Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL

Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute-Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population.     

A randomized,open‐label,multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine,cyclophosphamide and rituximab versus fludarabine,cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia

Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B‐cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open‐label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty‐seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression‐free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.     

Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed,refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study

Bendamustine + rituximab (BR) has demonstrated high response rates in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL). However, progression‐free survival (PFS) after BR is <18 months. This study was designed to determine if maintenance lenalidomide after BR induction could improve PFS in R/R CLL/SLL. Thirty‐four patients with R/R CLL/SLL who had received 1–5 prior chemotherapy regimens were treated with 6 cycles of BR induction. Patients achieving at least a minor response received twelve 28‐d cycles of lenalidomide 5–10 mg/d. The primary endpoint was PFS. The median age was 67 years, with a median of 2 prior therapies. Eleven patients had confirmed presence of 17p and/or 11q deletions. Twenty‐five (74%) completed 6 cycles of induction BR (response rate 56%). Nineteen (56%) patients received maintenance lenalidomide; only 6 patients completed the intended 12 cycles, highlighting the limited feasibility of lenalidomide in this setting, primarily due to haematological and infectious toxicities. The observed median PFS of 18·3 months is not significantly different from that of BR induction in R/R CLL/SLL without maintenance therapy (15·2 months). It is possible that lenalidomide maintenance may be more feasible and effective in the front‐line setting, which is being tested in an ongoing trial (NCT01754857).     

Is bendamustine an ideal partner for rituximab in the management of relapsed chronic lymphocytic leukemia? Results of a multicenter Phase II trial

First-line chemoimmunotherapy approaches offer prolonged disease-free survival in patients with chronic lymphocytic leukemia (CLL). Despite the improved results with purine analogs ± cyclophosphamide and rituximab (FCR) the disease remains incurable, and patients with CLL are destined to relapse after primary treatment. The prior therapy administered and the response, and duration of response to that therapy, are among the most important factors in determining the next therapy. Bendamustine, a bifunctional alkylating agent, combined with rituximab (BR) has been tested in patients with relapsed and/or refractory CLL in order to investigate the safety and efficacy of this combination. In conclusion, chemoimmunotherapy with BR showed interesting results, with the exception of patients carrying del(17p). Bendamustine appears to be a good choice for second-line therapy owing to its lack of significant cross-resistance with other alkylating agents or fludarabine.     

Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia

Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation.     

Akt inhibitor MK‐2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study

Akt is a downstream target of B cell receptor signaling and is a central regulator of CLL cell survival. We aim to investigate the safety and efficacy of the Akt inhibitor MK‐2206 in combination with bendamustine and rituximab (BR) in relapsed and/or refractory CLL in a phase I/II study. A standard phase I design was used with cohorts of three plus three patients to determine the maximum tolerated dose (MTD) of MK‐2206 in combination with BR in relapsed CLL. Single‐agent MK‐2206 (weekly dosed) was administered one‐week in advance before BR on cycle 1 and subsequently was given with BR at the same time for cycle 2‐6. Phase II employed the MTD of MK‐2206 with BR to evaluate safety and efficacy of this study combination. Thirteen relapsed/refractory CLL were treated for maximal 6‐cycle of therapy. The maximum tolerated dose of MK‐2206 was 90 mg by mouth once weekly. The most common grade 3/4 adverse events were neutropenia (46%), febrile neutropenia (23%), rash (15%), diarrhea (15%), and thrombocytopenia (15%). Overall response rate was 92% with a median progression free survival and treatment free survival of 16 and 24 months, respectively. Five patients (38%) achieved complete remission or complete remission with incomplete count recovery, two of whom were MRD negative. The efficacy and tolerability of this combination indicates that Akt inhibition combined with chemoimmunotherapy is a promising novel treatment combination in CLL and deserves further prospective clinical trial.     

Chemoimmunotherapy for relapsed/refractory and progressive 17p13‐deleted chronic lymphocytic leukemia (CLL) combining pentostatin,alemtuzumab, and low‐dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab‐containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short‐duration regimen combining pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab designed to decrease the risk of treatment‐associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13?) (n = 3). Thirteen (33%) patients had both 17p13? and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty‐six (67%) patients completed therapy, with only five (13%) patients having treatment‐limiting toxicity and no treatment‐related deaths. Twenty‐two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression‐free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B‐cell lymphoma (n = 6). Correlative studies showed that low‐dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab is a tolerable and effective therapy for CLL and that low‐dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. Am. J. Hematol. 89:757–765, 2014. © 2014 Wiley Periodicals, Inc.     

Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia

Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes.     

Advances in the treatment of relapsed/refractory chronic lymphocytic leukemia

Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients. New options include two agents targeting B cell receptor (BCR) signaling pathways (ibrutinib and idelalisib) and a B cell lymphoma-2 (BCL-2) inhibitor (venetoclax). Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative option for younger patients with a suitable donor.     

A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B‐cell lymphoma

Bendamustine in combination with rituximab (BR) has been associated with high response rates and acceptable toxicity in older patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL). Evaluation of BR is warranted in the front‐line setting for DLBCL patients not eligible for anthracyclines or for the elderly. In this phase II study, we enrolled DLBCL patients aged ≥65 years who were poor candidates for R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to determine the efficacy and safety of BR in previously untreated stage II–IV DLBCL. Twenty‐three patients were enrolled with a median age of 80 years. 52% of patients presented with poor functional status (Eastern Cooperative Oncology Group performance score of ≥2). The overall response rate was 78% with 12 complete responses (52%). At a median follow up of 29 months, the median overall survival was 10·2 months and the median progression‐free survival was 5·4 months. The most common grade 3/4 adverse events were haematological. Combination therapy with BR demonstrates high response rates as front‐line therapy in frail older patients with DLBCL, but survival rates were low. BR should be used with caution in future clinical trials involving older DLBCL patients with poor functional status.     

Advances in first‐line treatment of chronic lymphocytic leukemia: current recommendations on management and first‐line treatment by the German CLL Study Group (GCLLSG)

The management of patients with CLL is undergoing significant changes; during the last decade, the outcome of first‐line therapies has been markedly improved with the addition of anti‐CD20 antibodies to chemotherapy. Today, chemoimmunotherapy for physically fit patients ≤65 years should consist of fludarabine, cyclophosphamide, and rituximab (FCR). The combination of bendamustine and rituximab (BR) should be considered in physically fit patients >65 years and in patients with a higher risk of infections. Patients with reduced fitness and/or relevant comorbidity should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. Regardless of their fitness, patients with CLL carrying genetic aberrations such as del(17p) and/or TP53 mutation poorly respond to chemoimmunotherapy and therefore require different therapeutic approaches. An increasing understanding of the disease biology has led to the development of targeted drugs for the treatment of CLL, such as the BTK inhibitor ibrutinib and PI3K inhibitor idelalisib. These agents have shown efficacy in high‐risk and relapsed/refractory patients and are currently being evaluated in clinical trials for first‐line therapy. It is anticipated that these compounds and further other novel agents will profoundly change the therapy of CLL.     

Reduced‐dose fludarabine,cyclophosphamide, and rituximab (FCR‐Lite) plus lenalidomide,followed by lenalidomide consolidation/maintenance,in previously untreated chronic lymphocytic leukemia

Fludarabine, cyclophosphamide, and rituximab (FCR) remains the standard of care for fit chronic lymphocytic leukemia (CLL) patients requiring first therapy. However, side effects can be significant, and patients with poor risk features have inferior outcomes. The purpose of this study was to evaluate reduced‐dose FCR (FCR‐Lite) plus lenalidomide (FCR²) followed by lenalidomide maintenance as a strategy to shorten immunochemotherapy in untreated CLL. Patients received four to six cycles of FCR². Patients who were minimal residual disease (MRD) negative in peripheral blood (PB) and bone marrow (BM) initiated 12 months of lenalidomide maintenance after either four or six cycles (based on MRD status). The primary study endpoint was the complete response (CR) rate after four cycles of FCR². Twenty patients were evaluable. After four cycles of FCR², response rates were: CR, 45.0%; CR with incomplete blood count recovery (CRi), 5.0%; partial response (PR), 45.0%; and stable disease (SD), 5.0%. BM and PB samples from 27.8% and 52.9% of patients, respectively, were MRD negative. After six cycles, response rates were: CR, 58.3%; CRi, 16.7%; and PR, 25.0%. BM and PB samples from 50.0% and 72.7% of patients, respectively, were MRD negative. Overall, 75% of evaluable patients achieved a CR or CRi following FCR². After 17.4 months of median follow‐up, one progression and one death occurred. Our findings suggest that FCR² combines encouraging clinical activity with acceptable toxicity in previously untreated CLL. Lenalidomide can be safely added to FCR and may reduce chemotherapy exposure without compromising outcomes. Am. J. Hematol. 90:487–492, 2015. © 2015 Wiley Periodicals, Inc.     

Longer‐term follow‐up and outcome by tumour cell proliferation rate (Ki‐67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL‐001(EMERGE) pivotal trial

Patients with mantle cell lymphoma (MCL) generally respond to first‐line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL‐001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long‐term efficacy follow‐up of the prospective phase II MCL‐001 study (N = 134), including new exploratory analyses with baseline Ki‐67 (MIB1), a biological marker of tumour proliferation. With longer follow‐up, lenalidomide showed a 28% overall response rate [ORR; 8% complete response (CR)/CR unconfirmed (CRu)]. Median duration of response (DOR), progression‐free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki‐67. Ki‐67 data in 81/134 MCL‐001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki‐67–expressing groups, yet lower Ki‐67 levels demonstrated superior CR/CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post‐bortezomib.     

Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results

In 2008, we reported favorable 5-year outcomes of nonmyeloablative allogeneic stem cell transplantation after fludarabine, cyclophosphamide, rituximab (FCR) conditioning for relapsed and chemosensitive follicular lymphoma. However, innovative strategies were still needed to treat patients with chemorefractory disease. We therefore subsequently performed a trial in which (90)Y-ibritumomab tiuxetan (0.4 mCi/kg) was added to the fludarabine, cyclophosphamide conditioning regimen ((90)YFC). Here, we report updated results of the FCR trial and outcomes after (90)YFC. For the FCR group (N = 47), since the last update, one patient developed recurrent disease. With a median follow-up of 107 months (range, 72-142 months), the 11-year overall survival and progression-free survival rates were 78%, and 72%, respectively. For the (90)YFC group (N = 26), more patients had chemorefractory disease than did those in the FCR group (38% and 0%, P < .001). With a median follow-up of 33 months (range,17-94 months), the 3-year progression-free survival rates for patients with chemorefractory and chemosensitive disease were 80% and 87%, respectively (P = .7). The low frequency of relapse observed after a long follow-up interval of 9 years in the FCR group suggests that these patients are cured of their disease. The addition of (90)Y to the conditioning regimen appears to be effective in patients with chemorefractory disease. This trial was registered at www.clinicaltrials.gov as NCT00048737.     

Outcomes and treatments of patients with immunoglobulin light chain amyloidosis who progress or relapse postautologous stem cell transplant

Immunoglobulin light chain (AL) Amyloidosis is a condition whereby misfolded proteins generated by plasma cells deposit in tissues causing organ dysfunction. Chemotherapy and autologous stem cell transplant when eligible are standard treatment options. Several studies report long‐term outcomes of patients post‐transplant. However, there is a paucity of literature describing outcomes of relapsed patients post‐transplant. We performed a retrospective study to assess outcomes and therapies employed upon relapse after transplant. Between 1996 and 2009, 410 patients received transplant at the Mayo Clinic as first‐line therapy. Of those patients, 42 (10%) died within 3 months of transplant, 64 (16%) died without documented relapse, 158 (38%) were alive without documented progression, and 146 (36%) had documented progression. Those 146 patients are the subject of our study, and their median time to hematologic relapse/progression was 23.6 months (95%CI 18.3, 26.3 months). Their median overall survival and 5‐yrs overall survival from post‐transplant relapse/progression was 51.7 months (95%CI 34.1–62.3) and 39%, respectively. The most common first regimen for treatment after relapse was lenalidomide or thalidomide. In conclusion, our study indicates that patients with AL amyloidosis fare well post‐transplant relapse/progression. Additionally, it provides a yardstick to design clinical trials to determine best treatment options.     

The absolute percent deviation of IGHV mutation rather than a 98% cut‐off predicts survival of chronic lymphocytic leukaemia patients treated with fludarabine,cyclophosphamide and rituximab

The degree of somatic hypermutation, determined as percent deviation of immunoglobulin heavy chain gene variable region sequence from the germline (IGHV%), is an important prognostic factor in chronic lymphocytic leukaemia (CLL). Currently, a cut‐off of 2% deviation or 98% sequence identity to germline in IGHV sequence is routinely used to dichotomize CLL patients into mutated and unmutated groups. Because dissimilar IGHV% cut‐offs of 1–5% were identified in different studies, we wondered whether no cut‐off should be applied and IGHV% treated as a continuous variable. We analysed the significance of IGHV% in 203 CLL patients enrolled on the original frontline fludarabine, cyclophosphamide and rituximab (FCR) trial with a median of 10 years follow‐up. Using the Cox Proportional Hazard model, IGHV% was identified as a continuous variable that is significantly associated with progression‐free (PFS) and overall survival (OS) (P < 0·001). Furthermore, we validated this finding in 323 patients treated with FCR off‐protocol and in the total cohort (n = 535). Multivariate analysis revealed a continuous trend. Higher IGHV% levels were incrementally associated with favorable PFS and OS in both FCR‐treated cohorts (P < 0·001, both cohorts). Taken together, our data suggest that IGHV% is a continuous variable in CLL patients treated with FCR.     

Outcomes of patients with relapsed/refractory diffuse large B‐cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era

Salvage chemotherapy followed by autologous stem cell transplant (ASCT) remains the current standard of care for patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) with chemosensitive disease. The addition of rituximab results in improved overall survival (OS) after first‐line treatment, but cure rates of salvage therapy with ASCT are inferior when compared to historical controls. Historically, patients with DLBCL with disease progression following ASCT have had an extremely poor prognosis with a median OS of 3 months. However, there are little data regarding outcomes in the rituximab era. We performed a retrospective study of 56 patients with relapsed or refractory DLBCL with prior exposure to rituximab who had disease progression following ASCT. The median OS from progression following ASCT for the cohort was 9.9 months (95% CI: 5.3–13.1 months). Patients who progressed less than 1 year from ASCT had a significantly shorter OS than those who progressed at 1 year or greater from ASCT (8.2 vs. 26.7 months, P = 0.01). Patients with at least stable disease following ASCT had a longer OS than those who progressed immediately after ASCT (12.3 vs. 5.3 months, P = 0.01). Other factors associated with OS were International Prognostic Index (IPI) (P = 0.01) and LDH level (P = 0.0003) at the time of progression following ASCT. In the rituximab era, the prognosis for patients with disease progression following ASCT remains poor, but is improved when compared with historical controls. Ultimately, more work needs to be done to develop novel therapeutic strategies tailored to individual patients in this heterogeneous population. Am. J. Hematol. 88:890–894, 2013. © 2013 Wiley Periodicals, Inc.     

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

Patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1–12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow‐up of 28 months, overall response rate was 85% and estimated 30‐month progression‐free and overall survival rates were 57% [95% confidence interval (CI) 50–64] and 69% (95% CI 61–75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression‐free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult‐to‐treat CLL/SLL populations.     

An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia

Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52(+) B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m2 per day, oral cyclophosphamide 250 mg/m2 per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors.     

Real-world outcomes upon second-line treatment in patients with chronic lymphocytic leukaemia

For chronic lymphocytic leukaemia (CLL), targeted drugs have become the standard of care, in particular for second-line treatment. In this study, overall survival (OS), treatment-free survival (TFS) and adverse events (AE) were registered retrospectively in a Danish population-based cohort upon second-line treatment for CLL. Data were collected from medical records and the Danish National CLL register. For 286 patients receiving second-line treatment, three-year TFS was higher upon targeted treatment (ibrutinib/venetoclax/idelalisib) [63%, 95% confidence interval (CI) 50%–76%] compared with fludarabine, cyclophosphamide and rituximab or bendamustine and rituximab (FCR/BR) (37%, CI: 26%–48%) and chlorambucil+/−CD20-antibody (CD20Clb/Clb) (22%, CI: 10%–33%). Upon targeted treatment, three-year OS estimates were higher for targeted treatment (79%, CI: 68%–91%) compared with FCR/BR (70%, CI: 60%–81%) or CD20Clb/Clb (60%, CI: 47%–74%). The most common AEs were infections and haematological AEs; 92% of patients treated with targeted drugs had AEs, 53% of which were severe. Upon FCR/BR and CD20Clb/Clb, AEs were present for 75% and 53% respectively, of which 63% and 31% were severe. These real-world data demonstrate higher TFS and a tendency towards higher OS following targeted second-line treatment for CLL compared to chemoimmunotherapy, also for patients who may be frailer and more comorbid.