ASH 2010 meeting report—Top 10 clinically oriented abstracts in acute leukemia
Authors: Amber Fullmer, Jorge Cortes, Hagop Kantarjian, Elias Jabbour
Journal: American Journal of Hematology (2011)

At the 2010 American Society of Hematology (ASH) annual meeting, held in Orlando, FL from December 4–7, 2010, data was presented helping to advance therapy for acute leukemia. Newly designed chemotherapy regimens for acute myeloid leukemia (AML) with targeted therapy for specific molecular and cytogenetic abnormalities demonstrated efficacy in specific subsets. The inclusion of pegylated asparaginase (PEG-ASP) to adult lymphoblastic leukemia (ALL) was shown to improve survival. Strategies to improve outcomes in elderly leukemia patients were also recognized. The most clinically relevant abstracts, all published in the November 19, 2010 issue of Blood (volume 116, issue 21), are summarized below. All trans-retinoic acid (ATRA) has led to durable remissions in the majority of patients diagnosed with acute promyelocytic leukemia (APL)[1], however relapses, though rare, still occur. Arsenic trioxide (ATO) has gained acceptance as the preferred agent for salvage APL, yet the optimal management remains to be determined. The European LeukemiaNet (ELN) created a European registry of relapsed APL patients to evaluate the efficacy and safety of ATO. Of 89 patients (69 in first relapse, 11 in second, and later relapse), none received ATO as initial therapy. In all patients, initial therapy was comprised of ATRA and anthracycline +/− cytarabine. Relapsed patients enrolled in the registry received ATO 0.15 mg/kg/day in various schedules which was combined with ATRA in 40% of inductions and 50% of consolidations. In contrast to patients with molecular first relapse (n = 25), patients with hematologic (bone marrow) relapse (n = 42) experienced episodes of coagulapathy (0 vs. 25%, P = 0.004) and differentiation syndrome (0 vs. 21%, P = 0.02). Second molecular remission was achieved after induction and consolidation in 52% and 64% of patients with molecular relapse and 38% and 62% in patients with hematologic relapse. Responses were also evident in patients in second of later relapse previously exposed to ATO. Considering coagulopathy and differentiation syndrome only occurred in patients with hematologic relapse, molecular monitoring is warranted to detect early relapse and minimize the risk of bleeding and hyperleukocytosis. As ATO appears effective in patients previously exposed, the role of this agent in the management of newly diagnosed patients should be further explored. At MD Anderson Cancer Center (MDACC), arsenic combined with ATRA led to an overall response rate (ORR) of 92% and an estimated three-year overall survival (OS) of 85% [2] Gemtuzumab ozogamicin (GO) was administered as a one time dose in patients with a high WBC at start of therapy or if the WBC began to rise above 30,000 during induction, however safety concerns prompted a removal of this agent from the market. As a result, idarubicin has been used to control the WBC count during induction therapy. The use of ATO front-line may eventually lead to more durable remission and even less frequent relapses in this highly curable leukemia. Sorafenib, an orally available tyrosine kinase inhibitor, alone or in combination with chemotherapy has displayed activity in patients with AML that have the FLT3-ITD mutation [3-5]. Patients over the age of 60 years with AML were randomized to receive standard 7 + 3 induction plus 2 cycles of consolidation therapy with intermediate dose cytarabine in combination with sorafenib 400 mg twice daily between cycles after chemotherapy for up to one year or placebo. Complete remission (CR) was achieved in 48% of patients in the sorafenib group vs. 60% of patients in the placebo group. Median event free survival (EFS) (7 months vs. 5 months, P = 0.13) and OS (15 months vs. 13 months, P = 0.89) were similar between the treatment groups. Similar to the results in the overall population, EFS and OS were not impacted in the group of patients that were FLT3-ITD positive treated with sorafenib. Adverse events of Grade 3 or higher severity attributable to sorafenib included diarrhea, skin rash, mucositis, hypertension, and hand-foot syndrome. Older patients with AML face challenges with resistant disease and increased toxicity with chemotherapy, limiting long-term survival. In this study, the addition of sorafenib did not improve the rates of CR, EFS, or OS in patients over the age of 60 years, nor in patients with the FLT3-ITD mutation. However, in younger patients with FLT3-ITD positive AML, 93% achieved CR after treatment with sorafenib in combination with chemotherapy [5]. The optimal dose of sorafenib in combination with chemotherapy should be further explored, specifically in patients that are FLT3-ITD positive. CPX-351, a liposomal formulation of cytarabine and daunorubicin demonstrated activity in patients with AML[6]. This Phase 2 study randomized patients aged 60-75 years to receive CPX-351 100 units/m2 administered intravenously on days 1, 3, and 5 (n = 84) or to the control arm consisting of cytarabine 100 mg/m2 administered via continuous IV infusion for seven days in combination with daunorubicin 60 mg/m2 IV daily × three days (n = 41). CPX-351 demonstrated higher rates of CR and CR with incomplete platelet recovery (CRp) (40.5% and 26.2%) compared with the control arm (39% and 12.2%). Early mortality was lower for those patients treated with CPX-351. Thirty- and sixty-day mortality with CPX-351 was 3.5% and 4.7%, respectively, while 7.3% and 14.6% of patients treated with the control arm experienced mortality at the corresponding time points. Although early mortality was reduced, adverse events were more frequent with CPX-351. Febrile neutropenia (64.7% vs. 51.2%), infections of all grades (84.7% vs. 68.3%), bacteremia (40% vs. 22%), petechieae (32/9% vs. 12.2%), and ecchymoses (11.8% vs. 2.4%) had higher reported occurrence with CPX-351 compared to the control arm. In addition, the median time to neutrophil and platelet count recovery was longer in patients treated with CPX. The mean difference in the estimated OS in the first year was 2.2 months favoring CPX. CPX-351 100 units/m2, equivalent to 100 mg/m2 of cytarabine and 44 mg/m2 of daunorubicin, represents a conventional dose of daunorubicin. However, high-dose anthracycline (daunorubicin 90 mg/m2) leads to more rapid and higher response rates with similar toxicity to the conventional 45 mg/m2 dose in elderly patients [7]. CR rates of 64% were achieved with high-dose daunorubicin. Although CPX-351 increased the rates of CR and reduced early mortality in this study, determining if this compound formulated with the conventional dose of daunorubicin can produce comparable results to the escalated dose anthracyline requires Phase 3 study. In addition, high-dose cytarabine in combination with idarubicin is more effective than the traditional 7 + 3 regimens, thus future trials should consider comparison with this regimen. Older adults with AML have benefited from clofarabine as treatment for newly diagnosed disease [8]. Overall response rates (ORR) of 46% with acceptable toxicity have been reported when clofarabine is used as monotherapy [9]. The combination of clofarabine with low-dose cytarabine improves responses rates without added toxicity [10]. Fifty-seven patients over 60 years of age received induction therapy consisting of clofarabine 20 mg/m2 administered IV daily for five days in combination with cytarabine 20 mg subcutaneously twice daily for 10 days. During consolidation, clofarabine (three days) and cytarabine (seven days) were administered during cycles 1–2, 6–8, and 12–14. Decitabine 20 mg/m2 IV daily for five days was administered as consolidation therapy during cycles 3–5, 9–11, and 15–17. The reported rates of CR and CRp were 61% and 7% for an ORR of 68%. Eleven percent of patients required more than one course to respond. The median duration of CR is 14.1 months. Median survival has not yet been reached. Only one patient experienced mortality within 28 days of induction, and five additional patients died while on study due to myelosuppresion-associated infectious complications. The most frequent toxicities were rash (64%), nausea (61%), transaminase elevations (58%), bilirubinemia (51%), diarrhea (32%), mucositis (12%), creatinine elevations (12%), and headache (12%). In comparison to intensive chemotherapy regimens, the above regimen has an acceptable toxicity profile with a low likelihood of early mortality and a comparable ORR. Hypomethylating agents serve as an alternative in this patient population; however, single agent therapy does not achieve comparable responses rates to clofarabine regimens, but do demonstrate superiority over supportive care [11, 12, 13]. Further investigation assessing survival with clofarabine and low-dose cytarabine will determine this regimen's place in AML therapy. Deletion 5q with or without additional cytogenetic abnormalities is associated with a poor response to chemotherapy in patients with AML [14, 15]. Responses are achieved with lenalidomide in high risk MDS and AML, but with considerable myelosuppression [16]. Patients with IPSS intermediate 2 or high MDS or AML with del 5q received induction therapy consisting of lenalidomide 10 mg daily for 21 days and daunorubicin 45 mg/m2 daily (escalated to 60 mg/m2) for three days in combination with cytarabine 200 mg/m2 daily for seven days, followed by up to six consolidation cycles which each incorporated one dose of daunorubicin 45 mg/m2, five days of cytarabine 120 mg/m2 daily, and 15 days of lenalidomide 10 mg. Maintenance therapy was composed of 14 days of lenalidomide per month until disease progression. The ORR was 60%, and included 50% CR, 2% CR with incomplete blood count recovery (CRi), 2% partial response (PR), and 3% normalized peripheral blood count without marrow response. More patients with MDS achieved CR/CRi (66%) vs. those with AML (47%), though not statistically significant (P = 0.32). Disease free survival (DFS) at one year was 26.5% and estimated OS at two years was 30%. Similar to patients with FLT3-positive AML and the addition of targeted therapy to chemotherapy, the combination of lenalidomide and chemotherapy for patients with deletion of 5q produced favorable response rates without additional myelosuppressive toxicity [5]. Despite the high CR rate, the low rate of DFS warrants modifications to this regimen. More favorable results may be achieved with the escalation of the anthracycline dose to 90 mg/m2 [7, 17]. Prognosis of B-lineage ALL has traditionally been poor and those patients with CD20 positivity of at least 20% were associated with lower rates of CR duration and survival [18, 19]. However, the introduction of rituximab to intensive chemotherapy regimens has improved response rates and long-term outcomes [20]. CD20 positive ALL patients received one dose of rituximab 375 mg/m2 prior to two induction cycles followed by one dose with six consolidation cycles. Patients that were candidates for stem cell transplant (SCT) in the first CR (high risk patients) received three doses of rituximab with chemotherapy before transplant. Patients that received rituximab were compared to a cohort of patients that were treated separately without rituximab (n = 82). In the patients that were not candidates for SCT (n = 196), the CR rate with and without rituximab was similar (94% vs. 91%); however, the reduction in minimal residual disease (MRD) was higher for the rituximab group (57%) compared with the group that did not receive rituximab (27%) at 24 days. The probability of survival at five years was also higher for the rituximab group (71% vs. 57%). In the high risk subgroup, the addition of rituximab was associated with a higher molecular CR (64% vs. 40%) and five-year OS (55% vs. 36%) compared with the group that did not receive rituximab. Few relapses post SCT were apparent in the rituximab group with 67% of patients experiencing continuous complete remission compared with 37% of patients that did not receive rituximab. The addition of rituximab to the GMALL study 07/2003 results in similar rates of CR as rituximab in combination with the Hyper-CVAD regimen [21]. In comparison to the above regimen, the Hyper-CVAD regimen incorporates an equivalent amount of rituximab doses in a fewer amount of treatment cycles. In high-risk patients, reducing the tumor-load with rituximab prior to SCT led to less relapse post SCT, however in the regimen above, high risk patients received only three doses of rituximab. Thus, additional doses of rituximab pretransplant may further reduce the tumor burden and lead to more durable remissions post SCT. In pediatric regimens, asparaginase represents part of the backbone of ALL treatment, however the optimal preparation, schedule, and intensity in adults have not yet been determined. In this multicenter study, patients were treated with PEG-ASP 1000 units/m2 (n = 826) and 2000 units/m2 (n = 400) incorporated to the chemotherapy regimen [22]. The CR rate after induction was 91% for both treatment groups. Escalated PEG-ASP dose resulted in improved OS at three years (67% vs. 60%, P > 0.05), and was pronounced in patients with standard risk disease (SR). OS in patients with SR treated with the escalated dose (n = 190) had higher rates of three-year OS (80% vs. 68%, = 0.02) and remission durations (74% vs. 61%, P = 0.02) compared with patients treated with the lower dose (n = 407), respectively. Improved results with PEG-ASP 2000 units/m2 were evident in younger and older subgroups of patients (15–25 years, 15–45 years, and 45–55 years). Bilirubin elevation of Grades 3–4 were more frequent with the escalated dose (16% vs. 10%, P = 0.004), patients over 45 years of age (17% vs. 11%, P = 0.005), body mass index over 30 (18% vs. 12%, P = 0.04), and rituximab administration (18% vs. 11%, P = 0.009). Although CR was not improved with an escalated dose of PEG-ASP, improvements in OS and remission duration favored the higher dose, especially in SR patients. The Hyper-CVAD regimen achieves high rates of CR (96%), five-year OS and remission durations of 72% and 68%, respectively, without asparaginase [23]. The addition of asparaginase into frontline treatment regimens may further improve long-term survival and minimize relapse, though the increase in toxicity should be recognized. Including asparaginase and intensifying the dose increases the risk for toxicity, therefore leading to treatment delays and potentially compromising therapy. PEG-ASP should be explored in additional ALL treatment programs for assessments in efficacy and toxicity. The Philadelphia chromosome is apparent in approximately 25% of adults with ALL and is associated with a poor prognosis [24, 25]. The introduction of tyrosine kinase inhibitors (TKIs) to ALL treatment has improved response rates and outcomes for this subset of patients. Three groups were analyzed in this study: pre-imatinib—defined as patients that received induction therapy over two months followed by allogeneic SCT (alloSCT) (n = 266), late imatinib—defined as patients that received imatinib 600 mg daily during consolidation (n = 86), and early imatinib—defined as patients that received imatinib during the second induction course (n = 89). In both imatinib groups, patients continued to receive imatinib for an additional two years with maintenance. For the imatinib cohorts, CR was significantly higher than the pre-imatinib cohort. CR during induction was achieved in 67% of patients pre-imatinib, 73% late imatinib, and 80% early imatinib. The total CR includes patients that achieved CR later than post induction and were reported as follows: 82% pre-imatinib, 92% late imatinib, 92%, early imatinib. Patients treated with imatinib were more likely to receive alloSCT (44% vs. 28%) compared with patients in the pre-imatinib group. OS, EFS, and relapse free survival (RFS) at three years were significantly higher for patients treated with imatinib compared to patients not treated with imatinib (OS: 42% vs. 25%, EFS: 36% vs. 19%, RFS: 54% vs. 36%, P = 0.0001) and were higher for patients treated with imatinib earlier versus later in therapy (OS: 48% vs. 24%, P = 0.05, EFS: 45% vs. 29%, P = 0.04, RFS: 62% vs. 45%, P = 0.02). Early initiation of imatinib is important for survival. Although, the addition of imatinib at any point increases CR and survival for patients with Philadelphia positive ALL, there is need for improvement. Dasatinib, a more potent second generation TKI, has been evaluated as monotherapy and in combination with chemotherapy for Philadelphia-positive ALL [26, 27]. In combination with hyper-CVAD, dasatinib has led to CR rates of 94% and estimated 2-year OS of 64% [27]. The increased potency and multikinase inhibition suggest dasatinib has the ability to overcome the disadvantages with imatinib, and be used in the frontline treatment of newly diagnosed Philadelphia positive ALL patients. Dasatinib 140 mg daily and low-intensity chemotherapy consisting of a steroid prephase and weekly infusions of vincristine and dexamethasone 20 mg daily for two days was administered as induction therapy to 71 patients aged 55 years or above with newly diagnosed Philadelphia-positive ALL. Consolidation cycles 1, 3, and 5 consisted of dasatinib 100 mg daily administered sequentially with IV methotrexate 1000 mg/m2 on Day 1 and IM L-asparaginase 10,000 international units/m2 on Day 2. Cycles 2, 4, and 6 were composed of dasatinib 100 mg daily administered sequentially with cytarabine 1000 mg/m2 every 12 hr on Days 1, 3, and 5. Dasatinib alternating with 6-mercaptopurine and methotrexate every other month and vincristine administered every two months with dexamethasone was administered as maintenance therapy for up to 24 months. CR was achieved in 90% of patients and 56% had a major molecular response (MMR) at time of CR. The median RFS was 22.1 months, and OS 27.1 months. In patients with additional cytogenetic abnormalities, the median RFS was 19.2 months, but was not reached in patients with the isolated Philadelphia chromosome positivity. The need for therapies that induce durable remissions for elderly patients with Philadelphia-positive ALL should be recognized, as these patients are often not candidates for SCT. Low intensity therapy in combination with TKIs seems promising to induce and maintain remissions. All patients enrolled in the trial received induction therapy composed of daunorubicin, vincristine, asparaginase, and steroid followed by cyclophosphamide, cytarabine, 6-mercaptopurine, and methotrexate [29]. Both phases included CNS directed therapy. The comparison of patients 55 years of age or above (n = 100) and patients under 55 years of age (n = 1814) indicated that older patients have a higher incidence of Philadelphia-positive ALL (28% vs. 15%). Older patients had a lower rate of CR (70% vs. 90%, P< 0.0001), EFS at five years (19% vs. 37%, P < 0.0001, and OS at five years (21% vs. 41%, P < 0.001). More infections (18% vs. 4%, P < 0.0001), deaths during induction (18% vs. 4%, P < 0.0001) and dose reductions (47% vs. 27%, P = 0.0006) were reported in patients 55 years of age or above. Unfavorable factors in older patients included Philadelphia-positive ALL, unfavorable cytogenetic risk, and white blood cell count above 50 × 109/l. Inability to tolerate chemotherapy was evidenced by the high incidence of infections, deaths during induction, and dose reductions in older patients. Low intensity chemotherapy is warranted in this patient population. Targeted therapy with monoclonal antibodies and TKIs should be incorporated in specific subsets likely to benefit. The addition of targeted therapy to AML and ALL therapy improves response rates in specific subsets with minimal additional toxicity. Just as patients with Philadelphia-positive ALL benefit from the addition of a TKI, patients with AML benefit from the addition of targeted therapy tailored to the molecular or cytogenetic abnormality present. Treatment determined through molecular testing will further improve outcomes for acute leukemia. Elderly patients present age-related challenges with resistant disease and increased chemotherapy related toxicity. Further exploration should pursue investigational agents and low-intensity therapy to improve response rates and minimize early mortality in older patients diagnosed with leukemia. As new data recognized the importance of asparaginase in ALL treatment, the addition of this agent into additional adult ALL treatment programs should be evaluated as a means to improve survival.