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Advances in Adult ALL Likely to Come from Targeted Therapies

Goodman, Alice

doi: 10.1097/01.COT.0000295289.90018.f7
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Although huge advances have been made in treating childhood acute lymphoblastic anemia (ALL) (OT, 8/10/06), the most common malignancy in children, success in treating adults with ALL has been more elusive, noted the experts interviewed for this article.

Daniel J. DeAngelo, MD, PhD, of the Adult Leukemia Program at Dana-Farber Cancer Institute, explained that whereas with current treatments, 80% of children with the disease are cured, the three-year disease-free survival rate in adults (age 18 and over) is only 30% to 40%. Also, he and other said, advances in treating adult ALL are likely to come from the addition of targeted therapies directed at specific molecular features of the various subtypes of ALL.

Figure. Deb
Figure. Deb:
orah Thomas, MD, noted that rituximab has improved the outlook for the 5% to 10% of patients with ALL who have the Burkitt's subtype. Virtually 100% of patients with Burkitt's lymphoma and leukemia (B-ALL) express CD20. Elderly patients with B-ALL have historically had a very poor outcome. The three-year disease-free survival rate in patients over age 60 was 17% vs 77% in younger patients.

Young Adults

Young adults (age 16–21) pose a special problem, Dr. DeAngelo said, because it is not clear if they should be treated by pediatric or adult oncologists. Referral patterns for this age group reflect this dilemma, since those age 18 living with their parents are usually referred to a pediatric oncologist, while those living by themselves would most probably consult an adult oncologist.

Recent evidence from four retrospective studies (three from Europe and one from the US) suggests that patients age 16 to 21 treated on pediatric protocols have superior disease-free survival compared with those treated on adult protocols.

The reasons for this difference are not clear, but it may be that young adults with ALL are being undertreated by adult oncologists. “A 19-year-old and a 40-year-old are treated with the same regimen,” Dr. DeAngelo noted. “My fear is that we are undertreating younger adults.”

This is a difficult area to study, he continued. “Randomized trials will not be conducted, because there are too few people aged 16 to 21 with ALL. The best approach is to test intensive regimens in pilot studies.” Ongoing prospective trials are looking at the question of whether pediatric or adult protocols are better, he added.

Accrual has begun by a study by the Southwest Oncology Group (SWOG), Cancer and Leukemia Group B (CALGB), and the Children's Oncology Group to evaluate a pediatric regimen in older adolescents and younger adults with ALL. The study will be coordinated at Dana-Farber Cancer Institute,

“This study is very important, and it took years of planning,” noted Wendy Stock, MD, Assistant Professor of Medicine at the University of Chicago Pritzker School of Medicine, the lead author of a retrospective study showing that that 16 to 21-year olds treated with an adult CALGB protocol had dramatically worse disease-free survival rates compared with patients of the same age treated on a Childrens Cancer Group protocol.

“The question is why these differences in outcomes exist,” she said. “Is it the treatment? Is it the doctors? Is it the pediatric culture versus the adult culture? Is it the support system?” The prospective study should help to answer some of these questions, she said.

Targeted Therapies in Ph+ Patients

ALL is a heterogeneous disease, with many subtypes, some of which have not yet even been identified. Improved understanding of the molecular biology of ALL has led to the development of therapies targeted to various features of the disease. An example of where a targeted therapy has made a significant impact is the use of tyrosine kinase inhibitors in Philadelphia chromosome-positive (Ph+) ALL, Dr. Stock said.

“It is clear that the addition of imatinib in combination with chemotherapy improves response rates and possibly disease-free survival [in Ph+ patients],” said Deborah Thomas, MD, Assistant Professor in the Department of Leukemia at the University of Texas M. D. Anderson Cancer Center. Dr. Thomas was lead author of a Phase II study evaluating the addition of imatinib to a standard chemotherapy regimen (hyper-CVAD [intensive fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone]).

Survival rates were improved from 15% to 60% with the addition of imatinib, with two-year disease-free survival rate of 85%.

The standard approach for Ph+ ALL patients is to achieve complete remission and then receive allogeneic stem cell transplant. This study and those of other groups have shown that imatinib plus chemotherapy improved the rates of complete response and molecular response compared with chemotherapy alone.

Studies in the transplant setting show that the addition of imatinib prior to transplant improves remission rates and potentially, transplant outcomes.

“The question we are asking now is whether the addition of imatinib following transplant will further improve outcomes by getting rid of minimal residual disease,” Dr. Stock said. “This has been shown to be a feasible approach, but we don't yet know whether it will improve outcomes.”

PCR-positive status following transplant is a prognostic indicator for relapse, she continued. A German group has shown that a subset of PCR+ patients who receive imatinib achieve PCR-negative status. But this study still has a short follow-up, Dr. Stock noted. Patients who did not respond to imatinib all relapsed.

Alternative to Transplant

Younger patients who are Ph+ are offered allogeneic transplant after receiving imatinib, but the majority of Ph+ patients are older and only a minority are candidates for transplant. Dr. Thomas indicated that her study and that of the Japanese group are showing similar survival rates after imatinib and chemotherapy with or without allogeneic transplant in first complete remission.

European groups have shown that a course of imatinib increases disease-free survival in patients who are not eligible for or who are not good candidates for transplantation.

“In these studies, older patients did much better with imatinib and chemotherapy,” Dr. Stock said.

The hope is that newer tyrosine kinase inhibitors like dasatinib and nilotinib will achieve even better results. Resistance to these agents can develop when used as monotherapy in Ph+ patients refractory or resistant to imatinib, she said. “All patients treated with monotherapy will relapse.”

“In newly diagnosed Philadelphia chromosome-positive patients, the newer tyrosine kinase inhibitors improve results, but it is still too early to know whether these newer agents will be better than imatinib.”

Several clinical trials testing dasatinib in combination with chemotherapy are planned for both imatinib-resistant and de novo Ph+ ALL, Dr. Thomas said.

“Although there still is a lot of work to be done in Ph+ ALL, I'm encouraged by progress over the past few years,” Dr. Stock said. “What we call the ‘worst-prognosis group’ may not be the ‘worst-prognosis group’ any longer.”

Alemtuzumab

Alemtuzumab, a monoclonal antibody that has been available for several years, is being studied in older adults with ALL. “We know that more intensive chemotherapy is not the answer for elderly adults, and we are trying to identify targeted therapies for this age group,” Dr. Stock said.

Although there are a number of new therapies to study, alemtuzumab is a rational choice, since 68% of all adults with ALL express CD52, the antigen that is the target of alemtuzumab.

A Phase I study at University of Chicago demonstrated the feasibility of using alemtuzumab in elderly ALL patients. A Phase II study (CALGB 101/102) is now accruing patients to evaluate the optimal dosing and scheduling of alemtuzumab.

Patients in first remission will receive three cycles of chemotherapy, followed by one cycle of alemtuzumab, followed by more chemotherapy and then maintenance therapy. The hope is that alemtuzumab will cause remission of minimal residual disease, she said.

Rituximab

Rituximab, a humanized monoclonal antibody directed against the CD20 antigen, has improved the outlook for the 5% to 10% of patients with ALL who have the Burkitt's subtype. Virtually 100% of patients with Burkitt's lymphoma and leukemia (B-ALL) express CD20, Dr. Thomas explained.

Elderly patients with this B-ALL have historically had a very poor outcome. The three-year disease-free survival rate in patients over age 60 was 17% vs 77% in younger patients.

“Part of the reason for these failures was infection during induction chemotherapy and part was due to relapse. We decided to study rituximab after the promising data on CHOP plus rituximab in non-Hodgkin's lymphoma.”

Dr. Thomas was lead author of a Phase II study of rituximab added to the standard chemotherapy regimen of hyper-CVAD in “all comers” with ALL who expressed CD20. The most dramatic benefits were seen in elderly patients with B-ALL: a three-year disease-free survival rate of 89%.

“Now [with the addition of rituximab to chemotherapy], the outcome in elderly Burkitt's patients is the same as in younger ones,” Dr. Thomas said. “These are very impressive results, but it is only a Phase II study.”

The addition of rituximab to hyper-CVAD is also being evaluated in a Phase II study in patients with ALL (excluding Burkitt's, Ph+, and lymphoblastic lymphoma). The regimen is the same as was used in B-ALL, but treatment is for a total of three years (it is six months in Burkitt's), Dr. Thomas explained.

The study is still accruing patients, but preliminary analysis suggests there is a benefit with the addition of rituximab, she said.

Newer targeted agents have become available that are of interest in ALL, Dr. Thomas continued. These include other monoclonal antibodies such as epratuzumab and purine nucleoside phosphorylase inhibitors such as forodesine.

Older Adults with ALL

Older adults with ALL are difficult to treat, Dr. DeAngelo said. “People over age 60 do very poorly.” Remission rates are about 60%, and three-year disease-free survival is about 12% to 15%.

“It is unclear what the optimal management is for this age group. The big questions are whether they can tolerate the side effects of intensive chemotherapy and how to improve relapse rates. There are no specific trials that I am aware of to address that question in the over-60 population.”

It is not clear why older patients have a suboptimal response, he continued. There are many unanswered questions. It may be that the leukemia has a different biology in older people; Philadelphia-chromosome-positive disease is more common in people over age 60, and it is rare in children and young adults, and this disease may be more difficult to treat.

Few prospective clinical trials have been conducted in older patients. Older patients may metabolize chemotherapy differently than younger patients. Other issues related to older age that could compromise response include nutritional status, adherence to complex regimens, and comorbidities.

“Older patients are often not well hydrated, and drug absorption and volume of distribution may change as people age. Also, older patients may not have caretakers or family who can drive them to clinics for care,” Dr. DeAngelo said.

A clinical trial is planned for elderly ALL patients with de novo ALL, incorporating a gentler induction and consolidation chemotherapy regimen with or without a sphingosomal form of vincristine, which has been shown to improve drug delivery with less toxicity than standard vincristine, Dr. Thomas said.

SWOG, CALGB, Eastern Cooperative Oncology Group, and international sites will participate in this prospective study, which will be led by M.D. Anderson Cancer Center.

Notch Signaling Pathway

Jon C. Aster, MD, PhD, Associate Professor of Pathology at Brigham & Women's Hospital, commented that new insights in the biology of the Notch signaling pathway have led to the development of a potential treatment for T-cell ALL (T-ALL). Notch 1 mutations are the most common genetic lesions in this particular subtype of ALL.

The Notch signaling pathway normally regulates development and differentiation of T-cells, he explained. One Notch receptor (NOTCH 1) is essential for the development of T-cells. In fact, when Notch-1 is artificially activated, T-cells will arise from earlier progenitor cells at sites where they don't normally develop, such as the bone marrow.

Together with Dr. Tom Look's group at Dana-Farber, Dr. Aster and colleagues have elucidated the role of the Notch pathway in T-cell ALL. Fifty to 60 percent of all T-ALL cases have mutations in the Notch 1 receptor that cause it to be abnormally hyperactive, Dr. Aster noted.

There are two kinds of mutations. One, in the extracellular domain receptor, leads to increased receptor activation, which occurs through cutting by a protease complex called gamma secretase.

The second type, which involves the intracellular domain, increases the life span of the activated Notch-1 protein, Dr. Aster explained.

“A sizable number of all T-ALL tumors have both types of mutations, which acts together like a double whammy. When both mutations are present, the receptor is turned on more quickly and it stays on longer.”

Abnormal Notch signaling plays an important role in T-ALL, and as such, it is a therapeutic target. “As luck would have it, there are compounds available that inhibit Notch signaling,” he said.

The gamma secretase protease that cuts Notch and allows it to go to the nucleus also plays a role in Alzheimer's disease by cutting and activating another protein called beta-APP that is implicated in the formation of amyloid plaques. As a result, drug companies have been interested in identifying small molecules that inhibit gamma secretase.

“Gamma secretase inhibitors are potential therapies in T-ALL, as they cut off the growth of tumor cells by turning off Notch signaling,” Dr. Aster said.

“Activated Notch-1 drives the growth of T-ALL cells by increasing the expression of other genes. One gene that we have recently learned is activated by NOTCH-1 in T-ALL cells is C-MYC, a notorious oncogene known to be involved in T-ALL and a number of other cancers. By turning off Notch, you turn off C-MYC.”

A clinical trial using a gamma-secretase inhibitor has been opened at Dana-Farber Cancer Institute for adults and children with relapsed and refractory T-ALL. The compound under study is a drug from Merck, MK-0742, which is taken as a pill once a day.

If these studies pan out, this will be another example of how understanding of the biology of a disease leads to important new therapies. As understanding improves, more new therapies should become available and perhaps the future will look brighter for adults with ALL.

© 2006 Lippincott Williams & Wilkins, Inc.
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