Emergence of Chronic Leukemias as Major Research Targets in Leukemia

In the last 20 years of the past millennium, most clinical research in leukemia was directed toward improving prognosis of acute leukemia and studying the role of stem cell transplantation (SCT), both autologous and allogeneic, in these diseases. The emergence of new treatments and therapeutic approaches has dramatically changed the emphasis of clinical research in leukemia. The power of effective new agents to transform clinical research has been illustrated by the emergence of the tyrosine kinase inhibitor imatinib(Drug information on imatinib) mesylate (Gleevec, STI-571) in chronic myeloid leukemia and monoclonal antibodies in chronic lymphocytic leukemia (CLL). Major advances in the management of Philadelphia- chromosome-positive chronic myelogenous leukemia (Ph-1 CML) occurred following the introduction of interferon (IFN). Initial studies with human leukocyte interferon followed by those with recombinant alpha interferon and combinations of r-IFN-α plus Ara-C (cytosine arabinoside) led to a doubling of the expected survival during the past 20 years. Similarly, allogeneic bone marrow transplantation (allo-BMT) using either marrow or stem cells from peripheral blood became the "poster child" of transplantation. While a number of interferon-treated patients have remained free of recurrence, off IFN for a number of years, allo-SCT is considered the only proven curative strategy, particularly in patients under the age of 30. The development of STI-571 has been revolutionary. The ability of this agent to specifically inhibit ablbcr tyrosine kinase has led to an extremely high complete response rate in CML. Thus an oral preparation has transformed the expectation for this disease. Following promising phase I studies, the phase III (IRIS) trial (page 19) comparing STI-571 to interferon enrolled over 1,000 patients, and compared imatinib 400 mg/d to interferon plus Ara-C. The complete and major cytogenetic response rate with imatinib was dramatically superior to that with interferon/Ara-C. A second clinical trial called SPIRIT will try to confirm these earlier studies. At the American Society of Hematology meeting in 2001, investigators from the M. D. Anderson Cancer Center demonstrated a higher and more rapid complete response rate with imatinib 800 mg/d than with the conventional 400 mg/d dose. Whether these studies can lead to longer-term control is uncertain. STI-571 has also emerged as a major advance in the management of both the accelerated and blastic phases of CML. However, in these latter two conditions, responses are not as durable as in previously untreated patients. In brief, STI-571 is associated with a very high response rate, and at the present time the responses appear to be durable. A major issue that has arisen as the quality of responses has improved following STI-571 is the role of monitoring. It is obvious that the "gold standard" is still conventional cytogenetics. However, FISH (fluorescent in situ hybridization) studies were able to evaluate a larger number of cells and it appears more accurate than cytogenetics. But the FISH methodology does not discover the emergence of new chromosome abnormalities unless other FISH probes are added to the abl and bcr probes. In patients who achieve complete cytogenetic and FISH responses, real-time PCR assay is emerging as a major new technique for monitoring the number of gene copies, and in patients who have minimal residual disease, will probably be the method of choice in evaluating follow-up studies. The success of STI-571 has led to active debate as to the role of allogeneic transplant in the Gleevec era. This will not be resolved for a substantial period of time. Thus, some investigators believe that until there is demonstration that STI-571 is curative, patients under the age of 20 and possibly under 30 should continue to receive allogeneic SCT if a donor is available. The Future of CML
Studies are already emerging of combinations of STI-571 with interferon, Ara-C, and other agents. A combination of interferon plus STI-571 appears to be more myelosuppressive but otherwise well tolerated. There are different mechanisms of resistance to STI- 571, which may be related to additional mutations or chromosome abnormalities, bcr-abl amplification, drug efflux or other kinase mutations. Other new agents being explored include new tyrosine kinase inhibitors such as PD17 by the Memorial Sloan-Kettering group (page 20), PS-341 (a proteasome inhibitor), and farnesyl transferase inhibitors (FTI). Combinations of these agents are also being evaluated. Chronic Lymphocytic Leukemia
The other area of leukemia that is undergoing transformation is chronic lymphocytic leukemia. Whereas for many years this disease was in the doldrums, the emergence of the purine analogs as a major chemotherapy group has enlivened clinic research in this arena. A series of studies have now confirmed that fludarabine (Fludara) or 2-CDA (Leustatin) have higher response rates and longer time to treatment failure than alkylator-based regimens. As these patients are often salvaged with alternative regimens, there is no survival advantage demonstrated at the present time. The most influential clinical trials have been the fludarabine vs chlorambucil(Drug information on chlorambucil) (Leukeran) trial conducted in North America with Dr. Kanti Rai as the principal investigator, and the French Cooperative Group comparing fludarabine to CHOP (cyclophosphamide, doxorubicin(Drug information on doxorubicin), vincristine [Oncovin], prednisone(Drug information on prednisone)) and the French mini-CHOP. The latter study illustrated that the autoimmune hemolytic anemia incidence is similar in the three groups, whereas formerly it had been associated predominantly with the purine analogs. The discovery of the activity of two monoclonal antibodies, namely rituximab(Drug information on rituximab) (Rituxan) and alemtuzumab(Drug information on alemtuzumab) (Campath), is changing the status quo in CLL. While rituximab is minimally effective at conventional doses as salvage therapy in CLL, there is a high response rate of 70% to 80% when used as initial therapy (page 21). Most of these responses are partial responses and the remission durations are not long. In patients who have been previously treated, the activity of rituximab is enhanced by a doseintensive regimen with either a higher weekly dose or a three times a week schedule. The responses again are predominantly partial responses and median remission duration is 9 to 12 months. Campath-1H (alemtuzumab) has been approved for the management of patients with fludarabinerefractory disease (page 25). As opposed to former expectations of a response rate of approximately 20% and a median survival of 9 months in these patients, Campath-1H was able to achieve a 33% response rate with a median survival of 16 months. Many of these responses are long lasting. Alemtuzumab given as initial therapy by the subcutaneous route has been investigated by a Swedish group. The limitation of this subcutaneous route is local reactions, which occur initially, but the response rate demonstrates that alemtuzumab is almost as effective as fludarabine as a single agent in previously untreated CLL. While there are concerns about immunosuppression and transient myelosuppression with alemtuzumab and reactivation of cytomegalovirus (CMV), which occurs in approximately 20% of patients, the CMV reactivation can usually be readily managed with ganciclovir(Drug information on ganciclovir) (Cytovene) or foscarnet (Foscavir) and patients can continue on their therapy. Studies of alemtuzumab as treatment for minimal residual disease demonstrate that half the patients can become PCR negative in their bone marrow. This agent does not appear to be as effective in managing bulky lymph nodes. Combinations of monoclonal antibodies and other agents are promising to elevate the complete response rate above 50% for the first time. The Cancer and Leukemia Group B have compared fludarabine at conventional doses with either simultaneous or simultaneous rituximab. The overall and complete response rates are significantly superior for the simultaneous arm. There was an increase in neutropenia with sequential fludarabine/rituximab, but no increase in infections or other complications. The role of rituximab in maintenance of CLL is still uncertain. Combinations of fludarabine with cyclophosphamide(Drug information on cyclophosphamide) (FC) have demonstrated promising results in phase II clinical trials. Reports from the German CLL study group have demonstrated that FC is superior to fludarabine alone in salvage therapy as far as response rate goes. The group at M. D. Anderson has developed a combination of FC plus rituximab (FCR) and has demonstrated a significantly higher response rate in salvage therapy than had been demonstrated previously (page 24). In the salvage therapy setting, myelosuppression with associated infections was doselimiting. However, 25% of patients in relapse may achieve a complete response to the FCR combination. When FCR is given as initial therapy to patients with CLL who require therapy according to the NCI Working Group criteria, the complete remission rate is now 67%, with an overall response rate of 95% (page 21). In addition, 50% or more of the complete remissions become PCR negative for the immunoglobulin variable heavy chain region, an accomplishment that was unexpected when this study was initially conducted. Remission duration appears to be prolonged at the present time, but there is no evidence as yet that a survival advantage has been obtained. Transplantation modalities have been increasingly explored in CLL (page 22). In the relapse setting, after obtaining a response, autologous bone marrow transplantation may prolong remission but does not lead to cure. We await an update from the Dana-Farber Cancer Institute of their earlier study with autologous SCT as intensification of first-line chemotherapy-induced remissions. A number of investigators conclude that graft-vs-leukemia effect is powerful in CLL, and that allogeneic SCT is associated with longer disease-free survival than autologous SCT. The development of nonablative transplants (NSCT) or reduced intensity transplants (RIT) has expanded the range of allogeneic options so that patients up to the age of 70 to 75 are now being treated with NSCT. The Future of CLL
It is likely that the combinations of chemotherapy plus antibodies will become the new standard of care for frontline and salvage therapy in CLL. New agents are being investigated such as the bcl-2 antisense, PS- 341, and new monoclonal antibodies. NSCT will continue to emerge as a significant salvage opportunity, and well-conducted clinical trials will need to be established to prove the efficacy of these strategies. AML and MDS
Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) are in a phase where exploration of the biology of the disease is of major interest. Application of gene chip microarrays (page 29) is leading to determination of different gene profiles, which cluster in different forms of AML. Progress continues to be made in the implementation of combination strategies of retinoids such as ALL-transretinoic acid (ATRA) along with arsenic trioxide(Drug information on arsenic trioxide) and anti-CD33 antibodies in acute promyelocytic leukemia (APL). It is now considered tragic when a patient with APL does not achieve a long-lasting complete remission. Good responses continue to be obtained in the specific chromosome abnormalities t(8;21) and inv16 with high dose Ara-C regimens. The major remaining area is those with diploid karyotypes and these are now being identified as being associated with FLT-3 mutations in 20% to 30% of patients with AML. It is associated with high white cell counts and reduced long-term survival. This can be on the basis of internal tandem duplications, mis-sense mutations or in frame insertions. Inhibitors of FLT-3 continue to be explored with promising early results. The use of imatinib has been disappointing in AML despite its activity against c-kit. Farnesyl transferase inhibitors (FTIs) have been developed as a way of interfering with ras. A variety of FTIs inhibit this activity and R115777 has been shown to reduce bone marrow ras activity in patients with refractory AML and has resulted in complete and partial remissions in some patients with AML. Myelodysplastic syndrome continues to be a major area of concern, as the only proven active agent appears to be the growth factors, which increase production of red cells and neutrophils and occasionally platelets, but this is cumbersome and expensive. High-dose chemotherapy is useful in some MDS patients with either a diploid karyotype or specific translocations. Patients with adverse or poor cytogenetic parameters such as abnormalities in chromosomes 5 and 7 continue to be unaffected by present strategies. Reduced-intensity transplantation has been actively explored as therapy for induction and consolidation of remission in AML and MDS. The future of AML and MDS lies in the development of new treatment strategies that explore the improved understanding of the biology of these conditions. ALL
In adult ALL, the usefulness of imatinib is being explored in combination with a variety of chemotherapy programs. Most chemotherapy programs such as the BFM and hyper-CVAD regimens have high complete remission rates and an approximately 30% to 40% long-term survival fraction. However, patients who are Philadelphia chromosome-positive continue to relapse. There is a benefit from allogeneic SCT in this circumstance and the addition of Gleevec to these regimens is improving the complete remission rate. Monoclonal antibodies have an effect in CD20- positive ALL. For B-cell ALL in which CD20 is highly expressed, early studies report high response rates and longer remissions. These results will need to be confirmed. Patients with higher levels of CD20 appear to have an inferior prognosis in adult ALL and the addition of rituximab to chemotherapy promises to be useful. There are some reports of improved disease-free interval with allogeneic bone marrow transplant in ALL (page 27), but with no survival advantage being demonstrated at this time. The leukemias continue to be an important avenue for exploration of new treatment strategies. They continue to be a source of discovery of new agents and concepts. The maturation of studies of imatinib and combination chemoimmunotherapy in CML and CLL, respectively, is awaited with interest.