Ph-positive Adult Acute Lymphoblastic Leukemia Research Articles

Adult Acute Lymphocytic Leukemia: Strategies for Selection of Consolidation Therapy

The 2 primary treatment options for adult acute lymphoblastic leukemia (ALL) are pediatric-inspired Berlin-Frankfurt-Münster protocols and the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen—these treatment strategies are now being augmented with novel agents. Current strategies also emphasize measurable residual disease (MRD) quantification as a critical tool for determining the treatment course. For patients with MRD-positive ALL, the standard of care has shifted toward blinatumomab, resulting in improved outcomes and survival rates. Another novel agent, inotuzumab ozogamicin, is also being explored for the treatment of earlier stages of disease in patients with ALL. For Philadelphia chromosome (Ph)–negative ALL, the NCCN Guidelines recommend treatment with blinatumomab followed by allogeneic transplants for patients remaining MRD-positive after initial therapy. For patients achieving MRD negativity at the level of 10-4, blinatumomab is now recommended as consolidation, with or without subsequent allotransplant, depending on patient disease risk features. For Ph-positive ALL, the use of tyrosine kinase inhibitors in combination with blinatumomab has demonstrated excellent efficacy, indicating the growing importance of combination targeted therapies to improve outcomes and decrease the toxicity of therapy in adults with ALL.

Pediatric-inspired regimen with late intensification and increased dose of L-asparaginase for adult acute lymphoblastic leukemia: the KALLA 1406/1407 study.

Background/AimsThe objective of this study was to evaluate the efficacy and feasibility of the pediatric-inspired regimen of the adult acute lymphoblastic leukemia (ALL) Working Party, the Korean Society of Hematology.MethodsData of 99 patients with newly diagnosed ALL, who were treated with the KALLA 1406/1407 protocol, were retrospectively analyzed. All patients equally received age-adjusted daunorubicin, vincristine, and prednisolone. L-asparaginase was additionally administered to Philadelphia (Ph)-negative patients according to age, whereas Ph-positive patients received 600 mg/day of imatinib.ResultsA total of 99 patients were enrolled in this study, of whom 62 (62.6%) were diagnosed with Ph-negative ALL and 37 (37.3%) were diagnosed with Ph-positive ALL. The median age of patients in the Ph-negative ALL group was 46 years, and that of patients in the Ph-positive ALL group was 49 years. In patients with Ph-negative ALL, 57 (92%) patients achieved complete remission (CR) and CR with incomplete hematologic recovery (CRi). Disease-free survival (DFS) and overall survival (OS) rates at 2 years were estimated to be 42% and 63%, respectively. In patients with Ph-positive ALL, 32 (86%) patients achieved CR/CRi, and 2-year DFS and OS were 31.2% and 49.1%, respectively. Patients who were able to proceed to the allogeneic hematopoietic cell transplantation and younger patients showed significantly superior survival in both Ph-negative ALL and Ph-positive ALL. Neutropenic fever and bacterial infection were the most common and severe adverse events.ConclusionsThe KALLA 1406/1407 protocol showed tolerable toxicities in adult ALL patients. Especially, younger patients had more survival benefits with KALLA 1406/1407 protocol.

Durable Outcomes of a Prospective Double Cord Blood Transplantation Trial in Adults with Acute Lymphoblastic Leukemia: Different Outcomes According to the Presence of Philadelphia Chromosome

▪Background: Alternative donor hematopoietic cell transplantation (HCT) is an emerging topic in acute leukemia for patients without matched sibling donors (MSD) or unrelated donors (MUD). Cord blood transplantation (CBT) has been tried for several years in adult acute lymphoblastic leukemia (ALL), and the long-term survival outcomes were comparable to those treated with conventional donor HCT.Aim : We have conducted double CBT (DCBT) in patients without both MSD and MUD for final step, and here, we report our phase 2 study results of clinical outcomes for adult ALL patients treated with DCBT.Methods: During the period between 2005 and 2016, 67 patients (median age, 37 years [range, 16-59 years]; 34 Ph-negative ALL and 33 Ph-positive ALL) were treated with DCBT in CR1 (n=48), CR2 (n=15), and in advanced status (n=4). The indications for DCBT were unavailability of MSD and MUD, agreement for conduction of the transplantation procedure, and proper performance status and organ function to undertake transplantation. The median time to transplant was 198 days (range, 97-1751 days). All patients received DCBT following total body irradiation (TBI) 12.0 Gy plus cytarabine 9.0 g/m2 plus fludarabine 150 mg/m2, and graft versus host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.Results: The median time for neutrophil and platelet recovery was 25 days (23 days [range, 12-109] for Ph-negative ALL and 26 days [range, 9-59] for Ph-positive ALL, P=0.336) and 34 days (27.5 days [range, 8-123] for Ph-negative ALL and 40 days [range, 9-185] for Ph-positive ALL, P=0.022), respectively. The median CD34+ cell count was 1.21 x 105/kg (range, 0.4-5.85) and TNC was 4.04 x 107/kg (range, 1.58-7.88). In our data, extramedullary involvements were more frequently observed in Ph-negative ALL, while hyperleukocytosis was frequently observed in Ph-positive ALL. Except for 5 patients who died in aplasia, 28 developed acute GVHD (grade II in 23 and grade III in 5), and the cumulative incidence of acute GVHD at 1-year was 41.8%, and the incidence was 9.0% for acute GVHD with grade III-IV. Except for 11 patients with early deaths within 100 days, 17 developed chronic GVHD (11 mild, 4 moderate, 2 severe), resulting in a 4-year cumulative incidence of 23.0% (3.0% for severe chronic GVHD). After a median follow-up duration of 43.7 months (range: 6.5 - 135.3), the 4-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 15.6% and 29.6% (7.2% and 29.2% for CR1), respectively, and the 4-year disease-free survival (DFS) and overall survival (OS) rates were 52.5% and 53.9% (62.9% and 65.6% for CR1), respectively. The 4-year CIR, NRM and DFS for Ph-negative and Ph-positive subgroup was 9.6% and 21.6% (P=0.140), 21.0% and 38.9% (P=0.107), and 66.5% and 37.7% (P=0.017). The results of Ph-negative and Ph-positive subgroup in CR1 were 4.8% and 9.9% (P=0.357), 19.1% and 43.0% (P=0.088), and 76.1% and 45.0% (P=0.029), respectively. In multivariate analysis, advanced disease status≥CR2 (HR, 5.61; 95% CI, 1.4-22.2; P=0.014) was related with higher CIR rate, and older age (HR, 3.75; 95% CI, 1.5-9.3; P=0.004) and lower CD34+ cell count (HR, 4.96; 95% CI, 1.1-22.3; P=0.037) were related with higher NRM rates. Overall, Ph-chromosome (HR, 2.65; 95% CI, 1.2-5.8; P=0.016), longer time to transplant (HR, 4.18; 95% CI, 1.9-8.9; P <0.001), lower CD34+ cell count (HR, 3.66; 95% CI, 1.4-9.5; P=0.008) and the absence of acute GVHD (HR, 3.19; 95% CI, 1.4-7.4; P=0.006) were related to poorer DFS.Conclusion: Our data showed that DCBT can be a good alternative choice for providing a long-term disease control for adult ALL patients especially in Ph-negative subgroup. Since Ph-positive subgroup was related with poorer DFS and higher NRM rate in our data, another alternative haploidentical HCT should be considered. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Current treatment strategies for Philadelphia chromosome-positive adult acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is an aggressive hematological disease. The incorporation of tyrosine kinase inhibitors (TKIs) into the standard treatment regimen for Philadelphia (Ph)-positive ALL significantly improved clinical outcomes. TKI-based induction chemotherapy, followed by allogeneic hematopoietic cell transplantation (HCT) during the first complete remission (CR), is the standard of care for ALL patients. However, treatment with TKIs alone or TKIs plus low-intensity chemotherapy can achieve CR in some patients. Although this strategy is not enough to induce a deeper molecular response, it can reduce the incidence of treatment-related mortality. Despite promising results from pediatric trials, allogeneic HCT remains an important component of the treatment strategy for Ph-positive adult ALL. However, improving the highly sensitive BCR-ABL1 assays and introducing immunotherapy may decrease the demand for allogeneic HCT. Nevertheless, the treatment of Ph-positive ALL is still challenging, especially in cases with relapsed and refractory disease. Potent TKIs and monoclonal antibodies, such as blinatumomab and inotuzumab, have improved patient outcomes in relapse and refractory cases of ALL. The introduction of effective agents, such as potent TKIs and monoclonal antibodies, may improve the possibility of remission in Ph-positive ALL patients and hopefully cure this disease.

Efficacy and prognostic factors of imatinib plus CALLG2008 protocol in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia (ALL). We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome (Ph)-positive ALL enrolled into imatinib (400 mg/d) plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years (range, 18-68 years), with 81 (52.3%) males. The overall hematologic complete remission (CR) rate was 96.7% after induction. With a median follow-up of 24.2 months, the estimated 3-year overall survival (OS) and event-free survival (EFS) rates were 49.5%(95%confidence interval (CI): 38.5%-59.5%) and 49.2% (95% CI: 38.3%-59.2%), respectively. Fifty-eight (36 with haploidentical donor) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first CR. Among the patients in CR1 after induction, both the 3-year OS and EFS were significantly better in the allo-HSCT group than in the without allo-HSCT group (73.2%, 95% CI: 58.3%-83.5% vs. 22.2%, 95% CI: 8.7%-39.6% and 66.5%, 95% CI: 50.7%-78.2% vs. 16.1%, 95% CI: 5.1%-32.7%, respectively). Multivariate analysis showed that allo-HSCT and achievement of major molecular response were associated with favorable OS or EFS independently. Interestingly, in the allo-HSCT cohort, the donor type (haploidentical versus matched donors) had no significant impact on EFS or OS. All these results suggested that imatinib plus CALLG2008 was an effective protocol for Ph-positive ALL. Haploidentical donors can also be a reasonable alternative expedient donor pool.

Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD.Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043).Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. DisclosuresKim:ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

De-Intensification of the Chemotherapy Did Not Affect the Outcome of Ph-Positive Acute Lymphocytic Leukemia Patients in the Era of Tyrosine Kinase Inhibitors

Introduction. For more than a decade it's postulated that the addition oftyrosine kinase inhibitors (TKI) to chemotherapy has dramatically improved the long term outcome in Ph-positive adult acute lymphoblastic leukemia (Ph+ ALL). Nevertheless whether do we need chemotherapy at all and if yes - how intensive it should be, is still the matter of debates. The only randomized trial addressing this issue (GRAAL, Blood 2015, 125: 3711-3719) has demonstrated the lack of benefit of more intensive induction at all checkpoints: complete remission (CR) rate, major molecular complete remission (MMolCR), molecular complete remission (MolCR), progression disease (PD) and resistance. We have conducted two consecutive trials in Ph+ ALL aiming to evaluate the efficacy of more and less intensive chemotherapy approach in combination with constant non-stop 600 mg Imatinib application.Aim. Toanalyze of the protocol RALL-2009 with ITK and RALL-Ph+-2012 effectiveness in patients with Ph+ ALL. The primary objective was the major molecular complete remission (MMolCR) rate after induction (70th day), patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor.Patients and methods. Since Jan 2010 till July 2016, 120 new cases of ALL were verified in our National Research Center for Hematology with 68 (56,7%) of them being B-cell precursors ALL and 25 diagnosed as Ph-positive (36,8%). Since 2010 till 2012, 10 Ph+ ALL pts (median age 35 years (19-68), m/f (50%)/(50%), CNS disease=1, WBC> 30*109/l=5(50%), bcr/abl transcript p190/p210/p190+210 6(60%)/3(30%)/1(10%)) were treated according to RALL-2009 protocol (ClinicalTrials.gov public site; NCT01193933) with parallel Imatinib. This protocol includes 8 cytostatic drugs and no intervals between treatment phases. Since 2012 till now 15 other pts (median age 40 years (17-61); m/f 7(46,7%)/8(53,3%); CNS disease=1, WBC>30*109/l=5(33,3%), bcr/abl transcript p190/p210/p190+210 9(60%)/5(33%)/1(7%)) were included in RALL- Ph+-2012 protocol, based mainly on 600 mg Imatinib with prednisolone, VNCR, L-asp, followed by 6-MP and MTX. Both protocols suggested the shift to Dasatinib (100-140 mg) after non-achievement of MolCR at day 70 of treatment. MolCR was stated if no bcr/abl chimeric transcript was detected by PCR with 10-4 sensitivity. All patients were considered as candidates for allogeneic HSCT if HLA-identical donor was available.Results. At day 70th disregarding the chemotherapy intensity there was 40% of MolCR on both protocols (RALL-2009 - n=4 and RALL-2012 - n=6). No death within 2 months of induction/consolidation were registered on less intensive protocol in comparison with 2 cases on RALL-2009. Hematological CR was achieved in all pts (except two early deaths on RALL-2009) - 23 of 25 (92%). There was one autologous HSCT in older pts, included in RALL-2012 (n=3, aGVHD and severe infections, at a median +4 months after HSCT and more than 12 months of CR duration).The 3y OS, DFS and relapse probability (RP) for all 25 pts constituted 37,8%, 32,5% and 52,1% (Fig. 1). The long-term outcome on both protocols (RALL-2009 and RALL-2012) was similar: OS - 45% vs 27,7% (p=0,27), DFS - 45% vs 22,1% (p=0,94), RP - 35,7% vs 57% (p=0,29), respectively (Fig.2).Conclusion. De-intensification of the chemotherapy does not affect the effectiveness of the therapy Ph-positive acute lymphocytic leukemia in era of the tyrosine kinase inhibitors. We haven't seen differences in achievement of molecular remission when we deescalated chemotherapy (40% vs. 40%). However, when we reduced toxicity of the chemotherapy in ALL-2012 protocol, we were able to realize more extra allo-BMT and it could improve long-term results of the therapy Ph+ ALL. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Philadelphia chromosome-positive acute lymphoblastic leukemia: 8 years' experience from a tertiary care center in India.

Introduction:The Philadelphia chromosome (Ph) is the most common cytogenetic abnormality associated with adult acute lymphoblastic leukemia (ALL) occurring in 20% to 40% of patients. It is also detected in 2% to 5% of children with ALL. Historically, patients with Ph-positive ALL carried a dismal prognosis, with poor response to most chemotherapy combinations, short remission durations, and long-term disease-free survival rates of 10% to 20%. The advent of tyrosine kinase inhibitors (TKIs) has revolutionized therapy of Ph-positive ALL.Materials and Methods:This retrospective and descriptive single center study was carried out based on data retrieved of 508 patients treated for ALL from 2007 to 2014. Of these thirty patients were Ph-positive ALL and were available for analysis, and these patients were included in the study. Ph-positive ALL was defined as ALL carrying the t(9;22) translocation on standard karyotype and/or fluorescent in situ hybridization analysis and/or positivity for BCR-ABL fusion transcript detection by real-time quantitative polymerase chain reaction (RQ-PCR) analysis. Patients were treated with combination chemotherapy and oral TKIs and responses were classified as either CR defined by the absence of circulating blasts and <5% marrow blasts on a bone marrow examination done at the end of induction chemotherapy or failure, including persistent disease and early death.Results:There were 30 (5.9%) cases of Ph-positive ALL out of a total of 508 cases of ALL with a median age of 27.5 years (range: 7-55). The choice of first line TKI was Imatinib in 25 (83.3 %) patients and Dasatinib in 1 (3.3 %) patient. Fourteen patients (46.6 %) had a CR, 3 (10 %) had a partial response (PR), 8 (26.6 %) had persistence of disease at the end of induction chemotherapy. The overall survival in those who received sequential chemotherapy followed by TKI (n = 4) was 28.5 months (95% CI 10.78 to 46.21 months) compared with 13.98 months (95% CI 6.04 to 21.97 months) for patients who received concurrent chemotherapy and TKI (n = 20); log rank (Mantel Cox) X2 = 8.33, P = 0.040), however limited sample precluded meaningful subgroup analysis.Conclusion:The results of our study showed that we still have a long way to go to match outcomes of western published series, even when the same treatment protocol is used, probably due to the underutilization of Allogeneic SCT as an option in first CR.

Outcome of patients with adult acute lymphoblastic leukemia between 2000 and 2013: experience from single center

目的分析北京大学人民医院14年间连续收治的成人急性淋巴细胞白血病（ALL）患者2006年前后的疗效差异。方法回顾性分析北京大学人民医院2000年1月至2013年12月连续收治的成人ALL患者477例，其中Ph染色体阴性B细胞ALL（Ph−-B-ALL）276例（57.9%），T-ALL 69例（14.5%），Ph染色体阳性ALL（Ph+-ALL）132例（27.7%）；2006年之前收治111例（23.3%），2006年之后（含2006年）收治366例（76.7%）。获得完全缓解（CR）患者中，持续化疗187例（43.0%），接受异基因造血干细胞移植（allo-HSCT）患者248例（57.0%）。结果全部患者中位随访19个月，存活患者中位随访35个月，总CR率为92.0%，435例CR患者5年累积复发、无病生存（DFS）和总体生存（OS）率分别为42.5%、46.2％和47.6%。2006年之后与2006年之前相比：①Ph−-B-ALL、T-ALL患者总CR率差异无统计学意义，Ph+-ALL患者总CR率显著增高（P=0.036）；②全部CR患者5年DFS率（P=0.001）及OS率（P<0.001）显著增高，其中Ph−-B-ALL患者5年OS率显著增高（P=0.046），T-ALL（P=0.013和P=0.036）和Ph+-ALL（P=0.003和P<0.001）患者5年DFS率和OS率均显著增高，尤其是诱导期加用伊马替尼的Ph+-ALL患者（P<0.001和P<0.001）；③allo-HSCT患者5年DFS率（P=0.001）及OS率（P<0.001）显著增高，而未行移植患者差异无统计学意义。2006年之后，诱导期加用伊马替尼的Ph+-ALL患者5年DFS、OS率显著高于Ph−-B-ALL和T-ALL患者（P=0.009和P=0.001）。多因素分析显示，接受allo-HSCT和诱导期伊马替尼联合化疗是改善ALL患者预后的2个重要因素。结论在过去的14年间以2006年为界，ALL患者的治疗结果明显改善，尤以Ph+-ALL患者为著。

Novel agents and biomarkers for acute lymphoid leukemia.

New genetic markers for adult acute lymphoblastic leukemia (ALL) have been found to have prognostic impact, such as the lymphoid transcription factor gene IKZF1 alterations, which are associated with a high rate of leukemic relapse in B-ALL. Although complete remission rates by induction chemotherapy in ALL are now high, the long-term survival is still disappointing. Improvements in the survival outcome of ALL have been observed in young adults as a result of the use of pediatric inspired regimens and the broadening of the number of patients who are eligible for allogeneic SCT. Development of new and less toxic agents also provide promise to improve the outcome in adult ALL, such as tyrosine kinase inhibitors in Ph-positive ALL, rituximab in CD20-positive disease, blinatumomab in precursor B-ALL and nelarabine in T-lineage ALL. Challenges for the future are to implement genomic profiling into the clinical setting to guide risk stratification and providing novel targets for tailored therapies.

Autologous HSCT for Ph-Positive Adult Acute Lymphoblastic Leukemia: A Curative Option in the Era of Tyrosine Kinase Inhibitors? an Analysis From the Acute Leukemia Working Party of the EBMT

AbstractAbstract 233▪▪This icon denotes a clinically relevant abstractOutcome of patients with Ph-positive acute lymphoblastic leukemia (Ph+ ALL) improved markedly with the introduction of tyrosine kinase inhibitors (TKIs) used in combination with chemotherapy. However, despite very high rate of complete remissions the possibility of cure with conventional-dose treatment remains questionable. Hence, allogeneic hematopoietic stem cell transplantation (HSCT) is still considered a standard of care. Patients lacking appropriate donor are usually treated with TKI-based maintenance. Autologous HSCT could be an alternative approach, however, due to “negative” results of a series of prospective studies run in XX. century its use has been limited. The goal of the current analysis was to retrospectively analyze if results of autoHSCT for Ph+ ALL changed over time.Results of 171 autologous transplantations performed in the first complete remission between 1996–2010 and reported to the EBMT registry have been analyzed. Median patient age was 48.3 (19–65) years. Conditioning regimen was based on either TBI (63%) or chemotherapy (37%). Peripheral blood was used as a source of stem cells in 84% cases.With the median follow-up of 2 years, in the whole study group, the probability of the overall survival (OS) at 2 years was 45% (+/−4%) and leukemia-free survival (LFS) was 32% (+/−4%). The cumulative incidence of relapse (RI) and non-relapse mortality (NRM) was 54% (+/−4%) and 13% (+/−3%), respectively. LFS rates were comparable for TBI and chemotherapy-based conditioning (34% vs. 29%, p=0.53). As well, the source of stem cells had no impact on LFS (32% for PB vs. 33% for BM, p=0.91). The 2 year probability of LFS increased from 22% for transplants performed between 1996–2000 (n=70) to 32% between 2001–2006 (n=61) and 54% between 2007–2010 (n=40), p<0.001 (Fig). In respective periods the RI decreased from 65% to 47% and 46% (p=0.01), while NRM was 11%, 21% and 0% (p=0.03). In a multivariate analysis the year of transplantation (<2007 vs. 2007–2010) was the only factor independently influencing the risk of treatment failure (HR=2.98, 95%CI, 1.54–5.79; p=0.001).We conclude that results of autologous HSCT for Ph+ ALL improved markedly in recent period with more than half of patients being alive and leukemia-free at 2 years. Therefore, it appears than in the era of TKIs autologous HSCT may be considered potentially curative option. The advantage is probably associated with more profound responses achieved with TKIs, which, however requires confirmation in a separate analysis. As well, the role of post-transplant maintenance remains to be determined. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Philadelphia chromosome‐positive acute lymphoblastic leukemia

The Philadelphia chromosome (Ph) is the most common cytogenetic abnormality associated with adult acute lymphoblastic leukemia (ALL). Before the advent of tyrosine kinase inhibitors (TKIs), Ph-positive ALL carried a dismal prognosis and was characterized by a poor response to most chemotherapy combinations, short remission durations, and poor survival rates. Outcomes for patients with Ph-positive ALL improved substantially with the introduction of TKIs, and the TKI imatinib induced complete remissions in >95% of patients with newly diagnosed Ph-positive ALL when it was combined with chemotherapy. However, imatinib resistance remains a problem in a substantial proportion of patients with Ph-positive ALL, and multiple molecular mechanisms that contribute to imatinib resistance have been identified. Second-generation TKIs (eg, dasatinib and nilotinib) have demonstrated promising efficacy in the treatment of imatinib-resistant, Ph-positive ALL. Future strategies for Ph-positive ALL include novel, molecularly targeted treatment modalities and further evaluations of TKIs in combination with established antileukemic agents. For this article, the authors reviewed past, current, and future treatment approaches for adult and elderly patients with Ph-positive ALL with a focus on TKIs and combined chemotherapeutic regimens.

IKZF1(Ikaros) Deletions inBCR-ABL1–Positive Acute Lymphoblastic Leukemia Are Associated With Short Disease-Free Survival and High Rate of Cumulative Incidence of Relapse: A GIMEMA AL WP Report

The causes of the aggressive nature of BCR-ABL1-positive adult acute lymphoblastic leukemia (ALL) are unknown. To identify, at the submicroscopic level, oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed an investigation of genomic copy number alterations using single nucleotide polymorphism array, genomic polymerase chain reaction, and sequencing of candidate genes. Eighty-three patients with de novo adult Philadelphia chromosome (Ph) -positive ALL were enrolled onto institutional (n = 17) or Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Working Party delle Leucemia Acute (n = 66) clinical trials. Treatments included tyrosine kinase inhibitor (TKI) alone, conventional chemotherapy, or a combination of TKI and chemotherapy. A 7p12 deletion of IKZF1 (Ikaros) was identified in 52 (63%) of 83 patients. The pattern of deletion varied among different patients, but the two most common deletion types were loss of exons 4 to 7 in 31 (37%) of 83 patients and loss of exons 2 to 7 in 17 (20%) of 83 patients. Disease-free survival (DFS) was shorter in patients with IKZF1 deletion versus patients with IKZF1 wild type (10 v 32 months, respectively; P = .02). Furthermore, a significantly shorter cumulative incidence of relapse was recorded in patients with IKZF1 deletion versus patients with IKZF1 wild type (10.1 v 56.1 months, respectively; P = .001). Multivariate analysis confirmed the negative prognostic impact of IKZF1 deletion on DFS (P = .04). We conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.

The BCL-2 Antagonist ABT-737 Is Highly Effective on Primary Acute Lymphoblastic Leukemia Cells.

The treatment of adult acute lymphoblastic leukemia (ALL) remains unsatisfactory. A potential hope is now given to Philadelphia-positive cases by targeted treatment modalities. Among other pathways involved in cell proliferation, we have recently demonstrated (Blood 2007; 109:5473) the unfavorable role of ERK1/2 phosphorylation as an independent predictor of complete remission (CR) in adult ALL, suggesting the potential therapeutic value of other targeted therapies. The B-cell leukemia/lymphoma 2 (Bcl-2) family of proteins are important regulators of apoptosis and are frequently found aberrantly expressed, particularly in lymphoid malignancies. The role of Bcl-2 overexpression in tumorigenesis and chemoresistance prompted us to investigate whether the inhibition of the antiapoptotic function may result also in ALL in an attractive therapeutic strategy. In this study, we thus investigated the cell cycle and apoptotic effects of ABT-737 (kindly provided by Abbott Laboratories), a Bcl-2 (BH3) inhibitor, on both lymphoid leukemia cell lines and primary adult and childhood ALL cells. The lymphoid leukemia cell lines CEM and MOLT-4 were exposed to increasing concentrations of ABT-737 (from 0.1 to 1 μM) up to 72 hours. A dose- and time-dependent cell growth arrest and induction of apoptosis was found. In fact, measuring the subG0/1 peak at 48 hours, the levels of apoptosis increased in the CEM cell line from 14.1% (DMSO) to 34.4%, 64.5%, 86.5% and 98.6% at ABT-737 concentrations of 0.1, 0.25, 0.5 and 1 μM, respectively. Similarly, 48 hours of exposure to ABT-737 increased in MOLT-4 the Annexin V-positive cells from 7.2% to 64.2%. The effects of ABT-737 were then examined on primary blasts from 9 ALL patients (6 adults and 3 children). Bone marrow aspirates with a blast infiltration >70% were obtained at diagnosis from patients broadly characterized for clinical and biological parameters, as well as therapeutic response. ALL cells were cultured in vitro with ABT-737 (at increasing concentrations from 0.01 to 1 μM) for 24 hours. A significant decrease in viability was observed at 0.01 μM (p=0.008) with a remarkable dose-dependent increase of apoptosis. In fact, Annexin V-positive cells increased from a mean baseline value of 16.8% ± 8.8 to 43.6% ± 22.8 (p=0.04), 66% ± 21.3 (p=0.0001), 70.3% ± 26.9 (p=0.04), 74.6% ± 18.9 (p=0.03) and 76.2% ± 11.8 (p<0.0001) in the presence of ABT-737 at 0.01, 0.1, 0.25, 0.5 and 1 μM, respectively. A significant cell killing was demonstrated in all samples (9/9), including Ph-positive ALL. No significant cell cycle changes were instead detected even at higher concentration of ABT-737. In summary, our study shows for the first time a potent growth-inhibitory and pro-apoptotic activity of the Bcl-2 antagonist ABT-737, at nanomolar concentrations, on primary cells from adult and childhood ALL samples. These results prompt to further extend pre-clinical studies in the different biologically-defined subset of ALL and suggest a potential clinical development of a Bcl-2 family inhibitor in this disease.

Additional chromosomal abnormalities and variability of BCR breakpoints in Philadelphia chromosome/BCR-ABL-positive acute lymphoblastic leukemia in Taiwan.

From 1986 to 1998, 26 (23%) of 114 adult acute lymphoblastic leukemia (ALL) patients and 11 (4%) of 328 pediatric patients were found to have Philadelphia (Ph) chromosome. In the 30 patients with available data at diagnosis, 18 (60%) had extra-chromosomal abnormalities. They included 1q duplication (5/18, 28%), supernumerary Ph chromosome (4/18, 22%), 9p abnormalities (3/18, 17%), 7q deletion/monosomy 7 (3/18, 17%), trisomy 19 (1/18, 6%), and trisomy 8 (1/18, 6%). Excluding those with specific cytogenetic changes, only one patient had hyperdiploid karyotype with more than 50 chromosomes. The incidence of 1q duplication was higher and that of hyperdiploidy was lower in this study than has been previously reported. There was no prognostic implication of these additional cytogenetic abnormalities. With fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR), 14 (27%) of 53 unselected adult ALL patients and 2 (5%) of 38 unselected pediatric patients were BCR-ABL-positive, including one adult and two children without Ph chromosome. The BCR-ABL fusion genes/transcripts were also present in all other 16 selected Ph-positive ALL patients. The BCR-ABL fusion subtypes were determined in all these 32 patients: 91% (11/12) childhood cases showed m-type fusion gene while 45% (9/20) adult ones did so (P = 0.0083). The clinical outcome was similar between the two groups of patients with m-type and M-type BCR-ABL. In conclusion, both cytogenetic and molecular studies are very helpful for identifying the subgroup of ALL patients with Ph/BCR-ABL. The additional cytogenetic abnormalities and subtypes of BCR-ABL fusion genes/transcripts had no significant implications in this group of patients.

Philadelphia chromosome-positive acute lymphoblastic leukemia in Taiwan.

From January 1986 to December 1998, 26 (23%) of 114 acute lymphoblastic leukemia (ALL) patients older than 15 years were found to have Philadelphia (Ph) chromosome. They accounted for 28% (26 of 94) of the patients with B-lineage ALL. Compared with the other 88 ALL patients, the leukemic cells from all but one Ph-positive ALL patients were early pre-B cells with a higher rate of CD34 expression (92% vs 50%, P<0.05). At presentation, the Ph-positive adult ALL patients had higher circulating blasts (mean 21.4 vs 3.66x10(4)/microl, P<0.05) and lower initial platelet counts (mean 4.47 vs 7.34x10(4)/microl, P<0.01) and showed a trend toward higher frequency of initial central nerve system (CNS) involvement (25% vs 11%, P=0.098) than the others. Among patients with adequate chemotherapy, 16 (64%) of the 25 Ph-positive ALL patients achieved complete remission (CR), an incidence marginally lower than that of Ph-negative ALL (62 of 76, 82%, P=0.06) and significantly lower than that of Ph-negative B-lineage ALL (50 of 58, 86%, P=0.0037). However, all patients relapsed except for those who received allogeneic hemopoietic stem cell transplantation (allo-HSCT). The probabilities of 5-year continuous CR and 5-year survival for Ph-positive adult ALL patients were significantly inferior to those for Ph-negative adult ALL patients (0% vs 12%, P=0.0001, and 7% vs 19%, P=0.047, respectively), and those for Ph-negative B-lineage ALL (0% vs 14%, P<0.0001, and 7% vs 23%, P=0.002, respectively). Prognostic factors were analyzed among the Ph-positive ALL patients including the 26 adults mentioned above and an additional 11 children. No clinical or biological characteristics such as age, sex, initial circulating blast count, extramedullary involvement, or CD34 expression had an impact on the disease outcome. Allo-HSCT in first CR may improve the probability of 5-year continuous CR (100% vs. 0% for those without allo-HSCT, P=0.0091) although only three patients received it in this study. In conclusion, Ph-positive ALL patients tended to have a poor prognosis, regardless of whether other possible risk factors were present or not. Aggressive treatment, such as high-dose chemotherapy with allo-HSCT, should be considered for these patients to improve survival.

Outcome of Philadelphia Chromosome-Positive Adult Acute Lymphoblastic Leukemia

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) represents the most common cytogenetic abnormality in adult ALL. It is found in 15% to 30% of patients, and its incidence increases with age. As in children, prognosis in Ph-positive adult ALL is poor. No therapeutic approach has had substantial impact on its unfavorable course. We analyzed the characteristics and outcome of newly diagnosed adults with Ph-positive ALL treated at the M. D. Anderson Cancer Center between 1980 and 1997. The diagnosis of patients was based on typical morphological and immunophenotypic criteria of marrow aspirate and biopsy specimens. Cytogenetic and molecular studies were also performed. A total of 67 patients were included in this study. From 1980 until 1991, 38 patients with Ph-positive ALL were treated with vincristine, Adriamycin, and dexamethasone (VAD), or with acute myeloid leukemia (AML)-like induction protocols. Since 1992 a total of 29 patients received induction therapy with an intensified treatment protocol, called “hyper-CVAD”. The outcome of patients treated with standard and intensified treatment regimens was compared and results of our institution contrasted with data obtained from other centers.Ph-positive ALL was present in 67 of 498 patients with newly diagnosed ALL (13%). Patients with Ph-positive ALL had a higher median age (44 versus 34, P=0.007), higher median white blood cell (WBC) counts at presentation (25 versus 8, P=0.0002), and higher peripheral median percentage of blast counts (63 versus 40, P=0.023). FAB subtype L2 (70% versus 49%, P=0.001) and CALLA-positive pre-B immunophenotype (75% versus 37%, P<0.001) predominated among Ph-positive ALL. Myeloid marker coexpression was more frequent in Ph-positive ALL when compared with Ph-negative ALL (52% vs. 27% for CD13, P<0.001, and 44% vs. 27% for CD33, P=0.005). Among patients treated with hyper-CVAD, the complete remission (CR) rate was 90% versus 55% (P=0.002) with pre-hyper-CVAD regimens (VAD and AML-like induction protocols), the median CR duration was 43 weeks versus 32 weeks (P >0.5), median disease-free survival (DFS) was 42 weeks versus 29 weeks (P=0.008), and median survival was 66 weeks versus 45 weeks (P >0.5). Patients with hyper-diploid Ph-positive ALL on hyper-CVAD therapy achieved significantly longer CR duration and DFS than hypo- and pseudodiploid cases (59 weeks versus 42 and 31 weeks, P=0.02 and 0.04, respectively). In contrast, patients treated with regimens prior to hyper-CVAD had significantly shorter CR duration (21 weeks versus 33 and 29 weeks, P=0.03) and DFS with hyperdiploid karyotypes when compared to pseudodiploid and hypodiploid cases (16 weeks versus 30 and 13 weeks, P=0.008). In conclusion, our results demonstrate improved response rate and DFS with current intensive regimens (hyper-CVAD) in patients with Ph-positive ALL, but no advantage in overall survival.