Comparison of younger versus older B-cell chronic lymphocytic leukemia patients for clinical presentation and prognosis. A retrospective study of 53 cases

Abstract: Fifty-three patients affected with B-cell chronic lymphocytic leukemia (CLL) younger than 50 years and observed in two hematological institutions have been retrospectively evaluated in order to verify whether this disease has different clinico-hematological features at presentation and different prognosis as compared to older cases. In our experience young cases with B-CLL diagnosis, confirmed by immunophenotype in 90.5% of patients, accounted for 7.1% of the whole CLL population. Sex distribution, mean peripheral lymphocyte count, platelet count, distribution among Rai's and Binet's stages, total tumor mass (TTM) score, histological pattern of bone marrow infiltration and lymphocyte doubling time (LDT) were similar to a series of 201 CLL cases older than 50 years. Only hemoglobin mean level was significantly higher in younger patients (13.1 ± 2.1 vs 12.2 ± 2.6 g/dl; p<0.01). The overall median survival was 7.1 years. Rai and Binet staging classifications and TTM score system retained their prognostic value in this CLL population. In addition, cases fulfilling criteria of “smoldering” CLL, had a very long survival (75% survival probability at 16 years). Life-expectancy of younger patients was significantly longer than that of older ones (median survival, 7.1 versus 4.1 years; p < 0.05). However, when the background mortality due to non-CLL related deaths (i.e., cardiovascular complications, epithelial cancers) was removed, survival advantage of young cases disappeared. In conclusion this study confirms that prognosis of young CLL patients can be easily assessed using the current well-defined criteria. Since age is not by itself a criterion for intensifying treatment, further efforts to identify those young CLL patients who qualify for more aggressive therapy should be made.     

Changes in AgNOR configurations during the evolution and treatment of chronic lymphocytic leukemia

The evolution of the pattern of nucleolar organiser regions (AgNORs) in circulating lymphocytes during the stable phase and after chemotherapy in CLL was analysed. Peripheral blood smears were stained by the AgNOR technique at diagnosis, during observation follow-up in stable phase, or at the beginning and at the end of chemotherapy in patients with progressive disease. The changes in the AgNOR pattern were compared with those of TTM used as a tumour burden parameter. Among 52 cases that entered the study, 29 were in stable phase and 23 had progressive disease and received chemotherapy. During stable phase, the AgNORs as well as TTM remained constant. In treated patients, the relative reduction of tumour mass was correlated with a decrease in the percentage of lymphocytes containing one AgNOR cluster. The percentage of cells with one compact nucleolus before chemotherapy was inversely correlated with the relative amount of tumor reduction after treatment. We conclude that the AgNOR pattern in CLL describes the cell kinetic changes during the evolution of the disease and is a prognostic factor for tumor reduction after treatment.     

Changes in AgNOR configurations during the evolution and treatment of chronic lymphocytic leukemia

The evolution of the pattern of nucleolar organiser regions (AgNORs) in circulating lymphocytes during the stable phase and after chemotherapy in CLL was analysed. Peripheral blood smears were stained by the AgNOR technique at diagnosis, during observation follow-up in stable phase, or at the beginning and at the end of chemotherapy in patients with progressive disease. The changes in the AgNOR pattern were compared with those of TTM used as a tumour burden parameter. Among 52 cases that entered the study, 29 were in stable phase and 23 had progressive disease and received chemotherapy. During stable phase, the AgNORs as well as TTM remained constant. In treated patients, the relative reduction of tumour mass was correlated with a decrease in the percentage of lymphocytes containing one AgNOR cluster. The percentage of cells with one compact nucleolus before chemotherapy was inversely correlated with the relative amount of tumor reduction after treatment. We conclude that the AgNOR pattern in CLL describes the cell kinetic changes during the evolution of the disease and is a prognostic factor for tumor reduction after treatment.     

Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia

Prognosis of B-cell chronic lymphocytic leukemia (CLL) is based on clinical staging whose limitation is the failure to assess whether the disease will progress or remain stable in early stage (Binet A, or Rai 0, I, II) patients. We previously reported that soluble CD23 (sCD23), a protein derived from the B-cell membrane CD23 Ag, is selectively elevated in the serum of CLL patients. This prospective study assessed the predictive value of serum sCD23 level measured at study entry on the overall survival of all CLL patients and on disease progression of stage Binet A patients. Prognostic value of repeated measurements of sCD23 over time in stage A patients was also analyzed. One hundred fifty-three CLL patients were prospectively followed with a median follow-up of 78 months. Eight clinical or biological parameters were collected from the date of the first sCD23 measurement. At study entry, by Cox model, Binet staging (P = .0001) and serum sCD23 level (P = .03) appeared as prognostic factors for survival. Patients with sCD23 level above median value (> 574 U/mL) had a significantly worse prognosis than those with lower values (median survival of 53 v 100+ months, P = .0001). During follow-up, sCD23 doubling time increased by 3.2 the risk of death (P = .001). Among stage A patients (n = 100), sCD23 determination at study entry was the sole variable predictive of disease progression, patients with sCD23 level above 574 U/mL had a median time progression of 42 months versus 88 months for those with lower levels (P = .0001). Stage A patients who doubled their sCD23 level exhibited a 15-fold increased risk of progression (P = .0001) and, in addition, the sCD23 increase preceded by 48 months disease progression. We conclude that in CLL patients, serum sCD23 level provides significant additional prognostic information in terms of overall survival. Most interestingly, among early stage patients, sCD23 determination at diagnosis and during the course of the disease may help to the early identification of patients who will rapidly progress to upper stages.     

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

This phase II trial evaluated efficacy and tolerability of R‐CHOP for up to 8 courses in Richter transformation (RT) and up to 6 courses in CLL plus autoimmune cytopenia (AIC) or high‐risk (HR) features. HR was defined as fludarabine‐refractoriness or early relapse (<36 months) after fludarabine‐based treatment; 26 patients were included as HR, 19 patients had AIC, and 15 patients had RT. In the HR cohort, overall response rate was 54%, progression‐free and overall survival were 9 and 21 months. In AIC patients overall response rate was 74%, progression‐free and overall‐survival were 10 and 41 months, respectively, and median increase in hemoglobin was 3.4 g/L. RT patients responded in 67%, progression‐free was 10 and overall survival 21 months. The most common adverse events were hematologic toxicities in 92%. Severe infections occurred in 28%. Treatment was discontinued early in 45% of all patients mainly as a result of toxicity. This trial shows that R‐CHOP has no role in treating complicated CLL. R‐CHOP is associated with significant toxicities and fairly low efficacy compared with almost every other CLL‐regimen. In RT, it might still be used as an induction therapy before allogeneic stem cell transplantation. Am. J. Hematol. 89:E239–E243, 2014. © 2014 Wiley Periodicals, Inc.     

Chemosensitivity of lymphocytes from patients with B-cell chronic lymphocytic leukemia to chlorambucil, fludarabine, and camptothecin analogs

Chemosensitivity of B lymphocytes, obtained from 65 patients with B- cell chronic lymphocytic leukemia (B-CLL), Rai stages 0 through IV, was determined using the MTT assay. The results were expressed by the drug concentration required for 50% inhibition of cell viability (IC50). The cytotoxicity of chlorambucil (CLB) was compared with that of fludarabine and the DNA topoisomerase I inhibitors, camptothecin, 9- aminocamptothecin, 10,11-methylenedioxy-20(S)-camptothecin (10,11-MDC) and 9-amino-10,11-methylenedioxy-20(S)-campthothecin (9-A-10,11-MDC), and topotecan. Considerable heterogeneity in sensitivity to CLB was observed, with a median IC50 of 40.5 mumol/L in untreated patients. B- CLL cells from patients treated with CLB had a significantly higher median IC50 of 86.0 mumol/L (P < .01). Untreated as well as CLB-treated patients were divided into two subsets. For the purpose of this study, B-CLL lymphocytes with an IC50 CLB of less than 61.0 mumol/L were designated as "sensitive" and those with an IC50 CLB of > or = 61.0 mumol/L were designated as "resistant." After baseline assays, 15 untreated patients received CLB; after treatment, the IC50 increased in B-CLL lymphocytes from 13 of 15 patients. The response to CLB treatment, determined by its effect on the absolute lymphocyte count and by the Eastern Cooperative Oncology Group clinical criteria, was significantly better in patients whose lymphocytes had an IC50 CLB of less than 61.0 mumol/L before therapy (P < .01). B-CLL lymphocytes also had a variable degree of sensitivity in vitro to each of the other drugs. There was significant cross-resistance between CLB and fludarabine (P < 0.01). Whereas only 29% of CLB-resistant B-lymphocyte specimens obtained from individual patients were sensitive to fludarabine in vitro, 52% and 67% of CLB-resistant lymphocyte samples were sensitive to 10,11-MDC and 9-A-10,11-MDC, respectively. We have previously reported that p53 gene mutations were associated with aggressive B-CLL and a poor prognosis. B lymphocytes from seven patients with these mutations were resistant to CLB, and five of six were resistant to fludarabine. Lymphocytes from four of seven were resistant to 10,11-MDC, and three of four were resistant to 9-A-10,11- MDC. This study implies that the MTT assay may be useful in identifying subsets of CLL patients resistant to conventional chemotherapy. However, definitive conclusions can not be drawn in view of the small number of patients studied prospectively. In addition, these results suggest the potential of camptothecin-based therapy for patients unresponsive to standard treatment.     

Treatment practice in the elderly patient with chronic lymphocytic leukemia—analysis of the combined SEER and Medicare database

The median age at diagnosis of chronic lymphocytic leukemia (CLL) is 72, but patients enrolled in randomized trials are often a decade younger. Therapy selection and outcomes in the older, comorbid population are less understood. We evaluated treatment patterns and outcomes among 2,985 first primary CLL patients from the linked Surveillance, Epidemiology, and End Results–Medicare database. There were 151 chlorambucil (CLB), 594 rituximab monotherapy (R-mono), 696 rituximab?+?intravenous chemotherapy (R?+?IV Chemo), and 1,544 IV chemo-only patients. Patients administered CLB and R-mono were the oldest and had the highest comorbidity burden while patients receiving R?+?IV Chemo were the youngest and had the lowest comorbidity burden (p?<?0.0001). In the multivariate survival analysis, receipt of R?+?IV Chemo was associated with significantly lower mortality risk vs. IV Chemo-only (hazard ratio (HR)?=?0.73; 95 % confidence interval (CI) 0.62–0.87) and a non-significant mortality risk reduction with R-mono vs. CLB (HR?=?0.47; 95 % CI: 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. These findings suggest that chemoimmunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity, and this extends the conclusions from clinical trials in younger, medically fit patients.     

Ofatumumab retreatment and maintenance in fludarabine‐refractory chronic lymphocytic leukaemia patients

There are limited data on retreatment with monoclonal antibodies (mAb) in patients with chronic lymphocytic leukaemia (CLL). In a pivotal study, ofatumumab (human anti‐CD20 mAb) monotherapy demonstrated a 47% objective response rate (ORR) in fludarabine refractory CLL patients. From this study, a subset of 29 patients who had at least stable disease and then progressed were retreated with eight weekly ofatumumab infusions (induction treatment period), followed by monthly infusions for up to 2 years (maintenance treatment period). The ORR after 8 weeks of induction retreatment was 45% and 24% had continued disease control after maintenance at 52 weeks. Efficacy and safety of the retreated patients were compared with their initial results in the pivotal study. Response duration was 24·1 months vs. 6·8 months; time to next therapy was 14·8 months vs. 12·3 months; and progression‐free survival was 7·4 months vs. 7·9 months (medians). Upon retreatment, 72% had infusion reactions, mostly Grade 1–2. Three patients had fatal infections. In summary, ofatumumab retreatment and maintenance therapy was feasible in patients with heavily pretreated CLL and appeared to result in more durable disease control than initial ofatumumab treatment in this subset of patients who may have a more favourable disease profile.     

Early neutrophil-to-lymphocyte ratio reduction as a surrogate marker of prognosis in never smokers with advanced lung adenocarcinoma receiving gefitinib or standard chemotherapy as first-line therapy

Purpose

An inflammatory–immunological marker, neutrophil-to-lymphocyte ratio (NLR), was evaluated as a surrogate indicator for prognosis of advanced lung adenocarcinoma patients.

Methods

The subjects of this study were 199 never smokers with advanced lung adenocarcinoma, who were enrolled in a prospective randomized phase III study (First-SIGNAL) comparing gefitinib with gemcitabine plus cisplatin as first-line therapy. The values of NLR were assessed at two time points: at baseline (pretreatment) and on day 1 of the second cycle (posttreatment).

Results

A higher posttreatment NLR was associated with a worse tumor response (median posttreatment NLR, 1.56 for partial response, 1.64 for stable disease, and 2.70 for progressive disease; P?<?0.001). The risk of progression was higher when the posttreatment NLR was higher [hazard ratio (HR)?=?1.23, 95?% confidence interval (CI) 1.15–1.31; P?<?0.001]. A high posttreatment NLR was associated with an increased risk of death (HR?=?1.13, 95?% CI 1.06–1.21; P?<?0.001). These associations did not differ according to treatment arms. When total patients were divided into four groups according to the cutoff points of pre- and posttreatment NLRs, those with a high pretreatment NLR that declined substantially after treatment showed improved survival compared with those with a high pretreatment NLR that remained high even after treatment (median overall survival, 22.0 and 15.8?months, respectively; P?<?0.001).

Conclusions

A high posttreatment NLR is associated with poor prognosis. An early reduction in the NLR after effective treatment may indicate survival improvement in the patients with poor prognosis.     

Natural history of stage A chronic lymphocytic leukaemia untreated patients

S ummary . In chronic lymphocytic leukaemia (CLL), stage A was defined in 1979 as the best prognostic group of the three-stage (A, B, C) classification which was thereafter adopted by an International Workshop on CLL. Recently, the question of whether or not all stage A patients should be treated was raised by authors who described potential harmful effects of treatment among stage A patients and heterogeneity of stage A with respect to survival and disease progression.
In this work, we studied the natural history of stage A-CLL in order to determine on which grounds a decision to treat should be made. We performed a prognostic study on 309 untreated stage A-CLL patients enrolled in a randomized clinical trial from 1980 to 1985. Our aim was to segregate a subgroup with a low probability of disease progression and death. We used three endpoints: overall survival (50 deaths), disease progression to stage B or C (78 events) and disease progression to stage C (39 events). Multivariate analyses, using Cox's model, selected nine variables as having a prognostic value for at least one endpoint, namely age, sex, general symptoms, involved axillary lymph node, splenomegaly, haemoglobin, platelets, lymphocyte count and bone-marrow infiltration. By considering the three endpoints jointly, we obtained a proposed definition of smouldering CLL based on four variables, namely haemoglobin level, lymphocyte count, the number of enlarged areas and bone-marrow infiltration. However, we did not succeed in better defining smouldering CLL than in a previous proposal, based on haemoglobin level and lymphocyte count. Moreover, whatever the definition used, including other previous works, disease progression within 5 years was still observed for about 10% of patients with smouldering CLL. Future attempts to define smouldering CLL could perhaps benefit from using biological markers.     

Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) shows a remarkably heterogeneous clinical outcome; survival ranges from several months in advanced stages to more than 10 years in early stages. The Binet and Rai staging systems distinguish three major prognostic subgroups, but do not accurately predict the individual risk of disease progression in early CLL (Binet stage A or Rai stage 0 to II). Because most newly diagnosed CLL patients present with early disease, it seems desirable to search for additional prognostic factors to identify early CLL patients at high risk of rapid progression. It has been shown that elevated serum thymidine kinase (s-TK) levels predict disease progression in CLL. Therefore, this study aimed to assess the prognostic value of s-TK in 122 previously untreated patients with Binet stage A CLL (mean age +/- SD, 58.7 +/- 8.5 years). In univariate analyses, 18 of the 22 parameters investigated predicted progression-free survival (PFS). In a stepwise multiple regression analysis, only three parameters provided independent prognostic information on PFS: s-TK greater than 7.1 U/L; presence of lymphadenopathy; and white blood cell (WBC) count greater than 75, 000/microL. When added to the classification of smoldering versus nonsmoldering CLL, s-TK levels separated two groups within the group of nonsmoldering stage A patients: patients with s-TK values greater than 7.1 U/L had a median PFS of 8 months, whereas patients with s-TK values 相似文献   

Relationship between co‐morbidities at diagnosis,survival and ultimate cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study

The ultimate cause of death for most patients with newly diagnosed chronic lymphocytic leukaemia (CLL) and its relationship to co‐morbid health conditions is poorly defined. We conducted a prospective cohort study that systematically followed 1143 patients diagnosed with CLL between June 2002 and November 2014. Comorbid health conditions at the time of CLL diagnosis and their relationship to survival and cause of death were evaluated. Collectively, 1061 (93%) patients had at least one co‐morbid health condition at the time of CLL diagnosis (median number 3). Despite this, 89% of patients had a low‐intermediate Charlson Comorbidity Index score (CCI) at diagnosis. After a median follow‐up of 6 years, 225 patients have died. Death was due to CLL progression in 85 (46%) patients, infection in 14 (8%) patients, other cancer in 35 (19%) patients and comorbid health conditions in 50 (27%) patients. Higher CCI score and a greater number of major comorbid health conditions at the time of CLL diagnosis was associated with shorter non‐CLL specific survival, but not with shorter CLL‐specific survival on multivariate analysis. In conclusion, CLL and CLL‐related complications (infections and second cancers) are the overwhelming cause of death in patients with CLL, regardless of CCI score and number of comorbid health conditions at diagnosis.     

Leucocyte doubling time is a useful predictor of progression-free survival in chronic lymphocytic leukaemia

Abstract. Objective . To assess leucocyte doubling time (LDT) in relation to progression-free survival in patients with chronic lymphocytic leukaemia (CLL). In addition, to define the impact of a second LDT in both untreated and treated patients. Design . Retrospective study of LDT in previously untreated patients with CLL. Subjects and setting . Sixty patients diagnosed over a 13-year period at a county hospital. In forty-five of the 60 patients, an LDT could be defined. These patients were included in the final analysis. Main outcome measures . LDT below and above 12 months, progression-free and overall survival. Results . Patients in Binet stages B and C had a median LDT of 4 months as compared to 26 months in stage A patients (P < 0.01). The projected progression-free survival at 3 years was 24% in patients with an LDT of < 12 months. The corresponding figure for the remaining patients was 68% (P < 0.01). The overall 5-year survival did not differ significantly between patients with an LDT below and above 12 months, respectively. In seven untreated patients, a second LDT could be calculated which was shorter than the first recorded LDT. A second LDT was also identified in five patients post treatment that was consistently shorter than their first LDT. Conclusions . Measurement of LDT is a simple complement in predicting progression-free survival in patients with CLL. Thus, monitoring of LDT may add to the clinical evaluation and therapeutic decision making for the many elderly patients with this often indolent disease.     

Natural history of early chronic lymphocytic leukemia. A single institution study with emphasis on the impact of disease-progression on overall survival

BACKGROUND AND OBJECTIVE: Criteria for identifying patients with early chronic lymphocytic leukemia (CLL) who are likely to progress to a more advanced clinical stage rely on results of prospective clinical trials. Is not clear whether these same criteria apply to patients followed-up in the setting of clinical practice. With the aim of addressing this issue we investigated the clinical outcome of a series of patients with Binet stage A CLL. DESIGN AND METHODS: Two hundred and four Binet stage A CLL patients observed at a single institution over an 18-year period form the basis of this study. Different proposals for subclassifying Binet stage A were validated by using our patients as test-set cases. RESULTS: The survival of patients with early CLL (i.e., Binet stage A and Rai stage 0) was significantly different from that of an age- and sex-matched population. Three of 4 different criteria for subclassifying stage A (Rai substaging, Montserrat criteria, French Group proposal), when applied to our patients, gave similar results in terms of sample size, death rate and disease progression (DP) risk. The French Group proposal, based exclusively on blood counts and hemoglobin levels, was not effective in predicting the risk of DP. Forty-nine (23.5%) patients progressed to a more advanced clinical stage (30 to stage B and 19 to stage C); the risk of DP was 32.8% at 5 years and 49.6% at 10 years. When analyzed as a time-dependent variable (Mantel-Byar method), DP had a clear cut-impact on overall survival (p < 0.0001). Finally, outlook for survival of patients who experienced a change of clinical stage was similar to that of patients in that stage at the time of diagnosis. INTERPRETATION AND CONCLUSIONS: As many patients are now being diagnosed while asymptomatic and at a younger age than previously, an accurate evaluation of prognosis is mandatory in early CLL. How prognostic information translates into a policy of early or delayed therapy is still unclear. Our results further support a conservative approach for CLL in early stage; patients who progress into a more advanced stage have similar survival to those in that stage at diagnosis.     

Assessment of marrow trephine in relation to staging in chronic lymphocytic leukaemia

The prognostic value of the Rai clinical staging system and of a series of bone marrow features was examined in 167 untreated patients with CLL. The patients fell into three prognostic groups: those with limited disease, Rai stages 0 and I, median survival 107 months; those with intermediate disease, Rai stage II, median survival 44 months; and those with extensive disease, Rai stages III and IV, median survival 27 months. Two types of infiltration patterns, diffuse and nodular, were found in the bone marrow, and these were associated with significantly different median survival times: 34 and 115 months respectively.
It is suggested that diffuse and nodular patterns in the bone marrow relate to the rapidity of progress of the disease rather than to different stages in CLL.
The data suggest that a simplified clinical staging system together with an histological classification reflects both the extent as well as the rate of progression of CLL. The course of CLL may be monitored by sequential bone marrow biopsies to assess changes in the proliferation pattern, in the proliferative cell system and in the tumour mass, which give early warning of shifts in the rate of progression and therefore in the prognosis of the disease.     

Humoral immune failure defined by immunoglobulin class and immunoglobulin G subclass deficiency is associated with shorter treatment‐free and overall survival in Chronic Lymphocytic Leukaemia

Immune dysfunction attributed to hypogammaglobulinaemia is common in chronic lymphocytic leukaemia (CLL) and infection is a major contributor to morbidity and mortality. A higher incidence of multiple immunoglobulin and immunoglobulin G (IgG) subclass deficiency was associated with more advanced disease (P < 0·001 and P < 0·001, respectively) in a cohort of 147 CLL patients. Multiple immunoglobulin and IgG subclass deficiency were significantly associated with shorter treatment‐free survival (TFS) (P < 0·001 and P = 0·006, respectively). The association between disease stage and immune dysfunction demonstrated by these data suggest aspects of immune deficiency correlate with disease severity and may be associated with shorter TFS in CLL.     

Clinical and cell surface marker characterization of the early phase of chronic lymphocytic leukemia.

The immunologic surface markers on lymphocytes and clinical characteristics of 35 patients with established (stages 0-4) CLL with absolute lymphocyte counts greater than 15,000/cu mm were compared to those of a group of 25 patients with CLL in an early or preleukemic phase (counts of less than 15,000/cu mm). We found a monoclonal B cell proliferation in most cases in the latter group, in spite of the paucity of clinical and laboratory findings. Furthermore, early CLL can readily be distinguished from benign lymphocytosis by surface marker criteria. In untreated CLL, surface marker characteristics are stable with time and predominantly reflect expansion of clones expressing only B cell markers; however, small increase of blood T cells are often seen. Surface markers are a simple and clinically useful tool for definding and characterizing the preleukemic phase of CLL and its ultimate progression to established CLL.     

Salvage outcomes in patients with first relapse after fludarabine,cyclophosphamide, and rituximab for chronic lymphocytic leukemia: The French intergroup experience

The optimal management of patients with relapsed chronic lymphocytic leukemia (CLL) is dictated by the type of prior therapy, duration of prior response, presence of genomic aberrations, age, and comorbidities. The patterns of relapses and the clinical outcomes of second‐line options after fludarabine‐cyclophosphamide‐rituximab (FCR) is given as a frontline treatment are currently unknown. In this retrospective and non‐randomized study, we report the outcomes of 132 patients from databases of 14 French CLL study group centers who needed a second‐line treatment after FCR frontline. Bendamustine + rituximab (BR) was the most frequently used second‐line regimen, followed by alemtuzumab‐based regimens, R‐CHOP, and FCR. Median progression‐free survival (PFS) was 18 months after BR with a median overall survival (OS) not reached. We also found that response durations of < 36 months and the presence of del(17p) are critical factors that contribute to poor overall survival. BR appears to be an effective salvage regimen in our series, both in terms of progression‐free and overall survival. Patients who relapsed less than 36 months after FCR have a poor outcome, not significantly different in this study from patients with early relapses less than 12 or 24 months. Am. J. Hematol. 90:511–514, 2015. © 2015 Wiley Periodicals, Inc.     

Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia.

Ninety-six patients with stage III and stage IV chronic lymphocytic leukemia (CLL) were randomized into one of three treatment schedules. Prednisone was common to all three schedules and was given daily in an initial dosage of 0.8 mg/kg for the first 14 days, with successive halving of the daily dose on days 15 and 29 for a total 6-wk course. Prednisone was then given once a month at 0.8 mg/kg once a day for each of 7 consecutive days. Schedule I was prednisone plus chlorambucil (CLB) given as a once-a-month dose of 0.4-0.8 mg/kg; schedule II was both drugs, but the CLB was given as a daily dose of 0.08 mg/kg; schedule III was prednisone alone. Complete and partial remission (CR + PR) was 47% for schedule I, 38% for schedule II, and 11% for schedule III. Patients who responded (CR + PR) in each of the treatment schedules survived longer than the nonresponders. Complete remission was obtained in both CLB treatment schedules, but not with the prednisone alone regimen. Although overall survival was best in the intermittent CLB arm, there was no significant difference in survival time between the three treatment schedules. Toxicity was minimal in all three regimens. Augmentation of the intermittent monthly CLB, even to 1.5 and 2.0 mg/kg, was tolerated without undue marrow toxicity. About 22% of these patients either had diabetes mellitus at the time of entry on the study or manifested hyperglycemia during the course of treatment and observation.     

Platinum and high‐dose cytarabine‐based regimens are efficient in ultra high/high‐risk chronic lymphocytic leukemia and Richter's syndrome: results of a French retrospective multicenter study

Ultra high‐risk chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS) usually display a poor prognosis. Platinum and cytarabine‐based regimens have not been evaluated in large cohorts of patients with CLL or RS. This retrospective study was aimed to assess the efficacy of these regimens in 75 patients with relapsed/refractory (R/R) CLL or RS. Forty‐seven patients had R/R CLL (including 36 ultra high‐risk CLL) and 28 had RS. Median age was 62 years (range, 18–79 years). Median number of previous therapies was 3 (range, 1–7), including fludarabine‐based regimens (75%) and alemtuzumab (32%), and 61% of patients were refractory to their last treatment. Deletions of chromosomes 17p and 11q were found in 40% and 39% of cases, respectively. The overall response rates were 60% with 24% complete response (CR) in CLL, and 43% with 25% CR in RS. The median progression‐free survival and overall survival were 11 and 14.6 months, respectively. Fludarabine refractoriness and 17p deletion were not associated with a poorer outcome. The only factors predicting shorter survival were performance status ≥2 (P = 0.04) and albumin level <3.5 g/dL (P = 0.0004). Toxicities were mainly myelosuppression and infectious complications. Platinum and high‐dose cytarabine‐based regimens provide high response rates in high‐risk CLL and in RS. However, these results will be challenged by the new arriving agents at least in non‐transformed CLL.