Poor efficacy and tolerability of <scp>R‐CHOP</scp> in relapsed/refractory chronic lymphocytic leukemia and <scp>R</scp>ichter transformation

Langerbeins, Petra; Busch, Raymonde; Anheier, Nadine; Dürig, Jan; Bergmann, M.; Goebeler, Maria-Elisabeth; Hurtz, Hans-Jürgen; Stauch, Martina; Stilgenbauer, Stephan; Döhner, Hartmut; Fink, Anna‐Maria; Cramer, Paula; Fischer, Kirsten; Wendtner, Clemens‐Martin; Hallek, Michael; Eichhorst, Barbara

doi:10.1002/ajh.23841

Cited by 91 publications

(74 citation statements)

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“…[14][15][16][17][18] Due to a lack of controlled clinical trials in patients with relapsed CLL, therapeutic decisions often rely on the experience of the treating physician and on preliminary evidence from phase II trials. The aim of this meta-analysis was, therefore, to evaluate the outcome of patients treated with different first-line and relapse therapies in five large prospective trials by the German CLL Study Group (GCLLSG).…”

Section: Introductionmentioning

confidence: 99%

Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG)

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nfeasible in many cases because of the patient's age, fitness, burden of comorbidities or lack of a matching donor, intensive chemo(immuno)therapies, such as the combination of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) with or without rituximab or FC plus mitoxantrone (FCM), as well as an alemtuzumabbased regimen have often been used, even though these regimens are relatively toxic. [14][15][16][17][18] Due to a lack of controlled clinical trials in patients with relapsed CLL, therapeutic decisions often rely on the experience of the treating physician and on preliminary evidence from phase II trials. The aim of this meta-analysis was, therefore, to evaluate the outcome of patients treated with different first-line and relapse therapies in five large prospective trials by the German CLL Study Group (GCLLSG). The patients included in this meta-analysis were heterogeneous, because these five trials were designed for different target populations and were performed consecutively between 1999 and 2010, which is a period of great changes in the treatment of CLL. Although the most innovative treatment options for CLL, such as the kinase inhibitors ibrutinib and idelalisib or the novel antibodies are not included in this analysis, the results of this meta-analysis are clinically relevant as these novel agents are not yet widely available in all countries. MethodsThis analysis includes 1,659 CLL cases treated in five phase II/III trials, 2,5,8,[19][20][21] which were performed by the GCLLSG between 1999 and 2010. As 38 patients were identified who participated in two trials for different lines of treatment, the absolute number of patients is 1,621. The five trials evaluated the following treatment regimens: single agent chlorambucil (CLL5 trial) or fludarabine (CLL4 and CLL5 trials), FC (CLL4 and CLL8 trial), FC with rituximab (FCR) (CLL8 trial) or with alemtuzumab (FCA) (CLL2L trial) as well as bendamustine and rituximab (BR) (CLL2M-trial). CLL4, CLL5 and CLL8 were randomized phase III trials for firstline treatment while the CLL2L and CLL2M trials were phase II studies for both first-line and relapsed patients. Consequently, 91.6% (1,520) of all patients were included for first-line treatment and only 139 patients received a relapse therapy within one of the two phase II trials. With the exception of the 206 patients (12.4%) from the CLL5 trial with an advanced age >65 years, all other patients were required to be either younger, had a low burden of comorbidities and were physically fit for chemoimmunotherapy (for further details see Online Supplementary Table S1 as well as the original publications of the trials). 2,5,8,[19][20][21] As these five trials were run in an era of considerable changes in the treatment of CLL, the target populations, investigated regimens and therapeutic goals varied between the trials, resulting in a heterogeneous group of patients for this meta-analysis. The five studies were approved by the institutional revie...

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Section: Introductionmentioning

confidence: 99%

Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG)

et al. 2015

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“…Two out of 5 patients with Richter's transformation transplanted in our cohort remain alive. This condition is known to have a poor prognosis with only <20 % of patients remaining alive 1 year following diagnosis [23]. These patients are candidates to be considered for an allo-SCT upon the earliest possible achievement of best remission with current standard chemotherapeutic regimens.…”

Section: Discussionmentioning

confidence: 99%

Nonmyeloablative allogeneic stem cell transplantation for chronic lymphocytic leukaemia offers the possibility of disease control with minimal morbidity and mortality—a single institution experience

Chakupurakal

Leitzke

Langerbeins³

et al. 2015

Ann Hematol

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Allogeneic stem cell transplantation is a treatment option for patients with poor risk CLL. We conducted a retrospective analysis of all CLL patients allografted at our institution, the University Hospital of Cologne, Germany. Data was collected on 40 patients from 2004 to 2012. The mean age was 54, and the majority were male (75 %). On average, the patients were diagnosed 6 years (range 2-12) prior to transplant with an average of 4 years (range 1-8) from time of first-line therapy to transplant. The remission states at the time of transplant were complete remission (CR) (n = 4), stable disease (n = 10), partial remission (n = 20) and progressive disease (n = 6). Only reduced intensity conditioning regimens were employed. The average CD34(+) cell dose was 4.16 × 10(6)/kg. Neutrophil engraftment was seen by day +17 (range 10-23) post-transplant, and 88 % achieved 95-100 % donor chimerism by day 100. Overall survival, progression-free survival and non-relapse mortality at 2 years post-transplant were 65, 52.5 and 27.5 %, respectively. A total of 51 % of patients were found to be minimal residual disease (MRD)-negative at 1 year post-transplant. Our single-centre experience confirms the valuable role of allogeneic stem cell transplantation (allo-SCT) in the treatment of poor risk CLL patients with promising long-term survival and acceptable transplant-related mortality. The advent of newer therapeutic agents should not hinder the consideration of allo-SCT for this patient cohort as it remains the only curative option for these patients.

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“…For instance, a chemoimmunotherapy regimen combining cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) is commonly prescribed for treatment of RS [14]. A phase II study of the German CLL Study Group evaluated the efficacy of CHOP-R in 15 patients (median age, 69 years) with RS [15]. Responses were reported as follow: complete remission (CR) of 7% and partial response (PR) of 60%.…”

Section: Treatment Of Rs Chemoimmunotherapy Combinationsmentioning

confidence: 99%

Hematopoietic Cell Transplantation for Richter Syndrome

El-Asmar

Kharfan‐Dabaja

2016

Biology of Blood and Marrow Transplantation

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Treatment combining chemotherapy with immunotherapy as well as novel targeted therapies have shown limited efficacy in Richter syndrome. Overall response rates after chemoimmunotherapy range from 43% to 67%, but remissions are generally short-lived. In chronic lymphocytic leukemia (CLL), allogeneic hematopoietic cell transplantation (all-HCT) is considered a potentially curative treatment modality, yielding 3-year overall survival rates exceeding 50% and a plateau in survival curves. In Richter syndrome, efficacy of allo-HCT depends on demonstrating an objective response (complete remission or partial response) before allografting, with resulting 3-year survival rates of 41% to 75%. On the other hand, the efficacy of autologous HCT is limited, especially when considering that patients autografted for Richter syndrome might relapse with CLL in 35% of cases. Notwithstanding the scarcity of published data, we recommend that patients with Richter syndrome should be referred to transplant centers as soon as the diagnosis is confirmed to evaluate their candidacy for allo-HCT. Establishing a clonal relationship to CLL is important considering the more aggressive disease course in clonally related Richter syndrome. Moreover, achievement of a complete remission or partial response to salvage therapy must be a prerequisite before moving forward with allografting for Richter syndrome. Patients who fail to demonstrate an objective response to salvage therapy should be considered for enrollment in clinical trials.

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Poor efficacy and tolerability of R‐CHOP in relapsed/refractory chronic lymphocytic leukemia and Richter transformation

Cited by 91 publications

References 27 publications

Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG)

Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG)

Nonmyeloablative allogeneic stem cell transplantation for chronic lymphocytic leukaemia offers the possibility of disease control with minimal morbidity and mortality—a single institution experience

Hematopoietic Cell Transplantation for Richter Syndrome

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