematology, Unit of Blood Diseases and Stem Cell Transplantation, University of Brescia, Brescia, Italy); C. Stelitano, MD (Division of Haematology, Reggio Calabria, Italy); L. Trentin, MD (Department of Medicine, Haematology and Clinical Immunology Branch, University of Padova, Padova, Italy). AA and LG designed the study and wrote the paper; CC-S, PC, and AS analysed the data and wrote the paper; LG and CC-S, analysed and interpreted the data; FS, CR, AP, AS, SH, PP, SV, EB, SL and SH acquired and interpreted the data. All Authors approved the submitted manuscript. The authors report no potential conflict of interests.
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Introduction: The present study was conducted to evaluate oral mucositis in oral cancer patients receiving head and neck radiotherapy.
Methods: Sixty oral cancer patients who had received at least 40 grays of radiation were included in the study. Mucositis was scored by oroscopy using WHO scale. Grades of mucositis were then compared with total dose of radiation received by the patients.
Results: The cases were receiving the mean cumulative dose of standard radiation therapy of 2Gy per fraction, 5 fractions per week. All the patients developed oral mucositis. The majority had grade I mucositis, followed by grade III, II and IV. The grade of mucositis was directly proportional to the dose of radiation exposure.
Conclusion: Oral mucositis occurs among all the patients undergoing head and neck radiotherapy and grade of mucositis is proportional to the dose of radiation exposure.
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Background Mucositis is a disabling effect of radiotherapy in head and neck cancers. There is no current standard on management of radiation-induced mucositis. Honey has been shown to reduce radiation-induced mucositis. Methods A systematic review and meta-analysis were undertaken to assess the ability of honey in reducing the severity of oral mucositis, time to mucositis, weight loss, and treatment interruptions. Results Eight studies were included and showed that honey was significantly better in lowering the risk for treatment interruptions, weight loss, and delaying time to mucositis, but not severity of mucositis. Conclusion There is current evidence that honey is beneficial for patients with head and neck cancers by decreasing treatment interruptions, weight loss, and delaying the onset of oral mucositis, but not in decreasing peak mucositis score. In light of the results, honey is a reasonable treatment for radiation-induced mucositis, but more randomized clinical trials (RCTs) should be done. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1119–1128, 2016
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OBJECTIVE The high rate of mutagenesis in malignant cells has been considered to be a primary factor in the appearance of chemotherapy-resistant cell clones in glioblastomas. Quinacrine binds strongly to deoxyribonucleic acid, preventing mutagenesis. We investigated whether quinacrine could improve carmustine therapy in C6 cell cultures and in C6 malignant gliomas implanted subcutaneously into Wistar rats. METHODS A potential chemopreventive effect of quinacrine on acquired resistance to carmustine therapy was studied in vitro and in vivo. Deoxyribonucleic acid damage was measured in cultured C6 cells by using the micronucleus test. Wistar rats with subcutaneously implanted C6 gliomas were treated with carmustine, quinacrine, or carmustine plus quinacrine, using pharmacological schemes similar to those used for human patients. RESULTS The addition of quinacrine to cultured C6 cells did not modify carmustine-induced cytotoxicity; however, the deoxyribonucleic acid damage in surviving cells was minor, as indicated by the frequency of micronucleated cells. The surviving cells continued to be susceptible to a second exposure to carmustine, in contrast to non-quinacrine-treated control cells, which developed resistance to carmustine in a subsequent exposure (P < 0.05). The rate of tumor remission was higher for glioma-bearing rats treated with quinacrine plus carmustine, compared with rats treated with carmustine alone (P < 0.01). CONCLUSION The addition of quinacrine to carmustine therapy increases the antineoplastic effect of the carmustine therapy. Our results suggest that chemical inhibition of mutagenesis in malignant glial cells during chemotherapy prevents the appearance of resistant clones.
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Oral mucositis remains a concern in the treatment of head and neck malignancies.This small study included 11 patients treated by hypo-fractionated radiotherapy and assessed for oral mucositis.All patients received a radiation dose of 55 Gy in 20 fractions (2.75 Gy/fraction).At the end of the first week of radiation, three patients had Grade I oral mucositis.During the last week of radiation, most of the patients developed Grade II and III mucositis, 7 (64%) and 4 (36%), respectively.At one month follow-up, 5 (46%) of them had Grade I, while 2 (18%) had developed Grade II mucositis.At three months, 2 (18%) had Grade I mucositis, and none of the patients showed Grade II/III oral mucositis.Grade II oral mucositis was the most common grade found mainly in the last week of radiation therapy.None had Grade IV oral mucositis.
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Otlertuzumab (TRU-016) is a humanized anti-CD37 protein therapeutic that triggers direct caspase-independent apoptosis of malignant B cells and induces antibody-dependent cell-mediated cytotoxicity. Patients with relapsed chronic lymphocytic leukaemia (CLL) received either otlertuzumab (20 mg/kg) weekly by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles and IV bendamustine (70 mg/m2 ) on Days 1 and 2 of each cycle for up to six 28-day cycles or bendamustine alone. Thirty-two patients were treated with otlertuzumab and bendamustine and 33 with bendamustine alone. Overall response rate according to the International Workshop on Chronic Lymphocytic Leukaemia criteria was 69% in the otlertuzumab and bendamustine arm and 39% in the bendamustine alone arm (P = 0·025). Median progression-free survival (PFS) was 15·9 months in the otlertuzumab and bendamustine arm and 10·2 months in the bendamustine alone arm (P = 0·0192). There was a higher incidence of pyrexia (34% vs. 12%) and neutropenia (59% vs. 39%) with the combination but this did not result in a higher incidence of severe (grade 3/4) infections (13% vs. 27%). This combination significantly increased the response rate and prolonged the PFS over single agent bendamustine in patients with relapsed or refractory CLL.
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