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42nd Annual Meeting of the American Society of Clinical Oncology

Atlanta, Georgia / June 2-6, 2006

Standard doses of the tyrosine kinase inhibitor (TKI) imatinib of 400 mg/day have proven to be highly active in chronic-phase (CP) chronic myeloid leukemia (CML) in the great majority of patients. Nevertheless, it has been postulated that higher doses may be more effective than the standard dose, producing both faster responses and a higher proportion of molecular remissions in this patient population.

In an updated analysis of previously untreated CP CML patients followed for 2.5 years, Dr. Etsuko Aoki, Clinical Fellow, University of Texas M.D. Anderson Cancer Center, Houston, reported that cytogenetic responses (CyRs) were faster and more complete, and there were more major molecular responses when patients received imatinib 400 mg b.i.d. compared with the standard 400 mg once-daily dose.

A total of 288 patients received high-dose imatinib. This group’s results were compared with those of a previous study involving 50 patients who received the standard 400 mg q.d. dose. Complete hematologic responses (HRs) were achieved in 98% of both standard-dose and the high-dose groups, and comparable CyRs were also seen at 98% in the 400-mg group and 96% in the 800-mg group. However, complete CyRs were higher at 91% in the 800-mg group vs. 78% in the 400-mg group.

Over three-quarters of patients in the 800-mg group had also achieved a complete CyR by three months, Dr. Aoki observed. At 60 months, progression-free survival rates were over 90% in both groups, and transformation-free survival rates approached 100% in the 800-mg group vs. approximately 90% in the standard-dose group. Some 39% of patients receiving the higher dose required a reduction in the dose at some point during the study, but otherwise, treatment was initiated at full dose from day 1 and treatment was reasonably well tolerated, she added.

Investigators concluded, “High-dose imatinib provides higher rates of complete CyRs and earlier molecular responses, although there is some increase in myelosuppression,” which they characterized as “transient” and “manageable.”

Myeloproliferative Disease

A similar high-dose strategy was recruited in a multi-institutional trial in which imatinib was evaluated in the treatment of polycythemia vera. As reported by Dr. Eric J. Feldman, Professor of Medicine, Leukemia and Bone Marrow Failure Program, Weill Medical College of Cornell University, New York, and co-investigators, a total of 37 such patients were involved in the phase II trial. Men were initially phlebotomized to a hematocrit (HCT) equal to or less than 45% and women to a HCT equal to or less than 42%. The TKI was started at 400 mg/day, escalating 100 mg every two weeks to a maximum of 800 mg for persistent phlebotomy requirements or for platelet counts over 600 x 10 /L, investigators reported.

All patients received low-dose ASA (81 mg/day) as well. Prior to initiation of treatment, the mean number of phlebotomy requirements each year was nine. After receiving treatment with imatinib for one year, mean phlebotomy requirements dropped to a mean of two, and there were 10 complete remissions and nine partial remissions in the group overall.

A reduction in spleen size of greater than 50% was also documented in 86% of the group. Edema and diarrhea were the main side effects reported in this study. “Imatinib is effective in reducing phlebotomy requirements and spleen size but less effective in lowering high platelet counts,” study authors concluded, “but dose increases of greater than 400 mg/day were commonly required.”

START Series: Addressing Different Phases of Leukemia

The novel dasatinib is an oral, multi-targeted TKI that is 325 times more potent than imatinib at inhibiting bcr-abl. It is also non-cross-resistant to imatinib and has demonstrated full activity against most known resistance mutations to imatinib.

Phase I studies showed that dasatinib was highly effective for the treatment of patients who had developed resistance to, or who could not tolerate imatinib in all phases of CML. Among the presentations detailing phase II results with dasatinib in various phases of CML, the START-L CA180015 study results were relatively typical of collective findings.

As presented by Dr. Steven Coutré, Associate Professor of Medicine, Division of Hematology, Stanford University School of Medicine, California, patients with CML in lymphoid BC or those with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the majority of whom were resistant to imatinib, received dasatinib, initially at a dose of 70 mg b.i.d. The dose was later escalated to 100 mg b.i.d., but reductions to either 40 or 50 mg b.i.d. were allowed in the study.

The average daily dose in both groups was 140 mg and the duration of therapy was between 2.3 and 2.7 months. The primary objective of the study was to establish the rates of major HR and overall HR to dasatinib, but secondary objectives were to determine the duration of all HRs, as well as CyR rates. A total of 94 patients with either Ph+ ALL or lymphoid BC CML were enrolled in the study. Approximately half had received prior high-dose imatinib therapy at over 600 mg/day.

Thirty-nine per cent of Ph+ ALL patients achieved a major HR to dasatinib, as did 33% of the lymphoid BC CML group. One-third of Ph+ ALL patients achieved a complete HR as did 29% of lymphoid BC CML patients. Dasatinib also elicited a major HR in a “notable proportion of patients” in both disease groups—specifically, 47% of Ph+ ALL patients and 27% of lymphoid BC CML patients who had undergone a prior stem cell transplant. Major CyRs were also seen in both treatment groups, investigators added, including a complete CyR in 44% of Ph+ ALL and 38% in lymphoid BC CML patients. The majority of Ph+ ALL patients with any mutation to imatinib also responded to dasatinib, the notable exception being those with the T315l mutation.

Hematologic toxicity was common in both groups but was present at baseline in a large proportion of patients, investigators observed. The most common non-hematologic toxicity was diarrhea; fluid retention, was manageable with dose modification, diuretics, and/or steroids. Rates of grade 3 to 4 toxicity for most side effects were under 5%.

“Some of the responses are out now to more than eight months. To put this in perspective, initial use of imatinib in this patient population is usually less than six months, and now we have a population that is resistant to imatinib and yet you are getting responses in some patients longer than the initial response to imatinib. So even though treatment with dasatinib is not likely to cure these patients, you can still get good responses, good quality of life and provide something meaningful for patients. So the main message from this study is that we have another treatment option for this very difficult-to-treat patient population,” Dr. Coutré observed.

Future studies are planned in which dasatinib is incorporated into standard chemotherapy regimens up-front to see if the relapse rate can be further improved.

Other Targeted Studies

Similar findings were posted for CML patients in myeloid BC enrolled in the START-B study. Under lead author Dr. Jorge Cortes, Associate Professor of Medicine, University of Texas M.D. Anderson Cancer Center, investigators reported on results from 109 patients treated with the same regimen of dasatinib. Over 90% of patients had proved resistant to imatinib.

The median daily dose in this group was 136 mg/day, and the median duration of therapy was 3.5 months. Twenty-five patients achieved a complete CyR to dasatinib and six patients achieved a partial CyR. Almost half of the group with any mutation to imatinib also responded to dasatinib, and major HRs have proven duration out to 10 months. Cytopenias and fluid retention were again the most important adverse events to emerge from these studies, but cytopenia was transient and resolved with dose modification or treatment interruption, as investigators pointed out.

The START-A study involved 174 accelerated-phase (AP) CML patients, all of whom were again imatinib-resistant or imatinib-intolerant. The dosage schedule was the same as for the START-L study and treatment duration was approximately seven months.

As noted by investigators, all patients in this study had received prior treatment with standard-dose imatinib and over half had received 600 mg/day or more of the same prior therapy. Following treatment with dasatinib, 59% of the patient cohort achieved a major HR, some 34% of them achieving a complete HR. Another 25% had no evidence of leukemia at study end. The time to achieve a major HR was also seen at approximately three months after initiation of treatment.

“Dasatinib also induced major CyRs in a substantial proportion of patients,” investigators observed, with major CyRs (complete and partial CyRs) documented in 34% of the group, 25% of them again being complete CyRs. As in previous studies, dasatinib proved active in the presence of most bcr-abl mutations. Cytopenias were again observed in a substantial proportion of patients but they were both “predictable and manageable,” as investigators pointed out. Non-hematologic toxicities, including fluid retention and gastrointestinal toxicities, were mild to moderate and similarly manageable.

Emerging Strategies

The novel compound nilotinib, formerly referred to as AMN107, is another highly selective and potent bcr-abl TKI that is 30-fold more potent than imatinib. As does dasatinib, it inhibits most known bcr-abl mutations, the one exception being the T315l mutation, which applies to both agents dasatinib and nilotinib.

Results from phase II studies in similar patient populations as were studied in the dasatinib phase II trials confirm that nilotinib has demonstrated good activity across all phases of CML.

Under lead author Dr. Hagop Kantarjian, Chair, Department of Leukemia, and Professor of Medicine, University of Texas M.D. Anderson Cancer Center, investigators evaluated the activity and safety of nilotinib in imatinib-resistant/imatinib-intolerant CP CML patients who had already received 600 mg/day or more of imatinib and had evidence of disease progression.

The novel agent was given at a dose of 400 mg b.i.d. but in the absence of safety concerns, the dose could be escalated to 600 mg b.i.d. if patients did not meet hematologic milestones. The median duration of treatment was 185 days and the median dose was 800 mg/day. “Of the 81 patients, 54 were not in complete hematologic remission at baseline, allowing assessment of the CyR,” according to the investigators.

Treatment led to a complete HR in 69% of patients and produced a major CyR in 46% of the group. Median time to complete HR was one month, and the median time to CyR was three months. Similar CyR rates were observed in imatinib-resistant and imatinib-intolerant patients.

The most frequent grade 3 to 4 non-hematological toxicities were rash (4%), arthralgia (5%) and fatigue (3%), but otherwise, treatment was well tolerated. In terms of grade 3 to 4 hematologic toxicities there was a 16% incidence of neutropenia and a 19% incidence of thrombocytopenia.

“Longer-term follow-up is required to assess for additional responses and to assess durability of response,” investigators concluded, “but nilotinib represents a novel investigational treatment option for patients with imatinib-resistant or imatinib-intolerant CP CML.”

Another phase II study under lead author Dr. Philipp le Coutre, Charité Campus Virchow-Klinikum, Berlin, Germany, evaluated the activity of nilotinib in imatinib-resistant or imatinib-intolerant Ph+ CML patients in AP. The agent was again administered at a dose of 400 mg b.i.d. with dose escalations of up to 600 mg b.i.d. if patients failed to return to CP, lost a HR or CyR to treatment or progressed on therapy.

The median duration of treatment was 148 days and the median dose intensity was 797 mg/day. Of the 25 patients involved in this study, 10 achieved a complete HR while four had a marrow response and two returned to CP disease. Disease stabilized in four others while 11 patients were not assessable. Seven patients also achieved a major CyR, four of them achieving a complete CyR. Rates of hematologic toxicity were relatively low, and grade 3 to 4 non-hematologic toxicity rates were very low.

Only three patients discontinued treatment due to an adverse event. “Overall, HR and major CyR rates of 40% and 28%, respectively, were observed,” investigators concluded, and “nilotinib was generally well tolerated, as indicated by a median dose intensity of nearly 800 mg/day over the course of the study.”

In BC or relapsed or refractory Ph+ ALL, the same agent also has activity. Under lead author Dr. Francis Giles, Associate Professor of Medicine, University of Texas M.D. Anderson Cancer Center, 24 CML patients in BC and 16 with Ph+ ALL again received nilotinib 400 mg b.i.d. for a median of 68 to 75 days and a median dose intensity of approximately 800 mg/day.

Among patients in lymphoid BC, a complete HR was seen in one patient and a complete CyR was achieved in two patients. As well, in one patient in myeloid BC a complete CyR was also achieved. A complete response was also seen in four Ph+ ALL patients.

In this more advanced-disease patient group, treatment was still generally well tolerated, as indicated by median dose intensity of nearly 800 mg/day over the course of the study, as investigators pointed out.

Multicentre investigators under Dr. Oliver G. Ottmann, Universitätsklinik Frankfurt, Germany, also reported that in a group of Ph+ ALL patients—virtually all of whom were resistant to imatinib—45% had mutations at baseline, yet overall response rates to nilotinib were relatively similar to those with and without bcr-abl baseline mutations.

Minimal Residual Disease

Despite the activity of current and new TKIs in CML, the frequency of polymerase chain reaction (PCR) negativity following treatment with imatinib remains low and most CML patients are left with minimal residual disease. Thus, the idea of using a vaccine to elicit CML-specific immune responses in an attempt to suppress or eliminate minimal residual disease has validity.

In one study of one such vaccine, Dr. Peter Maslak, Chief, Hematology Laboratory Service, Memorial Sloan-Kettering Cancer Center, New York, and colleagues tested a synthetic cross-reactive bcr-abl exon junction-specific peptide engineered to have greater T-cell avidity than earlier vaccine candidates. As a consequence, the new synthetic vaccines are more likely to provoke activation of CD8-cells and native killing of tumour cells.

For the study, the researchers administered a synthetic analogue breakpoint-specific peptide vaccine to 11 CML patients in major or complete cytogenetic remission. The vaccine was given five times every two weeks and then for 11 further vaccinations over one year. Looking for CD8-cell responses, investigators found that after the fifth dose, eight patients had been able to mount significant immunologic responses, as measured by one of several assays. The vaccine was also well tolerated, with only local skin reactions at the injection site.

“These preliminary results suggest vaccination with synthetic analogue peptides derived from CML proteins results in immunologic responses and may be associated with molecular improvement,” investigators concluded. They added, however, that they have yet to determine if these candidate vaccines are able to reduce or eliminate minimal residual disease.

Continuing Research in Treatment for an Elderly Leukemia Patient Population

In a phase II study presented by Dr. Robert Geller, New Haven, Connecticut, 44 patients with de novo AML and 46 patients with secondary AML (median age, 72) received treatment with the alkylating agent cloretazine at 600 mg/m2 for the induction phase, while a lower dose of 400 mg/m2 was used during the consolidation phase. In addition to advanced age, patients all had adverse features, including unfavourable cytogenetics, and the majority had at least one other adverse risk factor, such as declining performance status and comorbid conditions.

Fifty per cent of de novo patients responded to treatment, as did 11% of those with secondary AML. Median survival in responders was 171 days vs. 47 days in non-responders and 30% of those who responded to cloretazine were still alive at one year. Induction mortality rates were under 20%, a more acceptable rate than induction mortality rates of between 50 and 60% that have been reported for poor-risk elderly AML patients.

“This is a patient population who generally receives palliative or best supportive care, so there really isn’t a comparator drug to this treatment. It’s a promising new agent and we are in the process of carrying out another phase II study and hopefully see if the drug continues to be active in these patients,” Dr. Geller told delegates.

More encouraging news for the same type of AML patient who would not be considered suitable for standard intensive treatment was heard about clofarabine.

As confirmed by lead author Dr. Alan Burnett, Head, Department of Haematology, Cardiff University, Wales, UK, low-dose cytosine arabinoside (Ara-C) remains the standard of care in elderly AML patients not considered suitable for standard intensive chemotherapy. Yet outcomes with this regimen are poor, with a median survival of less than three months. The compound clofarabine is a next-generation purine nucleoside analogue developed to be less toxic than early-generation molecules, with less neurotoxicity in particular.

A total of 66 patients over the age of 65 with untreated AML were enrolled in the study. “All patients received clofarabine 30 mg/m2 for five consecutive days, repeated every 28 days (one course), for a maximum of six courses,” investigators stated. The primary end point of the study was the overall response rate (complete response, incomplete peripheral count recovery or partial response). As the authors noted, 19 out of 63 patients for whom cytogenetic data were available had an adverse cytogenetic prognostic risk profile.

At a median age of 68 years, the overall response rate was 53%, some 42% of those being complete responses. Median survival was greater than six months, and the toxicity associated with treatment was both acceptable and manageable for this elderly group of patients.

“Elderly AML patients over the age of 65 years who are unsuitable for standard, intensive treatment represent a population with a major unmet medical need,” investigators observed, and indicated that clofarabine “demonstrated significant efficacy in this patient population.”

Summary

Standard-dose imatinib continues to play a pivotal role in CP CML, producing low rates of disease progression in most patients, but especially in those who achieve a complete CyR with significant decreases in bcr-abl copy numbers. Unfortunately, relapse occurs in virtually all patients when treatment is discontinued and it also occurs with increasing frequency over time as patients develop resistant mutations to imatinib. High-dose imatinib may provide more durable responses, but the newer TKIs, including dasatinib and nilotinib, offer new hope that both disease and quality of life can be maintained once patients fail on imatinib. Imatinib also appears to provide clinically meaningful responses in patients with polycythemia vera, reducing phlebotomy requirements and spleen size. Novel vaccine candidates are currently being developed and tested in an effort to reduce or eliminate minimal residual disease in CML patients, with some success. Finally, several new and much needed alternatives for elderly AML patients who are not suitable for standard intensive regimens hold out promise that even poor-risk patients may achieve meaningful responses to treatment.