Rituximab, Cyclophosphamide and Dexamethasone (RCD) Chemoimmunotherapy for Relapsed Chronic Lymphocytic Leukaemia.

High doses of corticosteroids in combination with rituximab remain an alternative in the treatment in relapsed or refractory chronic lymphocytic leukaemia (CLL) in the current era of targeted therapies. This study retrospectively evaluates the efficacy of an RCD (rituximab, cyclophosphamide and dexamethasone) regimen in the treatment of 51 patients with relapsed CLL (median age, 72 years). Unfavourable prognostic features, such as Rai stage III/IV, unmutated IGHV, del11q, TP53 mutation/deletion, complex karyotype and bulky lymphadenopathy, were frequent. The overall response or complete remission was of 57% and 7%, respectively, and the median progression-free survival (PFS) was of 12.3 months, median time to next treatment 23.1 months and median overall survival 39.2 months. Significant independent predictors of shorter PFS were TP53 deletion/mutation, advanced Rai stage and ≥2 previous lines of treatment. The incidence of neutropenia grade ≥ 3 was of 13%. Serious (CTCAE grade 3-5) infections were found in 20% of patients. Steroid-induced diabetes or diabetes decompensation occurred in 20% patients. Treatment-related adverse events resulted in RCD dose reduction in 35% of patients. In comparison with a historical R-Dex patient group, the treatment response and/or toxicity in our group was largely similar. However, the substantial differences in the baseline clinical characteristics of the groups may affect this comparison. In conclusion, the RCD regimen is an active, time-limited therapeutic strategy for elderly patients with relapsed CLL. Further, the results of our analysis indicate that the addition of cyclophosphamide to the R-Dex regimen maintains a similar efficacy, even after 50% reduction in the dexamethasone dose.

Experiences in the treatment of refractory chylothorax associated with lymphoproliferative disorders.

BACKGROUND: Chylothorax is a rare condition which can be associated with malignant lymphoproliferative disorders (LPDs). We retrospectively analyzed the results of the conservative treatment of 10 patients with persistent non-traumatic malignant chylothorax. RESULTS: Conservative treatment lead to a decline of chylothorax after mean of 66 days and consisted of the treatment of the underlying disease and of simultaneous long-term supportive care (drainage of the thoracic cavity, dietary measures and nutrition management). In most cases (80%), chylothorax disappeared only after a successful therapeutic response of the underlying disease. Low-dose radiotherapy had very good effects in two patients. CONCLUSION: Conservative treatment of malignant chylothorax can be considered a suitable method. Based on our results, successful treatment of the lymphoproliferative disorder seems to be a very important factor for the disappearance of chylothorax.

[Primary testicular lymphoma]. / Primární testikulární lymfomy.

Primary testicular lymphoma (PTL) is a rare form of extranodal lymphoma and accounts for approximately 1 to 2 % of all non-Hodgkins lymphoma and 5 % of testicular malignancies. PTL typically affects patients older than 60 years. The most common clinical symptom is painless scrotal swelling. The ultrasound of testicles followed by orchiectomy and histological and imunohistochemical examinations are the most important tools for diagnostic assessment. Diffuse large B cell lymphoma (DLBCL) is the most common histological type of PTL. Orchiectomy is an important part of the treatment, which includes the combination of systemic imunochemotherapy and prophylactic modalities such as radiotherapy of contralateral testis and central nervous system (CNS) prophylaxis. This combined treatment approach improved the outcome of patients with PTL, however, the high frequency of extranodal relapses including CNS involvement represents a significant problem. The prognosis of PTL still remains less favorable in comparison to the some subtypes of non-Hodgkins lymphomas.Key words: central nervous system lymphoma involvement prophylaxis - primary testicular lymphoma - prognosis - radiotherapy - relapse.

Five years of experience with rituximab plus high-dose dexamethasone for relapsed/refractory chronic lymphocytic leukemia.

INTRODUCTION: High-dose methylprednisolone (HDMP) in combination with rituximab is active in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), but serious infections are frequent. Recently published data suggested that high-dose dexamethasone might be equally effective as HDMP despite a lower cumulative dose. MATERIAL AND METHODS: We performed retrospective analysis of 60 patients with relapsed/refractory CLL (median age: 66 years; range: 37-86) treated with rituximab plus dexamethasone (R-dex) at a single tertiary center between September 2008 and October 2012. The schedule of R-dex consisted of rituximab 500 mg/m(2) i.v. day 1 (375 mg/m(2) in cycle 1) and dexamethasone 40 mg orally on days 1-4 and 10-13 repeated every 3 weeks for a maximum of 8 cycles. Unfavorable prognostic features were frequent (Rai stages III/IV in 67%, unmutated IgVH 82%, del 11q 43%, TP53 mutation/deletion 23%, bulky lymphadenopathy 58% of patients). RESULTS: Overall response (OR)/complete remission (CR) was achieved in 75/3%. At the median follow-up of 21 months, median progression-free survival (PFS) was 8 months, median time to next treatment 12.9 months and median overall survival 25.5 months. Refractoriness to fludarabine (p = 0.04) and age ≥ 65 years (p = 0.03) were significant predictors of shorter PFS. R-dex was successfully used for debulking before allogenic stem cell transplantation in 7 patients (12%). Serious (CTCAE grade III/IV) infections occurred in 27% of patients; 20% of patients developed steroid diabetes requiring temporary short-acting insulin. CONCLUSIONS: Our results show that R-dex is an active and well-tolerated regimen for patients with relapsed/refractory CLL; however, major infections remain frequent despite combined antimicrobial prophylaxis.

[Rituximab infusion-related toxicity in patients with chronic lymphocytic leukemia]. / Infuzní toxicita rituximabu u nemocných s chronickou lymfocytární leukemií.

BACKGROUND AND AIMS: Rituximab in combination with chemotherapy is an effective treatment of patients (pts) with chronic lymphocytic leukemia (CLL). The most frequent adverse event of rituximab is infusion-related toxicity, e.g. cytokine-release syndrome that occurs usually during the first infusion. However, there is scarce data on feasibility and tolerability of rituximab infusions in CLL outside clinical trials. Therefore, we performed a single-center retrospective analysis of the frequency of rituximab infusion-related adverse events during the first- and the second line CLL treatment administered in the routine practice. We also analyzed its relation to parameters of tumor load and possible association with treatment efficacy. The safety of rapid infusion of rituximab in CLL pts was also evaluated. PATIENTS AND METHODS: We analyzed 108 pts with CLL treated with rituximab-containing regimens between March 2005 and May 2011 at our institution. The most common first-line regimens (n = 66, 47 males, median age 63 years) were FCR (43 pts) and low-dose FCR (13 pts); 10 pts were treated by other protocols. Forty-two pts (32 males, median age, 65 years) underwent second line treatment: 18 pts rituximab-dexamethasone, 7 pts FCR, 7 pts low-dose FCR and 10 pts other regimens. Intravenous hydration (2000 ml daily on days 0 and 1 of cycle), allopurinol 300-600 mg p. o. daily and premedication with methylprednisolone 80 mg i. v., acetaminophen 1000 mg p. o. and bluepine 1 mg i. v. were administered before rituximab infusion. Rituximab was given by fractionated infusion (100 mg for 2 hours, then if tolerated well, the rest of the dose with infusion rate escalation from 100 mg/hour up to 400 mg/hour) at the dose of 375 mg/m2 in the first cycle. Subsequent doses (500 mg/m²) were administered by rapid-infusion protocol. RESULTS: Rituximab infusion-related toxicity occurred in 32 % pts (n = 21) during the first line treatment and 19% pts (n = 8) during the second line treatment. Adverse events were predominantly mild and NCI CTCAE grade III/IV occurred rarely (3% in the first line, 2% in the second line). Infusion toxicity manifested predominantly as rigors, chills, fever and hypotension. All patients with adverse events could finish rituximab infusion as initially planned on the same day. Treatment response analysis did not demonstrate statistically significant differences between patients with and without rituximab infusion toxicity. Patients who developed rituximab infusion toxicity had higher absolute lymphocyte count (first line, 87 vs 56 × 109/l, p = 0.21; second line, 101 vs 14 × 109/l, p = 0.043). At the median follow-up of 36 months, there were no statistically significant differences in PFS or OS in both cohorts. CONCLUSIONS: Rituximab infusion-related toxicity in pts with CLL is relatively frequent (32%). However, occurrence of infusion-related symptoms can be reduced by proper premedication and severe adverse events are uncommon. In our experience, all patients were able to receive the planned dose of rituximab. Subsequent doses of rituximab could be safely administered by rapid-infusion protocol. We did not find statistically significant association between rituximab infusion toxicity and effectiveness of treatment.

The outcome of chronic lymphocytic leukemia patients who relapsed after fludarabine, cyclophosphamide, and rituximab.

BACKGROUND: There are minimal data about the efficacy of subsequent therapy in patients with relapse after FCR (fludarabine, cyclophosphamide, and rituximab) chemoimmunotherapy. METHODS: We retrospectively analyzed the outcomes of 119 patients who relapsed after standard-dose FCR. The patient cohort consisted of patients who relapsed after FCR administered as first-line therapy (Group 1, n = 63) and patients relapsing after FCR administered in second/subsequent line; (Group 2, n = 56). RESULTS: Basic parameters (age, clinical stage, cytogenetics, molecular genetics) did not differ significantly between these subgroups. Likewise, median progression-free survival (PFS) was not considerably different after FCR (18.6 vs. 14.7 months). Subsequent therapy for relapsed disease included FCR retreatment, R-CHOP, alemtuzumab, or rituximab plus high-dose dexamethasone. Overall response rates for the two groups did not significantly differ (59% vs. 44%). Although PFS after subsequent therapy was relatively short, longer PFS was observed in Group 1 (13.3 vs. 5.9 months; P = 0.01), in patients with response duration ≥ 24 months after previous FCR (13 vs. 6.1 months; P < 0.01), and in patients who achieved complete remission after FCR (10.8 vs. 7.9 months in partial remission; P = 0.01). Newly detected 17p deletions were observed in 5/62 patients, and new p53 mutations in 6/34 FCR-treated patients. CONCLUSION: Our data indicate that the prognosis of patients who relapse after FCR remains poor regardless of the subsequent treatment regimen.

Rituximab in combination with high-dose dexamethasone for the treatment of relapsed/refractory chronic lymphocytic leukemia.

BACKGROUND: High-dose methylprednisolone is active in treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) but infectious toxicity is serious. The aim of this project was to retrospectively assess efficacy and safety of high-dose dexamethasone combined with rituximab (R-dex) in this setting. PATIENTS AND METHODS: We treated 54 patients (pts) with relapsed/refractory CLL using R-dex regimen at two tertiary centers. Two schedules of rituximab were used (not randomized - based on the choice of the center): group 1, rituximab 500 mg/m(2)day 1, 8, 15, 22 (375 mg/m(2) in 1st dose) every 4 weeks (n=29); group 2, 500 mg/m(2)day 1 (375 mg/m(2) in 1st cycle) repeated every 3 weeks (n=25). The target dose of dexamethasone was 40 mg on days 1-4 and 10-13 or 15-18. Rai III/IV stages were present in 82%, unmutated IgVH genes in 82%, del 11q in 38% and del 17p in 19% pts; 46% had bulky lymph nodes; 82% were pretreated with fludarabine and 29% with alemtuzumab. RESULTS: Overall response rate/complete remissions were 62/21% (Group 1) and 72/4% (Group 2). In three patients, R-dex was successfully used for debulking before nonmyeloablative allogeneic stem cell transplantation. R-dex was particularly effective in improvement of anemia and thrombocytopenia (p=0.0055 and p=0.0036); B-symptoms resolved after treatment in 11/17 pts. Hematological toxicity was mild. Serious infections occurred in 32% pts. At the median follow-up of 9 and 10 months, median progression-free survival was 6 months in Group 1 and 6.9 months in Group 2 (p=ns); median overall survival was 14.1 months in Group 1 vs. not reached in Group 2 (p=ns). CONCLUSIONS: R-dex appears to be an active and feasible treatment for relapsed/refractory CLL. Infectious toxicity remains an important issue. Further investigation of this regimen in larger studies appears fully warranted.