Martin Šimkovič

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.

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

There are minimal data about the efficacy of subsequent therapy in patients with relapse after FCR (fludarabine, cyclophosphamide, and rituximab) chemoimmunotherapy.

Venous thromboembolism in patients with chronic lymphocytic leukemia

INTRODUCTION Venous thromboembolism (VTE) is a major cause of morbidity and mortality in patients (pts) with malignant tumors. Increased risk of VTE is well described in a variety of hematologic malignancies; however, data regarding VTE in chronic lymphocytic leukemia (CLL) is very limited. PATIENTS AND METHODS We retrospectively analyzed clinical and laboratory data of 346 consecutive pts with CLL followed up at 4th Department of Internal Medicine - Hematology, University Hospital, Hradec Kralove, Czech Republic, diagnosed between 1999 and 2011 (males, 64%; median age, 64 years; low/intermediate/high Rai modified risk in 41/47/12%). RESULTS After a median follow-up of 72 months (range, 26-138), at least one episode of VTE occurred in 38 patients (11%). VTE developed after a median of 34 months from CLL diagnosis. Incidence of VTE was 1.67% per patient year of follow-up. There was a high proportion of unfavourable prognostic factors (advanced Rai stages, unmutated IgVH genes, unfavourable cytogenetics) in pts with VTE. The presence of 0/1/2/3 additional risk factors for VTE was identified in 2/16/14/6 patients. The most common risk factors for VTE besides age (n=24) were corticosteroid therapy (n=13), other malignancies (n=9) and obesity (n=7). Recurrence of VTE was diagnosed in 7 pts. Performance status ≥ 2 and inherited thrombophilia were significant risk factors for VTE development in univariate and multivariate analysis. VTE was not associated with shorter overall survival. CONCLUSION Based on our results, VTE is a relatively frequent complication in patients with CLL. Although most patients had other known risk factors for VTE including CLL treatment, 29% had no risk factors or only age ≥ 60 years. These findings demonstrate the possible role of CLL in the development of VTE.

Practical approach to management of chronic lymphocytic leukemia

Revolutionary progress has recently changed the landscape of chronic lymphocytic leukemia (CLL). Powerful prognostic factors, especially p53 mutation and/or deletion and IGHV mutation status, have refined individual patient prognosis. Purine analogs and monoclonal antibodies paved the way from palliative treatment to chemoimmunotherapy capable of eradication of minimal residual disease and prolongation of survival. Obinutuzumab (GA-101) and ofatumumab have been recently approved for the treatment of comorbid patients. Bendamustine is available for first-line treatment of patients ineligible for fludarabine, cyclophosphamide, and rituximab (FCR). High-dose glucocorticoids combined with rituximab represent a promising option for refractory CLL; ofatumumab is approved for fludarabine- and alemtuzumab-refractory patients. Allogeneic stem cell transplantation is the only curative option but is feasible in a highly selected group of patients only. The novel small molecule inhibitors ibrutinib and idelalisib have been recently approved for relapsed/refractory CLL. This review provides practical advice for diagnosis, prognostication and treatment of CLL.

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/m2 i.v. day 1 (375 mg/m2 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.

Therapy-related myeloid neoplasms in epithelial ovarian cancer patients carrying BRCA1 mutation: Report of two cases

Major progress has been achieved during the past few decades in the therapy of epithelial ovarian carcinoma (EOC). Although the disease in most patients with advanced disease is still incurable, the survival has been substantially prolonged. Currently, the standard fi rst line regimen in advanced EOC is the combination of paclitaxel and platinum (cisplatin or carboplatin), with the response rate to this combination being about 60 – 70% [1]. Recurrent EOC responds to repeat administration of paclitaxel/platinum combination [2]. Marked prolongation of survival resulting from the multimodality treatment is changing the natural course of the disease, with more patients living long enough to develop hitherto unusual late sequels, including metastases in unusual sites (e.g. brain), or second primary tumors. We present here two cases of BRCA1 mutation carriers with repeat responsiveness of recurrent EOC to paclitaxel/platinum that fi nally succumbed to therapy-related myeloid neoplams. Case 1 was a woman with history of hysterec-tomy for leiomyomas who presented in February 2002, at the age of 49 years, with pleural effusion in the right hemithorax. Cytological examination of the effusion revealed malignant cells suggestive of adenocarcinoma. A mass in the right breast was found on subsequent examination. Triple negative breast carcinoma was diagnosed in an excisional biopsy. Systemic chemotherapy with the combina-tion of doxorubicin (50 mg/m

Léčba chronické lymfocytární leukemie u nemocných vyššího věku a s významnými přidruženými onemocněními

V poslednich letech se udaly významne změny v lecbě chronicke lymfocytarni leukemie (CLL). K pokroku doslo kombinaci konvencni chemoterapie s monoklonalnimi protilatkami. Režim FCR (fludarabin, cyklofosfamid a rituximab) je nyni zlatým standardem v lecbě mladsich a fyzicky zdatných pacientů. Starsi a komorbidni nemocni, kteři tvoři větsinu CLL populace, nejsou zpravidla schopni podstoupit intenzivni lecbu z důvodu vysokeho rizika nepřijatelných nežadoucich ucinků. U teto skupiny nemocných lze tedy dosud považovat chlorambucil jako hlavni lecebnou volbu. Nizkodavkovane fludarabinove režimy stejně jako kombinace chlorambucilu s monoklonalnimi anti-CD20 protilatkami jsou nyni zkouseny v randomizovaných klinických studiich. Dalsi lecebne možnosti, u kterých zatim chybi podrobnějsi data pro skupinu starsich a komorbidnich nemocných a ktere musi být přisně individualizovany, představuji použiti bendamustinu v 1. linii, alemtuzumabu, vysokodavkovaných glukokortikoidů ci ofatumumabu v lecbě relapsu/refrakterni CLL. Přidružene choroby, tělesna výkonnost a biologický věk jsou důležitými prognostickými faktory, ktere ovlivňuji rozhodovani o volbě lecby. Clanek poskytuje přehled soucasných a budoucich lecebných možnosti u starsich a komorbidnich pacientů s CLL.Besonders wichtig wird in Zukunft die sorgfaltige Auswahl von geeigneten Patientinnen fur die Strahlentherapie sein. In einer Ubersicht werden die vorhandenen Daten uber den Wert der Strahlenbehandlun

Alternating R‐CHOP and R‐cytarabine is a safe and effective regimen for transplant‐ineligible patients with a newly diagnosed mantle cell lymphoma

Implementation of cytarabine into induction therapy became standard of care for younger patients with mantle cell lymphoma (MCL). On the basis of its beneficial impact, many centers incorporated cytarabine at lower doses also into first‐line treatments of elderly patients. We conducted a multicenter observational study that prospectively analyzed safety and efficacy of alternating 3 + 3 cycles of R‐CHOP and R‐cytarabine for newly diagnosed transplant‐ineligible MCL patients. A total of 73 patients were enrolled with median age 70 years. Most patients had intermediate (39.7%) and high‐risk (50.7%) disease according to MCL international prognostic index. Rituximab maintenance was initiated in 58 patients. Overall response rate reached 89% by positron emission tomography–computed tomography, including 75.3% complete remissions. Two patients (2.7%) did not complete the induction therapy because of toxicity. Three patients (4.1%) were considered nonresponders, which led to therapy change before completion of induction. Estimated progression‐free survival and overall survival were 51.3% and 68.6% at 4 years, respectively. Mantle cell lymphoma international prognostic index, bulky disease (≥ 5 cm), and achievement of positron emission tomography–negativity independently correlated with progression‐free survival. Grade 3 to 4 hematologic and nonhematologic toxicity was documented in 48% and 20.5% patients, respectively. Alternation of R‐CHOP and R‐cytarabine represents feasible and very effective regimen for elderly/comorbid MCL patients. This study was registered at GovTrial (clinicaltrials.gov) NCT03054883.

Maintenance rituximab in newly diagnosed mantle cell lymphoma patients: a real world analysis from the Czech lymphoma study group registry†

Abstract We analyzed 495 MCL patients from the Czech Lymphoma Study Group data registry. With the median follow-up of 4.4 years, 51.7% patients progressed or relapsed and 34.1% died. Five-year overall survival reached 65.3% and five-year progression free survival 44.1% of the patients. Maintenance rituximab (MR) after first line therapy improved overall and progression free survival compared to the patients under observation only (both p < .001). Elevated beta-2-microglobulin (p = .003), presence of systemic symptoms (p = .002), ECOG >0 (p = .003), age (p = .014), and MIPI (p < .001) were associated with MR failure. Patients who did not achieve complete remission have had two-fold higher risk of MR failure (p < .001). Autologous stem cell transplant reduced the risk of MR failure by 69% (p < .001). The MIPI and the beta-2-microglobulin were identified as independent predictors of MR failure (p = .02 and p = .03, respectively). Patients who relapsed/progressed on MR reached shorter OS calculated from the MR start compared to patients without failure (HR = 15.0; p < .001).

Potential loss of prognostic significance of minimal residual disease assessment after R-CHOP-based induction in elderly patients with mantle cell lymphoma in the era of rituximab maintenance

Rituximab maintenance (RM) prolongs survival of elderly patients with mantle cell lymphoma (MCL). Persistent minimal residual disease (MRD) after induction repeatedly correlated with shorter progression‐free survival (PFS). However, none of the published studies analyzed patients treated with RM. The main purpose was to analyze prognostic significance of MRD in the elderly patients with newly diagnosed MCL treated according to the recently published observational trial protocol (alternation of R‐CHOP and R‐cytarabine, 3 + 3 cycles, GovTrial number NCT03054883) at the centers that implemented RM. Minimal residual disease was evaluated by a EuroMRD standardized real‐time PCR approach after 3 and 6 cycles of the induction therapy. Prognostic significance of MRD was analyzed in a subcohort of patients treated at the centers that implemented RM as a standard approach. Bone marrow proved to be a significantly more sensitive source for MRD detection than peripheral blood. In either compartment MRD (positive versus negative) after 3 or 6 cycles of the induction therapy did not correlate with PFS. The observed loss of prognostic significance of MRD after the R‐CHOP‐based induction appears to be a consequence of RM immune control over the residual lymphoma.