Intensive Imatinib in Combination with High-Dose Chemotherapy Extends Survival in Children with Philadelphia Chromosome-Positive ALL

ATLANTA—Increasing the number of days of imatinib therapy in combination with high-dose maintenance chemotherapy improved the two-year event-free survival rate in children with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in a Children's Oncology Group (COG) study presented here at the ASH Annual Meeting.Figure: Kirk R. Schultz, MD: “As the dose of the targeted agent increased, we saw increasing survival rates. At the most intensive dose, the two-year event-free survival was twice that seen previously in historical controls—38 percent—from previous COG studies. The data are still early, not conclusive, but they are interesting and exciting.”The researcher who reported the data, Kirk R. Schultz, MD, Director of Pediatric Oncology Research and the CIHR/Wyeth Clinical Research Chair in Transplantation and Associate Professor of Pediatrics at BC Children's Hospital in Vancouver, noted that Ph+ ALL remains one of the highest-risk subsets of childhood ALL. Imatinib has established activity against Ph+ ALL, with transient activity in Phase I and II trials. At last year's ASH Annual Meeting, a COG study had shown that imatinib in combination with high-dose chemotherapy was tolerable. 5 Cohorts In the new study, 93 children were enrolled in one of five cohorts. The patients received a single dose of 340 mg/m2 of imatinib for 42 days (8 patients), 63 days (12 patients), 84 days (11 patients), 126 days (12 patients), or 280 days (50 patients), respectively, prior to maintenance chemotherapy. Bone marrow transplantation (BMT) was performed after two cycles of imatinib therapy only if a sibling donor was available; otherwise chemotherapy was continued. The total duration of treatment in the chemotherapy arm was 2.5 years. Patients who received a BMT started imatinib four to six months after the transplant for six months. Of the 93 patients who were treated, 10 had not responded to induction therapy and were removed from the study analysis. The patients received frontline induction/consolidation for four to six weeks. Consolidation Block #1 consisted of ifosfamide/etoposide on Days 1–5 and methotrexate on Day 1 followed by imatinib on Days 1–21 (21 days or continuous in Cohort 5). Consolidation Block #2 consisted of methotrexate on Day 1/Ara-C on Days 2 and 3 followed by imatinib on Days 1–21 (21 days or continuous in Cohort 5). Then patients received chemotherapy or were referred for BMT. The researchers observed that minimal residual disease (MRD) positivity was significantly lower in Cohorts 3–5 with Consolidation Block 1 and in Cohorts 2–5 with Consolidation Block 2. Increasing imatinib exposure resulted in an improved two-year event-free survival (EFS) rate of 41% for the first and second cohorts, 70% for the third and fourth, and 85% for the fifth cohort. “As the dose of the targeted agent increased, we saw increasing survival rates,” Dr. Schultz said in an interview after an ASH news conference that featured the study. “At the most intensive dose, the two-year EFS was twice that seen previously in historical controls—38 percent—from previous Children's Oncology Group studies. The data are still early, not conclusive, but they are interesting and exciting.” A total of 21 patients had matched sibling transplants, eight in Cohorts 1–4 and 13 in Cohort 5. Eleven of 83 (13%) patients were removed from the study by treating institutions for alternative donor BMT. The intent-to-treat analysis shows 70% two-year event-free survival in those patients in Cohort 5 treated without sibling donor BMT and 64% two-year EFS in patients who received a matched sibling donor BMT, which is not a statistically significant difference, he said. Cohort 5 chemotherapy treatment group outcomes were not significantly affected after removal of patients receiving off-protocol BMT, he noted. Compared Favorably with Transplantation At the news conference, Dr. Schultz said that treatment with imatinib compared favorably with transplantation: “The outcome was equivalent. We can infer that chemotherapy is better than transplantation, but the difference is not significant.” He also noted that this group of patients has been considered incurable with induction chemotherapy. “These children now have hope and a better chance of survival,” he said, addng that this very intensive regimen can be extrapolated into young adults in their 20s who have Ph+ ALL. In an interview after the press conference, Armand Keating, MD, Epstein Chair & Director of the Cell Therapy Program at the Princess Margaret Hospital/Ontario Cancer Institute in Toronto, Canada, said that “perhaps in this group of patients, it may not be necessary to do transplantation if we use intensive chemotherapy with imatinib.” Only a relatively small percentage of Ph+ ALL patients are children, he noted. “We are learning how to use imatinib outside of chronic-phase chronic myeloid leukemia (CML) for children and adults with ALL. “Should it be used only with intensive chemotherapy, or in the post-transplant setting? We also are learning how to use imatinib in the context of blast-crisis CML. At the moment, that is still investigational, and further studies need to be done,” said Dr. Keating. Dr. Schultz concluded that the study found that “imatinib given in combination with intensive chemotherapy resulted in a significant improvement in early event-free survival and reduction in early minimal residual disease. Imatinib given following a BMT also improved outcomes in related-donor bone marrow transplants. “Intensive imatinib with intensive chemotherapy gives equivalent two-year EFS to patients treated with allogeneic-related or alternative-donor BMTs,” he said. Longer observation is required to determine if this result produces a clinically significant difference in long-term EFS, he said. For future studies, he added, he and his colleagues will consider the initiation of tyrosine kinase inhibitors, such as imatinib, in induction therapy, as well as an increase in duration of tyrosine kinase inhibitor therapy after BMT. Timing In the question-and-answer session after his presentation, Dr. Schultz was asked how comfortable he was in stopping imatinib after only two and a half years when CML patients continue to take the drug for five years. “We may see an increase in relapse. We will see in the next year if this is occurring or not,” Dr. Schultz replied. ‘Took Resources of Large Cooperative Group’ In children, it has taken the resources of a large cooperative group trial to demonstrate safety and efficacy in this vulnerable population, said the moderator of a news conference that featured the study, Richard A. Larson, MD, Professor of Medicine in the Section of Hematology/Oncology and Director of Hematologic Malignancies at the University of Chicago Medical Center. “I congratulate the Children's Oncology Group for the completion of the clinical trial.” In his introductory talk about the study at the session at which it was presented, Dr. Larson noted that it is now nearly 50 years ago that the Philadelphia chromosome was discovered. Then in 1973 researchers discovered the abnormalities in chromosome 22, including translocations in chromosome 9 and 22, and the fusion gene Bcr-Abl, which also occurs in ALL. The incidence of Ph+ ALL is age-related, and includes only three to five percent of children, he said. The disease has been observed in children under age two, and for 20- to 60-year olds, the incidence is 25 percent and for those over age 60, the incidence is 40 percent.Figure: Richard A. Larson, MD: “I congratulate the Children's Oncology Group for the completion of the clinical trial.”Standard treatment includes multiple agents, including chemotherapy for induction followed by allogeneic stem-cell transplantation if a donor is available. “In December 1999 at ASH, we heard for the first time about a treatment called imatinib,” Dr. Larson said. “Brian Druker reported on this potent oral tyrosine kinase inhibitor in patients with advanced CML, and subsequently, in Phase II trials imatinib was shown to be a single agent active in patients with relapse/refractory Ph+ ALL. Imatinib led to high response rates, including cytogenetic responses, but most patients had a short time until disease progression.” For adults, imatinib became the first-line therapy that was well tolerated and led to high cytogenetic and molecular response rates, Dr. Larson continued in his Introduction. “Compared with historical results, imatinib led to markedly better EFS and overall survival, with or without subsequent allogeneic stem-cell transplantation.”

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