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When should patients with chronic lymphocytic leukemia (CLL) be transplanted in the era of new agents?

Posted By CBMTG, Saturday, October 21, 2017
Updated: Thursday, October 26, 2017


When one thinks of a young, fit, transplant-eligible patient with CLL, the standard “go-go” approach prevails, the aim of which is the deepest remission/highest efficacy, usually at the expense of increased toxicity of the treatment. Allogeneic stem cell transplantation is at the extreme end of the therapy spectrum for CLL, and is currently the only potential curative option, accompanied by a significant risk of morbidity from chronic GVHD, and treatment-related mortality. For most patients with this “disease of the elderly”, this approach is not possible, and as a result new, efficacious and well-tolerated therapies have developed over the last decade that have completely changed the way this disease is being treated, including the role of allogeneic stem cell transplant. 

Allogeneic HSCT is recommended for patients with high risk CLL, and traditionally this included patients with disease associated with deletion 17p/TP53 mutations, and/or disease refractory to purine analogues (i.e. disease relapse within 2 years after purine analogue combination therapy). The basis of HSCT in CLL is a strong graft-versus-leukemia effect, supported by lower relapse risk after chronic GVHD1, higher relapse risk associated with T-cell depletion2, and MRD clearance in the context of chronic GVHD or immune interventions such as tapering of immunosuppression or donor lymphocyte infusion3,4. The 5-year progression-free survival is 30-35%, with 5-year overall survival 50-60%, with better outcomes in those who are chemosensitive, with non-bulky disease at time of HSCT5,6. Reduced-intensity conditioning has improved early mortality of HSCT, increasing tolerability, and allowing older patients with co-morbidities (i.e. the typical CLL patient) to proceed with HSCT. However, non-relapse mortality is still high in this patient population, approximately 20-30%, with GVHD and its associated complications the main cause of death. Moreover, in those who survive HSCT, chronic GVHD, which is frequently extensive, significantly impairs the quality of life long-term in about 25% of patients. 

Greater understanding of the pathobiology behind CLL has led to the development of more targeted therapies, such as ibrutinib and idelalisib, which target the Bruton tyrosine kinase and phosphatidylinositol 3-kinase, respectively, in the B-cell receptor signaling pathway. Long-term results with ibrutinib in the relapsed setting are now available, and with a median of 4 prior lines of therapy, the use of ibrutinib resulted in a median PFS of 52 months, and overall survival was not reached7. In patients without del17p or del 11q, the 5-year PFS was 66-91%, and OS was 80-91%. Patients with del17p had median PFS of 26 months, and this was 55 months for del11q, both of which were significantly higher than expected outcomes with FCR in the front line setting. This has led to the use of ibrutinib as first line therapy for del17p associated CLL. This drug is generally well tolerated, with fatigue, arthralgias, rash, and infections being common but mild side effects, and hypertension and atrial fibrillation (in up to 10% of patients) and increased risk of bleeding being long-term effects of the drug. Idelalisib has also shown efficacy in patients with relapsed disease in patients without del17p, and is another suitable option for these patients, at the expense of high rates of opportunistic infections (CMV, PJP pneumonia), and inflammatory conditions (e.g. colitis, pneumonitis)8. Based on the available data, all patients who have relapsed after FCR, regardless of duration of initial response, should be treated with one of these novel agents prior to consideration for allogeneic stem cell transplantation. 

BCL2 has also become a key target, as it is an important antiapoptotic protein. Venetoclax is an oral active potent small molecule BCL2 protein inhibitor, displacing sequestered antiapoptotic proteins, and has been shown to have durable responses in CLL after failure of ibrutinib and/or idelalisib. In a study of 64 patients with relapsed/refractory disease (43 prior ibrutinib of which 39 were resistant; 21 prior idelalisib), the 12 month PFS was 80% and OS was 90%.9 The drug is very well tolerated, and the major side effects noted included tumor lysis, which is now well managed with risk stratification, and neutropenia. These data suggest that Venetoclax is a reasonable salvage therapy in patients who have failed another novel agent. 

Richter’s transformation, defined as a transformation from CLL into an aggressive lymphoma (most commonly DLBCL, rarely Hodgkin lymphoma), occurs in up to 10% of CLL patients, with median time to occurrence 1.8-5 years from diagnosis. Risk factors for this unfortunate complication includes advanced stage and bulky disease (>3 cm LN) at time of diagnosis, IGHV unmutated status, and del17p. Median survival after transformation is 8-14 months due to poor response rates to chemotherapy. Allogeneic HSCT in this setting as a post remission therapy is important, with 3 year survival probability of 75% for those transplanted in CR or PR, compared to 21% for patients who undergo HSCT after relapsed/refractory disease, or 27% who responded to chemotherapy but do not undergo HSCT10. Data for the use of the novel agents in Richter’s transformation is lacking at this time.

Similar to what was seen when TKIs were introduced for CML, the availability of targeted therapies for CLL has clearly changed our definition of “high-risk CLL”, and this will lead to less stem cell transplants for this disease, with better outcomes and quality of life for the majority of patients with CLL. It is important, however, that HSCT not be considered a last resort treatment, offered to patients only after all other options have been exhausted. Based on the current available data, in fit patients with a suitable donor, I would recommend allogeneic HSCT in the following cases:

(a) Del17p-associated CLL

(b) Relapse after ibrutinib or idelalisib

(c)  Richter’s transformation in first remission after treatment.

For these patients, I generally proceed with HSCT once maximal response to therapy has been achieved. 

CLL treatment will continue to advance and evolve quite rapidly, thus it is necessary to continually factor in new evidence that will lead to adjustment of these recommendations.  

When one thinks of a young, fit, transplant-eligible patient with CLL, the standard “go-go” approach prevails, the aim of which is the deepest remission/highest efficacy, usually at the expense of increased toxicity of the treatment. Allogeneic stem cell transplantation is at the extreme end of the therapy spectrum for CLL, and is currently the only potential curative option, accompanied by a significant risk of morbidity from chronic GVHD, and treatment-related mortality. For most patients with this “disease of the elderly”, this approach is not possible, and as a result new, efficacious and well-tolerated therapies have developed over the last decade that have completely changed the way this disease is being treated, including the role of allogeneic stem cell transplant. 

Allogeneic HSCT is recommended for patients with high risk CLL, and traditionally this included patients with disease associated with deletion 17p/TP53 mutations, and/or disease refractory to purine analogues (i.e. disease relapse within 2 years after purine analogue combination therapy). The basis of HSCT in CLL is a strong graft-versus-leukemia effect, supported by lower relapse risk after chronic GVHD1, higher relapse risk associated with T-cell depletion2, and MRD clearance in the context of chronic GVHD or immune interventions such as tapering of immunosuppression or donor lymphocyte infusion3,4. The 5-year progression-free survival is 30-35%, with 5-year overall survival 50-60%, with better outcomes in those who are chemosensitive, with non-bulky disease at time of HSCT5,6. Reduced-intensity conditioning has improved early mortality of HSCT, increasing tolerability, and allowing older patients with co-morbidities (i.e. the typical CLL patient) to proceed with HSCT. However, non-relapse mortality is still high in this patient population, approximately 20-30%, with GVHD and its associated complications the main cause of death. Moreover, in those who survive HSCT, chronic GVHD, which is frequently extensive, significantly impairs the quality of life long-term in about 25% of patients. 

Greater understanding of the pathobiology behind CLL has led to the development of more targeted therapies, such as ibrutinib and idelalisib, which target the Bruton tyrosine kinase and phosphatidylinositol 3-kinase, respectively, in the B-cell receptor signaling pathway. Long-term results with ibrutinib in the relapsed setting are now available, and with a median of 4 prior lines of therapy, the use of ibrutinib resulted in a median PFS of 52 months, and overall survival was not reached7. In patients without del17p or del 11q, the 5-year PFS was 66-91%, and OS was 80-91%. Patients with del17p had median PFS of 26 months, and this was 55 months for del11q, both of which were significantly higher than expected outcomes with FCR in the front line setting. This has led to the use of ibrutinib as first line therapy for del17p associated CLL. This drug is generally well tolerated, with fatigue, arthralgias, rash, and infections being common but mild side effects, and hypertension and atrial fibrillation (in up to 10% of patients) and increased risk of bleeding being long-term effects of the drug. Idelalisib has also shown efficacy in patients with relapsed disease in patients without del17p, and is another suitable option for these patients, at the expense of high rates of opportunistic infections (CMV, PJP pneumonia), and inflammatory conditions (e.g. colitis, pneumonitis)8. Based on the available data, all patients who have relapsed after FCR, regardless of duration of initial response, should be treated with one of these novel agents prior to consideration for allogeneic stem cell transplantation. 

BCL2 has also become a key target, as it is an important antiapoptotic protein. Venetoclax is an oral active potent small molecule BCL2 protein inhibitor, displacing sequestered antiapoptotic proteins, and has been shown to have durable responses in CLL after failure of ibrutinib and/or idelalisib. In a study of 64 patients with relapsed/refractory disease (43 prior ibrutinib of which 39 were resistant; 21 prior idelalisib), the 12 month PFS was 80% and OS was 90%.9 The drug is very well tolerated, and the major side effects noted included tumor lysis, which is now well managed with risk stratification, and neutropenia. These data suggest that Venetoclax is a reasonable salvage therapy in patients who have failed another novel agent. 

Richter’s transformation, defined as a transformation from CLL into an aggressive lymphoma (most commonly DLBCL, rarely Hodgkin lymphoma), occurs in up to 10% of CLL patients, with median time to occurrence 1.8-5 years from diagnosis. Risk factors for this unfortunate complication includes advanced stage and bulky disease (>3 cm LN) at time of diagnosis, IGHV unmutated status, and del17p. Median survival after transformation is 8-14 months due to poor response rates to chemotherapy. Allogeneic HSCT in this setting as a post remission therapy is important, with 3 year survival probability of 75% for those transplanted in CR or PR, compared to 21% for patients who undergo HSCT after relapsed/refractory disease, or 27% who responded to chemotherapy but do not undergo HSCT10. Data for the use of the novel agents in Richter’s transformation is lacking at this time.

Similar to what was seen when TKIs were introduced for CML, the availability of targeted therapies for CLL has clearly changed our definition of “high-risk CLL”, and this will lead to less stem cell transplants for this disease, with better outcomes and quality of life for the majority of patients with CLL. It is important, however, that HSCT not be considered a last resort treatment, offered to patients only after all other options have been exhausted. Based on the current available data, in fit patients with a suitable donor, I would recommend allogeneic HSCT in the following cases:

(a) Del17p-associated CLL

(b) Relapse after ibrutinib or idelalisib

(c)  Richter’s transformation in first remission after treatment.

For these patients, I generally proceed with HSCT once maximal response to therapy has been achieved. 

CLL treatment will continue to advance and evolve quite rapidly, thus it is necessary to continually factor in new evidence that will lead to adjustment of these recommendations.  

When one thinks of a young, fit, transplant-eligible patient with CLL, the standard “go-go” approach prevails, the aim of which is the deepest remission/highest efficacy, usually at the expense of increased toxicity of the treatment. Allogeneic stem cell transplantation is at the extreme end of the therapy spectrum for CLL, and is currently the only potential curative option, accompanied by a significant risk of morbidity from chronic GVHD, and treatment-related mortality. For most patients with this “disease of the elderly”, this approach is not possible, and as a result new, efficacious and well-tolerated therapies have developed over the last decade that have completely changed the way this disease is being treated, including the role of allogeneic stem cell transplant. 

Allogeneic HSCT is recommended for patients with high risk CLL, and traditionally this included patients with disease associated with deletion 17p/TP53 mutations, and/or disease refractory to purine analogues (i.e. disease relapse within 2 years after purine analogue combination therapy). The basis of HSCT in CLL is a strong graft-versus-leukemia effect, supported by lower relapse risk after chronic GVHD1, higher relapse risk associated with T-cell depletion2, and MRD clearance in the context of chronic GVHD or immune interventions such as tapering of immunosuppression or donor lymphocyte infusion3,4. The 5-year progression-free survival is 30-35%, with 5-year overall survival 50-60%, with better outcomes in those who are chemosensitive, with non-bulky disease at time of HSCT5,6. Reduced-intensity conditioning has improved early mortality of HSCT, increasing tolerability, and allowing older patients with co-morbidities (i.e. the typical CLL patient) to proceed with HSCT. However, non-relapse mortality is still high in this patient population, approximately 20-30%, with GVHD and its associated complications the main cause of death. Moreover, in those who survive HSCT, chronic GVHD, which is frequently extensive, significantly impairs the quality of life long-term in about 25% of patients. 

Greater understanding of the pathobiology behind CLL has led to the development of more targeted therapies, such as ibrutinib and idelalisib, which target the Bruton tyrosine kinase and phosphatidylinositol 3-kinase, respectively, in the B-cell receptor signaling pathway. Long-term results with ibrutinib in the relapsed setting are now available, and with a median of 4 prior lines of therapy, the use of ibrutinib resulted in a median PFS of 52 months, and overall survival was not reached7. In patients without del17p or del 11q, the 5-year PFS was 66-91%, and OS was 80-91%. Patients with del17p had median PFS of 26 months, and this was 55 months for del11q, both of which were significantly higher than expected outcomes with FCR in the front line setting. This has led to the use of ibrutinib as first line therapy for del17p associated CLL. This drug is generally well tolerated, with fatigue, arthralgias, rash, and infections being common but mild side effects, and hypertension and atrial fibrillation (in up to 10% of patients) and increased risk of bleeding being long-term effects of the drug. Idelalisib has also shown efficacy in patients with relapsed disease in patients without del17p, and is another suitable option for these patients, at the expense of high rates of opportunistic infections (CMV, PJP pneumonia), and inflammatory conditions (e.g. colitis, pneumonitis)8. Based on the available data, all patients who have relapsed after FCR, regardless of duration of initial response, should be treated with one of these novel agents prior to consideration for allogeneic stem cell transplantation. 

BCL2 has also become a key target, as it is an important antiapoptotic protein. Venetoclax is an oral active potent small molecule BCL2 protein inhibitor, displacing sequestered antiapoptotic proteins, and has been shown to have durable responses in CLL after failure of ibrutinib and/or idelalisib. In a study of 64 patients with relapsed/refractory disease (43 prior ibrutinib of which 39 were resistant; 21 prior idelalisib), the 12 month PFS was 80% and OS was 90%.9 The drug is very well tolerated, and the major side effects noted included tumor lysis, which is now well managed with risk stratification, and neutropenia. These data suggest that Venetoclax is a reasonable salvage therapy in patients who have failed another novel agent. 

Richter’s transformation, defined as a transformation from CLL into an aggressive lymphoma (most commonly DLBCL, rarely Hodgkin lymphoma), occurs in up to 10% of CLL patients, with median time to occurrence 1.8-5 years from diagnosis. Risk factors for this unfortunate complication includes advanced stage and bulky disease (>3 cm LN) at time of diagnosis, IGHV unmutated status, and del17p. Median survival after transformation is 8-14 months due to poor response rates to chemotherapy. Allogeneic HSCT in this setting as a post remission therapy is important, with 3 year survival probability of 75% for those transplanted in CR or PR, compared to 21% for patients who undergo HSCT after relapsed/refractory disease, or 27% who responded to chemotherapy but do not undergo HSCT10. Data for the use of the novel agents in Richter’s transformation is lacking at this time.

Similar to what was seen when TKIs were introduced for CML, the availability of targeted therapies for CLL has clearly changed our definition of “high-risk CLL”, and this will lead to less stem cell transplants for this disease, with better outcomes and quality of life for the majority of patients with CLL. It is important, however, that HSCT not be considered a last resort treatment, offered to patients only after all other options have been exhausted. Based on the current available data, in fit patients with a suitable donor, I would recommend allogeneic HSCT in the following cases:

(a) Del17p-associated CLL

(b) Relapse after ibrutinib or idelalisib

(c)  Richter’s transformation in first remission after treatment.

For these patients, I generally proceed with HSCT once maximal response to therapy has been achieved. 

CLL treatment will continue to advance and evolve quite rapidly, thus it is necessary to continually factor in new evidence that will lead to adjustment of these recommendations.  

 

References:

1. Farina et al. Qualitative and quantitative polymerase chain reaction monitoring of minimal residual disease in relapsed chronic lymphocytic leukemia: early assessment can predict long-term outcome after reduced intensity allogeneic transplantation. Haematologica. 2009. 94(5)654-662

2. Gribben et al. Autologous and allogeneic stem cell transplantation for poor risk chronic lymphocytic leukemia. Blood 2005. 106 (13):4389-4396

3. Hahn et al. Timing of immunosuppression tapering, chronic GVHD, and minimal residual disease (MRD) eradication in patients allografted for poor-risk chronic lymphocytic leukemia (CLL). EBMT consensus criteria: a single center experience [abstract]. Bone Marrow Transplant 2013. 48(S2): S72

4. Moreno et al. Clinical significance of minimal residual disease, as assessed by different techniques, after stem cell transplantation for chronic lymphocytic leukemia. Blood 2006. 107(11): 4563-4569

5. Sorror et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloblative conditioning. J Clin Oncol2008. 26(30): 4912-4920.

6. Brown et al. Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia 2013 27(2): 362-369

7. O’Brien et al. 5-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia [abstract]: ASH Meeting 2016 Abstract 233

8. Furman et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Eng J med2014. 370: 997-1007

9. Jones et al. Venetoclax (VN) monotherapy for patients with chronic lymphocytic leukemia (CLL who relapsed after or were refractory to ibrutinib or idelalisib [abstract]. ASH Meeting 2016 Abstract 637

10. Tsimberidou et al. Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem cell transplantation. J Clin Oncol 2006 24(15): 2343-2351

 

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