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Shifting paradigms in the treatment of chronic lymphocytic leukemia
Philip A Thompson1, Elizabeth J Shpall2 & Michael J Keating*,1
ABSTRACT The treatment of chronic lymphocytic leukemia (CLL) is evolving rapidly. Insight into the genetics and biology of the disease, including the importance of intracellular signaling pathways and interactions with the microenvironment has led to the development of rational targeted therapies which are having a major impact on the survival of patients with relapsed and high-risk disease. In addition, an exciting array of cellular therapies and immunotherapy options are in various stages of development. We review the current understanding of CLL genetics and biology, current treatment strategies in specific patient groups and opportunities for future treatment combinations which will bring the goal of cure or long-term disease control with minimal toxicity within reach for the majority of patients.
Chronic lymphocytic leukemia (CLL) is a clonal disorder of mature B-lymphocytes. Almost all cases arise from pre-existing monoclonal B-cell lymphocytosis (MBL), which occurs in 5–15% of individuals over age 60 years. However, only ∼1% of MBL patients progress to CLL per year [1,2] . The majority of patients diagnosed at age 0.35%/day are more likely to have active or progressive disease [7] . Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA Department of Stem Cell Transplantation & Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA *Author for correspondence: [email protected] 1 2
10.2217/FON.14.288 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(4), 641–657
part of
ISSN 1479-6694
641
Perspective Thompson, Shpall & Keating ●●Resistance to apoptosis
This occurs via several mechanisms; BCL2 overexpression occurs in 95% of CLL [8] . In CLL, only ∼4% of patients have a BCL2 gene translocation [8] . Alternate mechanisms for BCL2 overexpression include loss of miR-15-a and miR-16-1 [9] and gene hypomethylation [8] . Located on chromosome 13q (deletion of which is the most common cytogenetic abnormality in CLL), miR-15-a and miR-16-1 are deleted or downregulated in 68% of CLL [9] . These have been shown to negatively regulate BCL2 at a posttranscriptional level. ●●Lymphocyte trafficking, BCR signaling
& microenvironmental interactions
Normal lymphocytes traffic between blood and secondary lymphoid tissues as part of immune surveillance, directed by chemokine receptors on lymphocytes and integrin/selectin interactions between lymphocytes and vascular endothelial cells [10] . The microenvironment within lymphatic tissues is important in CLL growth and survival, with a complex interactions between the CLL cells and mesenchymal stromal cells, nurse-like cells and T cells [11] . Comparative gene expression profiling has shown that CLL cells derived from secondary lymphoid tissues are more proliferative and have upregulation of the B-cell receptor (BCR) and NF-kB signaling pathways relative to those cells from the peripheral blood or marrow [12] , results recapitulated by a mouse model showing significantly higher fractions of actively cycling cells in the spleen than the peripheral blood [13] . BCR-signaling is normally tightly controlled and mediated by antigen engagement within lymphoid tissues, but in CLL, there is tonic activation of BCR signaling that occurs due to either antigen-dependent or antigen-independent, cell-autonomous signaling [10,14] . Signal transduction through the BCR is mediated by the BCR-associated kinases SYK, BTK and PI3Kδ [15] and results in upregulation of genes responsible for proliferation and survival. The role of BCR signaling has been reviewed here [10] . In a subset of CLL cases, malignant B-cells display an anergic signature [16–18] . These cells show insensitivity to antigenic stimulation via the BCR, similar to autoreactive normal B-cells and a correspondingly lower rate of spontaneous apoptosis. These patients are more likely to have be ZAP 70 negative, CD38 negative
642
Future Oncol. (2015) 11(4)
have mutated IGHV gene and have an indolent clinical course [19] . ●●Escape from immunological surveillance
& immunodeficiency
Despite expressing tumor-specific antigens on MHC molecules and thus being recognized by cytotoxic T-lymphocytes (CTLs), CLL cells escape effective immunological surveillance through a variety of mechanisms [20] , including expression of co-inhibitory molecules resulting in impaired T-cell function. CD200, CD274 (PD-L1) and CD276 (B7-H3) are upregulated on CLL cells relative to normal cells and binding of these co-inhibitory molecules to their ligands on T cells, CD200-R, CD279 (PD1) and CD272 (BTLA) impairs Rho-GTPase activity and actin polymerization with resultant impairment of immunological synapse formation [21] . Both CD4 and CD8 + T cells from CLL patients show increased PD-1 expression, which parallels disease aggressiveness [22] . When allogeneic T cells from a normal donor are cultured with CLL cells, similar functional abnormalities are induced [23–25] . Pretreatment with antibodies that block these co-inhibitory molecules in vitro prevents development of functional T-cell abnormalities in allogeneic T cells co-cultured with CLL cells. These functional defects can also be prevented by treatment with lenalidomide which downregulates tumor cell co-inhibitory molecule expression [21] . Patients with CLL are at increased risk of infection. This relates both to immune defects caused by the underlying disease and related to therapy [26] . Specific immune defects include cellular immune deficiency as described above, neutropenia and neutrophil functional abnormalities, hypocomplementemia and hypo gammaglobulinemia [27,28] . Infections are a major cause of morbidity and mortality, with up to 80% of deaths in CLL due to infection [27] . Infections are predominantly bacterial [27] . Patients treated with fludarabine-based regimens are at higher risk of moderate to severe infections [29] and of herpes simplex virus and zoster. Pneumocystis infection is unusual with single agent fludarabine, but incidence is higher in patients receiving fludarabine, cyclophosphamide and rituximab (FCR) [30] . The pivotal Phase III study of fludarabine and cyclophosphamide (FC) versus FCR [31] in untreated patients used pneumocystis prophylaxis and the overall rate of opportunistic infections was low. The
future science group
Shifting paradigms in the treatment of chronic lymphocytic leukemia risk of major and opportunistic infections is higher when chemoimmunotherapy is given in the relapsed/refractory setting [32] . The impact of nonchemotherapy-based regimens used in the upfront setting on the risk of infection is unknown.
response. The latter is particularly important given the increasing availability of novel, nonchemotherapy-based treatment regimens, which have efficacy in patients previously predicted to be resistant to chemoimmunotherapy (such as those with 17p-).
●●Secondary malignancy
●●Predicting time-to-first therapy
Second malignancies occur with a frequency 2.2-times higher than in the general population; MDS/AML, Richter’s Syndrome, melanoma and cancer of the female breast occur with higher-than-expected frequency [33] . The impact of specific treatments on secondary malignancy risk is controversial; fludarabine-based treatment has been reported to increase risk of Richter’s syndrome [34] , while others suggest that second cancers in fludarabine-treated patients are similar to patients treated on other regimens [35] . Our experience suggests that, compared with patients treated with FCR, patients treated upfront with lenalidomide-based regimens have an equivalent risk of MDS/AML and solid tumors, but lower risk of Richter’s Syndrome [Keating M, Unpublished Data] .
Wierda et al. developed a nomogram predicting the time-to-first therapy (TTFT) at diagnosis, based on 930 new patients seen at MD Anderson Cancer Center from 2004–2009 [40] . On multivariate analysis unmutated IGHV gene, 11q- or 17p-, increased size of the largest palpated cervical lymph node, ≥3 involved lymph node sites and higher serum LDH correlated with shorter TTFT. Unmutated IGHV gene was the strongest predictor of shorter treatment-free interval (HR 10.68). ZAP 70 expression was discordant with IGHV mutation status in 28% and appeared to provide additional information. Similar predictive models have been developed from GIMEMA [41] and GCLLSG [42] data.
Indications for treatment in CLL There is no survival benefit from early institution of therapy with alkylating agents [36,37] . A recent study of FCR-treatment for high geneticrisk patients with early stage disease showed a progression-free survival (PFS), but no overall survival (OS) benefit [38] . It is unclear whether early institution of targeted therapies will benefit patients with high genetic-risk, early-stage disease; large, well-designed prospective studies are required to answer this important question. Demonstration of an OS, rather than PFS benefit should ideally be the primary end point of such study, but this requires very prolonged follow-up making such studies challenging to perform. Prognostic factors in CLL Numerous baseline prognostic variables correlate with outcome in CLL. Many, such as the Rai clinical staging system [39] were determined in an era where treatment was largely ineffective and where biological heterogeneity underlying clinical behavior and therapeutic response was not understood. It is useful to divide these variables into those predicting likelihood of progression to requiring therapy and those predicting for therapeutic
future science group
Perspective
●●Predicting survival in patients requiring
treatment
The GCLLSG CLL8 study demonstrated an overall survival benefit for FCR relative to FC in fit patients [31] . 17p-, serum β-2 microglobulin (B2M) >3 mg/l and FC rather than FCR treatment were associated with shorter PFS and OS. IGHV unmutated patients had poorer PFS but not OS, as did patients with WCC >50 × 109/l. Patients with ECOG performance status ≥1 and serum thymidine kinase ≥10 U/l had a poorer OS but not PFS. 17p- was associated with a very short median PFS of 11.3 months in the FCR arm. Patients with del(17p) did not benefit from the addition of rituximab and is the single strongest predictor of inferior outcome. In contrast, the addition of rituximab appeared to negate the negative prognostic impact of del(11q) and produce excellent outcomes in patients with trisomy 12 [31] . Thus, detection of del(17p) by FISH remains the single most important predictive factor in determining frontline therapy for CLL. TP53 mutations show strong correlation with the presence of del(17p), but even when present in the absence of del(17p), are associated with very poor outcomes with fludarabine-based chemotherapy [43–45] . Other novel genetic predictors of outcome are discussed in the ‘Individualized medicine: tailoring therapy based on genetic markers in CLL’ section.
www.futuremedicine.com
643
Perspective Thompson, Shpall & Keating Updates of results from the GCLLSG CLL8 study and the MD Anderson FCR300 cohort presented at the 2013 IWCLL meeting in Cologne show that a subpopulation of patients treated with FCR may achieve very long-term remissions. Patients with mutated IGHV gene treated in the FCR300 cohort [30,46] have a 10-year PFS of approximately 60%, with a plateau in the survival curve and very few relapses beyond 8 years (W Wierda, IWCLL 2013 oral presentation). By contrast, in patients with unmutated IGHV gene, there is a pattern of continued relapses, with very few long-term survivors.
older patients and in our experience is welltolerated [56,57] . Lenalidomide reverses CLLinduced immune dysregulation and enhances T-cell and NK-cell killing of CLL cells in vivo [58] . It appears more potent than Clb; 25/60 patients (40%) of patients achieved CR at a median of 25 months in a Phase II study [57] . Unfortunately, a phase III study of lenalidomide versus Clb was stopped early due to excess early deaths in the lenalidomide arm; these occurred largely in patients >80 years of age. Further study is required to identify subgroups of treatment-naive patients who could benefit from lenalidomide.
Age, ‘fitness’ & determining treatment strategy This has been reviewed elsewhere [47] . Accurate assessment of life expectancy and general physical health is of critical importance. Age is important in determining likely life expectancy and informing the goals of therapy; however, assessment of co-morbidities such as renal dysfunction are likely more important than age in terms of determining the ability of the patient to tolerate chemoimmunotherapy [47,48] . Nonetheless, standard chemoimmunotherapy with FCR usually cannot be tolerated by patients aged >70 years [47] . Objective measurements of comorbidities include the CIRS score [49] and the Charlston co-morbidity index [50] . However, neither of these indices are CLL-specific.
New options for patients with relapsed & ultra high-risk disease
Recent improvement in outcomes in patients unfit for chemoimmunotherapy ●●Novel anti-CD20 antibodies
Obinutuzumab (GA101 - G), is a type 2, glycoengineered CD20 monoclonal antibody (mAb) which has greater antibody-dependent cellular cytotoxicity (ADCC) and direct cell killing than rituximab in preclinical models [51,52] . The majority of CLL patients are >70 years of age and many have co-morbidities limiting treatment intensity. Chlorambucil (Clb) monotherapy, the standard treatment in this population, does not improve survival and CR is rare [53,54] . The combination of G+Clb improves OS compared with Clb alone, the first time a therapy has demonstrated an overall survival benefit in this population. PFS was superior with G+Clb relative to R+Clb, with a strong trend (p = 0.08) toward improved OS [55] . Lenalidomide is an immunomodulatory drug (iMID) with frontline activity in
644
Future Oncol. (2015) 11(4)
●●Importance of initial therapy & remission
duration
Patients with a remission duration of >3 years postinitial chemoimmunotherapy often respond to retreatment with a similar regimen. Additionally, FCR has been shown to improve PFS relative to FC after initial fludarabine monotherapy or nonpurine analogue-based initial treatment [59] . However, patients with short PFS (10 years) relapse-free survival. Both we and the patients are keen to limit long-term therapy-related toxicity, particularly secondary malignancies. Our experience with lenalidomide plus rituximab in treatment-naive patients is that treatment is well-tolerated and active, but ORR and CR rates are lower than with FC. The data are not yet mature enough to determine long-term outcomes. Randomized studies of FCR vs ibrutinib plus rituximab are actively accruing through the LRF in the UK and the GCLLSG. We would stress that, in the absence of 17p-, FCR remains standard-of-care for fit patients and novel therapies should only be explored in the context of a well-designed clinical trial. ●●Combinations of novel agents to improve
outcomes
Combinations need to be rationally designed to exploit mechanistic synergy and minimize toxicity. The combination of ABT199 and ibrutinib appears attractive; in vivo data show that Mcl-1 expression is a potential mechanism of escape from Bcl-2 inhibition [77] . Mcl-1 is downregulated by ibrutinib and this combination has shown in vitro synergy in both the activated B-cell subtype of diffuse large B-cell lymphoma [150] and CLL [Gandhi V, Pers. Comm.] cell lines. In vivo, ibrutinib has excellent ability to reduce nodal and splenic disease burden, but limited ability to induce marrow CRs or MRD-negativity. In contrast, even in very heavily pretreated patients, ABT199 can induce MRD-negative CRs [82] , making this a rational combination to pursue. As with FCR+ABT199, appropriate sequencing to avoid TLS will be essential – for example, several months of
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Future Oncol. (2015) 11(4)
ibrutinib monotherapy could be given to achieve disease debulking, before gradual introduction of ABT199 with slow dose escalation. A clinical study of ABT199 with obinutuzumab is currently accruing and a study of lenalidomide plus obinutuzumab in relapsed/ refractory CLL is also planned. In contrast, combinations of ibrutinib and CD20 monoclonal antibodies may not be rational combinations to pursue, as preclinical data have shown that ibrutinib downregulates CD20 and antagonizes mAb-induced CDC and ADCC. Idelalisib treatment, while still downregulating CD20, has lesser effects on CDC and negligible effects on ADCC [151] . While the biological relevance in vivo remains to be elucidated, these unexpected observations outline the importance of rational design of combination therapies based on robust, preclinical data. Finally, given the emergence of resistance mutations such as C481S, combinations of BCR signaling inhibitors (such as SYK + BTK inhibitors) may be useful to reduce the likelihood of these mutations developing. Additive toxicities are possible with these combinations, however. It is unclear whether these combinations will have curative potential, but we expect to see increased rates of MRD-negative CR relative to monotherapy with novel agents. ●●The role of immunotherapy in the era of
targeted therapies
Fit patients requiring treatment who have 17por TP53 mutation should be considered for alloSCT if a suitable donor is available [89] as this is the only therapy proven to provide long-term disease-free survival in this group. Our personal experience is that many of these patients derive great symptomatic benefit with novel agents such as ibrutinib and are therefore reluctant to accept the risks of alloSCT. The optimal time to transplant these patients is when their performance status is good, they have treatmentsensitive disease and their disease-burden is low, but many patients are now willing to undergo transplantation only when they have refractory disease with few other options, as a ‘last roll of the dice.’ In this situation, the efficacy of the treatment is lower and the treatment-related mortality higher. Additionally, we have seen a number of patients with 17p- treated with ibrutinib progress with Richter’s Syndrome despite initially good responses. Whether this would have been prevented by early alloSCT is unknown,
future science group
Shifting paradigms in the treatment of chronic lymphocytic leukemia
Perspective
EXECUTIVE SUMMARY Background ●●
Chronic lymphocytic leukemia (CLL) is not curable without allogeneic stem cell transplant (alloSCT), which is not appropriate for the majority of patients.
●●
Increasing understanding of disease pathobiology has led to availability of numerous potent and well-tolerated
targeted therapies, providing opportunities for novel combination therapies to improve long-term disease control and potentially, cure. Pathobiology of CLL ●●
Chronic lymphocytic leukemia (CLL) cells show resistance to apoptosis. Overexpression of BCL2 is almost universal.
●●
Microenvironmental interactions maintain the CLL clone and result in upregulation of B-cell receptor (BCR) signaling
through both antigen-dependent and antigen-independent mechanisms. BCR-signaling, transduced by SYK, BTK and PI3Kδ kinases, upregulates genes responsible for survival and proliferation. ●●
CLL escapes immunologic surveillance through upregulation of immune-checkpoint molecules such as PD-L1.
Indications for treatment & assigning treatment paradigm ●●
Available data do not show benefit of early intervention in asymptomatic patients. Novel targeted therapies are likely to be tested in genetically high-risk patients not meeting IWCLL 2008 indications for therapy.
●●
Accurate assessment of life expectancy and general physical health is critically important to determine treatment
paradigm: pursuit of deep, durable remissions in fit patients is ideal. By contrast, minimizing toxicity and achieving more modest/less durable disease burden reduction may be reasonable in elderly/unfit patients. Recent improvements in frontline treatments for ‘unfit’ patients ●●
Novel anti-CD20 mAbs: Obinutuzumab + chlorambucil improves survival relative to chlorambucil monotherapy and is a new ‘standard-of-care’.
●●
Lenalidomide monotherapy is well-tolerated and active as initial therapy in older patients but toxicity may be prohibitive in patients >80 years old.
Novel targeted therapies are transforming the outlook for patients with relapsed & ultra high-risk disease ●●
Initial remission duration
Shifting paradigms in the treatment of chronic lymphocytic leukemia
Philip A Thompson1, Elizabeth J Shpall2 & Michael J Keating*,1
ABSTRACT The treatment of chronic lymphocytic leukemia (CLL) is evolving rapidly. Insight into the genetics and biology of the disease, including the importance of intracellular signaling pathways and interactions with the microenvironment has led to the development of rational targeted therapies which are having a major impact on the survival of patients with relapsed and high-risk disease. In addition, an exciting array of cellular therapies and immunotherapy options are in various stages of development. We review the current understanding of CLL genetics and biology, current treatment strategies in specific patient groups and opportunities for future treatment combinations which will bring the goal of cure or long-term disease control with minimal toxicity within reach for the majority of patients.
Chronic lymphocytic leukemia (CLL) is a clonal disorder of mature B-lymphocytes. Almost all cases arise from pre-existing monoclonal B-cell lymphocytosis (MBL), which occurs in 5–15% of individuals over age 60 years. However, only ∼1% of MBL patients progress to CLL per year [1,2] . The majority of patients diagnosed at age 0.35%/day are more likely to have active or progressive disease [7] . Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA Department of Stem Cell Transplantation & Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA *Author for correspondence: [email protected] 1 2
10.2217/FON.14.288 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(4), 641–657
part of
ISSN 1479-6694
641
Perspective Thompson, Shpall & Keating ●●Resistance to apoptosis
This occurs via several mechanisms; BCL2 overexpression occurs in 95% of CLL [8] . In CLL, only ∼4% of patients have a BCL2 gene translocation [8] . Alternate mechanisms for BCL2 overexpression include loss of miR-15-a and miR-16-1 [9] and gene hypomethylation [8] . Located on chromosome 13q (deletion of which is the most common cytogenetic abnormality in CLL), miR-15-a and miR-16-1 are deleted or downregulated in 68% of CLL [9] . These have been shown to negatively regulate BCL2 at a posttranscriptional level. ●●Lymphocyte trafficking, BCR signaling
& microenvironmental interactions
Normal lymphocytes traffic between blood and secondary lymphoid tissues as part of immune surveillance, directed by chemokine receptors on lymphocytes and integrin/selectin interactions between lymphocytes and vascular endothelial cells [10] . The microenvironment within lymphatic tissues is important in CLL growth and survival, with a complex interactions between the CLL cells and mesenchymal stromal cells, nurse-like cells and T cells [11] . Comparative gene expression profiling has shown that CLL cells derived from secondary lymphoid tissues are more proliferative and have upregulation of the B-cell receptor (BCR) and NF-kB signaling pathways relative to those cells from the peripheral blood or marrow [12] , results recapitulated by a mouse model showing significantly higher fractions of actively cycling cells in the spleen than the peripheral blood [13] . BCR-signaling is normally tightly controlled and mediated by antigen engagement within lymphoid tissues, but in CLL, there is tonic activation of BCR signaling that occurs due to either antigen-dependent or antigen-independent, cell-autonomous signaling [10,14] . Signal transduction through the BCR is mediated by the BCR-associated kinases SYK, BTK and PI3Kδ [15] and results in upregulation of genes responsible for proliferation and survival. The role of BCR signaling has been reviewed here [10] . In a subset of CLL cases, malignant B-cells display an anergic signature [16–18] . These cells show insensitivity to antigenic stimulation via the BCR, similar to autoreactive normal B-cells and a correspondingly lower rate of spontaneous apoptosis. These patients are more likely to have be ZAP 70 negative, CD38 negative
642
Future Oncol. (2015) 11(4)
have mutated IGHV gene and have an indolent clinical course [19] . ●●Escape from immunological surveillance
& immunodeficiency
Despite expressing tumor-specific antigens on MHC molecules and thus being recognized by cytotoxic T-lymphocytes (CTLs), CLL cells escape effective immunological surveillance through a variety of mechanisms [20] , including expression of co-inhibitory molecules resulting in impaired T-cell function. CD200, CD274 (PD-L1) and CD276 (B7-H3) are upregulated on CLL cells relative to normal cells and binding of these co-inhibitory molecules to their ligands on T cells, CD200-R, CD279 (PD1) and CD272 (BTLA) impairs Rho-GTPase activity and actin polymerization with resultant impairment of immunological synapse formation [21] . Both CD4 and CD8 + T cells from CLL patients show increased PD-1 expression, which parallels disease aggressiveness [22] . When allogeneic T cells from a normal donor are cultured with CLL cells, similar functional abnormalities are induced [23–25] . Pretreatment with antibodies that block these co-inhibitory molecules in vitro prevents development of functional T-cell abnormalities in allogeneic T cells co-cultured with CLL cells. These functional defects can also be prevented by treatment with lenalidomide which downregulates tumor cell co-inhibitory molecule expression [21] . Patients with CLL are at increased risk of infection. This relates both to immune defects caused by the underlying disease and related to therapy [26] . Specific immune defects include cellular immune deficiency as described above, neutropenia and neutrophil functional abnormalities, hypocomplementemia and hypo gammaglobulinemia [27,28] . Infections are a major cause of morbidity and mortality, with up to 80% of deaths in CLL due to infection [27] . Infections are predominantly bacterial [27] . Patients treated with fludarabine-based regimens are at higher risk of moderate to severe infections [29] and of herpes simplex virus and zoster. Pneumocystis infection is unusual with single agent fludarabine, but incidence is higher in patients receiving fludarabine, cyclophosphamide and rituximab (FCR) [30] . The pivotal Phase III study of fludarabine and cyclophosphamide (FC) versus FCR [31] in untreated patients used pneumocystis prophylaxis and the overall rate of opportunistic infections was low. The
future science group
Shifting paradigms in the treatment of chronic lymphocytic leukemia risk of major and opportunistic infections is higher when chemoimmunotherapy is given in the relapsed/refractory setting [32] . The impact of nonchemotherapy-based regimens used in the upfront setting on the risk of infection is unknown.
response. The latter is particularly important given the increasing availability of novel, nonchemotherapy-based treatment regimens, which have efficacy in patients previously predicted to be resistant to chemoimmunotherapy (such as those with 17p-).
●●Secondary malignancy
●●Predicting time-to-first therapy
Second malignancies occur with a frequency 2.2-times higher than in the general population; MDS/AML, Richter’s Syndrome, melanoma and cancer of the female breast occur with higher-than-expected frequency [33] . The impact of specific treatments on secondary malignancy risk is controversial; fludarabine-based treatment has been reported to increase risk of Richter’s syndrome [34] , while others suggest that second cancers in fludarabine-treated patients are similar to patients treated on other regimens [35] . Our experience suggests that, compared with patients treated with FCR, patients treated upfront with lenalidomide-based regimens have an equivalent risk of MDS/AML and solid tumors, but lower risk of Richter’s Syndrome [Keating M, Unpublished Data] .
Wierda et al. developed a nomogram predicting the time-to-first therapy (TTFT) at diagnosis, based on 930 new patients seen at MD Anderson Cancer Center from 2004–2009 [40] . On multivariate analysis unmutated IGHV gene, 11q- or 17p-, increased size of the largest palpated cervical lymph node, ≥3 involved lymph node sites and higher serum LDH correlated with shorter TTFT. Unmutated IGHV gene was the strongest predictor of shorter treatment-free interval (HR 10.68). ZAP 70 expression was discordant with IGHV mutation status in 28% and appeared to provide additional information. Similar predictive models have been developed from GIMEMA [41] and GCLLSG [42] data.
Indications for treatment in CLL There is no survival benefit from early institution of therapy with alkylating agents [36,37] . A recent study of FCR-treatment for high geneticrisk patients with early stage disease showed a progression-free survival (PFS), but no overall survival (OS) benefit [38] . It is unclear whether early institution of targeted therapies will benefit patients with high genetic-risk, early-stage disease; large, well-designed prospective studies are required to answer this important question. Demonstration of an OS, rather than PFS benefit should ideally be the primary end point of such study, but this requires very prolonged follow-up making such studies challenging to perform. Prognostic factors in CLL Numerous baseline prognostic variables correlate with outcome in CLL. Many, such as the Rai clinical staging system [39] were determined in an era where treatment was largely ineffective and where biological heterogeneity underlying clinical behavior and therapeutic response was not understood. It is useful to divide these variables into those predicting likelihood of progression to requiring therapy and those predicting for therapeutic
future science group
Perspective
●●Predicting survival in patients requiring
treatment
The GCLLSG CLL8 study demonstrated an overall survival benefit for FCR relative to FC in fit patients [31] . 17p-, serum β-2 microglobulin (B2M) >3 mg/l and FC rather than FCR treatment were associated with shorter PFS and OS. IGHV unmutated patients had poorer PFS but not OS, as did patients with WCC >50 × 109/l. Patients with ECOG performance status ≥1 and serum thymidine kinase ≥10 U/l had a poorer OS but not PFS. 17p- was associated with a very short median PFS of 11.3 months in the FCR arm. Patients with del(17p) did not benefit from the addition of rituximab and is the single strongest predictor of inferior outcome. In contrast, the addition of rituximab appeared to negate the negative prognostic impact of del(11q) and produce excellent outcomes in patients with trisomy 12 [31] . Thus, detection of del(17p) by FISH remains the single most important predictive factor in determining frontline therapy for CLL. TP53 mutations show strong correlation with the presence of del(17p), but even when present in the absence of del(17p), are associated with very poor outcomes with fludarabine-based chemotherapy [43–45] . Other novel genetic predictors of outcome are discussed in the ‘Individualized medicine: tailoring therapy based on genetic markers in CLL’ section.
www.futuremedicine.com
643
Perspective Thompson, Shpall & Keating Updates of results from the GCLLSG CLL8 study and the MD Anderson FCR300 cohort presented at the 2013 IWCLL meeting in Cologne show that a subpopulation of patients treated with FCR may achieve very long-term remissions. Patients with mutated IGHV gene treated in the FCR300 cohort [30,46] have a 10-year PFS of approximately 60%, with a plateau in the survival curve and very few relapses beyond 8 years (W Wierda, IWCLL 2013 oral presentation). By contrast, in patients with unmutated IGHV gene, there is a pattern of continued relapses, with very few long-term survivors.
older patients and in our experience is welltolerated [56,57] . Lenalidomide reverses CLLinduced immune dysregulation and enhances T-cell and NK-cell killing of CLL cells in vivo [58] . It appears more potent than Clb; 25/60 patients (40%) of patients achieved CR at a median of 25 months in a Phase II study [57] . Unfortunately, a phase III study of lenalidomide versus Clb was stopped early due to excess early deaths in the lenalidomide arm; these occurred largely in patients >80 years of age. Further study is required to identify subgroups of treatment-naive patients who could benefit from lenalidomide.
Age, ‘fitness’ & determining treatment strategy This has been reviewed elsewhere [47] . Accurate assessment of life expectancy and general physical health is of critical importance. Age is important in determining likely life expectancy and informing the goals of therapy; however, assessment of co-morbidities such as renal dysfunction are likely more important than age in terms of determining the ability of the patient to tolerate chemoimmunotherapy [47,48] . Nonetheless, standard chemoimmunotherapy with FCR usually cannot be tolerated by patients aged >70 years [47] . Objective measurements of comorbidities include the CIRS score [49] and the Charlston co-morbidity index [50] . However, neither of these indices are CLL-specific.
New options for patients with relapsed & ultra high-risk disease
Recent improvement in outcomes in patients unfit for chemoimmunotherapy ●●Novel anti-CD20 antibodies
Obinutuzumab (GA101 - G), is a type 2, glycoengineered CD20 monoclonal antibody (mAb) which has greater antibody-dependent cellular cytotoxicity (ADCC) and direct cell killing than rituximab in preclinical models [51,52] . The majority of CLL patients are >70 years of age and many have co-morbidities limiting treatment intensity. Chlorambucil (Clb) monotherapy, the standard treatment in this population, does not improve survival and CR is rare [53,54] . The combination of G+Clb improves OS compared with Clb alone, the first time a therapy has demonstrated an overall survival benefit in this population. PFS was superior with G+Clb relative to R+Clb, with a strong trend (p = 0.08) toward improved OS [55] . Lenalidomide is an immunomodulatory drug (iMID) with frontline activity in
644
Future Oncol. (2015) 11(4)
●●Importance of initial therapy & remission
duration
Patients with a remission duration of >3 years postinitial chemoimmunotherapy often respond to retreatment with a similar regimen. Additionally, FCR has been shown to improve PFS relative to FC after initial fludarabine monotherapy or nonpurine analogue-based initial treatment [59] . However, patients with short PFS (10 years) relapse-free survival. Both we and the patients are keen to limit long-term therapy-related toxicity, particularly secondary malignancies. Our experience with lenalidomide plus rituximab in treatment-naive patients is that treatment is well-tolerated and active, but ORR and CR rates are lower than with FC. The data are not yet mature enough to determine long-term outcomes. Randomized studies of FCR vs ibrutinib plus rituximab are actively accruing through the LRF in the UK and the GCLLSG. We would stress that, in the absence of 17p-, FCR remains standard-of-care for fit patients and novel therapies should only be explored in the context of a well-designed clinical trial. ●●Combinations of novel agents to improve
outcomes
Combinations need to be rationally designed to exploit mechanistic synergy and minimize toxicity. The combination of ABT199 and ibrutinib appears attractive; in vivo data show that Mcl-1 expression is a potential mechanism of escape from Bcl-2 inhibition [77] . Mcl-1 is downregulated by ibrutinib and this combination has shown in vitro synergy in both the activated B-cell subtype of diffuse large B-cell lymphoma [150] and CLL [Gandhi V, Pers. Comm.] cell lines. In vivo, ibrutinib has excellent ability to reduce nodal and splenic disease burden, but limited ability to induce marrow CRs or MRD-negativity. In contrast, even in very heavily pretreated patients, ABT199 can induce MRD-negative CRs [82] , making this a rational combination to pursue. As with FCR+ABT199, appropriate sequencing to avoid TLS will be essential – for example, several months of
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ibrutinib monotherapy could be given to achieve disease debulking, before gradual introduction of ABT199 with slow dose escalation. A clinical study of ABT199 with obinutuzumab is currently accruing and a study of lenalidomide plus obinutuzumab in relapsed/ refractory CLL is also planned. In contrast, combinations of ibrutinib and CD20 monoclonal antibodies may not be rational combinations to pursue, as preclinical data have shown that ibrutinib downregulates CD20 and antagonizes mAb-induced CDC and ADCC. Idelalisib treatment, while still downregulating CD20, has lesser effects on CDC and negligible effects on ADCC [151] . While the biological relevance in vivo remains to be elucidated, these unexpected observations outline the importance of rational design of combination therapies based on robust, preclinical data. Finally, given the emergence of resistance mutations such as C481S, combinations of BCR signaling inhibitors (such as SYK + BTK inhibitors) may be useful to reduce the likelihood of these mutations developing. Additive toxicities are possible with these combinations, however. It is unclear whether these combinations will have curative potential, but we expect to see increased rates of MRD-negative CR relative to monotherapy with novel agents. ●●The role of immunotherapy in the era of
targeted therapies
Fit patients requiring treatment who have 17por TP53 mutation should be considered for alloSCT if a suitable donor is available [89] as this is the only therapy proven to provide long-term disease-free survival in this group. Our personal experience is that many of these patients derive great symptomatic benefit with novel agents such as ibrutinib and are therefore reluctant to accept the risks of alloSCT. The optimal time to transplant these patients is when their performance status is good, they have treatmentsensitive disease and their disease-burden is low, but many patients are now willing to undergo transplantation only when they have refractory disease with few other options, as a ‘last roll of the dice.’ In this situation, the efficacy of the treatment is lower and the treatment-related mortality higher. Additionally, we have seen a number of patients with 17p- treated with ibrutinib progress with Richter’s Syndrome despite initially good responses. Whether this would have been prevented by early alloSCT is unknown,
future science group
Shifting paradigms in the treatment of chronic lymphocytic leukemia
Perspective
EXECUTIVE SUMMARY Background ●●
Chronic lymphocytic leukemia (CLL) is not curable without allogeneic stem cell transplant (alloSCT), which is not appropriate for the majority of patients.
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Increasing understanding of disease pathobiology has led to availability of numerous potent and well-tolerated
targeted therapies, providing opportunities for novel combination therapies to improve long-term disease control and potentially, cure. Pathobiology of CLL ●●
Chronic lymphocytic leukemia (CLL) cells show resistance to apoptosis. Overexpression of BCL2 is almost universal.
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Microenvironmental interactions maintain the CLL clone and result in upregulation of B-cell receptor (BCR) signaling
through both antigen-dependent and antigen-independent mechanisms. BCR-signaling, transduced by SYK, BTK and PI3Kδ kinases, upregulates genes responsible for survival and proliferation. ●●
CLL escapes immunologic surveillance through upregulation of immune-checkpoint molecules such as PD-L1.
Indications for treatment & assigning treatment paradigm ●●
Available data do not show benefit of early intervention in asymptomatic patients. Novel targeted therapies are likely to be tested in genetically high-risk patients not meeting IWCLL 2008 indications for therapy.
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Accurate assessment of life expectancy and general physical health is critically important to determine treatment
paradigm: pursuit of deep, durable remissions in fit patients is ideal. By contrast, minimizing toxicity and achieving more modest/less durable disease burden reduction may be reasonable in elderly/unfit patients. Recent improvements in frontline treatments for ‘unfit’ patients ●●
Novel anti-CD20 mAbs: Obinutuzumab + chlorambucil improves survival relative to chlorambucil monotherapy and is a new ‘standard-of-care’.
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Lenalidomide monotherapy is well-tolerated and active as initial therapy in older patients but toxicity may be prohibitive in patients >80 years old.
Novel targeted therapies are transforming the outlook for patients with relapsed & ultra high-risk disease ●●
Initial remission duration
