- Email: [email protected]
OP25 Current therapy for ALL in adults
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Sessions / Symposia / Special Lectures
to relieve attenuation of Jun kinase and MAPK signaling. In a phase II study involving the liposomal formulation, treatment with TLK199 gave rise to multilineage hematologic improvement in more than 60% of evaluable patients. An orally bioavailable formulation recently completed phase I investigation and will enter efficacy studies later this year. Other inhibitory signal antagonists that have shown preliminary activity in lower risk patients include SCIO-469, which targets p38α MAPK, a pivotal effector of pro-apoptotic stimuli that is unregulated in MDS progenitors. The FTIs tipifarnib and lonifarnib continue investigations in higher risk patients, with new agents such as the SFK inhibitor dasatinib and clofarabine beginning clinical study. Given the biologic complexity of MDS, some of these agents are expected to complement existing therapies and provide a foundation for novel combinations.
OP24 Myelodysplastic syndrome management in Slovakia M. Mistrik. Department of Hematology and Transfusiology, University Hospital, Bratislava Despite progress in diagnostics, subcategorization (WHO) and risk evaluation system (IPSS), therapy of myelodysplastic syndrome (MDS) is generally unsatisfactory. That is the case even in countries with developed health care system. In this presentation we give information about current status in the field of myelodysplasia in Slovakia. Slovak hematologists followed up and reported 558 patients with myelodysplastic syndrome in the year 1999 and 765 patients in the year 2006. Only 12 young patients underwent allogeneic SCT, all but one from HLA identical sibling. Wast majority of MDS patients are followed up and treated with non-transplant approach according to their specialist decission. Supportive therapy and hematopoietic growth factors are the most frequent ways of MDS cytopenia management. Erythrocyte transfusion support is only occasionally accompanied by iron chelation therapy with deferoxamin. Exjade (deferasirox) has been registered in our country recently, but is still not available for clinical practice. Sporadic patients with sideroblastic anemia responded to pyridoxin (vitamin B6 ) 2x100 mg/d. Immunosuppressive therapy (CsA or ATG) was used in rare patients with hypocellular bone marrow biopsies. First 2 (transfusion dependent) patients with 5qsyndrome are using revlimid. Azacytidine and decitabine were not used yet. There is a steady increase in the number of patients with MDS in Slovakia. Most probably this increment reflects better knowledge and diagnostic possibilities, and population aging as well. It is reasoneble to implement modern and effective medicaments into complex MDS management.
Acute lymphoblastic leukemia – current therapy OP25 Current therapy for ALL in adults D. Hoelzer. Department of Internal Medicine, J.W. Goethe University Hospital, Frankfurt, Germany Current treatment strategies in adult acute lymphoblastic leukemia include (1) intensification of induction and high dose therapy in consolidation, (2) new approaches for stem cell transplantation (SCT) (3) antibody therapy, (4) molecular targeting of the signal transduction pathways, (5) evaluation of minimal residual disease (MRD) for monitoring and treatment decisions and (6) microarray techniques for identification of markers with potential diagnostic and prognostic relevance. New approaches for induction therapy in adults are using higher doses of ALL specific drugs, such as Croticosteroids, Asperaginase, Vinceralkaloids successful in childhood ALL. In recent trials remission rates of 90% were reached, but it seems more important to increase molecular remission rates. For this stricter time/dose intensity, new consolidation cycles e.g. including HDMTX, HDAC and several new drugs, e.g. purine analogues, PNP inhibitors, liposomal drugs are under investigation. Regarding antibody therapy the use of Rituximab has substantially improved the outcome of patients with mature B-ALL and Burkitt/Burkitt-like NHL. Rituximab is now explored in B-lineage CD20+ ALL in elderly, in CD20+ standard risk patients and as an “in vivo purging” for adult high risk B lineage CD20+ ALL before SCT. For adult T-ALL and T-lymphoblastic lymphoma antiCD52 (Campath) and Nelarabine were explored in relapsed or refractory and MRD+ patients and they are now part of front-line regimens. New molecular therapeutic strategies are evaluated particularly in Ph/bcr-abl-positive ALL such as the specific abl-tyrosine kinase inhibitor Imatinib; given (1) concomitant to induction therapy in younger Ph/bcr-abl-positive ALL patients resulting in several multicentre trials in CR rates of >90%, (2) after allo or auto SCT according to MRD and (3) in elderly Ph/bcr-abl-positive patients trials showed a CR rate of more than 90% in patients receiving four weeks Imatinib single drug therapy. In patients MRD positive after Imatinib, new tyrosine kinase inhibitors are applied, e.g. Dasatinib and Nilotinib. Front line studies with these drugs are under way and combinations should be explored. Measurement of MRD based on IgH and TCR-rearrangements can be used to analyse individual response to therapy. The MRD level and kinetic during the early treatment period is now used for treatment decisions, such as patient selection for SCT in CR1. In SCT new approaches are directed to (1) the extension of SCT indications e.g. by the inclusion of mini-transplants in elderly patients, (2) the improvement of antileukemic effectivity by new conditioning regimens and MRD based
Sessions / Symposia / Special Lectures post transplant regimens. Allo MUD results in adult ALL are substantially improving. For auto SCT the transplant of MRD negative graft in MRD neg. patients may be a new treatment concept.
OP26 Therapy of Burkitt’s and lymphoblastic lymphoma, and PH+ ALL at MDACC D. Thomas. USA Abstract not submitted.
OP27 More intensive chemotherapy for young adults with ALL? J.P. Marrie, S. Haïat, O. Legrand. Department of Hematology and edical Oncology, Hôtel Dieu Hospital, Paris, France Background: Adult acute lymphoblastic leukemia (ALL) still have poor outcome compared with childhood ALL, with an expected long time survival of less than 40%. Adolescents aged from 15 to 20 years have improved complete remission (CR) and event free survival (EFS) rates when treated with pediatric protocol instead of adult one. EORTC Leukemia Group and HOVON developed a phase II protocol (HOVON70) using the frame of FRALLE 2000 (French pediatric ALL trial) for “young” adult (18-35 yo). Aim: In a pilot study, Hôtel-Dieu have tested the feasibility and the efficiency of this French pediatric protocol FRALLE 2000 to treat adult ALL aged up to 55 years. Methods: 20 consecutive adults Philadelphia negative ALL aged from 15 to 55 years received treatment courses according to the French pediatric protocol FRALLE 2000 from 2001 to 2006. After a prednisone prephase and a four-drugs induction (prednisone, daunorubicin, vincristine and 9 infusions of L-asparaginase), patients in CR received a consolidation course, two delayed intensifications with L-asparaginase separed by an interphase, a CNS irradiation and a maintenance chemotherapy during two years. Results were compared with the outcome from 20 consecutive patients treated in our institution with the historic EORTC ALL-4 adults protocol from 1998 to 2001. Median age, WHO performans status, white blood count at diagnosis, phenotype and cytotogenetics risk groups were statistically similar in both groups. Results: Tolerance was excellent in 18-30 yo patients, acceptable in 30-45 yo patients, but drug schedule needs to be adapted in 45-55 yo patients. G-CSF, parenteral nutrition and prophylactic antibiotherapy are mandatory during induction therapy. Cortico-sensitivity and chemo-sensitivity was assessed for 15 and 17 patients respectively and CR rate was 85% after FRALLE induction, and 100% after a salvage therapy with high doses cytarabine. All patients who achieved cortico and chemo-sensitivity were in persistant CR with a median follow-up of 31 months. Minimal residual disease (MRD) study was available for 12 patients, using IgH/TCR rearrangement or E2A/PBX1 transcript. Among the 10 pa-
S45
tients with an indetectable MRD at D90, no one experienced relapse. Overall, with a median follow-up of alive patients of 31 months, the 4-years EFS and overall survival are 84±8% vs 47±12%, (p=0.04) and 88±8% vs 35±16%, (p=0.04) respectively. This better outcome is not explained by significant differences in patients characteristics nor by a better CR rate but rather by a lower relapse rate in the pediatric treatment group (more than two-fold lower). This indicates a major role of the drugs indication and the dose intensity, especially in L-asparaginase administration. No treatment related mortality and no severe side effect were observed during treatment when supportive cares including parenteral nutrition, granular growth factor, infectious prophylaxis, and antithrombine III infusions were given. Summary/Conclusion: This pilot study shows that adults up to 45 years could tolerate a pediatric ALL protocol. Patients treated with this approach have a dramatically better outcome when there are treated with childhood ALL protocol without any major side effect. This therapeutic strategy has to be confirmed by the current prospective study performed by the EORTC group.
OP28 Novel agents for ALL S. O’Brien. Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston TX, USA Acute lymphocytic leukemia is the most frequent malignancy in children and accounts for 20% of acute leukemias in adults. Children with ALL have had a much better prognosis than adults. Although some of this may be accounted for by differences in tolerance to chemotherapy, recent studies have shown that molecular abnormalities are quite different between pediatric and adult ALL. Favorable abnormalities including hyperdiploidy and rearrangement of the TEL gene are found in almost half of patients with pediatric ALL and are rare in adults, whereas the poor prognostic abnormality of Philadelphia chromosome positivity accounts for up to a third of patients with adult ALL. The principals of ALL therapy have included induction, consolidation, and prolonged maintenance for 2-3 years, usually with an oral 6 MP and methotrexate regimen. Studies in adult ALL have shown a high CR rate with most regimens, on the order of 70-80%, but a long-term survival of only 25-30%, owing to relapse of disease. For the past seven years the ALL regimen used at MD Anderson has been the hyper-CVAD regimen which involves rotating cycles of fractionated cytoxan, given with Vincristine, Adriamycin and Decadron (odd # cycles) and high dose methotrexate and ara-C (even # cycles), along with risk adapted CNS prophylaxis. Maintenance has been with POMP with periodic reconsolidations. Recent evaluation of over 200 patients revealed a complete remission rate of 91% and a low induction death rate of 6%. Four-year leukemia free survival is approximately 45%. CNS relapse rates are low indicating that prophylaxis with intrathecal therapy is effective without the use of cranial irradiation and its concomitant morbidities.
Sessions / Symposia / Special Lectures
to relieve attenuation of Jun kinase and MAPK signaling. In a phase II study involving the liposomal formulation, treatment with TLK199 gave rise to multilineage hematologic improvement in more than 60% of evaluable patients. An orally bioavailable formulation recently completed phase I investigation and will enter efficacy studies later this year. Other inhibitory signal antagonists that have shown preliminary activity in lower risk patients include SCIO-469, which targets p38α MAPK, a pivotal effector of pro-apoptotic stimuli that is unregulated in MDS progenitors. The FTIs tipifarnib and lonifarnib continue investigations in higher risk patients, with new agents such as the SFK inhibitor dasatinib and clofarabine beginning clinical study. Given the biologic complexity of MDS, some of these agents are expected to complement existing therapies and provide a foundation for novel combinations.
OP24 Myelodysplastic syndrome management in Slovakia M. Mistrik. Department of Hematology and Transfusiology, University Hospital, Bratislava Despite progress in diagnostics, subcategorization (WHO) and risk evaluation system (IPSS), therapy of myelodysplastic syndrome (MDS) is generally unsatisfactory. That is the case even in countries with developed health care system. In this presentation we give information about current status in the field of myelodysplasia in Slovakia. Slovak hematologists followed up and reported 558 patients with myelodysplastic syndrome in the year 1999 and 765 patients in the year 2006. Only 12 young patients underwent allogeneic SCT, all but one from HLA identical sibling. Wast majority of MDS patients are followed up and treated with non-transplant approach according to their specialist decission. Supportive therapy and hematopoietic growth factors are the most frequent ways of MDS cytopenia management. Erythrocyte transfusion support is only occasionally accompanied by iron chelation therapy with deferoxamin. Exjade (deferasirox) has been registered in our country recently, but is still not available for clinical practice. Sporadic patients with sideroblastic anemia responded to pyridoxin (vitamin B6 ) 2x100 mg/d. Immunosuppressive therapy (CsA or ATG) was used in rare patients with hypocellular bone marrow biopsies. First 2 (transfusion dependent) patients with 5qsyndrome are using revlimid. Azacytidine and decitabine were not used yet. There is a steady increase in the number of patients with MDS in Slovakia. Most probably this increment reflects better knowledge and diagnostic possibilities, and population aging as well. It is reasoneble to implement modern and effective medicaments into complex MDS management.
Acute lymphoblastic leukemia – current therapy OP25 Current therapy for ALL in adults D. Hoelzer. Department of Internal Medicine, J.W. Goethe University Hospital, Frankfurt, Germany Current treatment strategies in adult acute lymphoblastic leukemia include (1) intensification of induction and high dose therapy in consolidation, (2) new approaches for stem cell transplantation (SCT) (3) antibody therapy, (4) molecular targeting of the signal transduction pathways, (5) evaluation of minimal residual disease (MRD) for monitoring and treatment decisions and (6) microarray techniques for identification of markers with potential diagnostic and prognostic relevance. New approaches for induction therapy in adults are using higher doses of ALL specific drugs, such as Croticosteroids, Asperaginase, Vinceralkaloids successful in childhood ALL. In recent trials remission rates of 90% were reached, but it seems more important to increase molecular remission rates. For this stricter time/dose intensity, new consolidation cycles e.g. including HDMTX, HDAC and several new drugs, e.g. purine analogues, PNP inhibitors, liposomal drugs are under investigation. Regarding antibody therapy the use of Rituximab has substantially improved the outcome of patients with mature B-ALL and Burkitt/Burkitt-like NHL. Rituximab is now explored in B-lineage CD20+ ALL in elderly, in CD20+ standard risk patients and as an “in vivo purging” for adult high risk B lineage CD20+ ALL before SCT. For adult T-ALL and T-lymphoblastic lymphoma antiCD52 (Campath) and Nelarabine were explored in relapsed or refractory and MRD+ patients and they are now part of front-line regimens. New molecular therapeutic strategies are evaluated particularly in Ph/bcr-abl-positive ALL such as the specific abl-tyrosine kinase inhibitor Imatinib; given (1) concomitant to induction therapy in younger Ph/bcr-abl-positive ALL patients resulting in several multicentre trials in CR rates of >90%, (2) after allo or auto SCT according to MRD and (3) in elderly Ph/bcr-abl-positive patients trials showed a CR rate of more than 90% in patients receiving four weeks Imatinib single drug therapy. In patients MRD positive after Imatinib, new tyrosine kinase inhibitors are applied, e.g. Dasatinib and Nilotinib. Front line studies with these drugs are under way and combinations should be explored. Measurement of MRD based on IgH and TCR-rearrangements can be used to analyse individual response to therapy. The MRD level and kinetic during the early treatment period is now used for treatment decisions, such as patient selection for SCT in CR1. In SCT new approaches are directed to (1) the extension of SCT indications e.g. by the inclusion of mini-transplants in elderly patients, (2) the improvement of antileukemic effectivity by new conditioning regimens and MRD based
Sessions / Symposia / Special Lectures post transplant regimens. Allo MUD results in adult ALL are substantially improving. For auto SCT the transplant of MRD negative graft in MRD neg. patients may be a new treatment concept.
OP26 Therapy of Burkitt’s and lymphoblastic lymphoma, and PH+ ALL at MDACC D. Thomas. USA Abstract not submitted.
OP27 More intensive chemotherapy for young adults with ALL? J.P. Marrie, S. Haïat, O. Legrand. Department of Hematology and edical Oncology, Hôtel Dieu Hospital, Paris, France Background: Adult acute lymphoblastic leukemia (ALL) still have poor outcome compared with childhood ALL, with an expected long time survival of less than 40%. Adolescents aged from 15 to 20 years have improved complete remission (CR) and event free survival (EFS) rates when treated with pediatric protocol instead of adult one. EORTC Leukemia Group and HOVON developed a phase II protocol (HOVON70) using the frame of FRALLE 2000 (French pediatric ALL trial) for “young” adult (18-35 yo). Aim: In a pilot study, Hôtel-Dieu have tested the feasibility and the efficiency of this French pediatric protocol FRALLE 2000 to treat adult ALL aged up to 55 years. Methods: 20 consecutive adults Philadelphia negative ALL aged from 15 to 55 years received treatment courses according to the French pediatric protocol FRALLE 2000 from 2001 to 2006. After a prednisone prephase and a four-drugs induction (prednisone, daunorubicin, vincristine and 9 infusions of L-asparaginase), patients in CR received a consolidation course, two delayed intensifications with L-asparaginase separed by an interphase, a CNS irradiation and a maintenance chemotherapy during two years. Results were compared with the outcome from 20 consecutive patients treated in our institution with the historic EORTC ALL-4 adults protocol from 1998 to 2001. Median age, WHO performans status, white blood count at diagnosis, phenotype and cytotogenetics risk groups were statistically similar in both groups. Results: Tolerance was excellent in 18-30 yo patients, acceptable in 30-45 yo patients, but drug schedule needs to be adapted in 45-55 yo patients. G-CSF, parenteral nutrition and prophylactic antibiotherapy are mandatory during induction therapy. Cortico-sensitivity and chemo-sensitivity was assessed for 15 and 17 patients respectively and CR rate was 85% after FRALLE induction, and 100% after a salvage therapy with high doses cytarabine. All patients who achieved cortico and chemo-sensitivity were in persistant CR with a median follow-up of 31 months. Minimal residual disease (MRD) study was available for 12 patients, using IgH/TCR rearrangement or E2A/PBX1 transcript. Among the 10 pa-
S45
tients with an indetectable MRD at D90, no one experienced relapse. Overall, with a median follow-up of alive patients of 31 months, the 4-years EFS and overall survival are 84±8% vs 47±12%, (p=0.04) and 88±8% vs 35±16%, (p=0.04) respectively. This better outcome is not explained by significant differences in patients characteristics nor by a better CR rate but rather by a lower relapse rate in the pediatric treatment group (more than two-fold lower). This indicates a major role of the drugs indication and the dose intensity, especially in L-asparaginase administration. No treatment related mortality and no severe side effect were observed during treatment when supportive cares including parenteral nutrition, granular growth factor, infectious prophylaxis, and antithrombine III infusions were given. Summary/Conclusion: This pilot study shows that adults up to 45 years could tolerate a pediatric ALL protocol. Patients treated with this approach have a dramatically better outcome when there are treated with childhood ALL protocol without any major side effect. This therapeutic strategy has to be confirmed by the current prospective study performed by the EORTC group.
OP28 Novel agents for ALL S. O’Brien. Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston TX, USA Acute lymphocytic leukemia is the most frequent malignancy in children and accounts for 20% of acute leukemias in adults. Children with ALL have had a much better prognosis than adults. Although some of this may be accounted for by differences in tolerance to chemotherapy, recent studies have shown that molecular abnormalities are quite different between pediatric and adult ALL. Favorable abnormalities including hyperdiploidy and rearrangement of the TEL gene are found in almost half of patients with pediatric ALL and are rare in adults, whereas the poor prognostic abnormality of Philadelphia chromosome positivity accounts for up to a third of patients with adult ALL. The principals of ALL therapy have included induction, consolidation, and prolonged maintenance for 2-3 years, usually with an oral 6 MP and methotrexate regimen. Studies in adult ALL have shown a high CR rate with most regimens, on the order of 70-80%, but a long-term survival of only 25-30%, owing to relapse of disease. For the past seven years the ALL regimen used at MD Anderson has been the hyper-CVAD regimen which involves rotating cycles of fractionated cytoxan, given with Vincristine, Adriamycin and Decadron (odd # cycles) and high dose methotrexate and ara-C (even # cycles), along with risk adapted CNS prophylaxis. Maintenance has been with POMP with periodic reconsolidations. Recent evaluation of over 200 patients revealed a complete remission rate of 91% and a low induction death rate of 6%. Four-year leukemia free survival is approximately 45%. CNS relapse rates are low indicating that prophylaxis with intrathecal therapy is effective without the use of cranial irradiation and its concomitant morbidities.