Dan Douer, MD, Division of Hematology, University of Southern CaliforniaDecember 9-12, 2006Orlando, FloridaDan Douer, MD, Division of Hematology, University of Southern California
Several studies presented at the 2006 American Society of Hematology (ASH) Meeting focused on improving the outcome of acute lymphoblastic leukemia (ALL), especially in adults. The stage was set at the educational session by Dr. Sallan who reminded the audience that the more favorable outcome of children compared to adults cannot be explained by biological differences between the two groups but rather by the way the patients are treated.  The treatment of adult ALL with intensified pediatric protocols and the role of allogeneic transplantation in first complete remission were highlighted at this meeting.
Pediatric Protocol in Newly Diagnosed Adolescents and Adults with ALL
Several groups reported on treating adolescents or adults according to more intensified pediatric protocols, showing that such an approach is feasible with a gradual improvement in the overall outcome. The FRALLE Pediatric Group from France intensified the treatment for patients aged 15-20 years and showed a substantial improvement in outcome despite a decrease in stem cell transplantation (SCT).  Using pediatric intensive protocols, they showed that 74 patients treated in the year 2000 and beyond had a 5-year event-free survival (EFS) of 86%. This result was significantly higher than those for patients enrolled in clinical trials during the 90s and 80s: 71% and 42%, respectively.
The French GRAAL group used a pediatric protocol in adults with Philadelphia negative ALL patients aged 15-55 years. The researchers intensified the doses of the non-myelosuppressive drugs: Elspar® (asparaginase), vincristine and prednisone.  In 212 patients, the CR rate was 93%, and the 2-year EFS was 56%. These results were significantly higher than those from their previous LALA 94 study (712 patients) with CR and EFS rates of 88% and 41%, respectively. The difference in this study from the pediatric protocol was that high risk patients with a donor were offered allogeneic SCT. However, the improvement over the LALA 94 study was consistent, even if the patients were censored at the time of SCT. This fact underlines the role played by the intensified chemotherapy. Interestingly, the benefit of the pediatric approach was no longer statistically significant after age 40 years due to lower tolerance to the intensified treatment.
In a multi-center study from the U.S. , 71 patients aged 18-50 received the intense high risk arm of a recent pediatric protocol.  Among the drugs intensified was Elspar, given in high doses weekly for 30 weeks, an approach that has not been yet tested in adults. The estimated EFS rate at a median follow up of 1.5 years was 75%. Eighteen (73%) of 23 patients that could be evaluated for asparaginase administration completed all 30 weeks of the drug. Similar results were reported from a group in Canada with acceptable toxicity.  Interestingly, as in the pediatric experience, the ability to deliver more than 80% of the targeted Elspar dose appeared to improve the outcome. These studies pave the path to confirmatory larger studies with longer follow ups and a dose-intensified pediatric-like strategy.
Stem Cell Transplantation in Adult ALL
Another approach in improving the outcome of adults with ALL is SCT in first complete remission (CR). According to guidelines of CIBMTR, SCT is recommended for patients with high risk ALL, as several studies in the past have shown it benefited this group of patients. For patients with low risk, the role of SCT was unclear, and the procedure was, therefore, not recommended.
Reported in the plenary session were results of the largest study (approximately 2000 patients) addressing the role of SCT in adults with ALL. The study was performed by both by the Medical Research Council (MRC) in Britain and the Eastern Cooperative Group (ECOG) in the U.S.  Patients younger than 50 (55 since 2004) in first CR were assigned to allogeneic SCT if they had a matched sibling donor. The other patients were randomized to receive intensive chemotherapy or autologous SCT. The analysis was done for Philadelphia negative patients. The EFS rate of patients with a donor was 50%, which was significantly higher than those without a donor (41%). The relapse rate was significantly lower in patients with a donor (29% vs. 54%). However, this benefit of SCT was seen only in patients with standard risk ALL: EFS of 59% in patients with a donor compared to 48% in those without a donor. This overall advantage was not seen in high risk patients, defined as age greater than 35 years or high WBC >30,000 for B-lineage or >100,000 for T-cell lineage. Although the relapse rate in high risk patients with a donor was lower, 36% compared to 63% of patients without a donor, a high transplant related mortality, 39%, abrogated its effect on the overall outcome. These results are in contrast to smaller studies showing a survival advantage with allogeneic SCT only in high risk patients.
The study was initiated in 1993, and perhaps patients transplanted in more recent years had lower transplant related mortality, allowing the benefit of the low relapse rate to increase the overall outcome of SCT in high risk patients. Variations in defining the risk factors and in the intensity of chemotherapy may explain the differences in outcome of standard risk patients.
It would be interesting to see if using more intensified protocols as described above might reduce the need for allogeneic SCT in the different risk groups. It is clear from this study, however, that autologous SCT has a worse outcome than does chemotherapy and should not be done in ALL patients.
SCT is the only curative approach in relapse. The ability to undergo SCT was studied in 421 patients who relapsed in the LALA 94 study.  It was clear from the study that the survival was better when SCT was done in second CR compared to SCT done at the time of relapse or after failure of re-induction. In fact, survival from SCT from matched unrelated donor (MUD) was even slightly better than from a matched related donor. However, overall, only 94 patients received SCT from MUD or matched related donor. Only 187 (44%) of the patients achieved a CR and only 61 of them had a SCT. This study highlights the practical difficulties in the ability to perform SCT after relapse and the need to organize the procedure as soon as possible.
Elspar in Pediatric and Adult ALL
Elspar is a drug used only in ALL and is a major component in almost all pediatric and adult protocols. Several randomized clinical trials have shown that intense and prolonged administration of this drug during consolidation improves the overall survival in children. Two studies reported alternatives to the native E. coli asparaginase. Erwinia asparaginase is used for patients who become allergic to the native form but, due to its shorter half life, may produce suboptimal serum concentrations if given at the same frequency.
A study from the DFCI Consortium reported on 44 children who developed allergy to once-weekly E.coli asparaginase. Patients were switched to twice weekly Erwinia asparaginase (instead of once-weekly).  The study showed that twice-weekly Erwinia asparaginase was well tolerated and achieved optimal therapeutic asparaginase concentrations in most patients allergic to the E. coli form, including almost all patients who developed anti-asparaginase antibodies.
A second alternative is Oncaspar® (pegaspargase), which is a pegylated form of E. coli asparaginase that has a much longer half-life and is less immunogenic. It has been approved by the FDA for patients who develop allergy to the E. coli form as well as in front line therapy of ALL. Asparaginases have generally been given intramuscularly (IM) in the U.S because of toxicity concerns of intravenous (IV) dosing. In a study by the DFCI consortium, a single dose of Oncaspar was given IV to 66 ALL children producing long therapeutic serum asparaginase concentrations (up to 18 days), similar to those seen after IM administration and with minimal toxicity.  Another study showed that sequencing Oncaspar after cytarabine plus thioguanine may help in overcoming cell resistance to cytarabine. 
Oncologists who treat adults are concerned about administering asparaginase, especially in high doses, because adults have appeared in the past to be less tolerant of the side effects of the drug. The studies reviewed above show that giving more asparaginase to adults as part of the pediatric-like treatment has acceptable toxicity.
How Precision Medicine in Oncology Has Dramatically Changed the Way Cancer is Diagnosed and Treated
And What Patients Need to Know
Intravenous Oncaspar was also studied in adults (aged 19-57) by a group at the University of Southern California .  They reported that multiple doses of the drug can be given safely with minimal allergic reactions and no antibody formation (20 patients). Interestingly, the duration of optimal serum concentrations increased with subsequent dosing without increasing toxicity.
In children and adults, it appears that IV Oncaspar can be given safely-producing long durations of optimal serum asparaginase concentrations with a low rate of allergic reactions-and could replace the short acting and more immunogenic E. asparaginase. A low rate of allergic reactions would have another advantage; 85% of 48 children who had a clinical allergic reaction to asparaginase had developed anti-asparaginase antibodies neutralizing to the drug and a concomitant loss of its activity. 
Several ASH abstracts addressed various aspects of treating ALL in children. Intensified treatment has improved the outcome of children over the last 20 years, which included double delayed intensification (DDI).
A study performed by the Children’s Cancer Group (CCG 1961) addressed the issue of whether a single delayed intensification (SDI) is sufficient in standard risk patients who have a favorable early marrow response to induction.  Indeed, in these patients, there was no benefit to DDI since the EFS and OS were nearly identical for patients receiving DDI or SDI.
The question of different treatment intensities for different risk groups was addressed in a study reported from Japan . Researchers used a risk-adaptive therapy in precursor B-cell ALL patients by intensifying the treatment and including SCT in high risk patients.  They showed that high risk patients achieved a high cure rate at 5 years, with an EFS rate of 72%. These results approach the EFS rates of 77% and 82% in intermediate and standard risk ALL, respectively.
The presence of minimal residual disease (MRD) early in the course of treatment is considered a poor prognostic factor. The Children’s Oncology Group (COG) looked at MRD (>0.1% cells by four color flow cytometry) in several of their B-precursor ALL protocols that had other prognostic factors.  In general, the study showed that MRD negativity both in the blood on day 8 and in the bone marrow on day 29 of induction was associated with an excellent outcome: a 4 year EFS rate of 93%. Further, other favorable prognostic factors were not as significant in MRD positive patients. For example, the prognostic significance of TEL-AML1 was dependent on a MRD negative status. In fact, in a multivariate analysis, day 29 MRD was the most important prognostic factor. The conclusion from this study is that the MRD is a major prognostic factor, even when other positive prognostic factors are accounted for.
Relapses in Pediatric ALL
Although relapses are now less common in children with ALL, they do occur and their outcome has not been well studied. One study looked at 1874 relapses from a total of 9585 patients enrolled on the Children’s Oncology Group protocols.  The best overall survival rate, 55%, was seen in patients with late marrow relapse (>36 months from diagnosis) and the worst, 10%, in patients who had marrow relapsed early (< 18 months from diagnosis). The survival was higher for isolated CNS or testicular relapses than for marrow relapse. Early relapses were seen mostly in high risk patients. In fact, patients treated on contemporary front line trials had inferior survival rates compared to patients treated on earlier trials. This is likely related to the fact that relapses after more aggressive protocols result in selection of more resistance to salvage chemotherapy. The authors concluded that increasing the treatment intensity after relapse is unlikely to improve the outcome, and therefore new agents are needed to treat relapsed ALL.
Arranon® (nelarabine) is an antimetabolite chemotherapy drug approved by the FDA for relapsed T-cell ALL. The Children’s Oncology Group combined the drug with an intensive chemotherapy regimen.  Sixty-one children with high risk T-ALL received nelarabine at doses of 400-650 mg/m2/day in combination with a BFM chemotherapy protocol with acceptable toxicity.
Clolar® (clofarabine) is a purine analogue approved for pediatric, relapsed ALL. A European multi-center group report confirmed the results of the previous pivotal trial in which children with ALL who received two or more prior regimens had a 26% response rate. 
Rituxan® (rituximab) is effective in B-cell lymphomas that are CD20+. Approximately half of ALL patients are CD20+. A study from M.D. Anderson Cancer Center reported that adding Rituxan to hyper-CVAD chemotherapy improved the DFS rate in CD20+ ALL patients to 80% versus 50% with chemotherapy alone. However, it did not have an effect on the overall survival. 
Gleevec® (imatinib) and nilotinib are bcr-abl tyrosine kinase inhibitors that are active in Philadelphia positive ALL, which occurs in 30% of precursor B-cell adult ALL patients carrying the fusion bcr-abl oncogene. Quiotas-Cardama and colleagues reported that in approximately 10% of T-ALL, abl is fused with NUP214, resulting in expression of NUP214-abl tyrosine kinase activity.  Further, they reported that both imatinib and nilotinib inhibit in vitro leukemia T-cells in ALL cell lines expressing this mutation. Thus, both drugs could be active in targeting this subset of patients with T-ALL.
Almost all adults with ALL achieve complete remission. From results presented at the 2006 ASH meeting it appears that intensifying the post remission treatment in adult ALL would increase the chances of maintaining the remission. Of the many chemotherapy drugs that are combined in adult ALL, the focus in this meeting was on asparaginase and its less long acting and less immunogenic form, Oncaspar. In pediatric ALL, treatment should be tailored to risk factors, and MRD at the end of induction is a major prognostic factor. The outcome of relapsed ALL remains poor, and new drugs are needed.
1 Sallan SE. Myths and Lessons from Adult/Pediatric Interface in Acute Lymphoblastic Leukemia. ASH Education Program Book 2006:128-132.
2 Baruchel A, Auclerc MF, Perel Y, et al . Two Decades of Progresses in Adolescents with Acute Lymphoblastic Leukemia (ALL) Treated in the FRALLE Protocols: Adolescence Is No More a Bad Prognostic Feature If an Intensive Chemotherapy Is Applied. Blood 2006;108:abstract #1852.
3 Huguet F, Raffoux E, Thomas X, et al. Towards a Pediatric Approach in Adults with Acute Lymphoblastic Leukemia (ALL): The GRAALL-2003 Study. Blood 2006;108:abstract #147.
4 DeAngelo DJ, Silverman LB, Couban S, et al . A Multicenter Phase II Study Using a Dose Intensified Pediatric Regimen in Adults with Untreated Acute Lymphoblastic Leukemia. Blood 2006;108:abstract #1858.
5Storring JM, Brandwein J, Gupta V, et al*.* Treatment of Adult Acute Lymphoblastic Leukemia (ALL) with a Modified DFCI Pediatric Regimen – The Princess Margaret Experience. Blood 2006;108:abstract #1875.
6Rowe JM, Buck G, Fielding A, et al*.* In Adults with Standard-Risk Acute Lymphoblastic Leukemia (ALL) the Greatest Benefit Is Achieved from an Allogeneic Transplant in First Complete Remission (CR) and an Autologous Transplant Is Less Effective Than Conventional Consolidation/Maintenance Chemotherapy: Final Results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2006;108:abstract #2.
7Tavernier E, Boiron JM, Huguet F, et al*.* Outcome of Treatment after First Relapse in Adults Patients with Acute Lymphoblastic Leukemia (ALL) Initially Treated by the LALA-94 Trial. Blood 2006;108:abstract #1876.
8Silverman LB, Neuberg D, Supko J, et al*.* Pharmacodynamics and Tolerability of Twice-Weekly Erwinia Asparaginase after E. coli Asparaginase Allergy in Children with ALL. Blood 2006;108:abstract #1857.
9Silverman LB, Stevenson K, Neuberg D, et al*.* Intravenous PEG Asparaginase during Remission Induction for Childhood ALL. Blood 2006;108:abstract #1854.
10Fu CH, Franklin JL, Gaynon P, et al. A Phase I Study of Oral 6-Thioguanine, Followed by Continuous Infusion Cytarabine, Followed by Intramuscular PEG-Asparaginase (TGAP) in Children with Relapsed or Refractory Acute Leukemia or Non-Hodgkin’s Lymphoma. Blood 2006;108:abstract # 4536.
11Douer D, Watkins K, Nathwani N. The Pharmacokinetics, Safety and Lack of Antibody Production from Multiple Doses of Intravenous Pegylated Asparaginase in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia. Blood 2006;108:abstract #1873.
12Tiwari PN, Monica Zielinski M, Quinn JJ, et al*.* Assessment of Anti-Asparaginase (ASNase) Antibodies (Ab) and ASNase Activity after Suspected Clinical Allergy. Blood 2006;108:abstract #1878
13Matloub Y, Angiolillo A, Bostrom B, et al*.* Double Delayed Intensification (DDI) Is Equivalent to Single DI (SDI) in Children with National Cancer Institute (NCI) Standard-Risk Acute Lymphoblastic Leukemia (SR-ALL) Treated on Childrens Cancer Group (CCG) Clinical Trial 1991 (CCG-1991). Blood 2006;108:abstract #146.
14Horibe K, Kudoh T, Hori H, et al*.* Effective Risk-Adapted Therapy for Childhood B-Precursor Acute Lymphoblastic Leukemia (ALL) with the Japan Association of Childhood Leukemia Study (JACLS) ALL-97 Protocol. Blood 2006;108:abstract #1874.
15Borowitz MJ, Devidas M, Bowman WP, et al*.* Prognostic Significance of Minimal Residual Disease (MRD) in Childhood B-Precursor ALL and Its Relation to Other Risk Factors. A Childrens Oncology Group (COG) Study. Blood 2006;108:abstract # 219.
16Nguyen K, Cheng SC , Raetz E, et al*.* Factors Influencing Survival after Relapse from Childhood ALL: A Childrens Oncology Group Study. Blood 2006;108:abstract # 1855.
17Dunsmore K, Devidas M, Borowitz MJ, et al*.* Nelarabine Can Be Safely Incorporated into an Intensive, Multiagent Chemotherapy Regimen for the Treatment of T-Cell Acute Lymphocytic Leukemia (ALL) in Children: A Report of the Childrens Oncology Group (COG) AALL00P2 Protocol for T-Cell Leukemia. Blood2006;108:abstract #1864.
18KearnsP, Michel G, Nelken B, et al. BIOV-111 a European Phase II Trial of Clofarabine (Evoltra®) in Refractory and Relapsed Childhood Acute Lymphoblastic Leukemia. Blood 2006;108:abstract #1859.
19Thomas DA, Kantarjian HM, Jorgensen JJ, et al. Outcome after Detection of Minimal Residual Disease during Treatment with the Modified Hyper-CVAD Regimen with or without Rituximab in Newly Diagnosed Adult Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LL). Blood 2006;108:abstract #1861.
20Quintas-Cardama A, Tong W, Manshouri T, et al*.* Frequency of NUP214-ABL1 Oncogene in Patients with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Analysis of the Activity of Imatinib and Nilotinib in NUP214-ABL1-Expressing T-ALL Cell Lines. Blood 2006;108:abstract #710.