Approved drugs by categories for the treatment of CLL
Abstract
Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a very variable clinical outcome. New biological markers, such as cytogenetic abnormalities or mutation status, have become important prognostic factors. Whole-genome sequencing studies have revealed novel genomic mutations, NOTCH1, SF3B1, BIRC3, TP53 and MYD88 being the most important. All these mutations have also been associated with the disease outcome. The treatment of CLL has evolved favourably in recent years. However, adverse events or chemorefractoriness occurs in some cases. Luckily, an increasing number of compounds are under development with promising results. Some of these new targeted therapies include B-cell receptor inhibitors, new anti-CD20 antibodies, Bcl-2 inhibitors, immunomodulatory drugs or chimeric antigen receptors (CARs). In this chapter, we will conduct a review of the new prognostic markers of CLL, the relationship they have with each other to build prognostic scores, the role they have in guiding treatment decisions and the novel therapies that have emerged recently with immunologic, biochemical and genetic targets.
Keywords
- Chronic lymphocytic leukaemia
- genetic abnormalities
- recurrent mutations
- targeted therapy
- signalling pathway
1. Introduction
Chronic lymphocytic leukaemia (CLL) is a neoplasm characterized by the proliferation and accumulation of monoclonal mature B lymphocytes in the peripheral blood, bone marrow, spleen and lymph nodes. It is the most frequent type of leukaemia in adults from Western countries, showing a predilection for the elderly, with a median age at diagnosis of 72 years old. It has been more prevalent in men than in women [1, 2].
The clinical course of CLL is highly heterogeneous. Some patients require treatment at the time of diagnosis, while others remain asymptomatic and may even never be treated. Therefore, median survival times range from a few months to many decades [3,4]. In order to define disease extent and prognosis, Rai and Binet staging systems were designed around 35–40 years ago and remain widely used in clinical practice [5,6]. They are based on physical examination and blood counts and are therefore inexpensive and easy to apply. However, some patients with early stages promptly progress and do not respond to therapy. For these reasons, over the last ten years, several biological markers such as immunoglobulin heavy-chain variable region (
CLL remains an incurable disease with the exception of allogeneic transplantation. Besides, some patients without treatment present survival rates similar to the normal population, and no benefit has been found when early treatment has been applied in this subset of patients. In addition, spontaneous cure has been reported in rare occasions [11]. For these reasons, only half of the patients diagnosed with CLL will require treatment during follow-up. Fortunately, survival rates of patients with CLL have improved significantly, thanks to the great advances in treatment over the past decades [12]. Glucocorticoids and alkylating drugs were the first treatments introduced, followed by purine analogues. Later, the arrival of targeted antibody therapy led by rituximab (anti-CD20) was the most revolutionary progress. Bendamustine, another alkylating agent used in Germany for more than 30 years, has also been approved for the treatment of CLL after showing its benefits for this disease in clinical trials [13,14]. All these drugs remain widely used in routine clinical practice, mainly in combination regimens. In fact, chemo-immunotherapy regimens are nowadays the standard approach to therapy of most patients with CLL, as they have demonstrated to produce a survival benefit with durable remissions [15–17]. Table 1 sums up approved drugs for the treatment of CLL by categories; and Table 2 summarizes the combination of suggested treatment regimens used for the treatment of CLL recommended by the NCCN (National Comprehensive Cancer Network) [17].
|
Chlorambucil |
Cyclophosphamide |
Bendamustine |
|
Fludarabine |
Pentostatin |
Cladribine |
|
|
Rituximab |
Ofatumumab |
Obinutuzumab |
|
Alemtuzumab |
|
Ibrutinib |
Idelalisib |
|
|
FCR | Fludarabine, cyclophosphamide, rituximab |
FR | Fludarabine, rituximab |
PCR | Pentostatin, cyclophosphamide, rituximab |
BR | Bendamustine, rituximab |
Chlorambucil + anti-CD20 | Rituximab/obinutuzumab/ofatumumab |
HDMP + rituximab | High-dose methylprednisolone, rituximab |
RR | Lenalidomide, rituximab |
RCHOP | Rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone |
Idelalisib + rituximab | Idelalisib, rituximab |
Alemtuzumab + rituximab | Alemtuzumab, rituximab |
Nevertheless, some of these regimens are not exempted from adverse events that limit their use in frail patients, especially the elderly. Moreover, some patients are chemo-resistant to these drugs, and a curative therapy is still absent for them. Knowledge of the pathogenesis of B-cell receptor (BCR) has led to the investigation of novel molecular targets like Bruton tyrosine kinase inhibitors or phosphatidylinositol 3-kinases (PI3Ks). New anti-CD20 antibodies such as ofatumumab or obinutuzumab have also been shown to have a promising activity in CLL. Other new target therapies under study include Bcl-2 inhibitors, immunomodulatory drugs (lenalidomide) or chimeric antigen receptors. The second part of this chapter will be dedicated to review novel therapies that have emerged recently with immunologic, biochemical and genetic targets.
2. Prognostic markers and risk stratification of CLL
The clinical course of CLL is extremely variable. Prognostic markers are important not only for patient management but also in understanding the disease biology. Many biological factors have been added to the classic staging systems of Rai and Binet with the intention to establish prognostic groups. However, as novel cytogenetic and molecular findings are discovered, our understanding on its prognostic value keeps in constant evolution. In this section, we will conduct a review of these “new” prognostic markers, focusing on genetic markers.
2.1. Genetic markers in CLL
2.1.1. Recurrent genomic abnormalities detected by interface fluorescence in situ hybridization (FISH)
FISH studies are able to detect clonal genomic aberrations in the majority (>80 %) of CLL patients. The most common recurrent chromosomal abnormalities include 13q deletion (13q-), 11q deletion (11q-), trisomy 12 (+12) and 17p deletion (17p-), defining five prognostic categories with different survival times [18].
2.1.1.1. 13q-
13q- is the most frequent chromosome aberration in CLL, observed in approximately 55 % of the cases, and entails the group of patients with a better prognosis. However, the deletions that occur at this chromosome are not homogeneous and neither is the prognosis for this subgroup of patients. The size of the deletion varies thumping. Two types of deletion have been proposed in accordance to their extent: 13q- type I or short deletions not comprising the
2.1.1.2. 11q-
Prevalence of 11q deletions is estimated below 20 % [18]. The presence of 11q- entails bad prognosis, and often patients present with progressive disease, B symptoms, bulky lymphadenopathy, short TTFT and a reduced OS. In addition, 11q- is associated with unmutated
2.1.1.3. +12
Trisomy 12 is the third most frequent cytogenetic aberration, occurring in up to 15 % of CLL cases. Patients with this aberration have been classically considered to have an intermediate prognosis; however, further work has considered this trisomy as a clinical heterogeneous entity [36]. +12 has been associated with an atypical morphology and immunophenotype [37] and has been connected with concurrent trisomy of chromosomes 18 and 19 [38]. Critical genes involved in this aberration remain unknown.
2.1.1.4. 17p-
17p deletion is observed in around 7 % of untreated CLL cases, but its incidence may amount up to 45 % in cases of relapsed or refractory CLL [43]. 17p- is invariably associated with a very poor outcome because of the loss of
2.1.2. IGHV mutation status
The somatic hypermutation of the variable region of the immunoglobulin heavy-chain genes (
2.1.3. Mutations of key tumour suppressor genes
2.1.3.1. TP53 mutations
CLL harbours
2.1.3.2. ATM gene mutations
ATM gene encodes for the ATM protein kinase, a member of the
2.1.4. Novel gene mutations
New deep sequencing technologies have discovered in the last five years novel recurrent mutations in CLL,
|
|
|
|
|
|
|
9 | +12 | NOTCH1 signalling | Poor | 10–15 % |
|
2 | 11q- | mRNA splicing | Poor | 5–10 % |
|
11 | 11q- | NF-κB pathway | Poor | 4 % |
|
3 | 13q- | NF-κB pathway | Good | 3 % |
|
11 | 11q- | DNA repair | Poor | 12 % |
|
17 | 17p- | DNA repair | Dreadful | 5–10 % |
2.1.4.1. NOTCH 1
2.1.4.2. SF3B1
2.1.4.3. BIRC3
2.1.4.4. MYD88
2.1.5. Other genetic abnormalities with prognostic relevance
Other genetic abnormalities have been reported in CLL in a very low proportion of cases. These include deletion of 6q, trisomy 3, trisomy 8, trisomy 18, trisomy 19, deletion of 5q and gains of 2p, 3q, 17q and 8q. These alterations have also been related to disease outcome in a recent study that used array comparative genomic hybridization to identify genomic imbalance. Three groups of patients were made according to their prognostic outcome: good outcome (13q- without any of these alterations: gain, 1p, 7p, 12, 18p, 18q, 19, and loss, 4p, 5p, 6q, 7p), adverse outcome (gain, 2p, 3q, 8q, 17q, and loss, 7q, 8p, 11q, 17p, 18p) or intermediate outcome (remainder). This study also identified gain of 3q, 8q and 17p- as independent unfavourable prognostic biomarkers [69]. Translocations are also rare in CLL, but when present, they entail a negative prognostic impact [70]. Finally, complex karyotypes, defined by 3 or more alterations, whether deletions or gains, have also been associated with progressive or refractory disease and
2.2. Other prognostic biomarkers in CLL
Many non-genetic markers predict disease outcome in CLL. A brief enumeration of them and their implication in prognosis will be detailed below. Serum markers LDH and β2-microglobulin have been widely used, indicating a more advance disease when their levels are high, and although they are not specific for CLL, they can be easily measured in clinical practice [71]. Lymphocyte double time, defined as the number of months that takes the lymphocyte count to double, is another classic prognostic marker that can be easily used in CLL. Hence, it has been proposed as one of the criteria to indicate therapy [72]. Several protein markers were investigated with the intention to find substitute markers for the arduous
2.3. Prognostic systems
Numerous prognostic markers have individually shown correlations with survival over the last decades. The current challenge is to build a prognostic model that is clinically relevant, easily applicable, oriented to take therapeutic decisions and feasible in the clinical practice setting. With these goals, some attempts have been done over time. A review of some of these models is summarized in Table 4 and detailed next [76].
|
|
|
|
-Haematological blood counts -Physical examination |
Low: lymphocytosis Intermediate: lymphadenopathy, visceromegaly High: anaemia or thrombocytopenia |
|
-Haematological blood counts -Physical examination |
A: < 3 areas lymphadenopathy B: no A, no B C: anaemia or thrombocytopenia |
|
-FISH | 13q-: median overall survival (OS) of 133 months Normal karyotype: 111 months +12: 114 months 11q-: 72 months 17p-: 32 months |
|
-Age -Absolute lymphocyte count -β2-microglobulin levels -Rai stage -Sex -Number of lymph node regions |
Calculate the 5-year and 10-year survival probability with specific nomogram |
|
-LDH -Number of lymph node regions -Size of lymph nodes on the neck -IGHV mutation status -FISH aberrations |
Calculate the 2-year and 4-year treatment-free probability with specific nomogram |
|
-Sex -Age -ECOG status -17p- (six points) -11q- - -β2-microglobulin levels -Thymidine kinase |
Male, 1 point; TK >10 U/L, 2 points; β2-microglobulin 1.7–3.5 mg/dL, 1 point; β2-microglobulin >3.5 mg/dL, 2 points; unmutated-CLL (U-CLL), 1 point; ECOG >0, 1 point; 11q-, 1 point; age >60 years, 1 point Low risk: score 0 to 2 Intermediate risk: score 3 to 5 High risk: score 6 to 10 Very high: score 11 to 14 |
|
-FISH -New mutations |
Very low risk: 13q- only Low risk: +12 or a normal FISH Intermediate risk: High risk: |
|
-Age -Leucocyte count -IgH translocations -Number of cytogenetic aberrations - |
Predicting OS: Age ≥ 65 years, 1 point; leucocyte count ≥20 × 109/l, 1 point; U-CLL,1 point; Favourable risk: 0–3 points Intermediate risk: 4–5 points Unfavourable risk: "/>5 points Predicting TTFT: U-CLL, 1 point; Favourable risk: 0–2 points Intermediate-1 risk: 3 points Intermediate-2 risk: 4 points Unfavourable risk: 5 points |
Rai and Binet prognostic systems [5,6] were the initial scores intended to predict prognosis in patients with CLL. These score systems still stand in routine clinical practice nowadays as they are good predictors for prognosis, inexpensive and able to identify the need for therapy. The biggest disadvantage of them is that a notable amount of patients with early stages progress.
3. Targeted therapy for CLL
Immuno-chemotherapy is the initial approach to the majority of CLL patients who require therapy nowadays. However, some patients relapse, become refractory or suffer important secondary adverse events. For these reasons, the emergence of new targeted treatments has and will revolutionize the treatment model for CLL. Hopefully, targeted therapy will be not only more effective in improving survival of CLL patients but also less toxic, ameliorating quality of life of patients under treatment. This part of the chapter will be dedicated to review the novel targeted treatments that have been already approved or are being studied for the treatment of CLL.
3.1. Second-generation anti-CD20 monoclonal antibodies
CLL cells express antigen CD20 with a low intensity, but enough for the chimeric mouse anti-human CD20 monoclonal antibody rituximab to lyse these cells. Rituximab acts by different mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-mediated cytotoxicity and direct toxicity. When used in combination with chemotherapy, rituximab has demonstrated superiority over chemotherapy regimens and has therefore become a standard of care in the treatment of CLL patients either in frontline or salvage therapy [14,15].
3.1.1. Ofatumumab
Ofatumumab is a fully humanized anti-CD20 that binds to a different CD20 epitope than rituximab, generating a greater cytotoxic potential than rituximab by complement-mediated cytotoxicity with the same ADCC. It has been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of fludarabine and alemtuzumab refractory CLL patients and recently by the FDA for previously untreated patients in combination with chlorambucil (Clb) in whom fludarabine-based therapy is considered inappropriate. The study that gave the indication of ofatumumab for previously treated patients consisted of a phase II trial including 138 patients with either fludarabine and alemtuzumab refractoriness or fludarabine refractoriness and bulky disease. Overall response (OR) rates were 58 % and 47 %, and median OS were 13.7 and 15.4 months, respectively. The most common adverse events were infusion reactions and infections, which were primarily grade 1 or 2 events [83]. The FDA approval of ofatumumab in combination with chlorambucil for previously untreated CLL patients was based on the results of a phase III trial only preliminary reported, comparing ofatumumab in combination with chlorambucil to single-agent chlorambucil in 447 patients in whom fludarabine-based therapy was considered to be inappropriate. The ofatumumab + chlorambucil arm demonstrated superiority with a higher OR (82 % vs. 69 %), CR (12 % vs. 1 %) and PFS (22.4 vs. 13.1 months) [84]. Anyway, a formal comparative trial of ofatumumab versus rituximab is missing, and therefore, the real value of ofatumumab remains to be determined.
3.1.2. Obinutuzumab (GA101)
Obinutuzumab is a new second-generation recombinant humanized anti-CD20, glycoengineered to increase its affinity in binding the type 2 CD20 epitope. Obinutuzumab produces an increased ADCC and direct cytotoxicity, with lower complement-mediated toxicity. The FDA approved this drug for its use in combination with chlorambucil for the treatment of patients with previously untreated CLL, in view of the primary results of the CLL-11 trial [85]. This study consisted of a phase III international clinical trial that compared chlorambucil (Clb) versus chlorambucil plus rituximab (R-Clb) versus chlorambucil plus obinutuzumab (O-Clb) in previously untreated CLL patients not candidates to receive fludarabine. Patients in the O-Clb arm achieved a higher OR rate and a prolonged PFS compared to patients in the R-Clb arm and a benefit in OS, PFS and OR rate than patients receiving Clb alone. Grade 3 and 4 neutropenia and infusion reactions were more common with O-Clb than with R-Clb, but the risk of infection was not increased. An updated analysis of this trial has been recently published, confirming the PFS benefit in the arm of O-Clb vs. R-Clb (29.2 versus 15.4 months,
3.2. B-Cell receptor signalling pathway
The B-cell receptor (BCR) signalling pathway is vital for CLL cell survival and proliferation and therefore constitutes an important new strategy for targeted therapy in CLL. Bruton tyrosine kinase (BTK) or phosphoinositide 3'-kinase (PI3K) constitutes some of the key kinases in this pathway. Inhibitors of these kinases have been under investigation in patients with CLL with promising clinical results and minimal toxicity. In fact, ibrutinib and idelalisib, two oral compounds given as continuous treatment, have been recently approved for treatment of CLL patients. They have demonstrated high efficacy even in the higher-risk patient subgroup. One important aspect of treatment with BCR inhibitors is the development of lymphocytosis, often transient, mediated by the migration of CLL cells from the bone marrow and lymph nodes to the peripheral blood, where cell survival is decreased.
3.2.1. Ibrutinib
Ibrutinib is an oral small molecule that acts as an irreversible covalent inhibitor of the BTK resulting in an inhibition of the BCR signalling pathway. It is the first BCR inhibitor approved by the FDA and EMA for the treatment of relapsed or refractory CLL and as a first-line treatment in cases of 17p- or
3.2.2. Idelalisib (CAL-101)
Idelalisib is an oral selective inhibitor of PI3K that produces apoptosis in CLL cells. It has been approved by the FDA and EMA for use in combination with rituximab for patients who have received at least one prior therapy or as first-line treatment in the presence of 17p deletion or
3.3. Bcl-2 inhibitors
B-cell lymphoma-2 (Bcl-2) proteins, encoded by the Bcl-2 gene, are expressed at high levels in CLL cells. These proteins contribute to the regulation of the apoptotic process and therefore constitute an important therapeutic target for CLL.
3.3.1. ABT-263 (navitoclax)
Navitoclax is an orally bioavailable BCL-2 inhibitor that binds to several antiapoptotic BCL-2 family proteins including BCL-2, BCL-XL, BCL-x and BCL-B. A phase I trial conducted to evaluate the biologic activity, safety and pharmacokinetics of ABT-263 demonstrated encouraging results for this molecule as a single agent, even in patients with fludarabine-refractory disease, bulky adenopathy or 17p-. However, its therapeutic use was limited because of severe thrombocytopenia, observed as an important adverse effect in 28 % of the patients due to the inhibition of BCL-XL.
3.3.2. GDC-0199/ABT-199 (venetoclax)
GDC-0199/ABT-199 is a small molecule reengineered to decrease the thrombocytopenia side effect of navitoclax. ABT-199 produces a selective inhibition BCL-2 with a reduced effect on BCL-XL. It has shown promising results in a phase I trial that enrolled 56 refractory or relapsed CLL patients, 29 % with 17p- and 32 % with fludarabine resistance [93]. The major side effects included tumour lysis syndrome and neutropenia. Interestingly, ABT-199 yielded an OR rate of 85 %, with 13 % of complete responses and 72% of partial responses. These encouraging results were also observed in high-risk patients, with a response rate of 88 % and 75 % in patients with 17p- and fludarabine refractory, respectively. Clearly, these data indicate that Bcl-2 inhibitors will play an important role in the future for the treatment of CLL patients, and therefore, ABT-199 is currently being investigated in combination with immuno-chemotherapy.
3.4. Immunomodulatory drugs
Changes in the microenvironment of tumour cells promote the selective survival of malignant CLL cells preventing apoptosis. Immunomodulatory drugs act by altering cellular features and the cytokines of tumour microenvironment. In fact, lenalidomide has been shown to be effective in CLL.
3.4.1. Lenalidomide
Lenalidomide is an oral second-generation immunomodulatory drug with antiangiogenic, cytokine activity modulating, and immunomodule properties. It has been demonstrated to be active in MDS, multiple myeloma and lymphoproliferative disorders. The first phase II trials that tested lenalidomide in relapsed or refractory CLL obtained an OR rate between 32 % and 47 %. The major adverse effects reported were myelotoxicity, tumour flare and tumour lysis syndrome, all of them ameliorated with lower doses of lenalidomide [94,95]. Lenalidomide was also tested as a front-line therapy for CLL patients in another two trials with a different dosing, but both with a low initial dose (2.5–5 mg daily) and a further escalation to a target of 25 mg. These trials obtained an OR rate between 56 % and 65 %. A high proportion of tumour flare reactions were observed in one of them, although they were mild. Grade 3 or 4 neutropenia was also frequent but without serious consequences. A recent update of one of these studies showed that at a median follow-up of 4 years, time to treatment failure had not been reached and OS was 86 %. These studies showed that lenalidomide is effective as first-line therapy for CLL and is well tolerated when administered in a dose escalation plan [96–98]. Lenalidomide has also been tested in combination with other drugs. In a phase II trial, patients with relapsed or refractory CLL received a combination of rituximab and lenalidomide obtaining an OR rate of 66 % including 12 % of complete responses. Seventy-three percent of patients showed neutropenia (grade 3 or 4), and only 1 episode of grade 3 tumour lysis was reported. Another phase II study of lenalidomide and rituximab was performed, this time as a first-line therapy. The OR rate was 88 %, including 15 % of complete responses. Again, neutropenia was the most common adverse event [99,100]. Additional combinations are currently under study, as well as maintenance therapy after chemo-immunotherapy.
3.5. Chimeric antigen receptors
Chimeric antigen receptors (CARs) are engineered constructs that combine the antigen recognition domain of an antibody with intracellular signalling domains into a single chimeric protein. CD19 antigen is exclusively expressed in B-cells and therefore is a very suitable target for the treatment of CLL with CARs. Indeed, a pivot clinical trial proved the important antitumor activity of this CAR-modified autologous T-cells targeted to CD19 (CART19 cells) in three patients with refractory CLL [101]. Two out of the three patients achieved a complete response lasting longer than two years and the other patient a partial stable response. Toxicities included hypogammaglobulinemia, decreased number of plasma-cells and B-cell aplasia. The CART19 cells expanded > 1,000-fold in vivo and expressed functional CARs for at least six months, and a proportion of them persisted as memory CART19 cells. On average, each infused CAR-expressing T-cell was calculated to eradicate at least 1,000 CLL cells. In another study, ten patients with refractory CLL or relapsed B-cell acute lymphoblastic leukaemia (ALL) were treated with CART19 modified to express a second-generation CAR anti-CD19. Three of the four evaluable patients with bulky CLL who received prior treatment with cyclophosphamide experienced either a significant reduction or a mixed response in lymphadenopathy without development of B-cell aplasia. The short-term persistence of infused T-cells was enhanced by previous administration of cyclophosphamide and was inversely proportional to the tumour burden in peripheral blood [102]. In addition, a longer follow-up from ten patients treated with CART19 was reported. The study included nine adults with relapse or refractory CLL, three patients with p53 deletion and a child with relapsed and refractory ALL [103]. CLL patients received chemotherapy regimens 4–6 days before CART19 infusions. Four of the nine evaluable patients achieved a complete response, including three patients with CLL. Two additional patients from the CLL group had a partial response lasting from three to five months, and three patients did not respond. In the four patients who achieved complete response, maximal expanded cells in peripheral blood were detected at an average of 27-fold higher than the infused dose. No patients with complete response relapsed. Patients who responded developed a cytokine release syndrome manifested by fever, as well as variable degrees of anorexia, nausea, transient hypotension and hypoxia. In responding CLL patients, cytokine levels were increased, and five patients with cytokine release required treatment. In summary, CART19 can induce potent and sustained responses in patients with advance, refractory and high-risk CLL. However, further research is needed to ascertain the efficacy of this therapy and minimize associated cytokine-mediated toxicities.
References
- 1.
Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995 Oct 19;333(16):1052–7. - 2.
Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment. Am J Hematol. 2013 Sep;88(9):803–16. - 3.
Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet. 2008 Mar 22;371(9617):1017–29. - 4.
Hernández JA, González M, Hernández JM. [Chronic lymphocytic leukemia]. Med Clínica. 2010 Jul 3;135(4):172–8. - 5.
Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219–34. - 6.
Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198–206. - 7.
Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764–75. - 8.
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1848–54. - 9.
Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840–7. - 10.
Rodríguez-Vicente AE, Díaz MG, Hernández-Rivas JM. Chronic lymphocytic leukemia: a clinical and molecular heterogenous disease. Cancer Genet. 2013 Mar;206(3):49–62. - 11.
Del Giudice I, Chiaretti S, Tavolaro S, De Propris MS, Maggio R, Mancini F, et al. Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood. 2009 Jul 16;114(3):638–46. - 12.
Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood. 2008 May 15;111(10):4916–21. - 13.
Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2009 Sep 10;27(26):4378–84. - 14.
Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol Off J Am Soc Clin Oncol. 2012 Sep 10;30(26):3209–16. - 15.
Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164–74. - 16.
Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, et al. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. J Clin Oncol Off J Am Soc Clin Oncol. 2014 Apr 20;32(12):1236–41. - 17.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Hodgkin’s Lymphomas. Version 1.2015 [Internet]. [cited 2015 Feb 1]. Available from: http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf - 18.
Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910–6. - 19.
Mosca L, Fabris S, Lionetti M, Todoerti K, Agnelli L, Morabito F, et al. Integrative genomics analyses reveal molecularly distinct subgroups of B-cell chronic lymphocytic leukemia patients with 13q14 deletion. Clin Cancer Res Off J Am Assoc Cancer Res. 2010 Dec 1;16(23):5641–53. - 20.
Parker H, Rose-Zerilli MJJ, Parker A, Chaplin T, Wade R, Gardiner A, et al. 13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia. Leukemia. 2011 Mar;25(3):489–97. - 21.
Chena C, Avalos JS, Bezares RF, Arrossagaray G, Turdó K, Bistmans A, et al. Biallelic deletion 13q14.3 in patients with chronic lymphocytic leukemia: cytogenetic, FISH and clinical studies. Eur J Haematol. 2008 Aug;81(2):94–9. - 22.
Van Dyke DL, Shanafelt TD, Call TG, Zent CS, Smoley SA, Rabe KG, et al. A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2010 Feb;148(4):544–50. - 23.
Puiggros A, Delgado J, Rodriguez-Vicente A, Collado R, Aventín A, Luño E, et al. Biallelic losses of 13q do not confer a poorer outcome in chronic lymphocytic leukaemia: analysis of 627 patients with isolated 13q deletion. Br J Haematol. 2013 Oct;163(1):47–54. - 24.
Garg R, Wierda W, Ferrajoli A, Abruzzo L, Pierce S, Lerner S, et al. The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia. Cancer. 2012 Jul 15;118(14):3531–7. - 25.
Dal Bo M, Rossi FM, Rossi D, Deambrogi C, Bertoni F, Del Giudice I, et al. 13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia. Genes Chromosomes Cancer. 2011 Aug;50(8):633–43. - 26.
Hernández JA, Rodríguez AE, González M, Benito R, Fontanillo C, Sandoval V, et al. A high number of losses in 13q14 chromosome band is associated with a worse outcome and biological differences in patients with B-cell chronic lymphoid leukemia. Haematologica. 2009 Mar;94(3):364–71. - 27.
Migliazza A, Bosch F, Komatsu H, Cayanis E, Martinotti S, Toniato E, et al. Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia. Blood. 2001 Apr 1;97(7):2098–104. - 28.
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524–9. - 29.
Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood. 1997 Apr 1;89(7):2516–22. - 30.
Neilson JR, Auer R, White D, Bienz N, Waters JJ, Whittaker JA, et al. Deletions at 11q identify a subset of patients with typical CLL who show consistent disease progression and reduced survival. Leukemia. 1997 Nov;11(11):1929–32. - 31.
Tsimberidou A-M, Tam C, Abruzzo LV, O’Brien S, Wierda WG, Lerner S, et al. Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia. Cancer. 2009 Jan 15;115(2):373–80. - 32.
Marasca R, Maffei R, Martinelli S, Fiorcari S, Bulgarelli J, Debbia G, et al. Clinical heterogeneity of de novo 11q deletion chronic lymphocytic leukaemia: prognostic relevance of extent of 11q deleted nuclei inside leukemic clone. Hematol Oncol. 2013 Jun;31(2):88–95. - 33.
Jain P, Keating M, Thompson P, Trinh L, Wang X, Wierda W, et al. High FISH percentage of deletion 11q in patients with chronic lymphocytic leukemia is an independent predictor of adverse outcome. Am J Hematol. 2015 Feb 14. - 34.
Rossi D, Gaidano G. ATM and chronic lymphocytic leukemia: mutations, and not only deletions, matter. Haematologica. 2012 Jan;97(1):5–8. - 35.
Rossi D, Fangazio M, Rasi S, Vaisitti T, Monti S, Cresta S, et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood. 2012 Mar 22;119(12):2854–62. - 36.
Puiggros A, Blanco G, Espinet B. Genetic abnormalities in chronic lymphocytic leukemia: where we are and where we go. BioMed Res Int. 2014;2014:435983. - 37.
Matutes E, Oscier D, Garcia-Marco J, Ellis J, Copplestone A, Gillingham R, et al. Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol. 1996 Feb;92(2):382–8. - 38.
Rosenquist R, Cortese D, Bhoi S, Mansouri L, Gunnarsson R. Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand? Leuk Lymphoma. 2013 Nov;54(11):2351–64. - 39.
Weissmann S, Roller A, Jeromin S, Hernández M, Abáigar M, Hernández-Rivas JM, et al. Prognostic impact and landscape of NOTCH1 mutations in chronic lymphocytic leukemia (CLL): a study on 852 patients. Leukemia. 2013 Dec;27(12):2393–6. - 40.
Balatti V, Lerner S, Rizzotto L, Rassenti LZ, Bottoni A, Palamarchuk A, et al. Trisomy 12 CLLs progress through NOTCH1 mutations. Leukemia. 2013 Mar;27(3):740–3. - 41.
Villamor N, Conde L, Martínez-Trillos A, Cazorla M, Navarro A, Beà S, et al. NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia. 2013 Apr;27(5):1100–6. - 42.
González-Gascón Y Marín I, Hernández-Sánchez M, Rodríguez-Vicente A-E, Sanzo C, Aventín A, Puiggros A, et al. A high proportion of cells carrying trisomy 12 is associated with a worse outcome in patients with chronic lymphocytic leukemia. Hematol Oncol. 2015 Feb 17. - 43.
Cramer P, Hallek M. Prognostic factors in chronic lymphocytic leukemia-what do we need to know? Nat Rev Clin Oncol. 2011 Jan;8(1):38–47. - 44.
Zenz T, Kröber A, Scherer K, Häbe S, Bühler A, Benner A, et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008 Oct 15;112(8):3322–9. - 45.
Zenz T, Vollmer D, Trbusek M, Smardova J, Benner A, Soussi T, et al. TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations. Leukemia. 2010 Dec;24(12):2072–9. - 46.
Zenz T, Häbe S, Denzel T, Mohr J, Winkler D, Bühler A, et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood. 2009 Sep 24;114(13):2589–97. - 47.
Tam CS, Shanafelt TD, Wierda WG, Abruzzo LV, Van Dyke DL, O’Brien S, et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood. 2009 Jul 30;114(5):957–64. - 48.
Döhner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G, et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995 Mar 15;85(6):1580–9. - 49.
Panovska-Stavridis I, Ivanovski M, Siljanovski N, Cevreska L, Efremov DG. Chronic lymphocytic leukemia patients with a V1-69 gene rearrangement do not have inferior survival with respect to patients that express other unmutated V(H) genes. Leuk Res. 2007 Feb;31(2):245–8. - 50.
Thorsélius M, Kröber A, Murray F, Thunberg U, Tobin G, Bühler A, et al. Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status. Blood. 2006 Apr 1;107(7):2889–94. - 51.
Dreger P, Schetelig J, Andersen N, Corradini P, Van Gelder M, Gribben J, et al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood. 2014 Dec 18;124(26):3841–9. - 52.
Rossi D, Khiabanian H, Spina V, Ciardullo C, Bruscaggin A, Famà R, et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood. 2014 Apr 3;123(14):2139–47. - 53.
Ouillette P, Li J, Shaknovich R, Li Y, Melnick A, Shedden K, et al. Incidence and clinical implications of ATM aberrations in chronic lymphocytic leukemia. Genes Chromosomes Cancer. 2012 Dec;51(12):1125–32. - 54.
Austen B, Powell JE, Alvi A, Edwards I, Hooper L, Starczynski J, et al. Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood. 2005 Nov 1;106(9):3175–82. - 55.
Rose-Zerilli MJJ, Forster J, Parker H, Parker A, Rodríguez AE, Chaplin T, et al. ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial. Haematologica. 2014 Apr;99(4):736–42. - 56.
Quesada V, Conde L, Villamor N, Ordóñez GR, Jares P, Bassaganyas L, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet. 2012 Jan;44(1):47–52. - 57.
Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011 Dec 29;365(26):2497–506. - 58.
Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011 Jul 7;475(7354):101–5. - 59.
Rossi D, Rasi S, Spina V, Fangazio M, Monti S, Greco M, et al. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. Br J Haematol. 2012 Aug;158(3):426–9. - 60.
Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012 Jan 12;119(2):521–9. - 61.
Paganin M, Ferrando A. Molecular pathogenesis and targeted therapies for NOTCH1-induced T-cell acute lymphoblastic leukemia. Blood Rev. 2011 Mar;25(2):83–90. - 62.
Rossi D, Bruscaggin A, Spina V, Rasi S, Khiabanian H, Messina M, et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood. 2011 Dec 22;118(26):6904–8. - 63.
Visconte V, Makishima H, Maciejewski JP, Tiu RV. Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders. Leukemia. 2012 Dec;26(12):2447–54. - 64.
Cazzola M, Rossi M, Malcovati L. Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative. Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms. Blood. 2013 Jan 10;121(2):260–9. - 65.
Hertlein E, Wagner AJ, Jones J, Lin TS, Maddocks KJ, Towns WH, et al. 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood. 2010 Jul 8;116(1):45–53. - 66.
Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim K-H, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011 Feb 3;470(7332):115–9. - 67.
Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012 Aug 30;367(9):826–33. - 68.
Martínez-Trillos A, Pinyol M, Navarro A, Aymerich M, Jares P, Juan M, et al. Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome. Blood. 2014 Jun 12;123(24):3790–6. - 69.
Houldsworth J, Guttapalli A, Thodima V, Yan XJ, Mendiratta G, Zielonka T, et al. Genomic imbalance defines three prognostic groups for risk stratification of patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Apr;55(4):920–8. - 70.
Cavazzini F, Hernandez JA, Gozzetti A, Russo Rossi A, De Angeli C, Tiseo R, et al. Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis. Br J Haematol. 2008 Aug;142(4):529–37. - 71.
Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do K-A, et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 2007 Jun 1;109(11):4679–85. - 72.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446–56. - 73.
Ibrahim S, Keating M, Do KA, O’Brien S, Huh YO, Jilani I, et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood. 2001 Jul 1;98(1):181–6. - 74.
Dürig J, Nückel H, Cremer M, Führer A, Halfmeyer K, Fandrey J, et al. ZAP-70 expression is a prognostic factor in chronic lymphocytic leukemia. Leukemia. 2003 Dec;17(12):2426–34. - 75.
Bulian P, Shanafelt TD, Fegan C, Zucchetto A, Cro L, Nückel H, et al. CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2014 Mar 20;32(9):897–904. - 76.
Zenz T, Mohr J, Eldering E, Kater AP, Bühler A, Kienle D, et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia. Blood. 2009 Apr 16;113(16):3801–8. - 77.
Bulian P, Tarnani M, Rossi D, Forconi F, Del Poeta G, Bertoni F, et al. Multicentre validation of a prognostic index for overall survival in chronic lymphocytic leukaemia. Hematol Oncol. 2011 Jun;29(2):91–9. - 78.
Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do K-A, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2011 Nov 1;29(31):4088–95. - 79.
Pflug N, Bahlo J, Shanafelt TD, Eichhorst BF, Bergmann MA, Elter T, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014 Jul 3;124(1):49–62. - 80.
Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013 Feb 21;121(8):1403–12. - 81.
Jeromin S, Weissmann S, Haferlach C, Dicker F, Bayer K, Grossmann V, et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia. 2014 Jan;28(1):108–17. - 82.
Cortese D, Sutton L-A, Cahill N, Smedby KE, Geisler C, Gunnarsson R, et al. On the way towards a “CLL prognostic index”: focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort. Leukemia. 2014 Mar;28(3):710–3. - 83.
Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2010 Apr 1;28(10):1749–55. - 84.
Robak T, Janssens A, Govindbabu K, Grosicki S, Mayer J, Panagiotidis P, et al. Ofatumumab + Chlorambucil Versus Chlorambucil Alone in Patients with Untreated Chronic Lymphocytic Leukemia (CLL): Results of the Phase III Study Complement 1 (OMB110911). Hillmen P, editor. Blood. 2013 Dec 6;122(21):528. - 85.
Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101–10. - 86.
Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LFC, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jan 30. - 87.
Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369(1):32–42. - 88.
Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213–23. - 89.
Barrientos JC, Barr PM, Flinn I, Burger JA, Salman Z, Clow F, et al. Ibrutinib in Combination with Bendamustine and Rituximab Is Active and Tolerable in Patients with Relapsed/Refractory CLL/SLL: Final Results of a Phase 1b Study. Brown JR, editor. Blood. 2013 Dec 6;122(21):525. - 90.
Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014 Sep;15(10):1090–9. - 91.
Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997–1007. - 92.
Furman RR, Barrientos JC, Wagner-Johnston ND, Flinn I, Sharman JP, Boyd T, et al. Idelalisib, a Selective Inhibitor of PI3Kδ, in Combination with Bendamustine, Fludarabine or Chlorambucil in Patients with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL). De Vos S, editor. Blood. 2013 Dec 6;122(21):2878. - 93.
Eymour J. Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). Hematol Oncol; 2013. - 94.
Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol Off J Am Soc Clin Oncol. 2006 Dec 1;24(34):5343–9. - 95.
Ferrajoli A, Lee B-N, Schlette EJ, O’Brien SM, Gao H, Wen S, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291–7. - 96.
Badoux XC, Keating MJ, Wen S, Lee B-N, Sivina M, Reuben J, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011 Sep 29;118(13):3489–98. - 97.
Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, et al. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood. 2013 Aug 1;122(5):734–7. - 98.
Chen CI, Bergsagel PL, Paul H, Xu W, Lau A, Dave N, et al. Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2011 Mar 20;29(9):1175–81. - 99.
Badoux XC, Keating MJ, Wen S, Wierda WG, O’Brien SM, Faderl S, et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2013 Feb 10;31(5):584–91. - 100.
James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, et al. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium. J Clin Oncol Off J Am Soc Clin Oncol. 2014 Jul 1;32(19):2067–73. - 101.
Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011 Aug 10;3(95):95-73. - 102.
Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011 Nov 3;118(18):4817–28. - 103.
Porter DL, Grupp SA, Kalos M, Loren AW, Lledo L, Gilmore J, et al. Chimeric antigen receptor T cells directed against CD19 induce durable responses and transient cytokine release syndrome in relapsed, refractory CLL and ALL. ASH Annu Meet Abstr. 2012 Nov 16;120(21):717.