REDUCED INTENSITY CONDITIONING (RIC) ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ADULT DE NOVO ACUTE LYMPHOBLASTIC LEUKEMIA: A PROSPECTIVE STUDY FROM THE UKALL14 TRIAL (ISRCTN 66541317)
(Abstract release date: 05/19/16)
EHA Library. Okasha D. 06/12/16; 135313; S819
Dr. Dina Okasha
Contributions
Contributions
Abstract
Abstract: S819
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C15
Background
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curable treatment modality for adults with acute lymphoblastic leukaemia (ALL) with significant improvement in overall survival (OS) and reduction in relapse incidence. However, in the donor versus no donor analysis of the UKALL12/E2993 trial in adult ALL, the OS benefit did not extend to older patients in whom myeloablative allogeneic hematopoietic cell transplant related mortality (TRM) was 35% at 2 years and outweighed the reduction in relapse risk. To address this elevated TRM, reduced intensity conditioning (RIC) has been introduced. In our current UK National Cancer Research Institute UKALL14 study all patients ≥41 years in CR, regardless of Philadelphia (Ph+) status and other high risk factors, are considered “high risk” and recommended a RIC alloHSCT with a matched sibling (sib) or matched unrelated donor (MUD) after a 2 course induction and high dose methotrexate.
Aims
The primary endpoint is event free survival (EFS). We report here the early outcome of 120 patients with at least day 100 follow up (FU) who received RIC alloHSCT on UKALL14 trial.
Methods
Standard reduced intensity conditioning was with fludarabine 30mg/m2 d -6 to -2, melphalan 140 mg/m2 d -2 and alemtuzumab 30mg d -2 to-1 (MUD) or d-1 (sib). Graft versus host disease (GVHD) prophylaxis was ciclosporin A only. A small group of patients did not receive the standard conditioning protocol. Multilineage chimerism (MC) and minimal residual disease (MRD) were assessed 3 monthly post alloHSCT. Escalating doses of donor lymphocyte infusions (DLI) were given for T-cell mixed chimerism or MRD, starting dose 1 x 106 CD3 cells/kg, escalating by half log increments every 3 months.
Results
Five hundred and ninety seven patients were registered on the trial to date, 173 were registered for a RIC alloHSCT, 122 have completed the transplant, 120 of whom have sufficient follow up to report. Median age was 51 years (range 29 to 64). Donor was sib in 39 and MUD in 81 patients, respectively. Median WBC at diagnosis was 8.7 x 109/L (0.6-557.23). 57 of 106 (54%) evaluable patients had high-risk cytogenetics, 31 (26%) were Ph+. 18 of 74 (24%) with MRD data were MRD +ve pre-alloHSCT.Post-alloHSCT, myeloid engraftment occurred in 111 patients at a median of 14 days, 9 had missing data. No graft failures were reported. Acute graft versus host disease (GVHD) occurred at grade 1 in 34 patients (28%) and grade 2-3 in 12 patients (10%). 47 patients developed chronic GVHD (40% of 117 patients surviving beyond D100), 20 limited and 27 extensive.Of 15 patients who suffered transplant-related mortality (TRM), 8 died of infection (one post-transplant lymphoproliferative disease). Other causes of TRM included organ toxicity (2) and GVHD (2). TRM was not associated with age or donor type. 27 patients relapsed at a median time of 230 days (range 97-1034) with a relapse risk of 27.5% (18.9-38.1) at 22 months post alloHSCT. Of those, 16 (of 25 with data) had high-risk cytogenetics (EFS, p=0.11) and 10 (of 19 with data) were MRD +ve pre-alloHSCT (EFS, HR 2.41, p=0.025).37 patients in total received 84 DLI (median maximum dose 1 x 106 CD3 cells/kg) including 20 for mixed chimerism, 6 for rising MRD and 9 for both. 5 patients (14%) developed post-DLI GVHD at grade 1 (n=4) and grade 2 (n=1).Serial MC data is available for 43 patients. By 6 months post transplant, 34 out of 43 patients (79%) achieved full donor total peripheral blood chimerism whereas only 15 (35%) achieved full donor chimerism in the T-cell compartment. With longer follow up, 26 patients (60%) achieved full donor T-Cell chimerism (median 9 months), 10 after receiving DLI (38%).Figure 1 shows Kaplan Meier curves of OS 66.3% (55.0-75.5, 95% CI) and EFS 59.4% (48.6-68.7) at 22 months (median follow-up).
Conclusion
This is early follow up from the first prospective data of RIC alloHSCT in older adults with ALL from a large, multicenter trial and the early results are promising. Severe GVHD and TRM were relatively low leading to a higher EFS than expected for this age group, however, longer follow up is needed. T-cell mixed chimerism was common at first MC assessment but early data indicate that conversion to full donor chimerism is achievable and safe with DLI. The impact of mixed chimerism and pre-emptive DLI on relapse remain to be evaluated.
Session topic: Stem cell transplantation - Clinical 2
Keyword(s): Acute lymphoblastic leukemia, Allogeneic hematopoietic stem cell transplant, Donor lymphocyte infusion, Reduced intensity transplantation
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C15
Background
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curable treatment modality for adults with acute lymphoblastic leukaemia (ALL) with significant improvement in overall survival (OS) and reduction in relapse incidence. However, in the donor versus no donor analysis of the UKALL12/E2993 trial in adult ALL, the OS benefit did not extend to older patients in whom myeloablative allogeneic hematopoietic cell transplant related mortality (TRM) was 35% at 2 years and outweighed the reduction in relapse risk. To address this elevated TRM, reduced intensity conditioning (RIC) has been introduced. In our current UK National Cancer Research Institute UKALL14 study all patients ≥41 years in CR, regardless of Philadelphia (Ph+) status and other high risk factors, are considered “high risk” and recommended a RIC alloHSCT with a matched sibling (sib) or matched unrelated donor (MUD) after a 2 course induction and high dose methotrexate.
Aims
The primary endpoint is event free survival (EFS). We report here the early outcome of 120 patients with at least day 100 follow up (FU) who received RIC alloHSCT on UKALL14 trial.
Methods
Standard reduced intensity conditioning was with fludarabine 30mg/m2 d -6 to -2, melphalan 140 mg/m2 d -2 and alemtuzumab 30mg d -2 to-1 (MUD) or d-1 (sib). Graft versus host disease (GVHD) prophylaxis was ciclosporin A only. A small group of patients did not receive the standard conditioning protocol. Multilineage chimerism (MC) and minimal residual disease (MRD) were assessed 3 monthly post alloHSCT. Escalating doses of donor lymphocyte infusions (DLI) were given for T-cell mixed chimerism or MRD, starting dose 1 x 106 CD3 cells/kg, escalating by half log increments every 3 months.
Results
Five hundred and ninety seven patients were registered on the trial to date, 173 were registered for a RIC alloHSCT, 122 have completed the transplant, 120 of whom have sufficient follow up to report. Median age was 51 years (range 29 to 64). Donor was sib in 39 and MUD in 81 patients, respectively. Median WBC at diagnosis was 8.7 x 109/L (0.6-557.23). 57 of 106 (54%) evaluable patients had high-risk cytogenetics, 31 (26%) were Ph+. 18 of 74 (24%) with MRD data were MRD +ve pre-alloHSCT.Post-alloHSCT, myeloid engraftment occurred in 111 patients at a median of 14 days, 9 had missing data. No graft failures were reported. Acute graft versus host disease (GVHD) occurred at grade 1 in 34 patients (28%) and grade 2-3 in 12 patients (10%). 47 patients developed chronic GVHD (40% of 117 patients surviving beyond D100), 20 limited and 27 extensive.Of 15 patients who suffered transplant-related mortality (TRM), 8 died of infection (one post-transplant lymphoproliferative disease). Other causes of TRM included organ toxicity (2) and GVHD (2). TRM was not associated with age or donor type. 27 patients relapsed at a median time of 230 days (range 97-1034) with a relapse risk of 27.5% (18.9-38.1) at 22 months post alloHSCT. Of those, 16 (of 25 with data) had high-risk cytogenetics (EFS, p=0.11) and 10 (of 19 with data) were MRD +ve pre-alloHSCT (EFS, HR 2.41, p=0.025).37 patients in total received 84 DLI (median maximum dose 1 x 106 CD3 cells/kg) including 20 for mixed chimerism, 6 for rising MRD and 9 for both. 5 patients (14%) developed post-DLI GVHD at grade 1 (n=4) and grade 2 (n=1).Serial MC data is available for 43 patients. By 6 months post transplant, 34 out of 43 patients (79%) achieved full donor total peripheral blood chimerism whereas only 15 (35%) achieved full donor chimerism in the T-cell compartment. With longer follow up, 26 patients (60%) achieved full donor T-Cell chimerism (median 9 months), 10 after receiving DLI (38%).Figure 1 shows Kaplan Meier curves of OS 66.3% (55.0-75.5, 95% CI) and EFS 59.4% (48.6-68.7) at 22 months (median follow-up).
Conclusion
This is early follow up from the first prospective data of RIC alloHSCT in older adults with ALL from a large, multicenter trial and the early results are promising. Severe GVHD and TRM were relatively low leading to a higher EFS than expected for this age group, however, longer follow up is needed. T-cell mixed chimerism was common at first MC assessment but early data indicate that conversion to full donor chimerism is achievable and safe with DLI. The impact of mixed chimerism and pre-emptive DLI on relapse remain to be evaluated.
Session topic: Stem cell transplantation - Clinical 2
Keyword(s): Acute lymphoblastic leukemia, Allogeneic hematopoietic stem cell transplant, Donor lymphocyte infusion, Reduced intensity transplantation
Abstract: S819
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C15
Background
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curable treatment modality for adults with acute lymphoblastic leukaemia (ALL) with significant improvement in overall survival (OS) and reduction in relapse incidence. However, in the donor versus no donor analysis of the UKALL12/E2993 trial in adult ALL, the OS benefit did not extend to older patients in whom myeloablative allogeneic hematopoietic cell transplant related mortality (TRM) was 35% at 2 years and outweighed the reduction in relapse risk. To address this elevated TRM, reduced intensity conditioning (RIC) has been introduced. In our current UK National Cancer Research Institute UKALL14 study all patients ≥41 years in CR, regardless of Philadelphia (Ph+) status and other high risk factors, are considered “high risk” and recommended a RIC alloHSCT with a matched sibling (sib) or matched unrelated donor (MUD) after a 2 course induction and high dose methotrexate.
Aims
The primary endpoint is event free survival (EFS). We report here the early outcome of 120 patients with at least day 100 follow up (FU) who received RIC alloHSCT on UKALL14 trial.
Methods
Standard reduced intensity conditioning was with fludarabine 30mg/m2 d -6 to -2, melphalan 140 mg/m2 d -2 and alemtuzumab 30mg d -2 to-1 (MUD) or d-1 (sib). Graft versus host disease (GVHD) prophylaxis was ciclosporin A only. A small group of patients did not receive the standard conditioning protocol. Multilineage chimerism (MC) and minimal residual disease (MRD) were assessed 3 monthly post alloHSCT. Escalating doses of donor lymphocyte infusions (DLI) were given for T-cell mixed chimerism or MRD, starting dose 1 x 106 CD3 cells/kg, escalating by half log increments every 3 months.
Results
Five hundred and ninety seven patients were registered on the trial to date, 173 were registered for a RIC alloHSCT, 122 have completed the transplant, 120 of whom have sufficient follow up to report. Median age was 51 years (range 29 to 64). Donor was sib in 39 and MUD in 81 patients, respectively. Median WBC at diagnosis was 8.7 x 109/L (0.6-557.23). 57 of 106 (54%) evaluable patients had high-risk cytogenetics, 31 (26%) were Ph+. 18 of 74 (24%) with MRD data were MRD +ve pre-alloHSCT.Post-alloHSCT, myeloid engraftment occurred in 111 patients at a median of 14 days, 9 had missing data. No graft failures were reported. Acute graft versus host disease (GVHD) occurred at grade 1 in 34 patients (28%) and grade 2-3 in 12 patients (10%). 47 patients developed chronic GVHD (40% of 117 patients surviving beyond D100), 20 limited and 27 extensive.Of 15 patients who suffered transplant-related mortality (TRM), 8 died of infection (one post-transplant lymphoproliferative disease). Other causes of TRM included organ toxicity (2) and GVHD (2). TRM was not associated with age or donor type. 27 patients relapsed at a median time of 230 days (range 97-1034) with a relapse risk of 27.5% (18.9-38.1) at 22 months post alloHSCT. Of those, 16 (of 25 with data) had high-risk cytogenetics (EFS, p=0.11) and 10 (of 19 with data) were MRD +ve pre-alloHSCT (EFS, HR 2.41, p=0.025).37 patients in total received 84 DLI (median maximum dose 1 x 106 CD3 cells/kg) including 20 for mixed chimerism, 6 for rising MRD and 9 for both. 5 patients (14%) developed post-DLI GVHD at grade 1 (n=4) and grade 2 (n=1).Serial MC data is available for 43 patients. By 6 months post transplant, 34 out of 43 patients (79%) achieved full donor total peripheral blood chimerism whereas only 15 (35%) achieved full donor chimerism in the T-cell compartment. With longer follow up, 26 patients (60%) achieved full donor T-Cell chimerism (median 9 months), 10 after receiving DLI (38%).Figure 1 shows Kaplan Meier curves of OS 66.3% (55.0-75.5, 95% CI) and EFS 59.4% (48.6-68.7) at 22 months (median follow-up).
Conclusion
This is early follow up from the first prospective data of RIC alloHSCT in older adults with ALL from a large, multicenter trial and the early results are promising. Severe GVHD and TRM were relatively low leading to a higher EFS than expected for this age group, however, longer follow up is needed. T-cell mixed chimerism was common at first MC assessment but early data indicate that conversion to full donor chimerism is achievable and safe with DLI. The impact of mixed chimerism and pre-emptive DLI on relapse remain to be evaluated.
Session topic: Stem cell transplantation - Clinical 2
Keyword(s): Acute lymphoblastic leukemia, Allogeneic hematopoietic stem cell transplant, Donor lymphocyte infusion, Reduced intensity transplantation
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C15
Background
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curable treatment modality for adults with acute lymphoblastic leukaemia (ALL) with significant improvement in overall survival (OS) and reduction in relapse incidence. However, in the donor versus no donor analysis of the UKALL12/E2993 trial in adult ALL, the OS benefit did not extend to older patients in whom myeloablative allogeneic hematopoietic cell transplant related mortality (TRM) was 35% at 2 years and outweighed the reduction in relapse risk. To address this elevated TRM, reduced intensity conditioning (RIC) has been introduced. In our current UK National Cancer Research Institute UKALL14 study all patients ≥41 years in CR, regardless of Philadelphia (Ph+) status and other high risk factors, are considered “high risk” and recommended a RIC alloHSCT with a matched sibling (sib) or matched unrelated donor (MUD) after a 2 course induction and high dose methotrexate.
Aims
The primary endpoint is event free survival (EFS). We report here the early outcome of 120 patients with at least day 100 follow up (FU) who received RIC alloHSCT on UKALL14 trial.
Methods
Standard reduced intensity conditioning was with fludarabine 30mg/m2 d -6 to -2, melphalan 140 mg/m2 d -2 and alemtuzumab 30mg d -2 to-1 (MUD) or d-1 (sib). Graft versus host disease (GVHD) prophylaxis was ciclosporin A only. A small group of patients did not receive the standard conditioning protocol. Multilineage chimerism (MC) and minimal residual disease (MRD) were assessed 3 monthly post alloHSCT. Escalating doses of donor lymphocyte infusions (DLI) were given for T-cell mixed chimerism or MRD, starting dose 1 x 106 CD3 cells/kg, escalating by half log increments every 3 months.
Results
Five hundred and ninety seven patients were registered on the trial to date, 173 were registered for a RIC alloHSCT, 122 have completed the transplant, 120 of whom have sufficient follow up to report. Median age was 51 years (range 29 to 64). Donor was sib in 39 and MUD in 81 patients, respectively. Median WBC at diagnosis was 8.7 x 109/L (0.6-557.23). 57 of 106 (54%) evaluable patients had high-risk cytogenetics, 31 (26%) were Ph+. 18 of 74 (24%) with MRD data were MRD +ve pre-alloHSCT.Post-alloHSCT, myeloid engraftment occurred in 111 patients at a median of 14 days, 9 had missing data. No graft failures were reported. Acute graft versus host disease (GVHD) occurred at grade 1 in 34 patients (28%) and grade 2-3 in 12 patients (10%). 47 patients developed chronic GVHD (40% of 117 patients surviving beyond D100), 20 limited and 27 extensive.Of 15 patients who suffered transplant-related mortality (TRM), 8 died of infection (one post-transplant lymphoproliferative disease). Other causes of TRM included organ toxicity (2) and GVHD (2). TRM was not associated with age or donor type. 27 patients relapsed at a median time of 230 days (range 97-1034) with a relapse risk of 27.5% (18.9-38.1) at 22 months post alloHSCT. Of those, 16 (of 25 with data) had high-risk cytogenetics (EFS, p=0.11) and 10 (of 19 with data) were MRD +ve pre-alloHSCT (EFS, HR 2.41, p=0.025).37 patients in total received 84 DLI (median maximum dose 1 x 106 CD3 cells/kg) including 20 for mixed chimerism, 6 for rising MRD and 9 for both. 5 patients (14%) developed post-DLI GVHD at grade 1 (n=4) and grade 2 (n=1).Serial MC data is available for 43 patients. By 6 months post transplant, 34 out of 43 patients (79%) achieved full donor total peripheral blood chimerism whereas only 15 (35%) achieved full donor chimerism in the T-cell compartment. With longer follow up, 26 patients (60%) achieved full donor T-Cell chimerism (median 9 months), 10 after receiving DLI (38%).Figure 1 shows Kaplan Meier curves of OS 66.3% (55.0-75.5, 95% CI) and EFS 59.4% (48.6-68.7) at 22 months (median follow-up).
Conclusion
This is early follow up from the first prospective data of RIC alloHSCT in older adults with ALL from a large, multicenter trial and the early results are promising. Severe GVHD and TRM were relatively low leading to a higher EFS than expected for this age group, however, longer follow up is needed. T-cell mixed chimerism was common at first MC assessment but early data indicate that conversion to full donor chimerism is achievable and safe with DLI. The impact of mixed chimerism and pre-emptive DLI on relapse remain to be evaluated.
Session topic: Stem cell transplantation - Clinical 2
Keyword(s): Acute lymphoblastic leukemia, Allogeneic hematopoietic stem cell transplant, Donor lymphocyte infusion, Reduced intensity transplantation
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